NUCLEIC ACID VACCINES

Information

  • Patent Application
  • 20240398931
  • Publication Number
    20240398931
  • Date Filed
    August 12, 2024
    8 months ago
  • Date Published
    December 05, 2024
    4 months ago
Abstract
The invention relates to compositions and methods for the preparation, manufacture, and therapeutic use of ribonucleic acid vaccines comprising polynucleotide molecules encoding one or more antigens.
Description
SEQUENCE LISTING

The instant application contains a Sequence Listing which has been submitted in electronic format via EFS-WEB and is hereby incorporated by reference in its entirety. The Sequence Listing is provided as a file entitled MTX401.xml, created on Jul. 29, 2024, which is 2,628,288 bytes in size.


FIELD OF THE INVENTION

The invention relates to compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of vaccines, specifically nucleic acid vaccines (NAVs). In particular, the invention relates to compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of ribonucleic acid (RNA) vaccines, e.g., mRNA vaccines.


BACKGROUND OF THE INVENTION

Vaccination is an effective way to provide prophylactic protection against infectious diseases, including, but not limited to, viral, bacterial, and/or parasitic diseases, such as influenza, AIDS, hepatotisis virus infection, cholera, malaria and tuberculosis, and many other diseases. For example, influenza infections are the seventh leading cause of death in the United States with 200,000 hospitalizations and 40,000 deaths seen in the United States per year and cause about 3-5 million hospitalizations and about 300,000 to 500,000 deaths worldwide per year. Millions of people receive flu vaccines to protect them from seasonal flu each year. Vaccination can also rapidly prevent the spread of an emerging influenza pandemic.


A typical vaccine contains an agent that resembles a weakened or dead form of the disease-causing agent, which could be a microorganism, such as bacteria, virus, fungi, parasites, or one or more toxins and/or one or more proteins, for example, surface proteins, (i.e., antigens) of such a microorganism. The antigen or agent in the vaccine can stimulate the body's immune system to recognize the agent as a foreign invader, generate antibodies against it, destroy it and develop a memory of it. The vaccine-induced memory enables the immune system to act quickly to protect the body from any of these agents that it later encounters.


Vaccine production used in the art e.g., antigen vaccine production, has several stages, including the generation of antigens, antigen purification and inactivation, and vaccine formulation. First, the antigen is generated through culturing viruses in cell lines, growing bacteria in bioreactors, or producing recombinant proteins derived from viruses and bacteria in cell cultures, yeast or bacteria. Recombinant proteins are then purified and the viruses and bacteria are inactivated before they are formulated with adjuvants in vaccines. It has been a challenge to drastically reduce the time and expense associated with current technologies in vaccine development.


Another obstacle to the development of new vaccine is the constant evolution of most infectious agents, such as viruses and bacteria. Viruses often mutate their surface proteins to generate new antigens which can help them skipping the active immune system that has been immunized by vaccines containing the viruses. In contrast, bacteria acquire and mutate key proteins to evade host defense and effective antibiotic applications.


For example, influenza A, B and C viruses are the etiological agents of influenza. Hemagglutinin (HA), the major envelop glycoprotein of influenza A and B viruses, or its homologue, hemagglutinin-esterase (HE) in influenza C virus, is the natural reservoir of the viruses. The rapid evolution of the hemagglutinin (HA) protein of the influenza virus results in the constant emergence of new strains, rendering the adaptive immune response of the host only partially protective to new infections. The biggest challenge for therapy and prophylaxis against influenza and other infections using traditional vaccines is the limitation of vaccines in breadth, providing protection only against closely related subtypes. In addition, today's length of the production process inhibits any fast reaction to develop and produce an adapted vaccine in a pandemic situation.


It is of great interest to develop new vaccines as well as new approaches to combatting infectious disease and infectious agents.


SUMMARY OF THE INVENTION

Described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs). In particular, described herein are compositions, methods, processes, kits and devices for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines, e.g., RNA vaccines and mRNA vaccines.


The present invention provides compositions, e.g., pharmaceutical compositions, comprising one or more nucleic acid vaccines or NAVs.


The NAVs or NAV compositions or the invention may be designed to comprise one or more nucleic acid molecules, e.g., polynucleotides, which encode one or more wild type or engineered proteins, peptides or polypeptides (e.g., antigens). In some embodiments, the nucleic acid molecule, e.g., polynucleotide, is RNA. In some embodiments the nucleic acid molecule, e.g., polynucleotide, is an mRNA. In some embodiments the NAV or NAV composition comprises a nucleic acid (e.g., a RNA polynucleotide) which is chemically modified. In some embodiments the infectious agent from which the antigen is derived or engineered includes, but is not limited to viruses, bacteria, fungi, protozoa, and/or parasites.


In some embodiments are provided methods of inducing, eliciting, boosting or triggering an immune response in a cell, tissue or organism, comprising contacting said cell, tissue or organism with any of the RNAVs described or taught herein.


Aspects of the invention provide nucleic acid vaccines (NAVs) comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated within a cationic lipid nanoparticle. Some aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated in a carrier having a molar ratio of about 20-60% cationic lipid:5-25% non-cationic lipid:25-55% sterol; and 0.5-15% PEG-modified lipid.


In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid:about 5-25% non-cationic lipid:about 25-55% sterol; and about 0.5-15% PEG-modified lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 50% cationic lipid, about 1.5% PEG-modified lipid, about 38.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid nanoparticle comprises a molar ratio of about 55% cationic lipid, about 2.5% PEG lipid, about 32.5% cholesterol and about 10% non-cationic lipid. In some embodiments, the cationic lipid is an ionizable cationic lipid and the non-cationic lipid is a neutral lipid, and the sterol is a cholesterol. In some embodiments, the cationic lipid nanoparticle has a molar ratio of 50:38.5:10:1.5 of cationic lipid: cholesterol: PEG2000-DMG:DSPC.


In some embodiments, the cationic lipid nanoparticle has a mean diameter of 50-150 nm. In some embodiments, the cationic lipid nanoparticle has a mean diameter of 80-100 nm. In some embodiments, the vaccine includes 1.5 mg/mL of RNA polynucleotide and 35-45 mg/mL lipids. In some embodiments, the NAV includes about 2 mg/mL of RNA polynucleotide and about 40 mg/mL lipids.


In some embodiments, the open reading frame is codon-optimized. In some embodiments, the first antigenic polypeptide is derived from an infectious agent. In some embodiments, the infectious agent is selected from a member of the group consisting of strains of viruses and strains of bacteria. In some embodiments, the one or more RNA polynucleotides encode a further antigenic polypeptide. In some embodiments, the further RNA polynucleotide comprises at least one chemical modification and a codon-optimized open reading frame, said open reading frame encoding an antigenic polypeptide.


In some embodiments, the one or more antigenic polypeptide is selected from those proteins listed in Tables 6-16, Tables 29-30, or fragments thereof. In some embodiments, the open reading frame of the one or more RNA polynucleotides and/or the open reading frame of the second RNA polynucleotide each, independently, encodes an antigenic polypeptide selected from Tables 6-16, Tables 29-30, or fragments thereof. In some embodiments, each of the open reading frame of the one or more RNA polynucleotides is selected from any of the RNA sequences Table 28, or fragments thereof.


In any of the embodiments provided herein, the infectious agent is a strain of virus selected from the group consisting of adenovirus; Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpes virus, type 8; Human papillomavims; BK virus; JC virus; Smallpox; polio virus; Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; Yellow Fever virus; Dengue virus; West Nile virus; Rubella virus; Hepatitis E virus; Human Immunodeficiency virus (HIV); Influenza virus; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabid virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytial virus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Banna virus; Human Enterovirus; Hanta virus; West Nile virus; Middle East Respiratory Syndrome Corona Virus; Japanese encephalitis virus; Vesicular exanthernavirus; and Eastern equine encephalitis.


In some embodiments, the virus is a strain of Influenza A or Influenza B or combinations thereof. In some embodiments, the strain of Influenza A or Influenza B is associated with birds, pigs, horses, dogs, humans or non-human primates. In some embodiments, the antigenic polypeptide encodes a hemagglutinin protein or fragment thereof. In some embodiments, the hemagglutinin protein is H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18, or a fragment thereof. In some embodiments, the hemagglutinin protein does not comprise a head domain (HAI). In some embodiments, the hemagglutinin protein comprises a portion of the head domain (HAI). In some embodiments, the hemagglutinin protein does not comprise a cytoplasmic domain. In some embodiments, the hemagglutinin protein comprises a portion of the cytoplasmic domain. In some embodiments, the truncated hemagglutinin protein. In some embodiments, the truncated hemagglutinin protein comprises a portion of the transmembrane domain. In some embodiments, the amino acid sequence of the hemagglutinin protein or fragment thereof comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99% identify with any of the amino acid sequences provided in Table 6-14. In some embodiments, the virus is selected from the group consisting of H1N1, H3N2, H7N9, and H10N8. In some embodiments, the antigenic polypeptide is selected from those proteins listed in Tables 6-14, or fragments thereof.


In some embodiments, the infectious agent is a strain of bacteria selected from Tuberculosis (Mycobacterium tuberculosis), clindamycin-resistant Clostridium difficile, fluoroquinolon-resistant Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA). In some embodiments, the bacteria is Clostridium difficile.


In some embodiments, the NAV is multivalent. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 antigenic polypeptides. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode at least 10, 15, 20 or 50 antigenic polypeptides. In some embodiments, the open reading frame of the one or more RNA polynucleotides encode 2-10, 10-15, 15-20, 20-50, 50-100 or 100-200 antigenic polypeptides.


In some embodiments, the RNA polynucleotide includes a chemical modification and the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide includes a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.


Other aspects provide a NAV comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, formulated within a nanoparticle, wherein the nanoparticle has a mean diameter of 50-200 nm. In some embodiments, the nanoparticle has a polydiversity value of less than 0.4. In some embodiments, the nanoparticle has a net neutral charge at a neutral pH. In some embodiments, the nanoparticle has a mean diameter of 80-100 nm. In some embodiments, the nanoparticle is a cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319).


Other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein at least 80% of the uracil in the open reading frame have a chemical modification. In some embodiments, 100% of the uracil in the open reading frame have a chemical modification. In some embodiments, the chemical modification is in the 5-position of the uracil. In some embodiments, the chemical modification is a N1-methyl pseudouridine. In some embodiments, the nucleic acid vaccine is formulated within a cationic lipid complex or cationic lipid nanoparticle.


Yet other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, at least one 5′ terminal cap and at least one chemical modification, formulated within a cationic lipid nanoparticle. In some embodiments, the 5′ terminal cap is 7mG(5′)ppp(5′)NlmpNp. In some embodiments, the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine. Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide further comprises a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.


In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid:about 5-25% non-cationic lipid:about 25-55% sterol; and about 0.5-15% PEG-modified lipid.


Some aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a hemagglutinin protein and a pharmaceutically acceptable carrier or excipient, formulated within a cationic lipid nanoparticle. In some embodiments, the hemagglutinin protein is selected from HA1, HA7 and HA10. In some embodiments, the RNA polynucleotide does not encode F protein. In some embodiments, the RNA polynucleotide further encodes neuraminidase protein. In some embodiments, the hemagglutinin protein is derived from a strain of Influenza A virus or Influenza B virus or combinations thereof. In some embodiments, the Influenza virus is selected from H1N1, H3N2, H7N9, and H10N8.


In some embodiments, the RNA polynucleotide includes a chemical modification and the chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the chemical modification is selected from the group consisting of pseudouridine, N1-methylpseudouridine, 2-thiouridine, 4′-thiouridine, 5-methylcytosine, 2-thio-1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-pseudouridine, 2-thio-5-aza-uridine, 2-thio-dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-pseudouridine, 4-methoxy-2-thio-pseudouridine, 4-methoxy-pseudouridine, 4-thio-1-methyl-pseudouridine, 4-thio-pseudouridine, 5-aza-uridine, Dihydropseudouridine, 5-methoxyuridine and 2′-O-methyl uridine. In some embodiments, the RNA polynucleotide further comprises a second chemical modification wherein said second chemical modification is selected from any of those listed in Tables 22 and 23. In some embodiments, the combination of first and second chemical modification is selected from those listed in Table 25.


In some embodiments, the cationic lipid nanoparticle comprises a cationic lipid, a PEG-modified lipid, a sterol and a non-cationic lipid. In some embodiments, the cationic lipid is selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319). In some embodiments, the cationic lipid nanoparticle has a molar ratio of about 20-60% cationic lipid:about 5-25% non-cationic lipid:about 25-55% sterol; and about 0.5-15% PEG-modified lipid.


In some embodiments, the RNA polynucleotide comprises SEQ ID NOs 197-392. In some embodiments, the RNA polynucleotide comprises a polynucleotide having at least 80% sequence identity to SEQ ID NOs 197-392. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 941. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 941. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 946. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 946. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 1022. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 1022. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding an amino acid sequence having at least 90% sequence identity to SEQ ID NO 1023. In some embodiments, the RNA polynucleotide comprises a polynucleotide encoding the amino acid sequence of SEQ ID NO 1023. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1024. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1024. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1025. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1025. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1026. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1026. In some embodiments, the RNA polynucleotide comprises SEQ ID NO 1027. In some embodiments, the RNA polynucleotide comprises a polynucleotide having 80-98% sequence identity to SEQ ID NO 1027.


Aspects of the invention provide nucleic acids comprising 80-95% sequence identity to SEQ ID NO 1027 or SEQ ID NO 1026. Other aspects provide a nucleic acid comprising SEQ ID NO: 395.


Yet other aspects provide a method of inducing an antigen specific immune response in a subject comprising administering any of the vaccines described herein to the subject in an effective amount to produce an antigen specific immune response. In some embodiments, the antigen specific immune response comprises a T cell response. In some embodiments, the antigen specific immune response comprises a B cell response. In some embodiments, the method of producing an antigen specific immune response involves a single administration of the vaccine. In some embodiments, the method further comprises administering a booster dose of the vaccine. In some embodiments, the vaccine is administered to the subject by intradermal or intramuscular injection.


In some embodiments, the booster dose of the vaccine is administered to the subject on day twenty one. In some embodiments, a dosage of between 10 μg/kg and 400 μg/kg of the vaccine is administered to the subject. In some embodiments, a dosage of 25 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, a dosage of 100 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, a dosage of 400 micrograms of the RNA polynucleotide is included in the vaccine administered to the subject. In some embodiments, the RNA polynucleotide accumulates at a 100 fold higher level in the local lymph node in comparison with the distal lymph node.


Aspects provide methods of preventing or treating influenza viral infection comprising administering to a subject any of the vaccines described herein. In some embodiments, the antigen specific immune response comprises a T cell response. In some embodiments, the antigen specific immune response comprises a B cell response. In some embodiments, the method of producing an antigen specific immune response involves a single administration of the vaccine. In some embodiments, the vaccine is administered to the subject by intradermal or intramuscular injection.


Yet other aspects provide methods of vaccinating a subject comprising administering to the subject a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, a dosage of between 10 μg/kg and 400 μg/kg of the nucleic acid vaccine is administered to the subject. In some embodiments, the nucleic acid vaccine is administered to the subject by intradermal or intramuscular injection. In some embodiments, the nucleic acid vaccine is administered to the subject on day zero. In some embodiments, a second dose of the nucleic acid vaccine is administered to the subject on day twenty one.


In some embodiments, a dosage of 25 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, a dosage of 100 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, a dosage of 400 micrograms of the RNA polynucleotide is included in the nucleic acid vaccine administered to the subject. In some embodiments, the RNA polynucleotide accumulates at a 100 fold higher level in the local lymph node in comparison with the distal lymph node.


Aspects of the invention provide a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and a pharmaceutically acceptable carrier or excipient, wherein an adjuvant is not included in the vaccine. In some embodiments, the stabilization element is a histone stem-loop. In some embodiments, the stabilization element is a nucleic acid sequence having decreased GC content relative to wild type sequence.


Aspects of the invention provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in the formulation for in vivo administration to a host, which confers an antibody titer superior to the criterion for seroprotection for the first antigen for an acceptable percentage of human subjects. In some embodiments, the antibody titer is a neutralizing antibody titer.


Also provided are NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in a formulation for in vivo administration to a host for eliciting a longer lasting high antibody titer than an antibody titer elicited by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide. In some embodiments, the RNA polynucleotide is formulated to produce a neutralizing antibodies within one week of a single administration. In some embodiments, the adjuvant is selected from a cationic peptide and an immunostimulatory nucleic acid. In some embodiments, the cationic peptide is protamine.


Aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide is present in the formulation for in vivo administration to a host such that the level of antigen expression in the host significantly exceeds a level of antigen expression produced by an mRNA vaccine having a stabilizing element or formulated with an adjuvant and encoding the first antigenic polypeptide.


Other aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, wherein the vaccine has at least 10 fold less RNA polynucleotide than is required for an unmodified mRNA vaccine to produce an equivalent antibody titer. In some embodiments, the RNA polynucleotide is present in a dosage of 25-100 micrograms.


Aspects of the invention also provide a unit of use vaccine, comprising between 10 ug and 400 μg of one or more RNA polynucleotides having an open reading frame comprising at least one chemical modification, the open reading frame encoding a first antigenic polypeptide, and a pharmaceutically acceptable carrier or excipient, formulated for delivery to a human subject. In some embodiments, the vaccine further comprises a cationic lipid nanoparticle.


Aspects of the invention provide methods of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals comprising administering to said individual or population an antigenic memory booster nucleic acid vaccine comprising (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient. In some embodiments, the vaccine is administered to the individual via a route selected from the group consisting of intramuscular administration, intradermal administration and subcutaneous administration. In some embodiments, the administering step comprises contacting a muscle tissue of the subject with a device suitable for injection of the composition. In some embodiments, the administering step comprises contacting a muscle tissue of the subject with a device suitable for injection of the composition in combination with electroporation.


Aspects of the invention provide methods of vaccinating a subject comprising administering to the subject a single dosage of between 25 μg/kg and 400 μg/kg of a nucleic acid vaccine comprising one or more RNA polynucleotides having an open reading frame encoding a first antigenic polypeptide in an effective amount to vaccinate the subject.


Aspects provide NAVs comprising one or more RNA polynucleotides having an open reading frame encoding a hemagglutinin protein fragment, wherein the hemagglutinin protein includes only a portion of at least one of: a head domain (HA1), a cytoplasmic domain, or a transmembrane domain. In some embodiments, the hemagglutinin protein is H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, H18. In some embodiments, the hemagglutinin protein does not comprise the head domain (HA1). In some embodiments, the hemagglutinin protein does not comprise the cytoplasmic domain. In some embodiments, the truncated hemagglutinin protein does not comprise the transmembrane domain. In some embodiments, the amino acid sequence of the hemagglutinin protein comprises at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97% 98%, or 99% identify with any of the amino acid sequences provided in Tables 6-16.


In some embodiments, the vaccine is formulated within a cationic lipid complex or cationic lipid nanoparticle. In some embodiments, the polynucleotide comprises at least one 5′ terminal cap and at least one chemical modification.


Aspects also provide any of the vaccines described herein for use in a method of inducing an antigen specific immune response in a subject. In some embodiments, the method comprises administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.


Other aspects provide a use of any of the vaccines described herein in the manufacture of a medicament for use in a method of inducing an antigen specific immune response in a subject, the method comprising administering the vaccine to the subject in an effective amount to produce an antigen specific immune response.


Aspects also provide for any of the vaccines described herein for use in a method of preventing or treating influenza viral infection, the method comprising administering the vaccine to a subject.


Other aspects provide a use any of the vaccines described herein in the manufacture of a medicament for use in a method of preventing or treating influenza viral infection, the method comprising administering the vaccine to a subject.


Other aspects provide nucleic acid vaccines for use in a method of vaccinating a subject wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, the method further comprises administering the vaccine to the subject.


Other aspects provide a use of a nucleic acid vaccine in the manufacture of a medicament for use in a method of vaccinating a subject wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, wherein the RNA polynucleotide does not include a stabilization element, and wherein an adjuvant is not coformulated or co-administered with the vaccine. In some embodiments, the method further comprises administering the vaccine to the subject.


Aspects of the invention provide an antigenic memory booster nucleic acid vaccine for use in a method of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals. In some embodiments, the antigenic memory booster nucleic acid vaccine comprises (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient; and wherein the method comprises administering to said individual or population the antigenic memory booster nucleic acid vaccine.


Other aspects provide a use of an antigenic memory booster nucleic acid vaccine in the manufacture of a medicament for use in a method of creating, maintaining or restoring antigenic memory to an influenza strain in an individual or population of individuals, wherein the antigenic memory booster nucleic acid vaccine comprises (a) at least one RNA polynucleotide, said polynucleotide comprising at least one chemical modification and two or more codon-optimized open reading frames, said open reading frames encoding a set of reference antigenic polypeptides, and (b) optionally a pharmaceutically acceptable carrier or excipient; and wherein the method comprises administering to said individual or population the antigenic memory booster nucleic acid vaccine.


Other aspects provide a nucleic acid vaccine for use in a method of vaccinating a subject, wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, and wherein the method comprises administering to the subject a single dosage of between 25 μg/kg and 400 μg/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject.


Other aspects provide a use of a nucleic acid vaccine in the manufacture of a medicament for use in a method of vaccinating a subject, wherein the nucleic acid vaccine comprises a first RNA polynucleotide having an open reading frame encoding a first antigenic polypeptide, and wherein the method comprises administering to the subject a single dosage of between 25 μg/kg and 400 μg/kg of the nucleic acid vaccine in an effective amount to vaccinate the subject.


In some embodiments, the NAV polynucleotides may encode one or more polypeptides of an influenza strain as an antigen. Such antigens include, but are not limited to those antigens encoded by the polynucleotides listed in the Tables presented herein. In the table, the GenBank Accession Number or GI Accession Number represents either the complete or partial CDS of the encoded antigen. The NAV polynucleotides may comprise a region of any of the sequences listed in the tables or entire coding region of the mRNA listed. They may comprise hybrid or chimeric regions, or mimics or variants.


The details of various embodiments of the invention are set forth in the description below. Other features, objects, and advantages of the invention will be apparent from the description and the drawings, and from the claims.





BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, features and advantages will be apparent from the following description of particular embodiments of the invention, as illustrated in the accompanying drawings in which like reference characters refer to the same parts throughout the different views. The drawings are not necessarily to scale, emphasis instead being placed upon illustrating the principles of various embodiments of the invention.



FIGS. 1A and 1B are schematics of a polynucleotide construct. FIG. 1A is a schematic of a polynucleotide construct taught in commonly owned co-pending U.S. patent application Ser. No. 13/791,922 filed Mar. 9, 2013, the contents of which are incorporated herein by reference. FIG. 1B is a schematic of a linear polynucleotide construct.



FIG. 2 is a schematic of a series of chimeric polynucleotides of the present invention.



FIG. 3 is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications and showing regions analogous to those regions of an mRNA polynucleotide.



FIG. 4 is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I.



FIG. 5 is a is a schematic of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I and further illustrating a blocked or structured 3′ terminus.



FIGS. 6A and 6B are schematics of circular constructs of the present invention.



FIGS. 7A-7B are schematics of circular constructs of the present invention.



FIGS. 8A-8B are schematics of a circular constructs of the present invention. FIG. 8A shows a circular construct comprising at least one sensor region and a spacer region. FIG. 8B shows a non-coding circular construct.



FIG. 9 is a schematic of a non-coding circular construct of the present invention.



FIG. 10 shows HA neutralization titres of a chemically modified mRNA influenza vaccine in comparison with protein and unmodified mRNA vaccines.



FIG. 11 shows hemagglutinin inhibition titers in mice following vaccination with different doses and formulations of mRNA encoding the hemagglutinin protein of the H1N1 virus.



FIGS. 12A-12D show percent survival of mice after vaccination and challenge with influenza A/PR/8/34 virus. FIG. 12A shows percent survival at 1 week post challenge. FIG. 12B shows percent survival at 2 weeks post challenge. FIG. 12C shows percent survival at 3 weeks post challenge. FIG. 12D shows percent survival at 4 weeks post challenge.



FIG. 13 shows the mean hemagglutination inhibition titers of mice after vaccination and challenge with influenza A/PR/8/34 virus



FIGS. 14A-14C shows CD4 T cell IFNγ cytokine responses. FIG. 14A shows IFNγ production upon H1 protein/peptide stimulation. FIG. 14B shows IFNγ production upon H7 protein/peptide stimulation. FIG. 14C shows IFNγ production upon PMA+ionomycin stimulation.



FIGS. 15A-15D shows IgG production following H1 and H7 protein/peptide stimulation.



FIG. 16 is a graph showing hemagglutinin inhibition titers (HAI) against H10 following administration of the H10N8/N1-methyl pseudouridine/C0 formulation MC3 vaccine at the indicated dosages.



FIG. 17 is a graph showing hemagglutinin inhibition titers (HAI) against H10 following administration of the H10N8/N1-methyl pseudouridine/C1 formulation MC3 vaccine at the indicated dosages.



FIG. 18 is a graph comparing hemagglutinin inhibition titers (HAI) against H7 following administration of 10 μg/dose of the H7N9/C0 formulation compared to the H7N9/C1 formulation.



FIG. 19 is a graph of the mean hemagglutinin inhibition titers (HAI) in serum samples from cynomolgus monkey at various time points prior to and after administration of the indicated formulations and dosages.



FIG. 20 is a graph showing the H7N9 viral load in ferrets challenged at day 21 after receiving a single immunization.



FIGS. 21A-21D present mouse survival and HAI titers in mice challenged with a lethal dose following administration of a single dose of mRNA NAV encoding H7N9. FIG. 21A shows survival at day 7 post challenge. FIG. 21B shows survival at day 21 post challenge. FIG. 21C shows survival at day 84 post challenge. FIG. 21D shows HAI titers.



FIGS. 22-1 through 22-51 show an alignment of amino acid sequences of hemagglutinin proteins from influenza A H7N9 strains relative to a consensus sequence. The sequences, from top to bottom, correspond to SEQ ID NOs: 1020, 8, 13, 7, 98, 99, 100, 96, 89, 92, 24, 29, 90, 57, 42, 27, 78, 74, 95, 30, 31, 32, 25, 39, 38, 35, 36, 37, 82, 91, 83, 104, 93, 94, 178, 133, 134, 132, 135, 136, 173, 175, 174, 73, 70, 33, 34, 41, 40, 76, 75, 72, 79, 80, 86, 105, 77, 11, 12, 4, 164, 150, 151, 171, 152, 165, 121, 166, 167, 156, 157, 168, 143, 169, 144, 145, 122, 113, 117, 119, 138, 137, 146, 147, 148, 158, 159, 160, 161, 162, 62, 129, 130, 141, 123, 124, 176, 125, 182, 183, 179, 180, 184, 181, 185, 186, 187, 188, 189, 190, 193, 177, 140, 49, 47, 48, 97, 50, 51, 191, 195, 196, 128, 131, 170, 111, 112, 118, 108, 120, 109, 107, 26, 106, 52, 53, 28, 192, 45, 46, 6, 44, 43, 126, 19, 21, 20, 59, 54, 71, 102, 10, 101, 2, 58, 23, 55, 5, 22, 103, 153, 154, 155, 172, 142, 114, 115, 116, 127, 149, 163, 139, 194, 110, 17, 81, 3, 85, 87, 88, 84, 61, 60, 1, 9, 14, 15, 16, 64, 63, 66, 65, 67, 68, 69, 18, and 56.



FIGS. 23-1 through 23-14 (SEQ ID NOS: 1021, 967-1019) shows an alignment of amino acid sequences of hemagglutinin proteins from influenza A H10N8 strains relative to a consensus sequence.





DETAILED DESCRIPTION

It is of great interest in the fields of therapeutics, diagnostics, reagents and for biological assays to be able design, synthesize and deliver a nucleic acid, e.g., a ribonucleic acid (RNA) for example, a messenger RNA (mRNA) encoding a peptide or polypeptide of interest inside a cell, whether in vitro, in vivo, in situ or ex vivo, such as to effect physiologic outcomes which are beneficial to the cell, tissue or organ and ultimately to an organism. One beneficial outcome is to cause intracellular translation of the nucleic acid and production of at least one encoded peptide or polypeptide of interest.


Of particular interest, is the ability to design, synthesize and deliver a nucleic acid, e.g., a ribonucleic acid (RNA), for example, a messenger RNA (mRNA), which encodes an antigen, e.g., an antigen derived from an infectious microorganism, for the purpose of vaccination.


Described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a nucleic acid molecule, e.g., a polynucleotide. In particular, described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a polynucleotide. In particular, described herein are compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of nucleic acid vaccines (NAVs) where at least one component of the NAV is a RNA polynucleotide, e.g., an mRNA polynucleotide which encodes an antigen, e.g., an antigen derived from an infectious microorganism. In certain embodiments, the invention relates to compositions (including pharmaceutical compositions) and methods for the selection, design, preparation, manufacture, formulation, and/or use of ribonucleic acid vaccines (RNAVs) where at least one component of the RNAV is a ribonucleic acid molecule, e.g., a mRNA which encodes an antigen, e.g., an antigen derived from an infectious microorganism. As such the present invention is directed, in part, to polynucleotides, specifically in vitro transcription (IVT) polynucleotides, chimeric polynucleotides and/or circular polynucleotides which may function as a vaccine or component of a vaccine.


Also provided are systems, processes, devices and kits for the selection, design and/or utilization of the NAVs described herein.


According to the present invention, the polynucleotides may be modified in a manner as to avoid the deficiencies of or provide improvements over other polynucleotide molecules of the art.


Although attempts have been made to produce functional RNA vaccines, including mRNA vaccines and self-replicating RNA vaccines, the therapeutic efficacy of these RNA vaccines have not yet been fully established. Quite surprisingly, the inventors have discovered a class of formulations for delivering mRNA vaccines in vivo that results in significantly enhanced, and in many respects synergistic, immune responses including enhanced antigen generation and functional antibody production with neutralization capability. These results are achieved even when significantly lower doses of the mRNA are administered in comparison with mRNA doses used in other classes of lipid based formulations. The formulations of the invention have demonstrated significant unexpected in vivo immune responses sufficient to establish the efficacy of functional mRNA vaccines as prophylactic and therapeutic agents.


The invention involves, in some aspects, the surprising finding that lipid nanoparticle (LNP) formulations significantly enhance the effectiveness of mRNA vaccines, including chemically modified and unmodified mRNA vaccines. The efficacy of mRNA vaccines formulated in LNP was examined in vivo using several distinct viral antigens and in a variety of different animal models. The results presented herein demonstrate the unexpected superior efficacy of the mRNA vaccines formulated in LNP over other mRNA vaccines formulated in other lipid based carriers as well as over protein antigens.


In addition to providing an enhanced immune response, the formulations of the invention generate a more rapid immune response following a single dose of antigen than other mRNA or protein based vaccines tested. A study described herein involved intravenous (IV), intramuscular (IM), or intradermal (ID) vaccination of mice, followed by challenge with a lethal dose of virus. In addition to all of the vaccinated animals surviving the lethal dose, significantly stronger early immune responses were observed (anti-viral activity via virus neutralization assay and HA inhibition (HAI)) in comparison to protein antigen and other lipid based formulations (lipoplex). The data demonstrates that as early as 1 week after vaccination two groups of animals receiving a mRNA-LNP formulation (ID or IM) displayed HAI titers over 40, at 60 and 114, respectively. An HAI titer of greater than 40 is deemed sufficient to protect from a lethal challenge of influenza. The rapid response was unexpected, particularly when compared to the response seen with protein antigen and mRNA vaccines formulated in other lipid carriers (lipoplex), which at one week and even at three weeks following vaccination continued to show ineffective HAI titers of less than 40.


At each of the later time points (3 weeks and 5 weeks), the formulations of the invention continued to provide significantly stronger therapeutic responses than did protein antigen. In fact both chemically unmodified and modified mRNA-LNP formulation administered by IV route had enhanced HAI titers with respect to the protein antigen. By week 3, all of the animals receiving an mRNA-LNP formulation by IM or ID administration displayed HAI activity over 40, as compared to protein antigen, which at one week and three weeks continued to show HAI titers of less than 40. By week 5 a mRNA-LNP formulation administered by ID route had a surprising HAI activity of greater than 10,000, in contrast to the HAI titer of around 400 for protein antigen at that time point. Mice receiving a mRNA-LNP formulation also displayed neutralizing activity of 79-250 (IM) and 250 (ID) by microneutralization assay, in comparison to protein antigen, which had undetectable neutralization activity at that time point. By week 5 following vaccination, five of the six LNP formulated groups showed high neutralizing activity between 789 and 24892. In contrast, the mice vaccinated with protein antigen displayed neutralizing activity in only 3 of 5 mice and ranging only between 79 and 250.


The mRNA-LNP formulations of the invention also produced quantitatively and qualitatively better immune responses than did mRNA vaccines formulated in a different lipid carrier (lipoplex). At week 5 the mRNA-lipoplex vaccine produced HAI titers of 197, in comparison to those achieved by the mRNA-LNP formulations of the invention (HAI titers of 635-10,152). At all other time points and for all of the mRNA-lipoplex vaccines, none of the HAI titers reached the critical level of greater than 40. Additionally, the mRNA-lipoplex vaccines did not result in any detectable neutralizing activity in the microneutralization activity, even as late as five weeks after vaccination.


The data described herein demonstrate that the formulations of the invention produced significant unexpected improvements over both existing protein antigen vaccines and mRNA vaccine formulations, including: 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine.


Additionally, the mRNA-LNP formulations of the invention were superior to other lipid formulations even when the dose of mRNA was significantly lower than in the other lipid formulations. For instance, the data described above was generated using 10 μg of mRNA in the mRNA-LNP formulations in contrast to 80 μg of mRNA in the mRNA-lipoplex formulation.


The formulations of the invention also showed strong efficacy in several non-rodent animal models, including non-human primates. Highly effective vaccination was observed in cynomoglus monkeys and ferrets. Cynomoglus monkeys were vaccinated with various doses of mRNA-LNP formulations (50 μg/dose, 200 μg/dose, 400 μg/dose). Quite surprisingly, the vaccine formulations of the invention at all doses measured significantly reduced viral titers in the lungs of ferrets when exposed to virus just 7 days following single vaccination. Statistically significant increases in antibody titer as measured by HAI and microneutralization were detected as early as 7 days following vaccination and through the entire length of the study (84 days). A single vaccination was able to eliminate all virus in most animals.


The LNP used in the studies described herein has been used previously to deliver siRNA various in animal models as well as in humans. In view of the observations made in association with the siRNA delivery of LNP formulations, the fact that LNP is useful in vaccines is quite surprising. It has been observed that therapeutic delivery of siRNA formulated in LNP causes an undesirable inflammatory response associated with a transient IgM response, typically leading to a reduction in antigen production and a compromised immune response. In contrast to the findings observed with siRNA, the LNP-mRNA formulations of the invention are demonstrated herein to generate enhanced IgG levels, sufficient for prophylactic and therapeutic methods rather than transient IgM responses.


I. Nucleic Acid Vaccines (NAVs)

Nucleic Acid Vaccines (NAVs) of the present invention comprise one or more polynucleotides, e.g., polynucleotide constructs, which encode one or more wild type or engineered antigens. Exemplary polynucleotides, e.g., polynucleotide constructs, include antigen-encoding RNA polynucleotides, e.g., mRNAs. In exemplary aspect, polynucleotides of the invention, e.g., antigen-encoding RNA polynucleotides, may include at least one chemical modification.


NAV compositions of the invention may comprise other components including, but not limited to, tolerizing agents or adjuvants.


Tolerizing Agent or Composition

Where auto-immunity mediated side effects occur, tolerizing mRNA and/or such as any of those taught for example in U.S. Ser. No. 61/892,556 filed Oct. 18, 2013, and PCT/US2014/61104 filed Oct. 17, 2014, the contents of which are incorporated herein by reference in their entirety) are co-administered with the NAV to induce antigen specific tolerance.


Adjuvants

Adjuvants or immune potentiators, may also be administered with or in combination with one or more NAVs.


In one embodiment, an adjuvant acts as a co-signal to prime T-cells and/or B-cells and/or NK cells as to the existence of an infection.


Advantages of adjuvants include the enhancement of the immunogenicity of antigens, modification of the nature of the immune response, the reduction of the antigen amount needed for a successful immunization, the reduction of the frequency of booster immunizations needed and an improved immune response in elderly and immunocompromised vaccinees. These may be co-administered by any route, e.g., intramusculary, subcutaneous, IV or intradermal injections.


Adjuvants useful in the present invention may include, but are not limited to, natural or synthetic. They may be organic or inorganic.


Adjuvants may be selected from any of the classes (1) mineral salts, e.g., aluminium hydroxide and aluminium or calcium phosphate gels; (2) emulsions including: oil emulsions and surfactant based formulations, e.g., microfluidised detergent stabilised oil-in-water emulsion, purified saponin, oil-in-water emulsion, stabilised water-in-oil emulsion; (3) particulate adjuvants, e.g., virosomes (unilamellar liposomal vehicles incorporating influenza haemagluttinin), structured complex of saponins and lipids, polylactide co-glycolide (PLG); (4) microbial derivatives; (5) endogenous human immunomodulators; and/or (6) inert vehicles, such as gold particles; (7) microorganism derived adjuvants; (8) tensoactive compounds; (9) carbohydrates; or combinations thereof.


Adjuvants for DNA nucleic acid vaccines (DNA) have been disclosed in, for example, Kobiyama, et al Vaccines, 2013, 1(3), 278-292, the contents of which are incorporated herein by reference in their entirety. Any of the adjuvants disclosed by Kobiyama may be used in the RNAVs of the present invention.


Other adjuvants which may be utilized in the RNAVs of the present invention include any of those listed on the web-based vaccine adjuvant database, Vaxjo; http://www.violinet.org/vaxjo/ and described in for example Sayers, et al., J. Biomedicine and Biotechnology, volume 2012 (2012), Article ID 831486, 13 pages, the content of which is incorporated herein by reference in its entirety.


Selection of appropriate adjuvants will be evident to one of ordinary skill in the art. Specific adjuvants may include, without limitation, cationic liposome-DNA complex JVRS-100, aluminum hydroxide vaccine adjuvant, aluminum phosphate vaccine adjuvant, aluminum potassium sulfate adjuvant, alhydrogel, ISCOM(s)™, Freund's Complete Adjuvant, Freund's Incomplete Adjuvant, CpG DNA Vaccine Adjuvant, Cholera toxin, Cholera toxin B subunit, Liposomes, Saponin Vaccine Adjuvant, DDA Adjuvant, Squalene-based Adjuvants, Etx B subunit Adjuvant, IL-12 Vaccine Adjuvant, LTK63 Vaccine Mutant Adjuvant, TiterMax Gold Adjuvant, Ribi Vaccine Adjuvant, Montanide ISA 720 Adjuvant, Corynebacterium-derived P40 Vaccine Adjuvant, MPL™ Adjuvant, AS04, AS02, Lipopolysaccharide Vaccine Adjuvant, Muramyl Dipeptide Adjuvant, CRL1005, Killed Corynebacterium parvum Vaccine Adjuvant, Montanide ISA 51, Bordetella pertussis component Vaccine Adjuvant, Cationic Liposomal Vaccine Adjuvant, Adamantylamide Dipeptide Vaccine Adjuvant, Arlacel A, VSA-3 Adjuvant, Aluminum vaccine adjuvant, Polygen Vaccine Adjuvant, Adjumer™, Algal Glucan, Bay R1005, Theramide®, Stearyl Tyrosine, Specol, Algammulin, Avridine®, Calcium Phosphate Gel, CTA 1-DD gene fusion protein, DOC/Alum Complex, Gamma Inulin, Gerbu Adjuvant, GM-CSF, GMDP, Recombinant hIFN-gamma/Interferon-g, Interleukin-1p, Interleukin-2, Interleukin-7, Sclavo peptide, Rehydragel LV, Rehydragel HPA, Loxoribine, MF59, MTP-PE Liposomes, Murametide. Murapalmitine, D-Murapalmitine, NAGO, Non-Ionic Surfactant Vesicles, PMMA, Protein Cochleates, QS-21, SPT (Antigen Formulation), nanoemulsion vaccine adjuvant, AS03, Quil-A vaccine adjuvant, RC529 vaccine adjuvant, LTR1920 Vaccine Adjuvant, E. coli heat-labile toxin, LT, amorphous aluminum hydroxyphosphate sulfate adjuvant, Calcium phosphate vaccine adjuvant, Montanide Incomplete Seppic Adjuvant, Imiquimod, Resiquimod, AF03, Flagellin, Poly(I:C), ISCOMATRIX®, Abisco-100 vaccine adjuvant, Albumin-heparin microparticles vaccine adjuvant. AS-2 vaccine adjuvant, B7-2 vaccine adjuvant, DHEA vaccine adjuvant, Immunoliposomes Containing Antibodies to Costimulatory Molecules, SAF-1, Sendai Proteoliposomes, Sendai-containing Lipid Matrices, Threonyl muramyl dipeptide (TMDP), Ty Particles vaccine adjuvant, Bupivacaine vaccine adjuvant, DL-PGL (Polyester poly (DL-lactide-co-glycolide)) vaccine adjuvant, IL-15 vaccine adjuvant, LTK72 vaccine adjuvant, MPL-SE vaccine adjuvant, non-toxic mutant E112K of Cholera Toxin mCT-E112K, and/or Matrix-S.


Other adjuvants which may be co-administered with the NAVs of the invention include, but are not limited to interferons, TNF-alpha, TNF-beta, chemokines such as CCL21, eotaxin, HMGB1, SA100-8alpha, GCSF, GMCSF, granulysin, lactoferrin, ovalbumin, CD-40L, CD28 agonists, PD-1, soluble PD1, L1 or L2, or interleukins such as IL-1, IL-2, IL-4, IL-6, IL-7, IL-10. IL-12, IL-13, IL-21. IL-23, IL-15, IL-17, and IL-18. These may be administered with the NAV on the same encoded polynucleotide, e.g., polycistronic, or as separate mRNA encoding the adjuvant and antigen.


Valency

NAVs of the present invention may vary in their valency. Valency refers to the number of antigenic components in the NAV or NAV polynucleotide (e.g., RNA polynucleotide) or polypeptide. In some embodiments, the NAVs are monovalent. In some embodiments, the NAVs are divalent. In some embodiments the NAVs are trivalent. In some embodiments the NAVs are multi-valent. Multivalent vaccines may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more antigens or antigenic moieties (e.g., antigenic peptides, etc.). The antigenic components of the NAVs may be on a single polynucleotide or on separate polynucleotides.


Therapeutics

The NAVs of the present invention can be used as therapeutic or prophylactic agents. They are provided for use in medicine and/or for the priming of immune effector cells, e.g., stimulate/transfect PBMCs ex vivo and re-infuse the activated cells. For example, a NAV described herein can be administered to a subject, wherein the polynucleotides is translated in vivo to produce an antigen. Provided are compositions, methods, kits, and reagents for diagnosis, treatment or prevention of a disease or condition in humans and other mammals. The active therapeutic agents of the invention include NAVs, cells containing NAVs or polypeptides translated from the polynucleotides contained in said NAVs.


Provided herein are methods of inducing translation of a polypeptide (e.g., antigen or immunogen) in a cell, tissue or organism using the polynucleotides of the NAVs described herein. Such translation can be in vivo, ex vivo, in culture, or in vitro. The cell, tissue or organism is contacted with an effective amount of a composition containing a NAV which contains a polynucleotide that has at least one a translatable region encoding the polypeptide of interest (e.g., antigen or immunogen).


An “effective amount” of the NAV composition is provided based, at least in part, on the target tissue, target cell type, means of administration, physical characteristics of the polynucleotide (e.g., size, and extent of modified nucleosides) and other components of the NAV, and other determinants. In general, an effective amount of the NAV composition provides an induced or boosted immune response as a function of antigen production in the cell, preferably more efficient than a composition containing a corresponding unmodified polynucleotide encoding the same antigen. Increased antigen production may be demonstrated by increased cell transfection (i.e., the percentage of cells transfected with the NAV), increased protein translation from the polynucleotide, decreased nucleic acid degradation (as demonstrated, e.g., by increased duration of protein translation from a modified polynucleotide), or altered innate immune response of the host cell.


Aspects of the invention are directed to methods of inducing in vivo translation of a polypeptide antigen in a mammalian subject in need thereof. Therein, an effective amount of a NAV composition containing a polynucleotide that has at least one structural or chemical modification and a translatable region encoding the polypeptide (e.g., antigen or immunogen) is administered to the subject using the delivery methods described herein. The polynucleotide is provided in an amount and under other conditions such that the polynucleotide is translated in the cell. The cell in which the polynucleotide is localized, or the tissue in which the cell is present, may be targeted with one or more than one rounds of NAV administration.


In certain embodiments, the administered NAVs comprising polynucleotides directs production of one or more polypeptides that provide a functional immune system-related activity which is substantially absent in the cell, tissue or organism in which the polypeptide is translated. For example, the missing functional activity may be enzymatic, structural, or gene regulatory in nature. In related embodiments, the administered polynucleotides directs production of one or more polypeptides that increases (e.g., synergistically) a functional activity related to the immune system which is present but substantially deficient in the cell in which the polypeptide is translated.


Additionally, the polypeptide antagonizes, directly or indirectly, the activity of a biological moiety present in, on the surface of, or secreted from the cell. Examples of antagonized biological moieties include lipids (e.g., cholesterol), a lipoprotein (e.g., low density lipoprotein), a nucleic acid, a carbohydrate, a protein toxin such as shiga and tetanus toxins, or a small molecule toxin such as botulinum, cholera, and diphtheria toxins. Additionally, the antagonized biological molecule may be an endogenous protein that exhibits an undesirable activity, such as a cytotoxic or cytostatic activity.


The proteins described herein may be engineered for localization within the cell, potentially within a specific compartment such as the cytoplasms or nucleus, or are engineered for secretion from the cell or translocation to the plasma membrane of the cell.


In some embodiments, polynucleotides of the NAVs and their encoded polypeptides in accordance with the present invention may be used for treatment of any of a variety of diseases, disorders, and/or conditions, including but not limited to viral infections (e.g., influenza, HIV, HCV, RSV), parasitic infections or bacterial infections.


The subject to whom the therapeutic agent may be administered suffers from or may be at risk of developing a disease, disorder, or deleterious condition. Provided are methods of identifying, diagnosing, and classifying subjects on these bases, which may include clinical diagnosis, biomarker levels, genome-wide association studies (GWAS), and other methods known in the art.


The agents can be administered simultaneously, for example in a combined unit dose (e.g., providing simultaneous delivery of both agents). The agents can also be administered at a specified time interval, such as, but not limited to, an interval of minutes, hours, days or weeks. Generally, the agents may be concurrently bioavailable, e.g., detectable, in the subject. In some embodiments, the agents may be administered essentially simultaneously, for example two unit dosages administered at the same time, or a combined unit dosage of the two agents. In other embodiments, the agents may be delivered in separate unit dosages. The agents may be administered in any order, or as one or more preparations that includes two or more agents. In a preferred embodiment, at least one administration of one of the agents, e.g., the first agent, may be made within minutes, one, two, three, or four hours, or even within one or two days of the other agent, e.g., the second agent. In some embodiments, combinations can achieve synergistic results, e.g., greater than additive results, e.g., at least 25, 50, 75, 100, 200, 300, 400, or 500% greater than additive results.


Modulation of the Immune Response
Activation of the Immune Response

According to the present invention, the NAVs comprising the polynucleotides disclosed herein, e.g., comprising RNA polynucleotides, may act as a single composition as a vaccine. As used herein, a “vaccine” refers to a composition, for example, a substance or preparation that stimulates, induces, causes or improves immunity in an organism, e.g., an animal organism, for example, a mammalian organism (e.g., a human.) Preferably, a vaccine provides immunity against one or more diseases or disorders in the organism, including prophylactic and/or therapeutic immunity. Exemplary vaccines includes one or more agents that resembles an infectious agent, e.g., a disease-causing microorganism, and can be made, for example, from live, attenuated, modified, weakened or killed forms of disease-causing microorganisms, or antigens derived therefrom, including combinations of antigenic components. In exemplary embodiments, a vaccine stimulates, induces causes or improves immunity in an organism or causes or mimics infection in the organism without inducing any disease or disorder. A vaccine introduces an antigen into the tissues, extracellular space or cells of a subject and elicits an immune response, thereby protecting the subject from a particular disease or pathogen infection. The polynucleotides of the present invention may encode an antigen and when the polynucleotides are expressed in cells, a desired immune response is achieved.


NAVs may be administered prophylactically or therapeutically as part of an active immunization scheme to healthy individuals or early in infection during the incubation phase or during active infection after onset of symptoms.


The NAVs of the present invention may also be administered as a second line treatment after the standard first line treatments such as antibiotics and antivirals have failed to induce passive immunity. In this regard, the NAVs of the present invention are useful in settings where resistance to first line treatments has developed and disease persists and induces chronic disease.


NAVs may be administered as part of a treatment regimen for latent bacterial infections, such as MRSA or Clostridium infections. In this embodiment, one or more polynucleotides are administered which ultimately produce proteins which result in the removal or alterations of the protective shield surrounding a bacterium making the bacterium more susceptible to antibiotic treatment.


In one embodiment, a polynucleotide encoding one or several generic or patient-specific antibiotic resistance genes is administered to a patient, e.g. NDM-1. The polynucleotide is then translated to produce the enzyme in vivo. This production may raise an antibody-mediated immune response to the secreted and/or the intracellular enzyme that neutralized the antibiotic resistance and provides the bacteria susceptible to the clearance by available antibiotics again. Given the broad range of mutations and variants in antibiotic resistance genes, it would be possible to sequence the specific bacteria genes hosted by the patients and design the exact vaccine for the specific variant in the infected patient.


The use of RNA in or as a vaccine overcomes the disadvantages of conventional genetic vaccination involving incorporating DNA into cells in terms of safeness, feasibility, applicability, and effectiveness to generate immune responses. RNA molecules are considered to be significantly safer than DNA vaccines, as RNAs are more easily degraded. They are cleared quickly out of the organism and cannot integrate into the genome and influence the cell's gene expression in an uncontrollable manner. It is also less likely for RNA vaccines to cause severe side effects like the generation of autoimmune disease or anti-DNA antibodies (Bringmann A. et al., Journal of Biomedicine and Biotechnology (2010), vol. 2010, article ID623687). Transfetion with RNA requires only insertion into the cell's cytoplasm, which is easier to achieve than into the nucleus. However, RNA is susceptible to RNase degradation and other natural decomposition in the cytoplasm of cells.


Various attempts to increase the stability and shelf life of RNA vaccines. US 2005/0032730 to Von Der Mulbe et al. discloses improving the stability of mRNA vaccine compositions by increasing G(guanosine)/C(cytosine) content of the mRNA molecules. U.S. Pat. No. 5,580,859 to Felgner et al. teaches incorporating polynucleotide sequences coding for regulatory proteins that binds to and regulates the stabilities of mRNA. While not wishing to be bound by theory, it is believed that the polynucleotides vaccines (NAVs) of the invention will result in improved stability and therapeutic efficacy due at least in part to the specificity, purity and selectivity of the construct designs.


Additionally, certain modified nucleosides, or combinations thereof, when introduced into the polynucleotides of the NAVs of the invention will activate the innate immune response. Such activating molecules are useful as adjuvants when combined with polypeptides and/or other vaccines. In certain embodiments, the activating molecules contain a translatable region which encodes for a polypeptide sequence useful as a vaccine, thus providing the ability to be a self-adjuvant.


In one embodiment, the polynucleotides of the NAVs of the present invention may be used in the prevention, treatment and diagnosis of diseases and physical disturbances caused by infectious agents. The polynucleotide of the present invention may encode at least one polypeptide of interest (antigen) and may be provided to an individual in order to stimulate the immune system to protect against the disease-causing agents. As a non-limiting example, the biological activity and/or effect from an antigen or infectious agent may be inhibited and/or abolished by providing one or more polynucleotides which have the ability to bind and neutralize the antigen and/or infectious agent.


As a non-limiting example, the polynucleotides encoding an immunogen may be delivered to cells to trigger multiple innate response pathways (see International Pub. No. WO2012006377 and US Patent Publication No. US20130177639; herein incorporated by reference in its entirety). As another non-limiting example, the polynucleotides of the NAVs of the present invention encoding an immunogen may be delivered to a vertebrate in a dose amount large enough to be immunogenic to the vertebrate (see International Pub. No. WO2012006372 and WO2012006369 and US Publication No. US20130149375 and US20130177640; the contents of each of which are herein incorporated by reference in their entirety).


A non-limiting list of infectious diseases that the polynucleotide vaccines may treat includes, viral infectious diseases such as AIDS (HIV), HIV resulting in mycobacterial infection, AIDS related Cacheixa, AIDS related Cytomegalovirus infection, HIV-associated nephropathy, Lipodystrophy, AID related cryptococcal meningitis, AIDS related neutropaenia, Pneumocysitis jiroveci (Pneumocystis carinii) infections, AID related toxoplasmosis, hepatitis A, B, C, D or E, herpes, herpes zoster (chicken pox), German measles (rubella virus), yellow fever, dengue fever etc. (flavi viruses), flu (influenza viruses), haemorrhagic infectious diseases (Marburg or Ebola viruses), bacterial infectious diseases such as Legionnaires' disease (Legionella), gastric ulcer (Helicobacter), cholera (Vibrio), E. coli infections, staphylococcal infections, salmonella infections or streptococcal infections, tetanus (Clostridium tetani), protozoan infectious diseases (malaria, sleeping sickness, leishmaniasis, toxoplasmosis, i.e. infections caused by plasmodium, trypanosomes, leishmania and toxoplasma), diphtheria, leprosy, measles, pertussis, rabies, tetanus, tuberculosis, typhoid, varicella, diarrheal infections such as Amoebiasis, Clostridium difficile-associated diarrhea (CDAD), Cryptosporidiosis, Giardiasis, Cyclosporiasis and Rotaviral gastroenteritis, encephalitis such as Japanese encephalitis, Wester equine encephalitis and Tick-borne encephalitis (TBE), fungal skin diseases such as candidiasis, onychomycosis, Tinea captis/scal ringworm, Tinea corporis/body ringworm, Tinea cruris/jock itch, sporotrichosis and Tinea pedis/Athlete's foot, Meningitis such as Haemophilus influenza type b (Hib), Meningitis, viral, meningococcal infections and pneumococcal infection, neglected tropical diseases such as Argentine haemorrhagic fever, Leishmaniasis, Nematode/roundworm infections, Ross river virus infection and West Nile virus (WNV) disease, Non-HIV STDs such as Trichomoniasis, Human papillomavirus (HPV) infections, sexually transmitted chlamydial diseases, Chancroid and Syphilis, Non-septic bacterial infections such as cellulitis, lyme disease, MRSA infection, pseudomonas, staphylococcal infections, Boutonneuse fever, Leptospirosis, Rheumatic fever, Botulism, Rickettsial disease and Mastoiditis, parasitic infections such as Cysticercosis, Echinococcosis, Trematode/Fluke infections, Trichinellosis, Babesiosis, Hypodermyiasis, Diphyllobothriasis and Trypanosomiasis, respiratory infections such as adenovirus infection, aspergillosis infections, avian (H5N1) influenza, influenza, RSV infections, severe acute respiratory syndrome (SARS), sinusitis, Legionellosis, Coccidioidomycosis and swine (H1N1) influenza, sepsis such as bacteraemia, sepsis/septic shock, sepsis in premature infants, urinary tract infection such as vaginal infections (bacterial), vaginal infections (fungal) and gonococcal infection, viral skin diseases such as B19 parvovirus infections, warts, genital herpes, orofacial herpes, shingles, inner ear infections, fetal cytomegalovirus syndrome, foodborn illnesses such as brucellosis (Brucella species). Clostridium perfringens (Epsilon toxin), E. Coli O157:H7 (Escherichia coli), Salmonellosis (Salmonella species), Shingellosis (Shingella), Vibriosis and Listeriosis, bioterrorism and potential epidemic diseases such as Ebola haemorrhagic fever, Lassa fever, Marburg haemorrhagic fever, plague, Anthrax Nipah virus disease, Hanta virus, Smallpox, Glanders (Burkholderia mallei), Melioidosis (Burkholderia pseudomallei), Psittacosis (Chlamydia psittaci). Q fever (Coxiella burnetii), Tularemia (Fancisella tularensis), rubella, mumps and polio.


NAVs of the present invention may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. As a non-limiting example, the NAVs of the present invention may be utilized to treat and/or prevent influenza infection, i.e. diseases and conditions related to influenza virus infection (seasonal and pandemic).


Symptoms of the influenza infection include dry cough, fever, chills, myalgias progressing to respiratory failure and the risk of secondary bacterial infections (e.g., MRSA). Seasonal influenza is ubiquitous and consists of three principal strains (A [H1N1], A [H3N2], and B), which are covered by the annual vaccine. Pandemic flu occurs because the viruses' unique reassortment ability allowing antigenic shift as well as transfer between avian and swine flu strains. One emerging concern in Southeast Asia is the pandemic potential of several new strains. Such pandemic outbreaks have a high mortality rate with few available treatments. Anti-virals only provide symptomatic relief and must be given in the first 48 hours.


The NAVs of the present invention have superior properties in that they produce much larger antibody titers, produce responses early than commercially available anti-virals and may be administered after the critical 48 hour period while retaining efficacy.


While not wishing to be bound by theory, the inventors hypothesize that the NAVs of the invention, as mRNA polynucleotides, are better designed to produce the appropriate protein conformation on translation as the NAVs co-opt natural cellular machinery. Unlike traditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the NAVs are presented to the cellular system in a more native fashion. Adding to the superior effects may also involve the formulations utilized which may neither serve to shield nor traffic the NAVs.


According to the present invention, NAVs represent a tailored active vaccine that not only can prevent infection but can limit transmission of influenza.


In some embodiments, the NAVs may be used to prevent pandemic influenza by reacting to emerging new strains with the very rapid NAV-based vaccine production process. In some embodiments, new NAV for treating or prophylactically preventing influenza outbreaks, including for emerging strains (e.g., H10N8), may be produced in less than six weeks, from the time of antigen identification to available vaccine.


In some embodiments a single injection of a single antigen encoding NAV polynucleotide may provide protection for an entire flu season.


The polynucleotides of the NAVs of the invention are not self-replicating RNA. Self-replicating RNA have been described, for instance in US Pub. No. US20110300205 and International Pub. No. WO2011005799 and WO2013055905, the contents of each of which are herein incorporated by reference in their entirety.


In one embodiment, the polynucleotides of the NAVs of the invention may encode amphipathic and/or immunogenic amphipathic peptides.


In on embodiment, a formulation of the polynucleotides of the NAVs of the invention may further comprise an amphipathic and/or immunogenic amphipathic peptide. As a non-limiting example, the polynucleotides comprising an amphipathic and/or immunogenic amphipathic peptide may be formulated as described in US. Pub. No. US20110250237 and International Pub. Nos. WO2010009277 and WO2010009065; each of which is herein incorporated by reference in their entirety.


In one embodiment, the polynucleotides of the NAVs of the invention may be immunostimulatory. As a non-limiting example, the polynucleotides may encode all or a part of a positive-sense or a negative-sense stranded RNA virus genome (see International Pub No. WO2012092569 and US Pub No. US20120177701, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the immunostimultory polynucleotides of the present invention may be formulated with an excipient for administration as described herein and/or known in the art (see International Pub No. WO2012068295 and US Pub No. US20120213812, each of which is herein incorporated by reference in their entirety). The polynucleotides may further comprise a sequence region encoding a cytokine that promotes the immune response, such as a monokine, lymphokine, interleukin or chemokine, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, INF-α, INF-γ, GM-CFS, LT-α, or growth factors such as hGH.


In one embodiment, the response of the vaccine formulated by the methods described herein may be enhanced by the addition of various compounds to induce the therapeutic effect. As a non-limiting example, the vaccine formulation may include a MHC II binding peptide or a peptide having a similar sequence to a MHC II binding peptide (see International Pub Nos. WO2012027365, WO2011031298 and US Pub No. US20120070493, US20110110965, each of which is herein incorporated by reference in their entirety). As another example, the vaccine formulations may comprise modified nicotinic compounds which may generate an antibody response to nicotine residue in a subject (see International Pub No. WO2012061717 and US Pub No. US20120114677, each of which is herein incorporated by reference in their entirety).


In one embodiment, the effective amount of the polynucleotides of the NAVs of the invention provided to a cell, a tissue or a subject may be enough for immune prophylaxis.


In one embodiment, the polynucleotides of the NAVs of the invention may be administrated with other prophylactic or therapeutic compounds. As a non-limiting example, the prophylactic or therapeutic compound may be an adjuvant or a booster. As used herein, when referring to a prophylactic composition, such as a vaccine, the term “booster” refers to an extra administration of the prophylactic composition. A booster (or booster vaccine) may be given after an earlier administration of the prophylactic composition. The time of administration between the initial administration of the prophylactic composition and the booster may be, but is not limited to, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 1 day, 36 hours, 2 days, 3 days, 4 days, 5 days, 6 days, 1 week, 10 days, 2 weeks, 3 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 18 months, 2 years, 3 years, 4 years, 5 years, 6 years, 7 years, 8 years, 9 years, 10 years, 11 years, 12 years, 13 years, 14 years, 15 years, 16 years, 17 years, 18 years, 19 years, 20 years, 25 years, 30 years, 35 years, 40 years, 45 years, 50 years, 55 years, 60 years, 65 years, 70 years, 75 years, 80 years, 85 years, 90 years, 95 years or more than 99 years.


In one embodiment, the polynucleotides of the NAVs of the invention may be administered intranasally similar to the administration of live vaccines. In another aspect the polynucleotide may be administered intramuscularly or intradermally similarly to the administration of inactivated vaccines known in the art.


In one embodiment, the NAVs of the invention may be used to protect against and/or prevent the transmission of an emerging or engineered threat which may be known or unknown.


In another embodiment, the NAVs may be formulated by the methods described herein. In one aspect, the formulation may comprise a NAV or polynucleotide which can have a therapeutic and/or prophylactic effect on more than one disease, disorder or condition. As a non-limiting example, the formulation may comprise polynucleotides encoding an antigen, including but not limited to a protein from an infectious agent such as a viral protein, a parasite protein or a bacterial protein.


In addition, the NAV antibodies of the present invention may be used for research in many applications, such as, but not limited to, identifying and locating intracellular and extracellular proteins, protein interaction, signal pathways and cell biology.


In another embodiment, the NAV may be used in to reduce the risk or inhibit the infection of influenza viruses such as, but not limited to, the highly pathogenic avian influenza virus (such as, but not limited to, H5N1 subtype) infection and human influenza virus (such as, but not limited to, H1N1 subtype and H3N2 subtype) infection. The polynucleotide described herein which may encode any of the protein sequences described in U.S. Pat. No. 8,470,771, the contents of which are herein incorporated by reference in its entirety, may be used in the treatment or to reduce the risk of an influenza infection.


In one embodiment, the NAV may be used to as a vaccine or modulating the immune response against a protein produced by a parasite. Bergmann-Leitner et al. in U.S. Pat. No. 8,470,560, the contents of which are herein incorporated by reference in its entirety, describe a DNA vaccine against the circumsporozoite protein (CSP) of malaria parasites. As a non-limiting example, the polynucleotide may encode the CR2 binding motif of C3d and may be used a vaccine or therapeutic to modulate the immune system against the CSP of malaria parasites.


In one embodiment, the NAV may be used as a vaccine and may further comprise an adjuvant which may enable the vaccine to elicit a higher immune response. As a non-limiting example, the adjuvant could be a sub-micron oil-in-water emulsion which can elicit a higher immune response in human pediatric populations (see e.g., the adjuvanted vaccines described in US Patent Publication No. US20120027813 and U.S. Pat. No. 8,506,966, the contents of each of which are herein incorporated by reference in its entirety).


II. Infectious Agents and Antigens

NAVs of the present invention may be used to protect, treat or cure infection arising from contact with an infectious agent, e.g., microorganism. Infectious agents include bacteria, viruses, fungi, protozoa and parasites.


A. Managing Infection

In one embodiment, provided are methods for treating or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial or viral infection, or a symptom thereof, in a subject, by administering a NAV comprising one or more polynucleotide encoding an anti-microbial polypeptide. The administration may be in combination with an anti-microbial agent (e.g., an anti-bacterial agent), e.g., an anti-microbial polypeptide or a small molecule anti-microbial compound described herein. The anti-microbial agents include, but are not limited to, anti-bacterial agents, anti-viral agents, anti-fungal agents, anti-protozoal agents, anti-parasitic agents, and anti-prion agents.


Conditions Associated with Bacterial Infection


Diseases, disorders, or conditions which may be associated with bacterial infections which may be treated using the NAVs of the invention include, but are not limited to one or more of the following: abscesses, actinomycosis, acute prostatitis, Aeromonas hydrophila, annual ryegrass toxicity, anthrax, bacillary peliosis, bacteremia, bacterial gastroenteritis, bacterial meningitis, bacterial pneumonia, bacterial vaginosis, bacterium-related cutaneous conditions, bartonellosis. BCG-oma, botryomycosis, botulism, Brazilian purpuric fever, Brodie abscess, brucellosis, Buruli ulcer, campylobacteriosis, caries, Carrion's disease, cat scratch disease, cellulitis, chlamydia infection, cholera, chronic bacterial prostatitis, chronic recurrent multifocal osteomyelitis, clostridial necrotizing enteritis, combined periodontic-endodontic lesions, contagious bovine pleuropneumonia, diphtheria, diphtheritic stomatitis, ehrlichiosis, erysipelas, piglottitis, erysipelas, Fitz-Hugh-Curtis syndrome, flea-borne spotted fever, foot rot (infectious pododermatitis), Garre's sclerosing osteomyelitis, Gonorrhea, Granuloma inguinale, human granulocytic anaplasmosis, human monocytotropic ehrlichiosis, hundred days' cough, impetigo, late congenital syphilitic oculopathy, legionellosis. Lemierre's syndrome, leprosy (Hansen's Disease), leptospirosis, listeriosis, Lyme disease, lymphadenitis, melioidosis, meningococcal disease, meningococcal septicaemia, methicillin-resistant Staphylococcus aureus (MRSA) infection, Mycobacterium avium-intracellulare (MAI), mycoplasma pneumonia, necrotizing fasciitis, nocardiosis, noma (cancrum oris or gangrenous stomatitis), omphalitis, orbital cellulitis, osteomyelitis, overwhelming post-splenectomy infection (OPSI), ovine brucellosis, pasteurellosis, periorbital cellulitis, pertussis (whooping cough), plague, pneumococcal pneumonia, Pott disease, proctitis, pseudomonas infection, psittacosis, pyaemia, pyomyositis, Q fever, relapsing fever (typhinia), rheumatic fever, Rocky Mountain spotted fever (RMSF), rickettsiosis, salmonellosis, scarlet fever, sepsis, serratia infection, shigellosis, southern tick-associated rash illness, staphylococcal scalded skin syndrome, streptococcal pharyngitis, swimming pool granuloma, swine brucellosis, syphilis, syphilitic aortitis, tetanus, toxic shock syndrome (TSS), trachoma, trench fever, tropical ulcer, tuberculosis, tularemia, typhoid fever, typhus, urogenital tuberculosis, urinary tract infections, vancomycin-resistant Staphylococcus aureus infection, Waterhouse-Friderichsen syndrome, pseudotuberculosis (Yersinia) disease, and yersiniosis


Bacterial Pathogens

The bacterium described herein can be a Gram-positive bacterium or a Gram-negative bacterium. Bacterial pathogens include, but are not limited to, Acinetobacter baumannii, Bacillus anthracis, Bacillus subtilis, Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella canis, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum, Clostridium dilficile, Clostridium perfringens, Clostridium tetani, coagulase Negative Staphylococcus, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli, E. coli O157:H7, Enterobacter sp., Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Listeria monocytogenes, Moraxella catarralis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Preteus mirabilis, Proteus sps., Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneri, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Vibrio cholerae, and Yersinia pestis.


Bacterial pathogens may also include bacteria that cause resistant bacterial infections, for example, clindamycin-resistant Clostridium difficile, fluoroquinolon-resistant Clostridium difficile, methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA).


Antibiotic Combinations

In one embodiment, the NAVs of the present invention, e.g., NAVs comprising one or more antigen-encoding polynucleotides of the present invention, may be administered in conjunction with one or more antibiotics.


Antibacterial Agents

Anti-bacterial agents include, but are not limited to, aminoglycosides (e.g., amikacin (AMIKIN®), gentamicin (GARAMYCIN®), kanamycin (KANTREX®), neomycin (MYCIFRADIN®), netilmicin (NETROMYCIN®), tobramycin (NEBCIN®), Paromomycin (HUMATIN®)), ansamycins (e.g., geldanamycin, herbimycin), carbacephem (e.g., loracarbef (LORABID®), Carbapenems (e.g., ertapenem (INVANZ®), doripenem (DORIBAX®), imipenem/cilastatin (PRIMAXIN®), meropenem (MERREM®), cephalosporins (first generation) (e.g., cefadroxil (DURICEF®), cefazolin (ANCEF®), cefalotin or cefalothin (KEFLIN®), cefalexin (KEFLEX®), cephalosporins (second generation) (e.g., cefaclor (CECLOR®), cefamandole (MANDOL®), cefoxitin (MEFOXIN®), cefprozil (CEFZIL®), cefuroxime (CEFTIN®, ZINNAT®)), cephalosporins (third generation) (e.g., cefixime (SUPRAX®), cefdinir (OMNICEF®, CEFDIEL®), cefditoren (SPECTRACEF®), cefoperazone (CEFOBID®), cefotaxime (CLAFORAN®), cefpodoxime (VANTIN®), ceftazidime (FORTAZ®), ceftibuten (CEDAX®), ceftizoxime (CEFIZOX®), ceftriaxone (ROCEPHIN®)), cephalosporins (fourth generation) (e.g., cefepime (MAXIPIME®)), cephalosporins (fifth generation) (e.g., ceftobiprole (ZEFTERA®)), glycopeptides (e.g., teicoplanin (TARGOCID®), vancomycin (VANCOCIN®), telavancin (VIBATIV®)), lincosamides (e.g., clindamycin (CLEOCIN®), lincomycin (LINCOCIN®)), lipopeptide (e.g., daptomycin (CUBICIN®)), macrolides (e.g., azithromycin (ZITHROMAX®, SUMAMED®, ZITROCIN®), clarithromycin (BIAXIN®), dirithromycin (DYNABAC®), erythromycin (ERYTHOCIN®, ERYTHROPED®), roxithromycin, troleandomycin (TAO®), telithromycin (KETEK®), spectinomycin (TROBICIN®)), monobactams (e.g., aztreonam (AZACTAM®)), nitrofurans (e.g., furazolidone (FUROXONE®), nitmfurantoin (MACRODANTIN®, MACROBID®)), penicillins (e.g., amoxicillin (NOVAMOX®, AMOXIL®), ampicillin (PRINCIPEN®), azlocillin, carbenicillin (GEOCILLIN®), cloxacillin (TEGOPEN®), dicloxacillin (DYNAPEN®), flucloxacillin (FLOXAPEN®), mezlocillin (MEZLIN®), methicillin (STAPHCILLIN®), nafcillin (UNIPEN®), oxacillin (PROSTAPHLIN®), penicillin G (PENTIDS®), penicillin V (PEN-VEE-K®), piperacillin (PIPRACIL®), temocillin (NEGABAN®), ticarcillin (TICAR®)), penicillin combinations (e.g., amoxicillin/clavulanate (AUGMENTIN®), ampicillin/sulbactam (UNASYN®), piperacillin/tazobactam (ZOSYN®), ticarcillin/clavulanate (TIMENTIN®)), polypeptides (e.g., bacitracin, colistin (COLY-MYCIN-S®), polymyxin B, quinolones (e.g., ciprofloxacin (CIPRO®, CIPROXIN®, CIPROBAY®), enoxacin (PENETREX®), gatifloxacin (TEQUIN®), levofloxacin (LEVAQUIN®), lomefloxacin (MAXAQUIN®), moxifloxacin (AVELOX®), nalidixic acid (NEGGRAM®), norfloxacin (NOROXIN®), ofloxacin (FLOXIN®, OCUFLOX®), trovafloxacin (TROVAN®), grepafloxacin (RAXAR®), sparfloxacin (ZAGAM®), temafloxacin (OMNIFLOX®)), sulfonamides (e.g., mafenide (SULFAMYLON®), sulfonamidochrysoidine (PRONTOSIL®), sulfacetamide (SULAMYD®, BLEPH-10®), sulfadiazine (MICRO-SULFON®), silver sulfadiazine (SILVADENE®), sulfamethizole (THIOSULFIL FORTE®), sulfamethoxazole (GANTANOL®), sulfanilimide, sulfasalazine (AZULFIDINE®), sulfisoxazole (GANTRISIN®), trimethoprim (PROLOPRIM®), TRIMPEX®), trimethoprim-sulfamethoxazole (co-trimoxazole) (TMP-SMX) (BACTRIM®, SEPTRA®)), tetracyclines (e.g., demeclocycline (DECLOMYCIN®), doxycycline (VIBRAMYCIN®), minocycline (MINOCIN®), oxytetracycline (TERRAMYCIN®), tetracycline (SUMYCIN®, ACHROMYCIN® V, STECLIN®)), drugs against mycobacteria (e.g., clofazimine (LAMPRENE®), dapsone (AVLOSULFON®), capreomycin (CAPASTAT®), cycloserine (SEROMYCIN®), ethambutol (MYAMBUTOL®), ethionamide (TRECATOR®), isoniazid (I.N.H.®), pyrazinamide (ALDINAMIDE®), rifampin (RIFADIN®, RIMACTANE®), rifabutin (MYCOBUTIN®), rifapentine (PRIFTIN®), streptomycin), and others (e.g., arsphenamine (SALVARSAN®), chloramphenicol (CHLOROMYCETIN®), fosfomycin (MONUROL®), fusidic acid (FUCIDIN®), linezolid (ZYVOX®), metronidazole (FLAGYL®), mupirocin (BACTROBAN®), platensimycin, quinupristin/dalfopristin (SYNERCID®), rifaximin (XIFAXAN®), thiamphenicol, tigecycline (TIGACYL®), tinidazole (TINDAMAX®, FASIGYN®)).


Conditions Associated with Viral Infection


In another embodiment, provided are methods for treating or preventing a viral infection and/or a disease, disorder, or condition associated with a viral infection, or a symptom thereof, in a subject, by administering aRNAV comprising one or more polynucleotides encoding an anti-viral polypeptide, e.g., an anti-viral polypeptide described herein in combination with an anti-viral agent, e.g., an anti-viral polypeptide or a small molecule anti-viral agent described herein.


Diseases, disorders, or conditions associated with viral infections which may be treated using the NAVs of the invention include, but are not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkitt lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV-2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, influenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, bronchiolitis, pneumonia, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster.


Viral Pathogens

Examples of viral infectious agents include, but are not limited to, adenovirus; Herpes simplex, type 1; Herpes simplex, type 2; encephalitis virus, papillomavirus, Varicella-zoster virus; Epstein-barr virus; Human cytomegalovirus; Human herpesvirus, type 8; Human papillomavirus; BK virus; JC virus; Smallpox; polio virus, Hepatitis B virus; Human bocavirus; Parvovirus B19; Human astrovirus; Norwalk virus; coxsackievirus; hepatitis A virus; poliovirus; rhinovirus; Severe acute respiratory syndrome virus; Hepatitis C virus; yellow fever virus; dengue virus; West Nile virus: Rubella virus: Hepatitis E virus; Human immunodeficiency virus (HIV); Influenza virus, type A or B; Guanarito virus; Junin virus; Lassa virus; Machupo virus; Sabis virus; Crimean-Congo hemorrhagic fever virus; Ebola virus; Marburg virus; Measles virus; Mumps virus; Parainfluenza virus; Respiratory syncytial virus; Human metapneumovirus; Hendra virus; Nipah virus; Rabies virus; Hepatitis D; Rotavirus; Orbivirus; Coltivirus; Hantavirus, Middle East Respiratory Coronavirus; Chikungunya virus or Banna virus.


Viral pathogens may also include viruses that cause resistant viral infections.


Antiviral Agents

Exemplary anti-viral agents include, but are not limited to, abacavir (ZIAGEN®), abacavir/lamivudine/zidovudine (Trizivir®), aciclovir or acyclovir (CYCLOVIR®, HERPEX®. ACIVIR®, ACIVIRAX®, ZOVIRAX®, ZOVIR®), adefovir (Preveon®, Hepsera®), amantadine (SYMMETREL®), amprenavir (AGENERASE®), ampligen, arbidol, atazanavir (REYATAZ®), boceprevir, cidofovir, darunavir (PREZISTA®), delavirdine (RESCRIPTOR®), didanosine (VIDEX®), docosanol (ABREVA®), edoxudine, efavirenz (SUSTIVA®, STOCRIN®), emtricitabine (EMTRIVA®), emtricitabine/tenofovir/efavirenz (ATRIPLA®), enfuvirtide (FUZEON®), entecavir (BARACLUDE®, ENNAVIR®), famciclovir (FAMVIR®), fomivirsen (VITRAVENE®), fosamprenavir (LEXIVA®, TELZIR®), foscarnet (FOSCAVIR®), fosfonet, ganciclovir (CYTOVENE®, CYMEVENE®, VITRASERT®), GS 9137 (ELVITEGRAVIR®), imiquimod (ALDARA®, ZYCLARA®, BESELNA®), indinavir (CRIXIVAN®), inosine, inosine pranobex (IMUNOVIR®), interferon type 1, interferon type 11, interferon type III, kutapressin (NEXAVIR®), lamivudine (ZEFFIX®, HEPTOVIR®, EPIVIR®), lamivudinelzidovudine (COMBIVIR®), lopinavir, loviride, maraviroc (SELZENTRY®, CELSENTRI®), methisazone, MK-2048, moroxydine, nelfinavir (VIRACEPT®), nevirapine (VIRAMUNE®), oseltamivir (TAMIFLIU®), peginterferon alfa-2a (PEGASYS®), penciclovir (DENAVIR®), peramivir, pleconaril, podophyllotoxin (CONDYLOX®), raltegravir (ISENTRESS®), ribavirin (COPEGUs®, REBETOL®, RIBASPHERE®, VILONA® AND VIRAZOLE®), rimantadine (FLUMADINE®), ritonavir (NORVIR®), pyramidine, saquinavir (INVIRASE®, FORTOVASE®), stavudine, tea tree oil (melaleuca oil), tenofovir (VIREAD®), tenofovir/emtricitabine (TRUVADA®), tipranavir (APTIVUS®), trifluridine (VIROPTIC®), tromantadine (ViRU-MERZ®), valaciclovir (VALTREX®), valganciclovir (VALCYTE®), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (RELENZA®), and zidovudine (azidothymidine (AZT), RETROVIR®, RETROVIS®).


Conditions Associated with Fungal Infections


Diseases, disorders, or conditions associated with fungal infections which may be treated using the NAVs of the invention include, but are not limited to, aspergilloses, blastomycosis, candidasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mycetomas, paracoccidioidomycosis, and tinea pedis. Furthermore, persons with immuno-deficiencies are particularly susceptible to disease by fungal genera such as Aspergillus, Candida, Cryptoccocus, Histoplasma, and Pneumocystis. Other fungi can attack eyes, nails, hair, and especially skin, the so-called dermatophytic fungi and keratinophilic fungi, and cause a variety of conditions, of which ringworms such as athlete's foot are common. Fungal spores are also a major cause of allergies, and a wide range of fungi from different taxonomic groups can evoke allergic reactions in some people.


Fungal Pathogens

Fungal pathogens include, but are not limited to, Ascomycota (e.g., Fusarium oxysporum, Pneumocystis jirovecii, Aspergillus spp., Coccidioides immitis/posadasii, Candida albicans), Basidiomycota (e.g., Filobasidiella neoformans, Trichosporon), Microsporidia (e.g., Encephalitozoon cuniculi, Enterocytozoon bieneusi), and Mucoromycotina (e.g., Mucor circinelloides, Rhizopus oryzae, Lichtheimia corymbifera).


Anti-Fungal Agents

Exemplary anti-fungal agents include, but are not limited to, polyene antifungals (e.g., natamycin, rimocidin, filipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF. CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticonazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), sulconazole, tioconazole), triazole antifungals (e.g., albaconazole fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole, terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinatine (LAMISIL®), naftifine (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g., polygodial, benzoic acid, ciclopirox, tolnaftate (TINACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosine, griseofulvin, haloprogin, sodium bicarbonate, allicin).


Conditions Associated with Protozoal Infection


Diseases, disorders, or conditions associated with protozoal infections which may be treated using the NAVs of the invention include, but are not limited to, amoebiasis, giardiasis, trichomoniasis, African Sleeping Sickness, American Sleeping Sickness, leishmaniasis (Kala-Azar), balantidiasis, toxoplasmosis, malaria, Acanthamoeba keratitis, and babesiosis.


Protozoan Pathogens

Protozoal pathogens include, but are not limited to, Entamoeba histolytica, Giardia lambila, Trichomonas vaginalis, Trypanosoma brucei. T. cruzi, Leishmania donovani, Balantidium coli, Toxoplasma gondii, Plasmodium spp., and Babesia microti.


Anti-Protozoan Agents

Exemplary anti-protozoal agents include, but are not limited to, eflornithine, furazolidone (FUROXONE®, DEPENDAL-M®), melarsoprol, metronidazole (FLAGYL®), omidazole, paromomycin sulfate (HUMATIN®), pentamidine, pyrimethamine (DARAPRIM®), and tinidazole (TINDAMAX®, FASIGYN®).


Conditions Associated with Parasitic Infection


Diseases, disorders, or conditions associated with parasitic infections which may be treated using the NAVs of the invention include, but are not limited to, Acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiasis, baylisascariasis, chagas disease, clonorchiasis, cochliomyia, cryptosporidiosis, diphyllobothriasis, dracunculiasis, echinococcosis, elephantiasis, enterobiasis, fascioliasis, fasciolopsiasis, filariasis, giardiasis, gnathostomiasis, hymenolepiasis, isosporiasis, katayama fever, leishmaniasis, lyme disease, malaria, metagonimiasis, myiasis, onchocerciasis, pediculosis, scabies, schistosomiasis, sleeping sickness, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis, and trichuriasis.


Parasitic Pathogens

Parasitic pathogens include, but are not limited to, Acanthamoeba, Anisakis, Ascaris lumbricoides, botfly, Balantidium coli, bedbug, Cestoda, chiggers, Cochliomyia hominivorax, Entamoeba histolytica, Fasciola hepatica, Giardia lamblia, hookworm, Leishmania, Linguatula serrata, liver fluke, Loa loa, Paragonimus, pinworm, Plasmodium falciparum, Schistosoma, Strongyloides stercoralis, mite, tapeworm, Toxoplasma gondii, Trypanosoma, whipworm, Wuchereria bancofti.


Anti-Parasitic Agents

Exemplary anti-parasitic agents include, but are not limited to, antinematodes (e.g., mebendazole, pyrantel pamoate, thiabendazole, diethylcarbamazine, ivermectin), anticestodes (e.g., niclosamide, praziquantel, albendazole), antitrematodes (e.g., praziquantel), antiamoebics (e.g., rifampin, amphotericin B), and antiprotozoals (e.g., melarsoprol, eflornithine, metronidazole, tinidazole).


B. Therapeutic Settings and/or Situations


NAVs of the present invention may be utilized in various settings depending on the prevalence of the infection or the degree or level of unmet medical need. Some applications of the NAVs of the invention are outlined in Table 1.









TABLE 1







Infectious Agents by prevalence and Medical Need









Unmet Need (Infectious Agent Target)











Short term





benign
Short term




Long term
morbidity but
Short term mortality;


Prevalence
sequelae
some treatment
no treatment available





Ubiquitous
HPV, HCV,
Dengue,
seasonal and



UTRIs
Chikungunya,
pandemic influenza,




ETEC and GI
MRSA and TB




bacteria and






S. Pneumo PNA




At risk
VZV, Lyme
Noroviruses,

Klebsiella,



populations
and Chlamydia,
HEV,

Pseudomonas,




N. gonorrhea
CMV, HIV and
Rabies and



and HSV
N. meningitis

C. difficile



Rare

VEV
toxin-mediated


disease


diseases, hantavirus,





arborviruses such as





JE, WNV and EEE





Certain abbreviations include:


HPV—Human Papillomavirus;


HCV—Hepatitis C Virus;


HEV—Human Enterovirus;


MERS-CoV: Middle East Respiratory Syndrom Corona Virus;


VZV—Varicella-zoster Virus;


MRSA—Methicillin-resistant Staphareus;


TB—tuberculosis;


WNV—West Nile Virus;


VEV—vesicular exanthema virus;


EEE—Eastern equine encephalitis,


JE—Japanese encephalitis,


ETEC—Enterotoxigenic E. coli.






Influenza (Seasonal and Pandemic)

Symptoms of the flu include dry cough, fever, chills, myalgias progressing to respiratory failure and the risk of secondary bacterial infections (e.g., MRSA). Seasonal influenza is ubiquitous and consists of three principal strains (A [H1N1], A [H3N2], and B), which are covered by the annual vaccine. Pandemic flu occurs because the viruses' unique reassortment ability allowing antigenic shift as well as transfer between avian and swine flu strains. One emerging concern in Southeast Asia is the pandemic potential of several new strains. Such pandemic outbreaks have a high mortality rate with few available treatments. Anti-virals only provide symptomatic relief and must be given in the first 48 hours.


The NAVs of the present invention have superior properties in that they produce much larger antibody titers, produce responses early than commercially available anti-virals and may be administered after the critical 48 hour period while retaining efficacy.


While not wishing to be bound by theory, the inventors hypothesize that the NAVs of the invention, as mRNA polynucleotides, are better designed to produce the appropriate protein conformation on translation as the NAVs co-opt natural cellular machinery. Unlike traditional vaccines which are manufactured ex vivo and may trigger unwanted cellular responses, the NAVs are presented to the cellular system in amore native fashion. Adding to the superior effects may also involve the formulations utilized which may either serve to shield or traffic the NAVs.


According to the present invention, NAVs represent a tailored active vaccine that not only can prevent infection but can limit transmission of influenza.


In some embodiments, the NAVs may be used to prevent pandemic influenza by reacting to emerging new strains with the very rapid NAV-based vaccine production process. In some embodiments, new NAV for treating or prophylactically preventing influenza outbreaks, including for emerging strains (e.g., H7N9 and H10N8), may be produced in less than six weeks, from the time of antigen identification to available vaccine.


In some embodiments a single injection of a single antigen encoding NAV polynucleotide may provide protection for an entire flu season.


Influenza: Maintenance of Antigenic Memory

The NAV compositions of the present invention may also be used to maintain or restore antigenic memory in a subject or population as part of a vaccination plan.


With the speed and versatility of the NAV technology of the present invention, it is now possible to create a vaccination plan that spans both temporal and viral strain space.


In one embodiment, NAV compositions may be created which include polynucleotides that encode one or more flu year antigens. As used herein a flu year antigen is an antigen which is selected from a strain of influenza used as a component of a flu vaccine from a particular year. For example, the influenza A strain, A/Port Chalmers/l/1973(H3N2)-like virus, represents one strain component of the Northern Hemisphere vaccine from 1974-1975.


According to the present invention, a vaccination scheme or plan is developed which allows for not only ongoing vaccination in the current year but antigenic memory booster vaccinations across years, strains, or groups thereof to establish and maintain antigenic memory in a population. In this manner, a population is less likely to succumb to any pandemic or outbreak involving recurrence of older strains or the appearance of antigens from older strains.


Any combination of prior vaccine component strains utilized to create or design an antigenic memory booster vaccine is referred to here as a reference set.


In one embodiment, NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory across a time period of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50 or more years.


In one embodiment, NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory for alternating historic years including every other year from the past vaccine component strains relative to a current year. In some embodiments the selection of the vaccine components can be from every 3rd, 4th, 5th, 6th, 7th, 8th, 9th, 10th or more years.


In one embodiment. NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory over ten year periods.


In some embodiments NAVs which are antigenic memory booster vaccines are administered to boost antigenic memory and are selected from a number of influenza type A strains as a first selection combined with a selection from a number of influenza type B strains or other strains listed herein. The number of selections of type A or type B may be independently, 1, 2, 1, 4, 5, 6, 7, 8, 9, 10 or more.


In all cases, the antigenic memory booster vaccine strains for antigen encoding in the NAVs may be selected from either the Northern or Southern hemisphere vaccine components independently.


In some embodiments, the NAV booster vaccine may be used in a population either once or periodically to create herd immunity. Such immunity is present when greater than 30% of a population is protected.


The components or strains of influenza which may be utilized in the antigenic memory booster vaccines include, but are not limited to, those in Tables 2-5.









TABLE 2







Influenza vaccine components by year















additional


Northern



B-strain


hemisphere
H1N1
H3N2
B-strain
for QIV





1974-1975
N/A
A/Port
B/HongKong/05/
N/A




Chalmers/1/1973
1972-like virus





(H3N2)-like virus




1975-1976
A/Scotland/840/74-
A/Port
B/HongKong/05/
N/A



like virus
Chalmers/1/1973
1972-like virus




H1N1
(H3N2)-like virus




1976-1977
N/A
A/Victoria/3/75
B/HongKong/05/
N/A




(H3N2)-like virus
1972-like virus



1977-1978
N/A
A/Victoria/3/75
B/HongKong/05/
N/A




(H3N2)-like virus
1972-like virus



1978-1979
A/USSR/90/77
A/Texas/1/77
B/HongKong/05/
N/A



(H1N1)-like virus
(H3N2)-like virus
1972-like virus



1979-1980
A/USSR/90/77
A/Texas/1/77
N/A
N/A



(H1N1)-like virus
(H3N2)-like virus




1980-1981
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1981-1982
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1982-1983
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1983-1984
A/Brazil/11/78
A/Philippines/2/82
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1984-1985
A/Chile/1/83
A/Philippines/2/82
B/USSR/100/83-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1985-1986
A/Chile/1/83
A/Philippines/2/82
B/USSR/100/83-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1986-1987
A/Chile/1/83
A/Christchurch/4/
B/Ann Arbor/1/86-
N/A



(H1N1)-like virus
1985(H3N2)-like
like virus





virus and






A/Mississippi/1/85






(H3N2)-like virus




1987-1988
A/Singapore/6/1986
A/Leningrad/360/
N/A
N/A



(H1N1)-like virus
1986(H3N2)-like






strain




1988-1989
A/Singapore/6/1986
A/Sichuan/02/87
B/Beijing/1/87-like
N/A



(H1N1)-like virus
(H3N2)-like virus
rivus



1989-1990
A/Singapore/6/1986
A/Shanghai/11/87
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1990-1991
A/Singapore/6/1986
A/Guizhou/54/89
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1991-1992
A/Singapore/6/1986
A/Beijing/353/89
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1992-1993
N/A
A/Beijing/353/89
B/Yamagata/16/88-
N/A




(H3N2)-like virus
like virus



1993-1994
A/Singapore/6/1986
A/Beijing/32/92
B/Panama/45/90-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1994-1995
A/Singapore/6/1986
A/Shangdong/9/93
B/Panama/45/90-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1995-1996
A/Singapore/6/1986
A/Johannesburg/33/
B/Beijing/184/93-
N/A



(H1N1)-like virus
94(H3N2)-like
virus like virus



1996-1997
A/Singapore/6/1986
A/Wuhan/359/95
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1997-1998
A/Bayern/7/95
A/Wuhan/359/95
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus
















TABLE 3







Influenza vaccine components by year-Southern Hemisphere















additional


Southern



B-strain for


Hemisphere
H1N1
H3N2
B-strain
QIV





1975
N/A
A/Port
B/HongKong/05/
N/A




Chalmers/1/1973
1972-like virus





(H3N2)-like virus




1976
A/Scotland/840/74-
A/Port
B/HongKong/05/
N/A



like virus
Chalmers/1/1973
1972-like virus




(H1N1)
(H3N2)-like virus




1977
N/A
A/Victoria/3/75
B/HongKong/05/
N/A




(H3N2)-like virus
1972-like virus



1978
N/A
A/Victoria/3/75
B/HongKong/05/
N/A




N(H32)-like virus
1972-like virus



1979
A/USSR/90/77
A/Texas/1/77
B/HongKong/05/
N/A



(H1N1)-like virus
(H3N2)-like virus
1972-like virus



1980
A/USSR/90/77
A/Texas/1/77
N/A
N/A



(H1N1)-like virus
(H3N2)-like virus




1981
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1982
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1983
A/Brazil/11/78
A/Bangkok/01/1979
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1984
A/Brazi1/11/78
A/Philippines/2/82
B/Singapore/222/
N/A



(H1N1)-like virus
(H3N2)-like virus
79-like virus



1985
A/Chile/1/83
A/Philippines/2/82
B/USSR/100/83-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1986
A/Chile/1/83
A/Philippines/2/82
B/USSR/100/83-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1987
A/Chile/1/83
A/Christchurch/4/
B/Ann Arbor/1/86-
N/A



(H1N1)-like virus
1985(H3N2)-like
like virus





virus and






A/Mississippi/1/85






(H3N2)-like virus




1988
A/Singapore/6/1986
A/Leningrad/360/
N/A
N/A



(H1N1)-like virus
1986(H3N2)-like






virus




1989
A/Singapore/6/1986
A/Sichuan/02/87
B/Beijing/1/87-like
N/A



(H1N1)-like virus
(H3N2)-like virus
virus



1990
A/Singapore/6/1986
A/Shanghai/11/87
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1991
A/Singapore/6/1986
A/Guizhou/54/89
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1992
A/Singapore/6/1986
A/Beijing/353/89
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1993
A/Singapore/6/1986
A/Beijing/353/89
B/Yamagata/16/88-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1994
A/Singapore/6/1986
A/Beijing/32/92
B/Panama/45/90-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1995
A/Singapore/6/1986
A/Shangdong/9/93
B/Panama/45/90-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1996
A/Singapore/6/1986
A/Johannesburg/33/
B/Beijing/184/93-
N/A



(H1N1)-like virus
94(H3N2)-like virus
like virus



1997
A/Singapore/6/1986
A/Wuhan/359/95
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like strain



1998
A/Bayern/7/95
A/Wuhan/359/95
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



1999
A/Beijing/262/95
A/Sydney/5/97
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus
















TABLE 4







Influenza Vaccine components by year-Northern Hemisphere















additional


Northern



B-strain for


hemisphere
H1N1
H3N2
B-strain
QIV





November
A/Beijing/262/95
A/Sydney/5/97
B/Beijing/184/93-
N/A


1998-April
(H1N1)-like virus
(H3N2)-like virus
like virus



1999






November
A/Beijing/262/95
A/Sydney/5/97
B/Beijing/184/93-
N/A


1999-April
(H1N1)-like virus
(H3N2)-like virus
like virus or



2000


B/Shangdong/7/97-






like virus



2000-2001
A/New
A/Moscow/10/99
B/Beijing/184/93-
N/A



Caledonia/20/99
(H3N2)-like virus
like virus




(H1N1)-like virus





2001-2002
A/New
A/Moscow/10/99
B/Sichuan/379/99-
N/A



Caledonia/20/99
(H3N2)-like virus
like virus




(H1N1)-like virus





2002-2003
A/New
A/Moscow/10/99
B/Hong
N/A



Caledonia/20/99
(H3N2)-like virus
Kong/330/2001-




(H1N1)-like virus

like virus



2003-2004
A/New
A/Moscow/10/99
B/Hong
N/A



Caledonia/20/99
(H3N2)-like virus
Kong/330/2001




(H1N1)-like virus

like virus



2004-2005
A/New
A/Fujian/411/2002
B/Shanghai/361/
N/A



Caledonia/20/99
(H3N2)-like virus
2002-like virus




(H1N1)-like virus





2005-2006
A/New
A/California/7/2004
B/Shanghai/361/
N/A



Caledonia/20/99
(H3N2)-like virus
2002-like virus




(H1N1)-like virus





2006-2007
A/New
A/Wisconsin/67/2005
B/Malaysia/2506/
N/A



Caledonia/20/99
(H3N2)-like virus
2004-like virus




(H1N1)-like





2007-2008
A/Solomon
A/Wisconsin/67/2005
B/Malaysia/2506/
N/A



Islands/3/2006
(H3N2)-like virus
2004-like virus




(H1N1)-like virus





2008-2009
A/Brisbane/59/2007
A/Brisbane/10/2007
B/Florida/4/2006-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



2009-2010
A/Brisbane/59/2007
A/Brisbane/10/2007
B/Brisbane/60/
N/A



(H1N1)-like virus
(H3N2)-like virus
2008-like virus



2010-2011
A/California/7/2009
A/Perth/16/2009
B/Brisbane/60/
N/A



(H1N1)-like virus
(H3N2)-like virus
2008-like virus



2011-2012
A/California/7/2009
A/Perth/16/2009
B/Brisbane/60/
N/A



(H1N1)-like virus
(H3N2)-like virus
2008-like virus



2012-2013
A/California/7/2009
A/Victoria/361/2011
B/Wisconsin/1/
B/Brisbane/



(H1N1)pdm09-like
(H3N2)-like virus
2010-like virus
60/2008-like



virus


virus


2013-2014
A/California/7/2009
A(H3N2) virus
B/Massachusetts/2/
B/Brisbane/



(H1N1)pdm09-like
antigenically like
2012-like virus
60/2008-like



virus
the cell-propagated

virus




prototype virus






A/Victoria/361/2011




2014-2015
A/California/7/2009
A/Texas/50/2012
B/Massachusetts/2/
B/Brisbane/



(H1N1)pdm09-like
(H3N2)-like virus
2012-like virus
60/2008-like



virus


virus
















TABLE 5







Influenza Vaccine components by year-Southern Hemisphere















additional


Southern



B-strain


hemisphere
H1N1
H3N2
B-strain
for QIV





1999
A/Beijing/262/95
A/Sydney/5/97
B/Beijing/184/93-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



May-October
A/New
A/Moscow/10/99
B/Beijing/184/93-
N/A


2000
Caledonia/20/99
(H3N2)-like virus
like virus or




(H1N1)-like virus

B/Shangdong/7/97-






like virus



May-October
A/New
A/Moscow/10/99
B/Sichuan/379/99-
N/A


2001
Caledonia/20/99
(H3N2)-like virus
like virus




(H1N1)-like virus





2002
A/New
A/Moscow/10/99
B/Sichuan/379/99-
N/A



Caledonia/20/99
(H3N2)-like virus
like virus




(H1N1)-like virus





2003
A/New
A/Moscow/10/99
B/Hong
N/A



Caledonia/20/99
(H3N2)-like virus
Kong/330/2001-




(H1N1)-like virus

like virus



2004
A/New
A/Fujian/411/2002
B/Hong
N/A



Caledonia/20/99
(H3N2)-like virus
Kong/330/2001-




(H1N1)-like virus

like virus



2005
A/New
A/Wellington/1/
B/Shanghai/361/
N/A



Caledonia/20/99
2004(H3N2)-like
2002-like virus




(H1N1)-like virus
virus




2006
A/New
A/California/7/2004
B/Malaysia/2506/
N/A



Caledonia/20/99
(H3N2)-like virus
2004-like virus




(H1N1)-like virus





2007
A/New
A/Wisconsin/67/
B/Malaysia/2506/
N/A



Caledonia/20/99
2005 (H3N2)-like
2004-like virus




(H1N1)-like
virus




2008
A/Solomon
A/Brisbane/10/2007
B/Florida/4/2006-
N/A



Islands/3/2006
(H3N2)-like virus
like virus




(H1N1)-like virus





2009
A/Brisbane/59/2007
A/Brisbane/10/2007
B/Florida/4/2006-
N/A



(H1N1)-like virus
(H3N2)-like virus
like virus



2010
A/California/7/2009
A/Perth/16/2009
B/Brisbane/60/
N/A



(H1N1)-like virus
(H3N2)-like virus
2008-like virus



2011
A/California/7/2009
A/Perth/16/2009
B/Brisbane/60/
N/A



(H1N1)-like virus
(H3N2)-like virus
2008-like virus



2013
A/California/7/2009
A/Perth/16/2009
B/Brisbane/60/
N/A



(H1N1)pdm09 like
(H3N2)-like virus
2008-like virus




virus





2013
A/California/7/2009
A/Victoria/361/2011
B/Wisconsin/1/
B/Brisbane/



(H1N1)pdm09-like
(H3N2)-like virus
2010-like virus
60/2008-like



virus


virus


2014
A/California/7/2009
A/Texas/50/2012
B/Massachusetts/2/
B/Brisbane/



(H1N1)pdm09-like
(H3N2)-like virus
2012-like virus
60/2008-like



virus


virus









Influenza Antigens

In some embodiments, the NAV polynucleotides may encode one or more polypeptides of an influenza strain as an antigen. Such antigens include, but are not limited to those antigens encoded by the polynucleotides listed in Tables 6-18. In the table, the GenBank Accession Number represents either the complete or partial CDS of the encoded antigen. The NAV polynucleotides may comprise a region of any of the sequences listed in the tables or entire coding region of the mRNA listed. They may comprise hybrid or chimeric regions, or mimics or variants.


Any of the strains referred to in Tables 6-14 may also be used in an antigenic memory booster vaccine as described herein.









TABLE 6







Influenza H1N1 Antigens











GenBank/GI


Strain/Protein
Length
Accession No.





Influenza A virus (A/Bayern/7/95 (H1N1) ) NA
1,459
AJ518104.1


gene for neuraminidase, genomic RNA
bp
GI:31096418



linear




mRNA



Influenza A virus (A/Brazil/11/1978
1,072
X86654.1


(X-71) (H1N1) ) mRNA for hemagglutinin HAI, escape
bp
GI:995549


variant 1
linear




mRNA



Influenza A virus (A/Brazil/11/1978
1,072
X86655,1


(X-71) (H1N1) ) mRNA for hemagglutinin HAI, escape
bp
GI:995550


variant 2
linear




mRNA



Influenza A virus (A/Brazil/11/1978
1,072
X86656.1


(X-71) (H1N1) ) mRNA for hemagglutinin HA1, escape
bp
GI:995551


variant 3
linear




mRNA



Influenza A virus (A/Brazil/11/1978
1,072
X86657.1


(X-71) (H1N1) ) mRNA for hemagglutinin HAI, escape
bp
GI:995552


variant 4
linear




mRNA



Influenza A virus
1,220
AF116575.1


(A/Brevig_Mission/1/18 (H1N1 } ) hemagglutinin
bp
GI:4325017


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus
1,410
AF250356.2


(A/Brevig_Mission/1/18 (H1N1) ) neuraminidase
bp
GI:13260556


(NA) gene, complete cds
linear




mRNA



Influenza A virus (A/Brevig
1,497
AY744935.1


Mission/1/1918 (H1N1) ) nucleoprotein (np)
bp
GI:55273940


mRNA, complete cds
linear




mRNA



Influenza A virus (A/Brevig
2,280
DQ208309.1


Mission/1/1918 (H1N1) ) polymerase PB2 (PB2)
bp
GI:76786704


mRNA, complete cds
linear




mRNA



Influenza A virus (A/Brevig
2,274
DQ208310.1


Mission/1/1918 (H1N1) ) polymerase PB1 (PB1)
bp
GI:76786706


mRNA, complete cds
linear




mRNA



Influenza A virus (A/Brevig
2,151
DQ208311.1


Mission/1/1918 (H1N1) ) polymerase PA (PA)
bp
GI:76786708


mRNA, complete cds
linear




mRNA



Influenza A virus
366 bp
M73975.1


(A/camel/Mongolia/1982 (H1N1) ) hemagglutinin
linear
GI:324242


mRNA, partial cds
mRNA



Influenza A virus
460 bp
M73978.1


(A/camel/Mongolia/1982 (H1N1) ) matrix protein
linear
GI:324402


mRNA, partial cds
mRNA



Influenza A virus
310 bp
M73976.1


(A/camel/Mongolia/1982 (H1N1) ) neuraminidase
linear
GI:324579


(NA) MRNA, partial cds
mRNA



Influenza A Virus A/camel/Mongolia/82 NS1
273 bp
M73977.1


protein mRNA, partial cds
linear
GI:324768



mRNA



Influenza A virus
227 bp
M73974.1


(A/camel/Mongolia/1982 (H1N1) } PA polymerase
linear
GI:324931


mRNA, partial cds
mRNA



Influenza A virus
531 bp
M73973.1


(A/camel/Mongolia/1982 (H1N1) ) PB1 protein
linear
GI:324971


mRNA, partial cds
mRNA



Influenza A Virus (A/camel/Mongolia/82 (H1N1) )
379 bp
M73972.1


polymerase 2 (P2) mRNA, partial cds
linear
GI:324993



mRNA



Influenza A virus (A/chicken/Hong
1,169
U46782.1


Kong/14/1976 (H1N1) ) hemagglutinin precursor
bp
GI:1912328


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus (A/Chonnam/07/2002 (H1N1) )
1,452
AY297141.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871990



linear




mRNA



Influenza A virus (A/Chonnam/07/2002 (H1N1) )
1,137
AY297154.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140347



linear




mRNA



Influenza A virus (A/Chonnam/18/2002 (H1N1) )
1,458
AY297143.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871994



linear




mRNA



Influenza A virus (A/Chonnam/18/2002 (H1N1) )
1,176
AY297156.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140355



linear




mRNA



Influenza A virus (A/Chonnam/19/2002 (H1N1) )
1,458
AY310410.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872389



linear




mRNA



Influenza A virus (A/Chonnam/19/2002 (H1N1) )
1,167
AY299502.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140392



linear




mRNA



Influenza A virus (A/Chonnam/51/2002 (H1N1) )
1,443
AY310412.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31873090



linear




mRNA



Influenza A virus (A/Chonnam/51/2002 (H1N1) )
1,161
AY299498.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140384



linear




mRNA



Influenza A virus (A/Chungbuk/50/2002 (H1N1) )
1,425
AY297150.1


neuraminidase (NA) mRNA, partial cds
bp
GI:31872010



linear




mRNA



Influenza A virus (A/Chungbuk/50/2002 (H1N1) )
1,161
AY299506.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140400



linear




mRNA



Influenza A virus (A/Denmark/40/2000 (H1N1) )
1,458
AJ518095.1


NA gene for neuraminidase, genomic RNA
bp
GI:31096400



linear




mRNA



Influenza A virus (A/Denver/1/57 (H1N1) )
379 bp
AF305216.1


neuraminidase mRNA, partial cds
linear
GI:10732818



mRNA



Influenza A virus (A/Denver/1/57 (H1N1) )
442 bp
AF305217.1


matrix protein gene, partial cds
linear
GI:10732820



mRNA



Influenza A virus (A/Denver/1/57 (H1N1) )
215 bp
AF305218.1


hemagglutinin gene, partial cds
linear
GI:10732822



mRNA



Influenza A virus
981 bp
U47309.1


(A/duck/Australia/749/80 (H1N1) ) hemagglutinin
linear
GI:1912348


precursor (HA) mRNA, partial cds
mRNA



Influenza A virus
1,777
AF091312.1


(A/duck/Australia/749/80 (H1N1) ) segment 4
bp
GI:4585166


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus (A/duck/Bavaria/1/77
1,777
AF091313.1


(H1N1) ) segment 4 hemagglutinin precursor
bp
GI:4585168


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus (A/duck/Bavaria/2/77 (H1N1) )
981 bp
U47308.1


hemagglutinin precursor (HA) mRNA, partial
linear
GI:1912346


cds
mRNA



Influenza A virus (A/duck/Eastern
1,458
EU429749.1


China/103/2003 (H1N1) ) segment 6 neuraminidase
bp
GI:167859463


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus (A/duck/Eastern
1,461
EU429751.1


China/152/2003 (H1N1) ) segment 6 neuraminidase
bp
GI:167859467


(NA) MRNA, complete cds
linear




mRNA



Influenza A virus (A/Duck/Ohio/118C/93
1,410
AF250361.2


(H1N1) ) neuraminidase (NA) gene, complete cds
bp
GI:13260576



linear




mRNA



Influenza A virus (A/Duck/Ohio/175/86 (H1N1) )
1,410
AF250358.2


neuraminidase (NA) gene, complete cds
bp
GI:13260565



linear




mRNA



Influenza A virus (A/Duck/Ohio/194/86 (H1N1) )
1,410
AF250360.2


neuraminidase (NA) gene, complete cds
bp
GI:13260573



linear




mRNA



Influenza A virus (A/Duck/Ohio/30/86 (H1N1) )
1,410
AF250359.2


neuraminidase (NA) gene, complete cds
bp
GI:13260570



linear




mRNA



Influenza A virus strain
1,460
AJ006954.1


A/Fiji/15899/83 (H1N1) mRNA for neuraminidase
bp
GI:4210707



linear




mRNA



Influenza A Virus (A/Fiji/15899/83 (H1N1) )
2,341
AJ564805.1


mRNA for PB2 protein
bp
GI:31442134



linear




mRNA



Influenza A Virus (A/Fiji/15899/83 (H1N1) )
2,113
AJ564807.1


partial mRNA for PBl protein
bp
GI:31442138



linear




mRNA



Influenza A virus (A/FM/1/47 (H1N1) )
1,395
AF250357.2


neuraminidase (NA) gene, complete cds
bp
GI:13260561



linear




mRNA



Influenza A virus (A/goose/Hong
1,091
U46021.1


Kong/8/1976 (H1N1) ) hemagglutinin precursor
bp
GI:1912326


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus (A/goose/Hong
261 bp
U48284.1


Kong/8/1976 (H1N1) ) polymerase (PB1) mRNA,
linear
GI:1912372


partial cds
mRNA



Influenza A virus (A/goose/Hong
1,395
U49093.1


Kong/8/1976 (H1N1) ) nucleoprotein (NP) mRNA,
bp
GI:1912384


partial cds
linear




mRNA



Influenza A virus
1,775
EU382986.1


(A/Guangzhou/1561/2006 (H1N1) ) segment 4
bp
GI:170762603


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,462
EU382993.1


(A/Guangzhou/1561/2006 (H1N1) ) segment 6
bp
GI:170762617


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,775
EU382987.1


(A/Guangzhou/1684/2006 (H1N1) ) segment 4
bp
GI:170762605


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,462
EU382994.1


(A/Guangzhou/1684/2006 (H1N1) ) segment 6
bp
GI:170762619


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus (A/Guangzhou/483/2006 (H1N1) ) segment 4
1,775
EU382981.1


hemagglutinin (HA) mRNA, complete cds
bp
GI:170762593



linear




mRNA



Influenza A virus
1,462
EU382988.1


(A/Guangzhou/483/2006 (H1N1) ) segment 6
bp
GI:170762607


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,775
EU382982.1


(A/Guangzhou/506/2006 (H1N1) ) segment 4
bp
GI:170762595


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,461
EU382989.1


(A/Guangzhou/506/2006 (H1N1) ) segment 6
bp
GI:170762609


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,775
EU382983.1


(A/Guangzhou/555/2006 (H1N1) ) segment 4
bp
GI:170762597


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,462
EU382990.1


(A/Guangzhou/555/2006 (H1N1) ) segment 6
bp
GI:170762611


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,775
EU382984.1


(A/Guangzhou/657/2006 (H1N1) ) segment 4
bp
GI:170762599


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,462
EU382991.1


(A/Guangzhou/657/2006 (H1N1) ) segment 6
bp
GI:170762613


neuraminidase (NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,775
EU382985.1


(A/Guangzhou/665/2006 (H1N1) ) segment 4
bp
GI:170762601


hemagglutinin (HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,462
EU382992.1


(A/Guangzhou/665/2006 (H1N1) ) segment 6
bp
GI:170762615


neuraminidase (NA) MRNA, complete cds
linear




mRNA



Influenza A virus (A/Gwangju/55/2002 (H1N1) )
1,431
AY297151.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872012



linear




mRNA



Influenza A virus (A/Gwangju/55/2002 (H1N1) )
1,179
AY299507.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140402



linear




mRNA



Influenza A virus (A/Gwangju/57/2002 (H1N1) )
1,446
AY297152.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872014



linear




mRNA



Influenza A virus (A/Gwangju/57/2002 (H1N1) )
1,167
AY299508.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140404



linear




mRNA



Influenza A virus (A/Gwangju/58/2002 (H1N1) )
1,434
AY297153.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872016



linear




mRNA



Influenza A virus (A/Gwang ju/58/2002 (H1N1) )
1,176
AY299509.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140406



linear




mRNA



Influenza A virus (A/Gwangju/90/2002 (H1N1) )
1,446
AY297147.1


neuraminidase : (NA) MRNA, complete cds
bp
GI:31872002



linear




mRNA



Influenza A virus (A/Gwangju/90/2002 (H1N1) )
1,164
AY299499.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140386



linear




mRNA



Influenza A virus (A/Hong
1,403
AJ518101.1


Kong/437/2002 (H1N1) ) partial NA gene for
bp
GI:31096412


neuraminidase, genomic RNA
linear




mRNA



Influenza A virus (A/Hong
1,352
AJ518102.1


Kong/747/2001 (H1N1) } partial NA gene for
bp
GI:31096414


neuraminidase, genomic RNA
linear




mRNA



Influenza A virus (A/London/1/1918 (H1N1) )
563 bp
AY184805.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:32395285



mRNA



Influenza A virus (A/London/1/1919 (H1N1) )
563 bp
AY184806.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:32395287



mRNA



Influenza A virus (A/Loygang/4/1957 (H1N1) )
1,565
M76604.1


nucleoprotein mRNA, complete cds
bp
GI:324255



linear




mRNA



Influenza A virus (A/Lyon/651/2001 (H1N1) )
1,318
AJ518103.1


partial NA gene for neuraminidase, genomic
bp
GI:31096416


RNA
linear




mRNA








(A/mallard/Alberta/119/98









Influenza A virus (A/mallard/Alberta/119/98
947 bp
AY664487.1


(H1N1) ) nonfunctional matriz protein mRNA,
linear
GI:51011891


partial sequence
mRNA



Influenza A virus
981 bp
U47310.1


(A/duck/Alberta/35/76 (H1N1) ) hemagglutinin
linear
GI:1912350


precursor (HA) mRNA, partial cds
mRNA



Influenza A virus
1,777
AF091309.1


(A/duck/Alberta/35/76 (H1N1) ) segment 4
bp
GI:4585160


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus
1,410
AF250362.2


(A/duck/Alberta/35/76 (H1N1) ) neuraminidase
bp
GI:13260579


(NA) gene, complete cds
linear




mRNA



Influenza A virus
981 bp
U47307.1


(A/mallard/Tennessee/11464/85 (H1N1) )
linear
GI:1912344


hemagglutinin precursor (HA) MRNA, partial
mRNA



cds




Influenza A virus
1,777
AF091311.1


(A/mallard/Tennessee/11464/85 (H1N1) ) segment
bp
GI:4585164


4 hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus (A/New
294 bp
HQ008884.1


Caledonia/20/1999 (H1N1) ) segment 7 matrix
linear
GI:302566794


protein 2 (M2) MRNA, complete cds
mRNA



Influenza A virus (A/New Jersey/4/1976 (H1N1) )
1,565
M76605.1


nucleoprotein mRNA, complete cds
bp
GI:324581



linear




mRNA



Influenza A virus (A/New Jersey/8/1976 (H1N1) )
1,565
M76606.1


nucleoprotein mRNA, complete cds
bp
GI:324583



linear




mRNA



Influenza A virus (A/New_York/1/18 (H1N1) )
1,220
AF116576.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:4325019



linear




mRNA



Influenza A virus (A/Ohio/3523/1988 (H1N1) )
1,565
M76602.1


nucleoprotein mRNA, complete cds
bp
GI:324889



linear




mRNA



Influenza A virus (A/Pusan/22/2002 (H1N1) )
1,455
AY310411.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872391



linear




mRNA



Influenza A virus (A/Pusan/22/2002 (H1N1) )
1,149
AY299503.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140394



linear




mRNA



Influenza A virus (A/Pusan/23/2002 (H1N1) )
1,440
AY297144.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871996



linear




mRNA



Influenza A virus (A/Pusan/23/2002 (H1N1) )
1,158
AY297157.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140357



linear




mRNA



Influenza A virus (A/Pusan/24/2002 (H1N1) )
1,449
AY297145.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871998



linear




mRNA



Influenza A virus (A/Pusan/24/2002 (H1N1) )
1,128
AY299494.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140376



linear




mRNA



Influenza A virus (A/Pusan/44/2002 (H1N1) )
1,431
AY297148.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872004



linear




mRNA



Influenza A virus (A/Pusan/44/2002 (H1N1) )
1,167
AY299504.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140396



linear




mRNA



Influenza A virus (A/Pusan/45/2002 (H1N1) )
1,434
AY297146.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872000



linear




mRNA



Influenza A virus (A/Pusan/45/2002 (H1N1) )
1,167
AY299496.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140380



linear




mRNA



Influenza A virus (A/Pusan/46/2002 (H1N1) )
1,422
AY310408.1


neuraminidase (NA) MRNA, complete cds
bp
GI:31872385



linear




mRNA



Influenza A virus (A/Pusan/46/2002 (H1N1) )
1,176
AY299497.1


hemagglutinin (HA) MRNA, partial cds
bp
GI:32140382



linear




mRNA



Influenza A virus (A/Pusan/47/2002 (H1N1) )
1,437
AY297149.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872008



linear




mRNA



Influenza A virus (A/Pusan/47/2002 (H1N1) )
1,170
AY299505.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140398



linear




mRNA



Influenza A virus (A/Saudi
789 bp
AJ519463.1


Arabia/7971/2000 (H1N1) ) partial NS1 gene for
linear
GI:31096450


non structural protein 1 and partial NS2 gene
mRNA



for non structural protein 2, genomic RNA




Influenza A virus (A/Seoul/11/2002 (H1N1) )
1,452
AY297142.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871992



linear




mRNA



Influenza A virus (A/Seoul/11/2002 (H1N1) )
1,176
AY297155.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140349



linear




mRNA



Influenza A virus (A/Seoul/13/2002 (H1N1) )
1,452
AY310409.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872387



linear




mRNA



Influenza A virus (A/Seoul/13/2002 (H1N1) )
1,167
AY299500.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140388



linear




mRNA



Influenza A virus (A/Seoul/15/2002 (H1N1) )
1,449
AY297140.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31871988



linear




mRNA



Influenza A virus (A/Seoul/15/2002 (H1N1) )
1,149
AY299501.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140390



linear




mRNA



Influenza A virus (A/Seoul/33/2002 (H1N1) )
1,437
AY310407.1


neuraminidase (NA) mRNA, complete cds
bp
GI:31872383



linear




mRNA



Influenza A virus (A/Seoul/33/2002 (H1N1) )
1,167
AY299495.1


hemagglutinin (HA) mRNA, partial cds
bp
GI:32140378



linear




mRNA



Influenza A virus
1,050
Z46437.1


(A/swine/Arnsberg/6554/1979 (H1N1) ) MRNA for
bp
GI:565609


hemagglutinin HA1
linear




mRNA



Influenza A virus
1,595
U46783.1


(A/swine/Beijing/47/1991 (H1N1) ) hemagglutinin
bp
GI:1912330


precursor (HA) mRNA, partial cds
linear




mRNA



Influenza A virus
1,565
U49091.1


(A/swine/Beijing/94/1991 (H1N1) ) nucleoprotein
bp
GI:1912380


(NP) mRNA, complete cds
linear




mRNA



Influenza A virus
1,778
AF091316.1


(A/swine/Belgium/1/83 (H1N1) ) segment 4
bp
GI:4585174


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus (A/swine/Cotes
1,116
AM490219.1


d'Armor/0118/2006 (H1N1) ) partial mRNA for
bp
GI:222062898


haemagglutinin precursor (HA1 gene)
linear




mRNA



Influenza A virus (A/swine/Cotes
1,043
AM490223.1


d'Armor/0136_18/2006 (H1N1) ) partial mRNA for
bp
GI:222062906


haemagglutinin precursor (HA1 gene)
linear




mRNA



Influenza A virus (A/swine/Cotes
1,089
AM490220.1


d'Armor/0184/2006 (H1N1) ) partial mRNA for
bp
GI:222062900


haemagglutinin precursor (HAl gene)
linear




mRNA



Influenza A virus (A/swine/Cotes
1,068
AM490221.1


d'Armor/0227/2005 (H1N1) ) partial mRNA for
bp
GI:222062902


haemagglutinin precursor (HA1 gene)
linear




mRNA



Influenza A virus (A/swine/Cotes
1,024
AM490222.1


d'Armor/0250/2006 (H1N1) ) partial mRNA for
bp
GI:222062904


haemagglutinin precursor (HAl gene)
linear




mRNA



Influenza A virus (A/swine/Cotes
1,011
AJ517820.1


d'Armor/736/2001 (H1N1) ) partial HA gene for
bp
GI:38422533


Haemagglutinin, genomic RNA
linear




mRNA



Influenza A virus (A/Swine/England/195852/92
1,410
AF250366.2


(H1N1) ) neuraminidase (NA) gene, complete cds
bp
GI:13260593



linear




mRNA



Influenza A virus PB2 gene for Polymerase 2
2,268
AJ311457.1


protein, genomic RNA, strain
bp
GI:13661037


A/Swine/Finistere/2899/82
linear




mRNA



Influenza A virus PB1 gene for Polymerase 1
2,341
AJ311462.1


protein, genomic RNA, strain
bp
GI:13661047


A/Swine/Finistere/2899/82
linear




mRNA



Influenza A virus PA gene for Polymerase A
2,233
AJ311463.1


protein, genomic RNA, strain
bp
GI:13661049


A/Swine/Finistere/2899/82
linear




mRNA



Influenza A virus
1,002
AJ316059.1


(A/swine/Finistere/2899/82 (H1N1) Ml gene for
bp
GI:20068128


matrix protein 1 and M2 gene for matrix
linear



protein 2, genomic RNA
mRNA



Influenza A virus
864 bp
AJ344037.1


(A/swine/Finistere/2899/82 (H1N1) ) NS1 gene
linear
GI:20068185


for non structural protein 1 and NS2 gene for
mRNA



non structural protein 2, genomic RNA




Influenza A virus
838 bp
X75786.1


(A/swine/Germany/2/1981 (H1N1) ) MRNA for PA
linear
GI:438106


polymerase
mRNA



Influenza A virus
305 bp
Z30277.1


(A/swine/Germany/2/1981 (H1N1) ) MRNA for
linear
GI:530399


neuraminidase (partial)
mRNA



Influenza A virus
1,730
Z30276.1


(A/swine/Germany/2/1981 (H1N1) ) mRNA for
bp
GI:563490


hemagglutinin
linear




mRNA



165. Influenza A virus
1,730
Z46434.1


(A/swine/Germany/8533/1991 (H1N1) ) mRNA for
bp
GI:565611


hemagglutinin precursor
linear




mRNA



Influenza A virus
1,690
AY852271.1


(A/swine/Guangdong/711/2001 (H1N1) )
bp
GI:60327789


nonfunctional hemagglutinin (HA) mRNA,
linear



partial sequence
mRNA



Influenza A virus
1,809
EU163946.1


(A/swine/Haseluenne/IDI2617/03 (H1N1) }
bp
GI:157679548


hemagglutinin mRNA, complete cds
linear




mRNA



Influenza A virus (A/swine/Hokkaido/2/81
981 bp
U47306.1


(H1N1) ) hemagglutinin precursor (HA) mRNA,
linear
GI:1912342


partial cds
mRNA



Influenza A virus (A/swine/Hokkaido/2/81
1,778
AF091306.1


(H1N1) ) segment 4 hemagglutinin precursor
bp
GI:4585154


(HA) mRNA, complete cds
linear




miRNA



Influenza A virus (A/swine/Hong
1,113
U44482.1


Kong/168/1993 (H1N1) ) hemagglutinin precursor
bp
GI:1912318


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus (A/swine/Hong
416 bp
U47817.1


Kong/168/1993 (H1N1) ) neuraminidase (NA) mRNA,
linear
GI:1912354


partial cds
mRNA



Influenza A virus (A/swine/Hong
286 bp
048286,1


Kong/168/1993 (H1N1) ) polymerase (PB2) mRNA,
linear
GI:1912358


partial cds
mRNA



Influenza A virus (A/swine/Hong
379 bp
U48283.1


Kong/168/1993 (H1N1) ) polymerase (PB1) mRNA,
linear
GI:1912370


partial cds
mRNA



Influenza A virus (A/swine/Hong
308 bp
U48850.1


Kong/168/1993 (H1N1 ) ) polymerase (PA) mRNA,
linear
GI:1912376


partial cds
mRNA



Influenza A virus (A/swine/Hong
1,397
U49096.1


Kong/168/1993 (H1N1) ) nucleoprotein (NP) MRNA,
bp
GI:1912390


partial cds
linear




mRNA



Influenza A virus (A/swine/Hong
1,315
U46020.1


Kong/172/1993 (H1N1 ) ) hemagglutinin precursor
bp
GI:1912324


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus (A/swine/Hong
1,113
U45451.1


Kong/176/1993 (H1N1) ) hemagglutinin precursor
bp
GI:1912320


(HA) mRNA, partial cds
linear




mRNA



Influenza A virus (A/swine/Hong
1,330
U45452.1


Kong/273/1994 (H1N1) ) hemagglutinin precursor
bp
GI:1912322


(HA) MRNA, partial cds
linear




mRNA



Influenza A virus (A/swine/Hong
241 bp
U47818.1


Kong/273/1994 (H1N1) ) neuraminidase (NA) MRNA,
linear
GI:1912356


partial cds
mRNA



Influenza A virus (A/swine/Hong
328 bp
048287.1


Kong/273/1994 (H1N1) } polymerase (PB2) mRNA,
linear
GI:1912360


partial cds
mRNA



Influenza A virus (A/swine/Hong
240 bp
U48282.1


Kong/273/1994 (H1N1 ) ) polymerase (PB1) mRNA,
linear
GI:1912368


partial cds
mRNA



Influenza A virus (A/swine/Hong
336 bp
U48851.1


Kong/273/1994 (H1N1 ) } polymerase (PA) MRNA,
linear
GI:1912378


partial cds
mRNA



Influenza A virus (A/swine/Hong
1,422
U49092.1


Kong/273/1994 (H1N1) ) nucleoprotein (NP) mRNA,
bp
GI:1912382


partial cds
linear




mRNA



Influenza A virus
1,761
EU163947.1


(A/swine/IDT/Re230/92hp (H1N1) ) hemagglutinin
bp
GI:157679550


mRNA, complete cds
linear




mRNA



Influenza A virus
1,550
L46849.1


(A/swine/IN/1726/1988 (H1N1) ) nucleoprotein
bp
GI:954755


(segment 5) mRNA, complete cds
linear




mRNA



Influenza A virus (A/swine/Iowa/15/30 (H1N1) )
981 bp
047305.1


hemagglutinin precursor (HA) mRNA, partial
linear
GI:1912340


cds
mRNA



Influenza A virus (A/swine/Iowa/15/30 (H1N1) )
1,778
AF091308.1


segment 4 hemagglutinin precursor (HA) mRNA,
bp
GI:4585158


complete cds
linear




mRNA



Influenza A virus (A/Swine/Iowa/30 (H1N1) )
1,410
AF250364.2


neuraminidase (NA) gene, complete cds
bp
GI:13260586



linear




mRNA



Influenza A virus (A/swine/Iowa/17672/88
981 bp
U47304.1


(H1N1) ) hemagglutinin precursor (HA) mRNA,
linear
GI:1912338


partial cds
mRNA



Influenza A virus
864 bp
AJ519462.1


(A/swine/Italy/3364/00 (H1N1) } partial NS1
linear
GI:31096447


gene for non structural protein 1 and partial
mRNA



NS2 gene for non structural protein 2,




genomic RNA




Influenza A virus (A/swine/Italy-
1,777
AF091315.1


Virus/671/87 (H1N1) ) segment 4 hemagglutinin
bp
GI:4585172


precursor (HA) mRNA, complete cds
linear




mRNA



Influenza A Virus
1,028
Z46436.1


(A/swine/Italy/v. 147/1981 (H1N1) ) MRNA for
bp
GI:854214


hemagglutinin HA1
linear




mRNA



Influenza A virus
1,118
AM490218.1


(A/swine/Morbihan/0070/2005 (H1N1) ) partial
bp
GI:222062896


mRNA for haemagglutinin precursor (HAI gene)
linear




mRNA



Influenza A virus
1,770
L09063.1


(A/swine/Nebraska/1/92 (H1N1) ) HA protein
bp
GI:290722


mRNA, complete cds
linear




mRNA



Influenza A virus
1,550
L11164.1


(A/swine/Nebraska/1/1992 (H1N1) ) segment 5
bp
GI:290724


nucleoprotein (NP) mRNA, complete cds
linear




mRNA



Influenza A virus
981 bp
U46943.1


(A/swine/Netherlands/12/1985 (H1N1) )
linear
GI:1912336


hemagglutinin (HA) mRNA, partial cds
mRNA



Influenza A virus
1,776
AF091317.1


(A/swine/Netherlands/12/85 (H1N1) ) segment 4
bp
GI:4585176


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus
539 bp
X75791.1


(A/swine/Netherlands/25/1980 (H1N1) ) mRNA for
linear
GI:438105


nucleoprotein
mRNA



Influenza A virus
981 bp
046942.1


(A/swine/Netherlands/3/1980 (H1N1) )
linear
GI:1912334


hemagglutinin (HA) mRNA, partial cds
mRNA



Influenza A virus
1,778
AF091314.1


(A/swine/Netherlands/3/80 (H1N1) ) segment 4
bp
GI:4585170


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



Influenza A virus (A/NJ/11/76 (H1N1) )
1,410
AF250363.2


neuraminidase (NA) gene, complete cds
bp
GI:13260583



linear




mRNA



Influenza A virus (A/Swine/Quebec/192/81
1,438
U86144.1


(SwQc81) ) neuraminidase mRNA, complete cds
bp
GI:4099318



linear




mRNA



Influenza A virus (A/Swine/Quebec/5393/91
1,438
U86145.1


(SwQc91) ) neuraminidase mRNA, complete cds
bp
GI:4099320



linear




mRNA



Influenza A virus (A/swine/Schleswig-
1,730
Z46435.1


Holstein/1/1992 (H1N1) ) mRNA for hemagglutinin
bp
GI:854216


precursor
linear




mRNA



Influenza A Virus (A/swine/Schleswig-
1,554
Z46438.1


Holstein/1/1993 (H1N1) ) mRNA for nucleoprotein
bp
GI:854222



linear




mRNA



Influenza A virus
1,778
AF091307.1


(A/swine/Wisconsin/1/61 (H1N1) ) segment 4
bp
GI:4585156


hemagglutinin precursor (HA) mRNA, complete
linear



cds
mRNA



212. Influenza A virus
1,565
M76607.1


(A/swine/Wisconsin/1/1967 (H1N1) )
bp
GI:325086


nucleoprotein mRNA, complete cds
linear




mRNA



Influenza A virus
1,565
M76608.1


(A/swine/Wisconsin/1915/1988 (H1N1) )
bp
GI:325088


nucleoprotein mRNA, complete cds
linear




mRNA



Influenza A virus
1,550
L46850.1


(A/swine/WI/1915/1988 (H1N1) ) nucleoprotein
bp
GI:954757


(segment 5) mRNA, complete cds
linear




mRNA



Influenza A virus
729 bp
AJ532568.1


(A/Switzerland/8808/2002 (H1N1) ) partial ml
linear
GI:31096461


gene for matrix protein 1 and partial m2 gene
miRNA



for matrix protein 2, genomic RNA




Influenza A virus
561 bp
AF362803.1


(A/human/Taiwan/0012/00 (H1N1) ) hemagglutinin
linear
GI:14571975


(HA) mRNA, partial cds
mRNA



Influenza A virus
561 bp
AF362779.1


(A/human/Taiwan/0016/00 (H1N1) ) hemagglutinin
linear
GI:14571927


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0016/2000 (H1N1) )
303 bp
AY303752.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330993


partial cds
mRNA



Influenza A virus
561 bp
AF362780.1


(A/human/Taiwan/0030/00 (H1N1) ) hemagglutinin
linear
GI:14571929


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0030/2000 (H1N1) )
303 bp
AY303704.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330897


partial cds
mRNA



Influenza A virus (A/Taiwan/0032/2002 (H1N1) )
494 bp
AY604804.1


hemagglutinin mRNA, partial cds
linear
GI:50727488



mRNA



Influenza A virus (A/Taiwan/0061/2002 (H1N1) )
494 bp
AY604795.1


hemagglutinin mRNA, partial cds
linear
GI:50727470



mRNA



Influenza A virus (A/Taiwan/0069/2002 (H1N1) )
494 bp
AY604803.1


hemagglutinin mRNA, partial cds
linear
GI:50727486



mRNA



Influenza A virus (A/Taiwan/0078/2002 (H1N1) )
494 bp
AY604805.1


hemagglutinin mRNA, partial cds
linear
GI:50727490



mRNA



Influenza A virus (A/Taiwan/0094/2002 (H1N1) )
494 bp
AY604797.1


hemagglutinin mRNA, partial cds
linear
GI:50727474



mRNA



Influenza A virus (A/Taiwan/0116/2002 (H1N1) )
494 bp
AY604796.1


hemagglutinin mRNA, partial cds
linear
GI:50727472



mRNA



Influenza A virus
564 bp
AF362781.1


(A/human/Taiwan/0130/96 (H1N1) ) hemagglutinin
linear
GI:14571931


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0130/96 (H1N1) )
303 bp
AY303707.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330903


partial cds
mRNA



Influenza A virus
564 bp
AF362782.1


(A/human/Taiwan/0132/96 (H1N1) ) hemagglutinin
linear
GI:14571933


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0132/96 (H1N1) )
303 bp
AY303708.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330905


partial cds
mRNA



Influenza A virus
564 bp
AF362783.1


(A/human/Taiwan/0211/96 (H1N1) ) hemagglutinin
linear
GI:14571935


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0211/96 (H1N1) )
303 bp
AY303709.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330907


partial cds
mRNA



Influenza A virus
564 bp
AF362784.1


(A/human/Taiwan/0235/96 (H1N1) ) hemagglutinin
linear
GI:14571937


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0235/96 (H1N1) )
303 bp
AY303710.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330909


partial cds
mRNA



Influenza A virus
564 bp
AF362785.1


(A/human/Taiwan/0255/96 (H1N1) ) hemagglutinin
linear
GI:14571939


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0255/96 (H1N1) )
303 bp
AY303711.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330911


partial cds
mRNA



Influenza A virus
564 bp
AF362786.1


(A/human/Taiwan/0337/96 (H1N1) ) hemagglutinin
linear
GI:14571941


(HA) MRNA, partial cds
mRNA



Influenza A virus
564 bp
AF362787.1


(A/human/Taiwan/0342/96 (H1N1) ) hemagglutinin
linear
GI:14571943


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0342/96 (H1N1) )
303 bp
AY303714.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330917


partial cds
mRNA



Influenza A virus
561 bp
AF362788.1


(A/human/Taiwan/0464/99 (H1N1) ) hemagglutinin
linear
GI:14571945


(HA) mRNA, partial cds
mRNA



Influenza A virus
564 bp
AF362789.1


(A/human/Taiwan/0562/95 (H1N1) ) hemagglutinin
linear
GI:14571947


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0562/95 (H1N1) )
303 bp
AY303720.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330929


partial cds
mRNA



Influenza A virus
564 bp
AF362790.1


(A/human/Taiwan/0563/95 (H1N1) ) hemagglutinin
linear
GI:14571949


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0563/95 (H1N1) )
303 bp
AY303721.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330931


partial cds
mRNA



Influenza A virus
564 bp
AF362791.1


(A/human/Taiwan/0657/95 (H1N1) ) hemagglutinin
linear
GI:14571951


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0657/95 (H1N1) )
303 bp
AY303724.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330937


partial cds
mRNA



Influenza A virus (A/Taiwan/0859/2002 (H1N1) )
494 bp
AY604801.1


hemagglutinin mRNA, partial cds
linear
GI:50727482



mRNA



Influenza A virus
561 bp
AF362792.1


(A/human/Taiwan/0892/99 (H1N1) } hemagglutinin
linear
GI:14571953


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/0983/2002 (H1N1) )
494 bp
AY604800.1


hemagglutinin mRNA, partial cds
linear
GI:50727480



mRNA



Influenza A virus (A/Taiwan/1007/2006 (H1N1) )
507 bp
EU068163.1


hemagglutinin (HA) MRNA, partial cds
linear
GI:158452199



mRNA



Influenza A virus (A/Taiwan/1015/2006 (H1N1) )
507 bp
EU068171.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452215



mRNA



Influenza A virus (A/Taiwan/112/1996-1 (H1N1) )
1,176
AF026153.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554950



linear




mRNA



Influenza A virus (A/Taiwan/112/1996-2 (H1N1) )
1,176
AF026154.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554952



linear




mRNA



Influenza A virus (A/Taiwan/117/1996-1 (H1N1) )
1,176
AF026155.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554954



linear




mRNA



Influenza A virus (A/Taiwan/117/1996-2 (H1N1) )
1,176
AF026156.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554956



linear




mRNA



Influenza A virus (A/Taiwan/117/1996-3 (H1N1) )
1,176
AF026157.1


haemagglutinin (HA) MRNA, partial cds
bp
GI:2554958



linear




mRNA



Influenza A virus (A/Taiwan/118/1996-1 (H1N1) )
1,176
AF026158.1


haemagglutinin (HA) MRNA, partial cds
bp
GI:2554960



linear




mRNA



Influenza A virus (A/Taiwan/118/1996-2 (H1N1) }
1,176
AF026159.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554962



linear




mRNA



Influenza A virus (A/Taiwan/118/1996-3 (H1N1) )
1,176
AF026160.1


haemagglutinin (HA) mRNA, partial cds
bp
GI:2554964



linear




mRNA



Influenza A virus
561 bp
AF362793.1


(A/human/Taiwan/1184/99 (H1N1) ) hemagglutinin
linear
GI:14571955


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/1184/99 (H1N1) )
303 bp
AY303726.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330941


partial cds
mRNA



Influenza A virus
564 bp
AF362794.1


(A/human/Taiwan/1190/95 (H1N1) ) hemagglutinin
linear
GI:14571957


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/1190/95 (H1N1) )
303 bp
AY303727.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330943


partial cds
mRNA



Influenza A virus (A/Taiwan/1523/2003 (H1N1) )
494 bp
AY604808.1


hemagglutinin mRNA, partial cds
linear
GI:50727496



mRNA



Influenza A virus (A/Taiwan/1566/2003 (H1N1) )
494 bp
AY604806.1


hemagglutinin mRNA, partial cds
linear
GI:50727492



mRNA



Influenza A virus (A/Taiwan/1769/96 (H1N1) )
875 bp
AF138710.2


matrix protein Ml (M) mRNA, partial cds
linear
GI:4996871



mRNA



Influenza A virus (A/Taiwan/1906/2002 (H1N1) )
494 bp
AY604799.1


hemagglutinin mRNA, partial cds
linear
GI:50727478



mRNA



Influenza A virus (A/Taiwan/1922/2002 (H1N1) )
494 bp
AY604802.1


hemagglutinin mRNA, partial cds
linear
GI:50727484



mRNA



Influenza A virus (A/Taiwan/2069/2006 (H1N1) )
507 bp
EU068168.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452209



mRNA



Influenza A virus (A/Taiwan/2157/2001 (H1N1) )
303 bp
AY303733.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330955


partial cds
mRNA



Influenza A virus (A/Taiwan/2175/2001 (H1N1) )
561 bp
AY303734.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:32330957



mRNA



Influenza A virus
564 bp
AF362795.1


(A/human/Taiwan/2200/95 (H1N1) ) hemagglutinin
linear
GI:14571959


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/2200/95 (H1N1) )
303 bp
AY303737.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330963


partial cds
mRNA



Influenza A virus (A/Taiwan/2966/2006 (H1N1) )
507 bp
EU068170.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452213



mRNA



Influenza A virus (A/Taiwan/3168/2005 (H1N1) )
507 bp
EU068174.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452221



mRNA



Influenza A virus
561 bp
AF362796.1


(A/human/Taiwan/3355/97 (H1N1) ) hemagglutinin
linear
GI:14571961


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/3355/97 (H1N1) )
303 bp
AY303739.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330967


partial cds
mRNA



Influenza A virus (A/Taiwan/3361/2001 (H1N1) )
303 bp
AY303740.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330969


partial cds
mRNA



Influenza A virus (A/Taiwan/3361/2001 (H1N1) }
561 bp
AY303741.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:32330971



mRNA



Influenza A virus (A/Taiwan/3518/2006 (H1N1) )
507 bp
EU068169.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452211



mRNA



Influenza A virus
581 bp
AF362797.1


(A/human/Taiwan/3825/00 (H1N1) ) hemagglutinin
linear
GI:14571963


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/3896/2001 (H1N1) )
303 bp
AY303746.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330981


partial cds
mRNA



Influenza A virus (A/Taiwan/3896/2001 (H1N1) )
561 bp
AY303747.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:32330983



mRNA



Influenza A virus (A/Taiwan/4050/2003 (H1N1) )
494 bp
AY604807.1


hemagglutinin mRNA, partial cds
linear
GI:50727494



mRNA



Influenza A virus (A/Taiwan/4054/2006 (H1N1) )
507 bp
EU068160.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452193



mRNA



Influenza A virus
561 bp
AF362798.1


(A/human/Taiwan/4360/99 (H1N1) ) hemagglutinin
linear
GI:14571965


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/4360/99 (H1N1) )
303 bp
AY303748.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330985


partial cds
mRNA



Influenza A virus
561 bp
AF362799.1


(A/human/Taiwan/4415/99 (H1N1) ) hemagglutinin
linear
GI:14571967


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/4415/99 (H1N1) )
303 bp
AY303749.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330987


partial cds
mRNA



Influenza A virus (A/Taiwan/4509/2006 (H1N1) )
507 bp
EU068165.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452203



mRNA



Influenza A virus
561 bp
AF362800.1


(A/human/Taiwan/4845/99 (H1N1) ) hemagglutinin
linear
GI:14571969


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/4845/99 (H1N1) )
303 bp
AY303750.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330989


partial cds
mRNA



Influenza A virus
561 bp
AF362801.1


(A/human/Taiwan/4943/99 (H1N1) ) hemagglutinin
linear
GI:14571971


(HA) MRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/5010/2006 (H1N1) )
507 bp
EU068167.1


hemagglutinin (HA) MRNA, partial cds
linear
GI:158452207



mRNA



Influenza A virus
561 bp
AF362802.1


(A/human/Taiwan/5063/99 (H1N1) ) hemagglutinin
linear
GI:14571973


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/5063/99 (H1N1) )
303 bp
AY303751.1


polymerase basic protein 1 (PB1) mRNA,
linear
GI:32330991


partial cds
mRNA



Influenza A virus (A/Taiwan/5084/2006 (H1N1) )
507 bp
EU068166.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452205



mRNA



Influenza A virus (A/Taiwan/511/96 (H1N1) )
875 bp
AF138708.2


matrix protein M1 (M) MRNA, partial cds
linear
GI:4996867



mRNA



Influenza A virus (A/Taiwan/557/2006 (H1N1) )
507 bp
EU068156.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452185



mRNA



Influenza A virus (A/Taiwan/562/2006 (H1N1) )
507 bp
EU068159.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452191



mRNA



Influenza A virus
561 bp
AF362778.1


(A/human/Taiwan/5779/98 (H1N1) ) hemagglutinin
linear
GI:14571925


(HA) mRNA, partial cds
mRNA



Influenza A virus (A/Taiwan/5779/98 (H1N1) )
303 bp
AY303702.1


polymerase basic protein 1 (PB1) MRNA,
linear
GI:32330893


partial cds
mRNA



Influenza A virus (A/Taiwan/6025/2005 (H1N1) )
507 bp
EU068172.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452217



mRNA



Influenza A virus (A/Taiwan/607/2006 (H1N1) )
507 bp
EU068157.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452187



mRNA



Influenza A virus (A/Taiwan/615/2006 (H1N1) )
507 bp
EU068162.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452197



mRNA



Influenza A virus (A/Taiwan/645/2006 (H1N1) )
507 bp
EU068164.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452201



mRNA



Influenza A virus (A/Taiwan/680/2005 (H1N1) )
507 bp
EU068173.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452219



mRNA



Influenza A virus (A/Taiwan/719/2006 (H1N1) )
507 bp
EU068158.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452189



mRNA



Influenza A virus
1,410
EU021285.1


(A/Thailand/CU124/2006 (H3N2) ) neuraminidase
bp
GI:154224724


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021265.1


(A/Thailand/CU32/2006 (H1N1) ) neuraminidase
bp
GI:154224704


(NA) MRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021264.1


(A/Thailand/CU32/2006 (H1N1) ) hemagglutinin
bp
GI:154224775


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021247.1


(A/Thailand/CU41/2006 (H1N1) ) neuraminidase
bp
GI:154224686


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021246.1


(A/Thailand/CU41/2006 (H1N1) ) hemagglutinin
bp
GI:154224757


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021259.1


(A/Thailand/CU44/2006 (H1N1) ) neuraminidase
bp
GI:154224698


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021258.1


(A/Thailand/CU44/2006 (H1N1) ) hemagglutinin
bp
GI:154224769


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021255.1


(A/Thailand/CU51/2006 (H1N1) ) neuraminidase
bp
GI:154224694


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021254.1


(A/Thailand/CU51/2006 (H1N1) ) hemagglutinin
bp
GI:154224765


(HA) MRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021249.1


(A/Thailand/CU53/2006 (H1N1) } neuraminidase
bp
GI:154224688


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021248.1


(A/Thailand/CU53/2006 (H1N1) ) hemagglutinin
bp
GI:154224759


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021257.1


(A/Thailand/CU57/2006 (H1N1) } neuraminidase
bp
GI:154224696


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021256.1


(A/Thailand/CU57/2006 (H1N1) ) hemagglutinin
bp
GI:154224767


(HA) MRNA, complete cds
linear




mRNA



Influenza A virus
1,413
E0021251.1


(A/Thailand/CU67/2006 (H1N1) ) neuraminidase
bp
GI:154224690


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021250.1


(A/Thailand/CU67/2006 (H1N1) ) hemagglutinin
bp
GI:154224761


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021261.1


(A/Thailand/CU68/2006 (H1N1) ) neuraminidase
bp
GI:154224700


(NA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021260.1


(A/Thailand/CU68/2006 (H1N1) ) hemagglutinin
bp
GI:154224771


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021263.1


(A/Thailand/CU75/2006 (H1N1) ) neuraminidase
bp
GI:154224702


(NA) MRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021262.1


(A/Thailand/CU75/2006 (H1N1) ) hemagglutinin
bp
GI:154224773


(HA) mRNA, complete cds
linear




mRNA



Influenza A virus
1,413
EU021253.1


(A/Thailand/CU88/2006 (H1N1) ) neuraminidase
bp
GI:154224692


(NA) MRNA, complete cds
linear




mRNA



Influenza A virus
1,698
EU021252.1


(A/Thailand/CU88/2006 (H1N1) ) hemagglutinin
bp
GI:154224763


(HA) mRNA, complete cds
linear




MRNA



Influenza A virus
1,565
M76603.1


(A/turkey/England/647/1977 (H1N1) )
bp
GI:325094


nucleoprotein mRNA, complete cds
linear




mRNA



Influenza A virus
1,445
AJ416626.1


(A/turkey/France/87075/87 (H1N1) ) N1 gene for
bp
GI:39840719


neuraminidase, genomic RNA
linear




mRNA



Influenza A virus
394 bp
Z30272.1


(A/turkey/Germany/3/91 (H1N1) ) mRNA for PB2
linear
GI:456652


polymerase (partial)
mRNA



Influenza A virus
97 bp
Z30275.1


(A/turkey/Germany/3/91 (H1N1) ) mRNA for
linear
GI:530398


neuraminidase (UTR)
mRNA



Influenza A virus
264 bp
Z30274.1


(A/turkey/Germany/3/91 (H1N1) ) MRNA for PA
linear
GI:530401


polymerase
mRNA



Influenza A virus
247 bp
Z30273.1


(A/turkey/Germany/3/91 (H1N1) ) mRNA for PBI
linear
GI:530403


polymerase (partial)
mRNA



Influenza A virus
1,038
Z46441,1


(A/turkey/Germany/3/91 (H1N1) ) mRNA for
bp
GI:854218


hemagglutinin HA1
linear




mRNA



Influenza A virus
981 bp
U46941.1


(A/turkey/Minnesota/1661/1981 (H1N1) )
linear
GI:1912332


hemagglutinin (HA) MRNA, partial cds
mRNA



Influenza A virus
1,777
AF091310.1


(A/turkey/Minnesota/1661/81 (H1N1) ) segment 4
bp
GI:4585162


hemagglutinin precursor (HA) MRNA, complete
linear



cds
mRNA



Influenza A virus (A/turkey/North
1,565
M76609.1


Carolina/1790/1988 (H1N1) ) nucleoprotein mRNA,
bp
GI:325096


complete cds
linear




mRNA



Influenza A virus (A/Weiss/43 (H1N1) )
1,410
AF250365.2


neuraminidase (NA) gene, complete cds
bp
GI:13260589



linear




mRNA



Influenza A virus (A/Wilson-Smith/1933 (H1N1) )
1,497
EU330203.1


nucleocapsid protein (NP) mRNA, complete cds
bp
GI:167989512



linear




mRNA



Influenza A virus
241 bp
U47816.1


(A/Wisconsin/3523/1988 (H1N1} ) neuraminidase
linear
GI:1912352


(NA) mRNA, partial cds
mRNA



Influenza A virus
1,565
M76610.1


(A/Wisconsin/3623/1988 (H1N1) ) nucleoprotein
bp
GI:325103


mRNA, complete cds
linear




mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) PB1
235 bp
U53156.1


(PB1) mRNA, partial cds
linear
GI:1399590



mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) PB2
168 bp
U53158.1


(PB2) mRNA, partial cds
linear
GI:1399594



mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) PA
621 bp
U53160.1


(PA) mRNA, partial cds
linear
GI:1399598



mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) )
1,778
U53162.1


hemagglutinin (HA) mRNA, complete cds
bp
GI:1399602



linear




mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) NP
200 bp
U53164.1


(NP) mRNA, partial cds
linear
GI:1399606



mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) )
1,458
U53166.1


neuraminidase (NA) mRNA, complete cds
bp
GI:1399610



linear




mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) M
1,027
053168.1


(M) mRNA, complete cds
bp
GI:1399614



linear




mRNA



Influenza A virus (A/WI/4754/1994 (H1N1) ) NS
890 bp
U53170.1


(NS) mRNA, complete cds
linear
GI:1399618



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) PB1
203 bp
U53157.1


(PB1) mRNA, partial cds
linear
GI:1399592



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) PB2
173 bp
U53159.1


(PB2) MRNA, partial cds
linear
GI:1399596



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) PA
621 bp
U53161.1


(PA) mRNA, partial cds
linear
GI:1399600



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) )
1,778
U53163.1


hemagglutinin (HA) mRNA, complete cds
bp
GI:1399604



linear




mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) NP
215 bp
U53165.1


(NP) mRNA, partial cds
linear
GI:1399608



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) )
209 bp
U53167.1


neuraminidase (NA) mRNA, partial cds
linear
GI:1399612



mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) M
1,027
U53169.1


(M) mRNA, complete cds
bp
GI:1399616



linear




mRNA



Influenza A virus (A/WI/4755/1994 (H1N1) ) NS
890 bp
U53171.1


(NS) MRNA, complete cds
linear
GI:1399620



mRNA



Influenza A virus (A/WSN/33) segment 5
543 bp
AF306656.1


nucleocapsid protein (NP) MRNA, partial cds
linear
GI:11935089



mRNA
















TABLE 7







Influenza H3N2 Antigens











GenBank/GI


Strain/Protein
Length
Accession No.





1. Influenza A virus
1,704 bp
EF614248.1


(A/Aichi/2/1968 (H3N2) ) hemagglutinin
linear
GI:148910819


(HA) mRNA, complete cds
mRNA



2. Influenza A virus
1,698 bp
EF614249.1


(A/Aichi/2/1968 (H3N2) ) hemagglutinin
linear
GI:148910821


(HA) mRNA, partial cds
mRNA



3. Influenza A virus
1,698 bp
EF614250.1


(A/Aichi/2/1968 (H3N2) ) hemagglutinin
linear
GI:148910823


(HA) mRNA, partial cds
mRNA



4. Influenza A virus
1,698 bp
EF614251.1


(A/Aichi/2/1968 (H3N2) ) hemagglutinin
linear
GI:148910825


(HA) mRNA, partial cds
mRNA



5. Influenza A virus
1,032 bp
U48444.1


(A/Akita/1/1995 (H3N2) )
linear
GI:1574989


haemagglutinin mRNA, partial cds
mRNA



6. Influenza A virus
1,041 bp
Z46392.1


(A/Beijing/32/1992 (H3N2) ) mRNA for
linear
GI:609020


haemagglutinin
mRNA



7. Influenza A virus
987 bp
AF501516.1


(A/Canada/33312/99 (H3N2) )
linear
GI:21314288


hemagglutinin (HA) mRNA, partial cds
mRNA



8. Influenza A virus
987 bp
AF297094.1


(A/Charlottesville/10/99 (H3N2) )
linear
GI:11228917


hemagglutinin mRNA, partial cds
mRNA



9. Influenza A virus
987 bp
AF297096.1


(A/Charlottesville/49/99 (H3N2) )
linear
GI:11228921


hemagglutinin mRNA, partial cds
mRNA



10. Influenza A virus
987 bp
AF297097.1


(A/Charlottesville/69/99 (H3N2) )
linear
GI:11228923


hemagglutinin mRNA, partial cds
mRNA



11. Influenza A virus
987 bp
AF297095.1


(A/Charlottesville/73/99 (H3N2) )
linear
GI:11228919


hemagglutinin mRNA, partial cds
mRNA



12. Influenza A virus
1,041 bp
Z46393.1


(A/England/1/1993 (H3N2) ) mRNA for
linear
GI:609024


haemagglutinin
mRNA



13. Influenza A virus
1,041 bp
Z46394.1


(A/England/247/1993 (H3N2) ) mRNA for
linear
GI:609025


haemagglutinin
mRNA



14. Influenza A virus
1,041 bp
Z46395.1


(A/England/269/93 (H3N2) ) MRNA for
linear
GI:609027


haemagglutinin
mRNA



15. Influenza A virus
1,041 bp
Z46396.1


(A/England/284/1993 (H3N2) ) mRNA for
linear
GI:609029


haemagglutinin
mRNA



16. Influenza A virus
1,041 bp
Z46397.1


(A/England/286/1993 (H3N2) ) mRNA for
linear
GI:609031


haemagglutinin
mRNA



17. Influenza A virus
1,041 bp
Z46398.1


(A/England/289/1993 (H3N2) ) mRNA for
linear
GI:609033


haemagglutinin
mRNA



18. Influenza A virus
1,041 bp
Z46399.1


(A/England/328/1993 (H3N2) ) mRNA for
linear
GI:609035


haemagglutinin
mRNA



19. Influenza A virus
1,041 bp
Z46400.1


(A/England/346/1993 (H3N2) ) mRNA for
linear
GI:609037


haemagglutinin
mRNA



20. Influenza A virus
1,041 bp
Z46401.1


(A/England/347/1993 (H3N2) ) mRNA for
linear
GI:609039


haemagglutinin
mRNA



21. Influenza A virus
1,091 bp
AF201875.1


(A/England/42/72 (H3N2) )
linear
GI:6470274


hemagglutinin mRNA, partial cds
mRNA



22. Influenza A virus
1,041 bp
Z46402.1


(A/England/471/1993 (H3N2) ) mRNA for
linear
GI:609041


haemagglutinin
mRNA



23. Influenza A virus
1,041 bp
Z46403.1


(A/England/67/1994 (H3N2) ) mRNA for
linear
GI:609043


haemagglutinin
mRNA



24. Influenza A virus
1,041 bp
Z46404.1


(A/England/68/1994 (H3N2) ) mRNA for
linear
GI:609045


haemagglutinin
mRNA



25. Influenza A virus
1,041 bp
Z46405.1


(A/England/7/1994 (H3N2) ) mRNA for
linear
GI:609047


haemagglutinin
mRNA



28. Influenza A virus
1,041 bp
Z46406.1


(A/Guangdong/25/1993 (H3N2) ) MRNA for
linear
GI:609049


haemagglutinin
mRNA



29. Influenza A virus (A/Hong
1,091 bp
AF201874.1


Kong/1/68 (H3N2) ) hemagglutinin mRNA,
linear
GI:6470272


partial cds
mRNA



30. Influenza A virus (A/Hong
1,041 bp
Z46407.1


Kong/1/1994 (H3N2) ) MRNA for
linear
GI:609051


haemagglutinin
mRNA



31. Influenza A virus (A/Hong
1,762 bp
AF382319.1


Kong/1143/99 (H3N2) ) hemagglutinin
linear
GI:14487957


mRNA, complete cds
mRNA



32. Influenza A virus (A/Hong
1,762 bp
AF382320.1


Kong/1143/99 (H3N2) ) hemagglutinin
linear
GI:14487959


mRNA, complete cds
mRNA



33. Influenza A virus (A/Hong
1,466 bp
AF382329.1


Kong/1143/99 (H3N2) ) neuraminidase
linear
GI:14487977


mRNA, complete cds
mRNA



34. Influenza A virus (A/Hong
1,466 bp
AF382330.1


Kong/1143/99 (H3N2) ) neuraminidase
linear
GI:14487979


mRNA, complete cds
mRNA



35. Influenza A virus (A/Hong
1,762 bp
AY035589.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14486403


mRNA, complete cds
mRNA



36. Influenza A virus (A/Hong
1,762 bp
AF382321.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14487961


mRNA, complete cds
mRNA



37. Influenza A virus (A/Hong
1,762 bp
AF382322.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14487963


mRNA, complete cds
mRNA



38. Influenza A virus (A/Hong
1,466 bp
AF382331.1


Kong/1144/99 (H3N2) ) neuraminidase
linear
GI:14487981


mRNA, complete cds
mRNA



39. Influenza A virus (A/Hong
1, 466 bp
AF382332.1


Kong/1144/99 (H3N2) ) neuraminidase
linear
GI:14487983


mRNA, complete cds
mRNA



40. Influenza A virus (A/Hong
1,762 bp
AY035590.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14486405


mRNA, complete cds
mRNA



41. Influenza A virus (A/Hong
1,762 bp
AF382323.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14487965


mRNA, complete cds
mRNA



42. Influenza A virus (A/Hong
1,762 bp
AF382324.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14487967


mRNA, complete cds
mRNA



43. Influenza A virus (A/Hong
1,762 bp
AY035591.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14486407


mRNA, complete cds
mRNA



44. Influenza A virus (A/Hong
1,762 bp
AF382325.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14487969


mRNA, complete cds
mRNA



45. Influenza A virus (A/Hong
1,762 bp
AF382326.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14487971


mRNA, complete cds
mRNA



46. Influenza A virus (A/Hong
1,762 bp
AF382327.1


Kong/1182/99 (H3N2) ) hemagglutinin
linear
GI:14487973


mRNA, complete cds
mRNA



47. Influenza A virus (A/Hong
1,762 bp
AF382328.1


Kong/1182/99 (H3N2) ) hemagglutinin
linear
GI:14487975


mRNA, complete cds
mRNA



48. Influenza A virus (A/Hong
1,041 bp
Z46408.1


Kong/2/1994 (H3N2) ) mRNA for
linear
GI:609055


haemagglutinin
mRNA



49. Influenza A virus (A/Hong
1,041 bp
Z46410.1


Kong/23/1992 (H3N2) ) mRNA for
linear
GI:609053


haemagglutinin
mRNA



50. Influenza A virus (A/Hong
1,041 bp
Z46409.1


Kong/34/1990 (H3N2) ) mRNA for
linear
GI:609057


haemagglutinin
mRNA



51. Influenza A virus
1,041 bp
Z46397.1


(A/England/286/1993 (H3N2) ) mRNA for
linear
GI:609031


haemagglutinin
mRNA



52. Influenza A virus
1,041 bp
Z46398.1


(A/England/289/1993 (H3N2) } mRNA for
linear
GI:609033


haemagglutinin
mRNA



53. Influenza A virus
1,041 bp
Z46399.1


(A/England/328/1993 (H3N2) ) mRNA for
linear
GI:609035


haemagglutinin
mRNA



54. Influenza A virus
1,041 bp
Z46400.1


(A/England/346/1993 (H3N2) ) mRNA for
linear
GI:609037


haemagglutinin
mRNA



55. Influenza A virus
1,041 bp
Z46401.1


(A/England/347/1993 (H3N2) ) mRNA for
linear
GI:609039


haemagglutinin
mRNA



56. Influenza A virus
1,091 bp
AF201875.1


(A/England/42/72 (H3N2) )
linear
GI:6470274


hemagglutinin mRNA, partial cds
mRNA



57. Influenza A virus
1,041 bp
Z46402.1


(A/England/471/1993 (H3N2) ) mRNA for
linear
GI:609041


haemagglutinin
mRNA



58. Influenza A virus
1,041 bp
Z46403.1


(A/England/67/1994 (H3N2) ) mRNA for
linear
GI:609043


haemagglutinin
mRNA



59. Influenza A virus
1,041 bp
Z46404.1


(A/England/68/1994 (H3N2) ) mRNA for
linear
GI:609045


haemagglutinin
mRNA



60. Influenza A virus
1,041 bp
Z46405.1


(A/England/7/1994 (H3N2) ) mRNA for
linear
GI:609047


haemagglutinin
mRNA



63. Influenza A virus
1,032 bp
U48442.1


(A/Guandong/28/1994 (H3N2) )
linear
GI:1574985


haemagglutinin mRNA, partial cds
mRNA



64. Influenza A virus
1,041 bp
Z46406.1


(A/Guangdong/25/1993 (H3N2) ) mRNA for
linear
GI:609049


haemagglutinin
mRNA



65. Influenza A virus
1,032 bp
U48447.1


(A/Hebei/19/1995 (H3N2) )
linear
GI:1574995


haemagglutinin mRNA, partial cds
mRNA



66. Influenza A virus
1,032 bp
U48441.1


(A/Hebei/41/1994 (H3N2) )
linear
GI:1574983


haemagglutinin mRNA, partial cds
mRNA



67. Influenza A virus (A/Hong
1,091 bp
AF201874.1


Kong/1/68 (H3N2) ) hemagglutinin mRNA,
linear
GI:6470272


partial cds
mRNA



68. Influenza A virus (A/Hong
1,041 bp
Z46407.1


Kong/1/1994 (H3N2) ) mRNA for
linear
GI:609051


haemagglutinin
mRNA



69. Influenza A virus (A/Hong
1,762 bp
AY035588.1


Kong/1143/99 (H3N2) ) hemagglutinin
linear
GI:14486401


mRNA, complete cds
mRNA



70. Influenza A virus (A/Hong
1,762 bp
AF382319.1


Kong/1143/99 (H3N2) ) hemagglutinin
linear
GI:14487957


mRNA, complete cds
mRNA



71. Influenza A virus (A/Hong
1,762 bp
AF382320.1


Kong/1143/99 (H3N2) ) hemagglutinin
linear
GI:14487959


mRNA, complete cds
mRNA



72. Influenza A virus (A/Hong
1,466 bp
AF382329.1


Kong/1143/99 (H3N2) ) neuraminidase
linear
GI:14487977


mRNA, complete cds
mRNA



73. Influenza A virus (A/Hong
1,466 bp
AF382330.1


Kong/1143/99 (H3N2) ) neuraminidase
linear
GI:14487979


mRNA, complete cds
mRNA



74. Influenza A virus (A/Hong
1,762 bp
AY035589.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14486403


mRNA, complete cds
mRNA



75. Influenza A virus (A/Hong
1,762 bp
AF382321.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14487961


mRNA, complete cds
mRNA



76. Influenza A virus (A/Hong
1,762 bp
AF382322.1


Kong/1144/99 (H3N2) ) hemagglutinin
linear
GI:14487963


mRNA, complete cds
mRNA



77. Influenza A virus (A/Hong
1,466 bp
AF382331.1


Kong/1144/99 (H3N2) ) neuraminidase
linear
GI:14487981


mRNA, complete cds
mRNA



78. Influenza A virus (A/Hong
1,466 bp
AF382332.1


Kong/1144/99 (H3N2) ) neuraminidase
linear
GI:14487983


mRNA, complete cds
mRNA



79. Influenza A virus (A/Hong
1,762 bp
AY035590.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14486405


mRNA, complete cds
mRNA



80. Influenza A virus (A/Hong
1,762 bp
AF382323.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14487965


mRNA, complete cds
mRNA



81. Influenza A virus (A/Hong
1,762 bp
AF382324.1


Kong/1179/99 (H3N2) ) hemagglutinin
linear
GI:14487967


mRNA, complete cds
mRNA



82. Influenza A virus (A/Hong
1,762 bp
AY035591.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14486407


mRNA, complete cds
mRNA



83. Influenza A virus (A/Hong
1,762 bp
AF382325.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14487969


mRNA, complete cds
mRNA



84. Influenza A virus (A/Hong
1,762 bp
AF382326.1


Kong/1180/99 (H3N2) ) hemagglutinin
linear
GI:14487971


mRNA, complete cds
mRNA



85. Influenza A virus (A/Hong
1,762 bp
AY035592.1


Kong/1182/99 (H3N2) ) hemagglutinin
linear
GI:14486409


mRNA, complete cds
mRNA



86. Influenza A virus (A/Hong
1,762 bp
AF382327.1


Kong/1182/99 (H3N2) ) hemagglutinin
linear
GI:14487973


mRNA, complete cds
mRNA



87. Influenza A virus (A/Hong
1,762 bp
AF382328.1


Kong/1182/99 (H3N2) ) hemagglutinin
linear
GI:14487975


mRNA, complete cds
mRNA



88. Influenza A virus (A/Hong
1,041 bp
Z46408.1


Kong/2/1994 (H3N2) ) mRNA for
linear
GI:609055


haemagglutinin
mRNA



89. Influenza A virus (A/Hong
1,041 bp
Z46410.1


Kong/23/1992 (H3N2) ) mRNA for
linear
GI:609053


haemagglutinin
mRNA



90. Influenza A virus (A/Hong
1,041 bp
Z46409.1


Kong/34/1990 (H3N2) ) mRNA for
linear
GI:609057


haemagglutinin
mRNA



91. Influenza A virus
987 bp
AF501534.1


(A/Indiana/28170/99 (H3N2) )
linear
GI:21314324


hemagglutinin (HA) mRNA, partial cds
mRNA



92. Influenza A virus
529 bp
AY961997.1


(A/Kinmen/618/03 (H3N2) )
linear
GI:68138151


hemagglutinin (HA) mRNA, partial cds
mRNA



93. Influenza A virus
383 bp
AY973325.1


(A/Kinmen/618/03 (H3N2) )
linear
GI:70673206


neuraminidase (NA) mRNA, partial cds
mRNA



94. Influenza A virus
882 bp
AY986986.1


(A/Kinmen/618/03 (H3N2) )
linear
GI:70728099


nucleoprotein (NP) mRNA, partial cds
mRNA



95. Influenza A virus
545 bp
AY962017.1


(A/Kinmen/621/03 (H3N2) )
linear
GI:68138191


hemagglutinin (HA) MRNA, partial cds
mRNA



96. Influenza A virus
386 bp
AY973326.1


(A/Kinmen/621/03 (H3N2) )
linear
GI:70673208


neuraminidase (NA) mRNA, partial cds
mRNA



97. Influenza A virus
882 bp
AY986987.1


(A/Kinmen/621/03 (H3N2) )
linear
GI:70728101


nucleoprotein (NP) MRNA, partial cds
mRNA



98. Influenza A virus
786 bp
AY962008.1


(A/Kinmen/639/04 (H3N2) )
linear
GI:68138173


hemagglutinin (HA) mRNA, partial cds
mRNA



99. Influenza A virus
381 bp
AY973327.1


(A/Kinmen/639/04 (H3N2) )
linear
GI:70673210


neuraminidase (NA) MRNA, partial cds
mRNA



100. Influenza A virus
882 bp
AY986988.1


(A/Kinmen/639/04 (H3N2) )
linear
GI:70728103


nucleoprotein (NP) MRNA, partial cds
mRNA



101. Influenza A virus
596 bp
AY962004.1


(A/Kinmen/641/04 (H3N2) )
linear
GI:68138165


hemagglutinin (HA) mRNA, partial cds
mRNA



102. Influenza A virus
785 bp
AY973328.1


(A/Kinmen/641/04 (H3N2) )
linear
GI:70673212


neuraminidase (NA) mRNA, partial cds
mRNA



103. Influenza A virus
576 bp
AY962001.1


(A/Kinmen/642/04 (H3N2) )
linear
GI:68138159


hemagglutinin (HA) mRNA, partial cds
mRNA



104. Influenza A virus
580 bp
AY973329.1


(A/Kinmen/642/04 (H3N2) )
linear
GI:70673214


neuraminidase (NA) mRNA, partial cds
mRNA



105. Influenza A virus
882 bp
AY986989.1


(A/Kinmen/642/04 (H3N2) )
linear
GI:70728105


nucleoprotein (NP) mRNA, partial cds
mRNA



106. Influenza A virus
789 bp
AY962009.1


(A/Kinmen/645/04 (H3N2) )
linear
GI:68138175


hemagglutinin (HA) MRNA, partial cds
mRNA



107. Influenza A virus
581 bp
AY973330.1


(A/Kinmen/645/04 (H3N2) )
linear
GI:70673216


neuraminidase (NA) mRNA, partial cds
mRNA



108. Influenza A virus
981 bp
AY986990.1


(A/Kinmen/645/04 (H3N2) )
linear
GI:70728107


nucleoprotein (NP) MRNA, partial cds
mRNA



109. Influenza A virus
2,341 bp
U62543.1


(A/LosAngeles/2/1987 (H3N2) )
linear
GI:1480737


polymerase protein basic 2 (PB2)
mRNA



mRNA, complete cds




110. Influenza A virus
1,041 bp
Z46411.1


(A/Madrid/252/1993 (H3N2) ) mRNA for
linear
GI:609067


haemagglutinin
mRNA



111. Influenza A virus
987 bp
AF501531.1


(A/Michigan/22568/99 (H3N2) )
linear
GI:21314318


hemagglutinin (HA) mRNA, partial cds
mRNA



112. Influenza A virus
987 bp
AF501518.1


(A/Michigan/22692/99 (H3N2) )
linear
GI:21314292


hemagglutinin (HA) mRNA, partial cds
mRNA



113. Influenza A virus
754 bp
AJ519454.1


(A/Moscow/10/99 (H3N2) ) partial NS1
linear
GI:31096423


gene for non structural protein 1
mRNA



and partial NS2 gene for non




structural protein 2, genomic RNA




114. Influenza A virus
987 bp
AY138518.1


(A/ningbo/17/2002 (H3N2) )
linear
GI:24895178


hemagglutinin (HA) mRNA, partial cds
mRNA



115. Influenza A virus
987 bp
AY138517.1


(A/ningbo/25/2002 (H3N2) )
linear



hemagglutinin (HA) MRNA, partial cds
mRNA
GI:24895169


116. Influenza A virus
1,765 bp
V01103.1


(A/NT/60/68/29C (H3N2) ) mRNA for
linear
GI:60800


haemagglutinin (HA1 and HA2 genes)
mRNA



117. Influenza A virus
1,701 bp
DQ059385.1


(A/Oklahoma/323/03 (H3N2) )
linear
GI:66933143


hemagglutinin mRNA, complete cds
mRNA



118. Influenza A virus
1,410 bp
DQ059384.2


(A/Oklahoma/323/03 (H3N2) )
linear



neuraminidase mRNA, complete cds
mRNA
GI:75859981


119. Influenza A virus
766 bp
AJ519458.1


(A/Panama/2007/99 (H3N2) ) partial NS1
linear
GI:31096435


gene for non structural protein 1
mRNA



and partial NS2 gene for non




structural protein 2, genomic RNA




120. Influenza A virus
987 bp
AF501526.1


(A/Pennsalvanya/20109/99 (H3N2) )
linear
GI:21314308


hemagglutinin (HA) mRNA, partial cds
mRNA



121. Influenza A virus
1,091 bp
AF233691.1


(A/Philippines/2/82 (H3N2) )
linear
GI:7331124


hemagglutinin mRNA, partial cds
MRNA



122. Influenza A virus
767 bp
AY962000.1


(A/Pingtung/303/04 (H3N2) )
linear
GI:68138157


hemagglutinin (HA) mRNA, partial cds
mRNA



123. Influenza A virus
783 bp
AY973331.1


(A/Pingtung/303/04 (H3N2) )
linear
GI:70673218


neuraminidase (NA) mRNA, partial cds
mRNA



124. Influenza A virus
928 bp
AY986991.1


(A/Pingtung/303/04 (H3N2) )
linear
GI:70728109


nucleoprotein (NP) mRNA, partial cds
mRNA



125. Influenza A virus
788 bp
AY961999.1


(A/Pingtung/313/04 (H3N2) )
linear
GI:68138155


hemagglutinin (HA) mRNA, partial cds
mRNA



126. Influenza A virus
787 bp
AY973332.1


(A/Pingtung/313/04 (H3N2) )
linear
GI:70673220


neuraminidase (NA) mRNA, partial cds
mRNA



127. Influenza A virus
882 bp
AY986992.1


(A/Pingtung/313/04 (H3N2) )
linear
GI:70728111


nucleoprotein (NP) mRNA, partial cds
mRNA



128. Influenza A virus (A/ruddy
927 bp
AY664458.1


turnstone/Delaware/142/99 (H3N2) )
linear
GI:51011862


nonfunctional matrix protein mRNA,
mRNA



partial sequence




129. Influenza A virus
1,041 bp
Z46413.1


(A/Scotland/142/1993 (H3N2) ) mRNA for
linear
GI:609059


haemagglutinin
mRNA



130. Influenza A virus
1,041 bp
Z46414.1


(A/Scotland/160/1993 (H3N2) ) mRNA for
linear
GI:609061


haemagglutinin
mRNA



131. Influenza A virus
1,041 bp
Z46416.1


(A/Scotland/173/1993 (H3N2) ) mRNA for
linear
GI:609063


haemagglutinin
mRNA



132. Influenza A virus
1,041 bp
Z46415.1


(A/Scotland/174/1993 (H3N2) ) mRNA for
linear
GI:609065


haemagglutinin
mRNA



133. Influenza A virus
1,041 bp
Z46412.1


(A/Scotland/2/1993 (H3N2) ) mRNA for
linear
GI:609069


haemagglutinin
mRNA



134. Influenza A virus
1,032 bp
U48439.1


(A/Sendai/c182/1994 (H3N2) )
linear
GI:1574979


haemagglutinin mRNA, partial cds
mRNA



135. Influenza A virus
1,032 bp
048445.1


(A/Sendai/c373/1995 (H3N2) )
linear
GI:1574991


haemagglutinin mRNA, partial cds
mRNA



136. Influenza A virus
1,032 bp
048440.1


(A/Sendai/c384/1994 (H3N2) )
linear
GI:1574981


haemagglutinin mRNA, partial cds
mRNA



137. Influenza A virus
1,041 bp
246417.1


(A/Shangdong/9/1993 (H3N2) ) mRNA for
linear
GI:609071


haemagglutinin
mRNA



138. Influenza A virus
987 bp
L19416.1


(A/Shanghai/11/1987/x99aE high yield
linear
GI:348117


reassortant (H3N2) ) hemagglutinin
mRNA



(HA) MRNA, partial cds




139. Influenza A virus
2,280 bp
AF225514.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462098


polymerase basic 2 (PB2) mRNA,
mRNA



complete cds




140. Influenza A virus
2,274 bp
AF225518.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462106


polymerase basic 1 (PB1) mRNA,
mRNA



complete cds




141. Influenza A virus
2,151 bp
AF225522.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462114


polymerase acidic (PA) mRNA,
mRNA



complete cds




142. Influenza A virus
1,497 bp
AF225534.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462146


nucleoprotein (NP) mRNA, complete
mRNA



cds




143. Influenza A virus
1,410 bp
AF225538.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462154


neuraminidase (NA) mRNA, complete
mRNA



cds




144. Influenza A virus
984 bp
AF225542.1


(A/sw/Shizuoka/110/97 (H3N2) )
linear
GI:27462162


hemagglutinin (HA1) mRNA, partial
mRNA



cds




145. Influenza A virus
2,280 bp
AF225515.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462100


polymerase basic 2 (PB2) MRNA,
mRNA



complete cds




146. Influenza A virus
2,274 bp
AF225519.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462108


polymerase basic 1 (PB1) mRNA,
mRNA



complete cds




147. Influenza A virus
2,151 bp
AF225523.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462116


polymerase acidic (PA) mRNA,
mRNA



complete cds




148. Influenza A virus
1,497 bp
AF225535.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462148


nucleoprotein (NP) mRNA, complete
mRNA



cds




149. Influenza A virus
1,410 bp
AF225539.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462156


neuraminidase (NA) mRNA, complete
mRNA



cds




150. Influenza A virus
984 bp
AF225543.1


(A/sw/Shizuoka/115/97 (H3N2) )
linear
GI:27462164


hemagglutinin (HA1) MRNA, partial
mRNA



cds




151. Influenza A virus
2,280 bp
AF225516.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462102


polymerase basic 2 (PB2) MRNA,
mRNA



complete cds




152. Influenza A virus
2,274 bp
AF225520.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462110


polymerase basic 1 (PB1) mRNA,
mRNA



complete cds




153. Influenza A virus
2,151 bp
AF225524.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462118


polymerase acidic (PA) mRNA,
mRNA



complete cds




154. Influenza A virus
1,497 bp
AF225536.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462150


nucleoprotein (NP) mRNA, complete
mRNA



cds




155. Influenza A virus
1,410 bp
AF225540.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462158


neuraminidase (NA) mRNA, complete
mRNA



cds




156. Influenza A virus
984 bp
AF225544.1


(A/sw/Shizuoka/119/97 (H3N2) )
linear
GI:27462166


hemagglutinin (HA1) mRNA, partial
mRNA



cds




159. Influenza A virus
1,410 bp
EU163948.1


(A/swine/Bakum/IDT1769/2003 (H3N2) )
linear
GI:157679552


neuraminidase mRNA, complete cds
mRNA



163. Influenza A virus
1,738 bp
AY857957.1


(A/swine/Fujian/668/01 (H3N2) )
linear
GI:58042507


nonfunctional hemagglutinin mRNA,
mRNA



complete sequence




164. Influenza A virus PB2 gene for
2,280 bp
AJ311459.1


Polymerase 2 protein, genomic RNA,
linear
GI:13661041


strain A/Swine/Italy/1523/98
mRNA



165. Influenza A virus PB1 gene for
2,274 bp
AJ311460.1


Polymerase 1 protein, genomic RNA,
linear
GI:13661043


strain A/Swine/Italy/1523/98
mRNA



166. Influenza A virus
821 bp
AJ344024.1


(A/swine/Italy/1523/98 (H3N2) ) NS1
linear
GI:20068146


gene for non structural protein 1
mRNA



and NS2 gene for non structural




protein 2, genomic RNA




167. Influenza A virus
1,465 bp
EU163949.1


(A/swine/Re220/92hp (H3N2) )
linear
GI:157679554


neuraminidase mRNA, complete cds
mRNA



168. Influenza A virus
2,280 bp
AF225517.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462104


polymerase basic 2 (PB2) mRNA,
mRNA



complete cds




169. Influenza A virus
2,274 bp
AF225521.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462112


polymerase basic 1 (PB1) MRNA,
mRNA



complete cds




170. Influenza A virus
2,151 bp
AF225525.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462120


polymerase acidic (PA) MRNA,
mRNA



complete cds




171. Influenza A virus
1,497 bp
AF225537.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462152


nucleoprotein (NP) mRNA, complete
mRNA



cds




172. Influenza A virus
1,410 bp
AF225541.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462160


neuraminidase (NA) mRNA, complete
mRNA



cds




173. Influenza A virus
984 bp
AF225545.1


(A/sw/Shizuoka/120/97 (H3N2) )
linear
GI:27462168


hemagglutinin (HA1) MRNA, partial
mRNA



cds




174. Influenza A virus
1,762 bp
AY032978.1


(A/Switzerland/7729/98 (H3N2) )
linear
GI:14161723


hemagglutinin mRNA, complete cds
mRNA



175. Influenza A virus
1,762 bp
AF382318.1


(A/Switzerland/7729/98 (H3N2) )
linear
GI:14487955


hemagglutinin mRNA, complete cds
mRNA



176. Influenza A virus
528 bp
AY962011.1


(A/Tainan/704/03 (H3N2) )
linear
GI:68138179


hemagglutinin (HA) mRNA, partial cds
mRNA



177. Influenza A virus
384 bp
AY973333.1


(A/Tainan/704/03(H3N2) )
linear
GI:70673222


neuraminidase (NA) mRNA, partial cds
mRNA



178. Influenza A virus
882 bp
AY986993.1


(A/Tainan/704/03 (H3N2) )
linear
GI:70728113


nucleoprotein (NP) mRNA, partial cds
mRNA



179. Influenza A virus
519 bp
AY962012.1


(A/Tainan/712/03 (H3N2) )
linear
GI:68138181


hemagglutinin (HA) MRNA, partial cds
mRNA



180. Influenza A virus
383 bp
AY973334.1


(A/Tainan/712/03 (H3N2) )
linear
GI:70673224


neuraminidase (NA) mRNA, partial cds
mRNA



181. Influenza A virus
882 bp
AY986994.1


(A/Tainan/712/03 (H3N2) )
linear
GI:70728115


nucleoprotein (NP) mRNA, partial cds
mRNA



182. Influenza A virus
784 bp
AY962005.1


(A/Tainan/722/03 (H3N2) )
linear
GI:68138167


hemagglutinin (HA) MRNA, partial cds
mRNA



183. Influenza A virus
592 bp
AY973335.1


(A/Tainan/722/03 (H3N2) )
linear
GI:70673226


neuraminidase (NA) mRNA, partial cds
mRNA



184. Influenza A virus
936 bp
AY986995.1


(A/Tainan/722/03 (H3N2) )
linear
GI:70728117


nucleoprotein (NP) MRNA, partial cds
mRNA



185. Influenza A virus
788 bp
AY961998.1


(A/Taipei/407/03 (H3N2) )
linear
GI:68138153


hemagglutinin (HA) mRNA, partial cds
mRNA



186. Influenza A virus
787 bp
AY973336.1


(A/Taipei/407/03 (H3N2) )
linear
GI:70673228


neuraminidase (NA) mRNA, partial cds
mRNA



187. Influenza A virus
882 bp
AY986996.1


(A/Taipei/407/03 (H3N2) )
linear
GI:70728119


nucleoprotein (NP) mRNA, partial cds
mRNA



188. Influenza A virus
787 bp
AY962007.1


(A/Taipei/416/03 (H3N2) )
linear
GI:68138171


hemagglutinin (HA) mRNA, partial cds
mRNA



189. Influenza A virus
782 bp
AY973337.1


(A/Taipei/416/03 (H3N2) )
linear
GI:70673230


neuraminidase (NA) mRNA, partial cds
mRNA



190. Influenza A virus
882 bp
AY986997.1


(A/Taipei/416/03 (H3N2) )
linear
GI:70728121


nucleoprotein (NP) MRNA, partial cds
mRNA



191. Influenza A virus
297 bp
AY303703.1


(A/Taiwan/0020/98 (H3N2) ) polymerase
linear



basic protein 1 (PB1) mRNA, partial cds
mRNA
GI:32330895


192. Influenza A virus
791 bp
AY604817.1


(A/Taiwan/0040/2003(H3N2) )
linear
GI:50727514


hemagglutinin mRNA, partial cds
mRNA



193. Influenza A virus
297 bp
AY303705.1


(A/Taiwan/0045/98 (H3N2) ) polymerase
linear
GI:32330899


basic protein 1 (PB1) mRNA, partial cds
mRNA



194. Influenza A virus
844 bp
AF362820.1


(A/human/Taiwan/0095/96 (H3N2) )
linear
GI:15055140


hemagglutinin (HA) mRNA, partial cds
mRNA



195. Influenza A virus
791 bp
AY604828.1


(A/Taiwan/0097/2003(H3N2) )
linear
GI:50727536


hemagglutinin mRNA, partial cds
mRNA



196. Influenza A virus
297 bp
AY303706.1


(A/Taiwan/0104/2001 (H3N2) )
linear
GI:32330901


polymerase basic protein 1 (PB1)
mRNA



mRNA, partial cds




197. Influenza A virus
844 bp
AF362805.1


(A/human/Taiwan/0118/98 (H3N2) )
linear
GI:15055110


hemagglutinin (HA) mRNA, partial cds
mRNA



198. Influenza A virus
791 bp
AY604823.1


(A/Taiwan/0122/2003(H3N2) )
linear
GI:50727526


hemagglutinin mRNA, partial cds
mRNA



199. Influenza A virus
844 bp
AF362806.1


(A/human/Taiwan/0149/00 (H3N2) )
linear
GI:15055112


hemagglutinin (HA) mRNA, partial cds
mRNA



200. Influenza A virus
297 bp
AY303712.1


(A/Taiwan/0275/2000 (H3N2) )
linear
GI:32330913


polymerase basic protein 1 (PB1)
mRNA



mRNA, partial cds




201. Influenza A virus
844 bp
AY303713.1


(A/Taiwan/0275/2000 (H3N2) )
linear
GI:32330915


hemagglutinin (HA) mRNA, partial cds
mRNA



202. Influenza A virus
844 bp
AF362807.1


(A/human/Taiwan/0293/98 (H3N2) )
linear
GI:15055114


hemagglutinin (HA) mRNA, partial cds
mRNA



203. Influenza A virus
297 bp
AY303715.1


(A/Taiwan/0346/98 (H3N2) ) polymerase
linear
GI:32330919


basic protein 1 (PB1) mRNA, partial
mRNA



cds




204. Influenza A virus
297 bp
AY303716.1


(A/Taiwan/0379/2000 (H3N2) )
linear
GI:32330921


polymerase basic protein 1 (PB1)
mRNA



mRNA, partial cds




205. Influenza A virus
844 bp
AY303717.1


(A/Taiwan/0379/2000 (H3N2) )
linear
GI:32330923


hemagglutinin (HA) mRNA, partial cds
mRNA



206. Influenza A virus
791 bp
AY625729.1


(A/Taiwan/0388/2001 (H3N2) )
linear
GI:50604415


hemagglutinin (HA) mRNA, partial cds
mRNA



207, Influenza A virus
844 bp
AF362808.1


(A/human/Taiwan/0389/99 (H3N2) )
linear
GI:15055116


hemagglutinin (HA) mRNA, partial cds
mRNA



208. Influenza A virus
844 bp
AF362809.1


(A/human/Taiwan/0423/98 (H3N2) )
linear
GI:15055118


hemagglutinin (HA) mRNA, partial cds
mRNA



209. Influenza A virus
297 bp
AY303718.1


(A/Taiwan/0423/98 (H3N2) ) polymerase
linear
GI:32330925


basic protein 1 (PB1) mRNA, partial
mRNA



cds




210. Influenza A virus
844 bp
AF362810.1


(A/human/Taiwan/0464/98 (H3N2) )
linear
GI:15055120


hemagglutinin (HA) mRNA, partial cds
mRNA



211. Influenza A virus
297 bp
AY303719.1


(A/Taiwan/0464/98 (H3N2) ) polymerase
linear
GI:32330927


basic protein 1 (PB1) mRNA, partial
mRNA



cds




212. Influenza A virus
791 bp
AY625730.1


(A/Taiwan/0568/2001 (H3N2) )
linear
GI:50604440


hemagglutinin (HA) MRNA, partial cds
mRNA



213. Influenza A virus
791 bp
AY604822.1


(A/Taiwan/0570/2003 (H3N2) )
linear
GI:50727524


hemagglutinin mRNA, partial cds
mRNA



214. Influenza A virus
791 bp
AY604827.1


(A/Taiwan/0572/2003 (H3N2) )
linear
GI:50727534


hemagglutinin mRNA, partial cds
mRNA



215. Influenza A virus
791 bp
AY604821.1


(A/Taiwan/0578/2003 (H3N2) )
linear
GI:50727522


hemagglutinin mRNA, partial cds
mRNA



216. Influenza A virus
791 bp
AY604820.1


(A/Taiwan/0583/2003(H3N2) )
linear
GI:50727520


hemagglutinin mRNA, partial cds
mRNA



217. Influenza A virus
297 bp
AY303722.1


(A/Taiwan/0646/2000 (H3N2) )
linear
GI:32330933


polymerase basic protein 1 (PB1)
mRNA



mRNA, partial cds




218. Influenza A virus
844 bp
AY303723.1


(A/Taiwan/0646/2000 (H3N2) )
linear
GI:32330935


hemagglutinin (HA) MRNA, partial cds
mRNA



219. Influenza A virus
844 bp
AF362811.1


(A/human/Taiwan/0830/99 (H3N2) )
linear
GI:15055122


hemagglutinin (HA) mRNA, partial cds
mRNA



220. Influenza A virus
791 bp
AY625731.1


(A/Taiwan/0964/2001 (H3N2) )
linear
GI:50604469


hemagglutinin (HA) MRNA, partial cds
mRNA



221. Influenza A virus
844 bp
AF362812.1


(A/human/Taiwan/1008/99 (H3N2) )
linear
GI:15055124


hemagglutinin (HA) mRNA, partial cds
mRNA



222. Influenza A virus
297 bp
AY303725.1


(A/Taiwan/1008/99 (H3N2) ) polymerase
linear
GI:32330939


basic protein 1 (PB1) mRNA, partial
mRNA



cds




223. Influenza A virus
750 bp
EU068138.1


(A/Taiwan/1219/2004 (H3N2) )
linear
GI:158452149


hemagglutinin (HA) MRNA, partial cds
mRNA



224. Influenza A virus
750 bp
EU068125.1


(A/Taiwan/1315/2005 (H3N2) )
linear
GI:158452123


hemagglutinin (HA) mRNA, partial cds
mRNA



225. Influenza A virus
750 bp
EU068153.1


(A/Taiwan/1511/2004 (H3N2) )
linear
GI:158452179


hemagglutinin (HA) mRNA, partial cds
mRNA



226. Influenza A virus
750 bp
EU068119.1


(A/Taiwan/1533/2003(H3N2) )
linear
GI:158452111


hemagglutinin (HA) mRNA, partial cds
mRNA



227. Influenza A virus
844 bp
AF362813.1


(A/human/Taiwan/1537/99 (H3N2) )
linear
GI:15055126


hemagglutinin (HA) MRNA, partial cds
mRNA



228. Influenza A virus
297 bp
AY303728.1


(A/Taiwan/1537/99 (H3N2) ) polymerase
linear
GI:32330945


basic protein 1 (PB1) mRNA, partial
mRNA



cds




229. Influenza A virus
791 bp
AY604826.1


(A/Taiwan/1566/2003 (H3N2) )
linear
GI:50727532


hemagglutinin mRNA, partial cds
mRNA



230. Influenza A virus
791 bp
AY604819.1


(A/Taiwan/1568/2003 (H3N2) )
linear
GI:50727518


hemagglutinin mRNA, partial cds
mRNA



231. Influenza A virus
750 bp
EU068116.1


(A/Taiwan/158/2003 (H3N2) )
linear
GI:158452105


hemagglutinin (HA) mRNA, partial cds
mRNA



232. Influenza A virus
875 bp
AF138709.2


(A/Taiwan/1600/96 (H3N2) ) matrix
linear
GI:4996869


protein M1 (M) mRNA, partial cds
mRNA



233. Influenza A virus
750 bp
EU068117.1


(A/Taiwan/1613/2003 (H3N2) )
linear
GI:158452107


hemagglutinin (HA) MRNA, partial cds
mRNA



234. Influenza A virus
750 bp
EU068148.1


(A/Taiwan/1651/2004 (H3N2) )
linear
GI:158452169


hemagglutinin (HA) mRNA, partial cds
mRNA



235. Influenza A virus
844 bp
AF362814.1


(A/human/Taiwan/1748/97 (H3N2) )
linear
GI:15055128


hemagglutinin (HA) MRNA, partial cds
mRNA



236. Influenza A virus
297 bp
AY303729.1


(A/Taiwan/1748/97 (H3N2) ) polymerase
linear
GI:32330947


basic protein 1 (PB1) mRNA, partial
mRNA



cds




237. Influenza A virus
872 bp
AF138707.2


(A/Taiwan/179/96 (H3N2) ) matrix
linear
GI:4996865


protein M1 (M) mRNA, partial cds
mRNA



238. Influenza A virus
750 bp
EU068139.1


(A/Taiwan/1817/2004 (H3N2) )
linear
GI:158452151


hemaqqlutinin (HA) MRNA, partial cds
mRNA



239. Influenza A virus
750 bp
EU068154.1


(A/Taiwan/1904/2003 (H3N2) )
linear
GI:158452181


hemagglutinin (HA) mRNA, partial cds
mRNA



240. Influenza A virus
750 bp
EU068155.1


(A/Taiwan/1921/2003(H3N2) )
linear
GI:158452183


hemagglutinin (HA) MRNA, partial cds
mRNA



241. Influenza A virus
844 bp
AF362815.1


(A/human/Taiwan/1986/96 (H3N2) )
linear
GI:15055130


hemagglutinin (HA) mRNA, partial cds
mRNA



242. Influenza A virus
297 bp
AY303730.1


(A/Taiwan/1990/96 (H3N2) ) polymerase
linear
GI:32330949


basic protein 1 (PB1) mRNA, partial
mRNA



cds




243. Influenza A virus
844 bp
AY303731.1


(A/Taiwan/1990/96 (H3N2) )
linear
GI:32330951


hemagglutinin (HA) MRNA, partial cds
mRNA



244. Influenza A virus
861 bp
AF139938.1


(A/Taiwan/20/98 (H3N2) ) H3
linear
GI:4972940


hemagglutinin (HA) mRNA, partial cds
mRNA



245. Influenza A virus
392 bp
AF140627.1


(A/Taiwan/20/98 (H3N2) ) N2
linear
GI:4972988


neuraminidase (NA) MRNA, partial cds
mRNA



246. Influenza A virus
875 bp
AF138715.2


(A/Taiwan/20/98 (H3N2) ) matrix
linear
GI:4996879


protein M1 (M) mRNA, partial cds
mRNA



247. Influenza A virus
844 bp
AF362816.1


(A/human/Taiwan/2031/97 (H3N2) )
linear
GI:15055132


hemagglutinin (HA) mRNA, partial cds
mRNA



248. Influenza A virus
861 bp
AF139937.1


(A/Taiwan/2034/96 (H3N2) ) H3
linear
GI:4972938


hemagglutinin (HA) MRNA, partial cds
mRNA



249. Influenza A virus
392 bp
AF140620.1


(A/Taiwan/2034/96 (H3N2) ) N2
linear
GI:4972974


neuraminidase (NA) mRNA, partial cds
mRNA



250. Influenza A virus
297 bp
AY303732.1


(A/Taiwan/2034/96 (H3N2) ) polymerase
linear
GI:32330953


basic protein 1 (PB1) mRNA, partial
mRNA



cds




251. Influenza A virus
791 bp
AY604818.1


(A/Taiwan/2040/2003(H3N2) )
linear
GI:50727516


hemagglutinin mRNA, partial cds
mRNA



252. Influenza A virus
750 bp
EU068131.1


(A/Taiwan/2072/2006(H3N2) )
linear
GI:158452135


hemagglutinin (HA) mRNA, partial cds
mRNA



253. Influenza A virus
861 bp
AF139934.1


(A/Taiwan/21/98 (H3N2) ) H3
linear
GI:4972932


hemagglutinin (HA) mRNA, partial cds
mRNA



254. Influenza A virus
392 bp
AF140624.1


(A/Taiwan/21/98 (H3N2) ) N2
linear
GI:4972982


neuraminidase (NA) MRNA, partial cds
mRNA



255. Influenza A virus
875 bp
AF138716.2


(A/Taiwan/21/98 (H3N2) ) matrix
linear
GI:4996881


protein M1 (M) mRNA, partial cds
mRNA



256. Influenza A virus
861 bp
AF139932.1


(A/Taiwan/2191/96(H3N2) ) H3
linear
GI:4972928


hemagglutinin (HA) MRNA, partial cds
mRNA



257. Influenza A virus
392 bp
AF140622.1


(A/Taiwan/2191/96 (H3N2) ) N2
linear
GI:4972978


neuraminidase (NA) mRNA, partial cds
mRNA



258. Influenza A virus
875 bp
AF138711.3


(A/Taiwan/2191/96 (H3N2) ) matrix
linear
GI:156147502


protein MI (M) MRNA, partial cds
mRNA



259. Influenza A virus
861 bp
AF139936.1


(A/Taiwan/2192/96 (H3N2) ) H3
linear
GI:4972936


hemagglutinin (HA) MRNA, partial cds
mRNA



260. Influenza A virus
392 bp
AF140626.1


(A/Taiwan/2192/96 (H3N2) ) N2
linear
GI:4972986


neuraminidase (NA) mRNA, partial cds
mRNA



261. Influenza A virus
297 bp
AY303735.1


(A/Taiwan/2195/96 (H3N2) ) polymerase
linear
GI:32330959


basic protein 1 (PB1) mRNA, partial
mRNA



cds




262. Influenza A virus
844 bp
AY303736.1


(A/Taiwan/2195/96 (H3N2) )
linear
GI:32330961


hemagglutinin (HA) mRNA, partial cds
mRNA



263. Influenza A virus
875 bp
AF138718.2


(A/Taiwan/224/98 (H3N2) ) matrix
linear
GI:4996885


protein Ml (M) mRNA, partial cds
mRNA



264. Influenza A virus
844 bp
AF362817.1


(A/human/Taiwan/2548/99 (H3N2) )
linear
GI:15055134


hemagglutinin (HA) MRNA, partial cds
mRNA



265. Influenza A virus
750 bp
EU068120.1


(A/Taiwan/268/2005 (H3N2) )
linear
GI:158452113


hemagglutinin (HA) mRNA, partial cds
mRNA



266. Influenza A virus
750 bp
EU068149.1


(A/Taiwan/3008/2004 (H3N2) )
linear
GI:158452171


hemagglutinin (HA) mRNA, partial cds
mRNA



267. Influenza A virus
750 bp
EU068152.1


(A/Taiwan/3075/2003 (H3N2) )
linear
GI:158452177


hemagglutinin (HA) mRNA, partial cds
mRNA



268. Influenza A virus
940 bp
AF362818.1


(A/human/Taiwan/3083/00 (H3N2) )
linear
GI:15055136


hemagglutinin (HA) mRNA, partial cds
mRNA



269. Influenza A virus
791 bp
AY604811.1


(A/Taiwan/3131/2002 (H3N2) )
linear
GI:50727502


hemagglutinin mRNA, partial cds
mRNA



270. Influenza A virus
750 bp
EU068145.1


(A/Taiwan/3154/2004 (H3N2) )
linear
GI:158452163


hemagglutinin (HA) mRNA, partial cds
mRNA



271. Influenza A virus
750 bp
EU068141.1


(A/Taiwan/3187/2004 (H3N2) )
linear
GI:158452155


hemagglutinin (HA) MRNA, partial cds
mRNA



272. Influenza A virus
750 bp
EU068134.1


(A/Taiwan/3245/2004 (H3N2) )
linear
GI:158452141


hemagglutinin (HA) mRNA, partial cds
mRNA



273. Influenza A virus
750 bp
EU068133.1


(A/Taiwan/3294/2005 (H3N2) )
linear
GI:158452139


hemagglutinin (HA) mRNA, partial cds
mRNA



274. Influenza A virus
861 bp
AF139935.1


(A/Taiwan/3351/97(H3N2) ) H3
linear
GI:4972934


hemagglutinin (HA) mRNA, partial cds
mRNA



275. Influenza A virus
392 bp
AF140625.1


(A/Taiwan/3351/97 (H3N2) ) N2
linear
GI:4972984


neuraminidase (NA) mRNA, partial cds
mRNA



276. Influenza A virus
875 bp
AF138713.2


(A/Taiwan/3351/97 (H3N2) ) matrix
linear
GI:4996875


protein M1 (M) MRNA, partial cds
mRNA



277. Influenza A virus
297 bp
AY303738.1


(A/Taiwan/3351/97 (H3N2) ) polymerase
linear
GI:32330965


basic protein 1 (PB1) mRNA, partial
mRNA



cds




278. Influenza A virus
750 bp
EU068132.1


(A/Taiwan/3387/2005 (H3N2) )
linear
GI:158452137


hemagglutinin (HA) mRNA, partial cds
mRNA



279. Influenza A virus
297 bp
AY303742.1


(A/Taiwan/3396/97 (H3N2) ) polymerase
linear
GI:32330973


basic protein 1 (PB1) mRNA, partial
mRNA



cds




280. Influenza A virus
844 bp
AY303743.1


(A/Taiwan/3396/97 (H3N2) )
linear
GI:32330975


hemagglutinin (HA) mRNA, partial cds
mRNA



281. Influenza A virus
861 bp
AF139930.1


(A/Taiwan/3427/97 (H3N2) ) H3
linear
GI:4972924


hemagglutinin (HA) MRNA, partial cds
mRNA



282. Influenza A virus
392 bp
AF140619.1


(A/Taiwan/3427/97 (H3N2) ) N2
linear
GI:4972972


neuraminidase (NA) MRNA, partial cds
mRNA



283. Influenza A virus
861 bp
AF139940.1


(A/Taiwan/346/98 (H3N2) ) H3
linear
GI:4972944


hemagglutinin (HA) mRNA partial cds
mRNA



284. Influenza A virus
392 bp
AF140787.1


(A/Taiwan/346/98 (H3N2) ) N2
linear
GI:4972992


neuraminidase (NA) mRNA, partial cds
mRNA



285. Influenza A virus
875 bp
AF138719.2


(A/Taiwan/346/98 (H3N2) ) matrix
linear
GI:4996887


protein Ml (M) mRNA, partial cds
mRNA



286. Influenza A virus
942 bp
AF362819.1


(A/human/Taiwan/3460/00 (H3N2) )
linear
GI:15055138


truncated hemagglutinin (HA) mRNA,
mRNA



partial cds




287. Influenza A virus
861 bp
AF139933.1


(A/Taiwan/3469/97 (H3N2) ) H3
linear
GI:4972930


hemagglutinin (HA) mRNA, partial cds
mRNA



288. Influenza A virus
392 bp
AF140623.1


(A/Taiwan/3469/97 (H3N2) ) N2
linear
GI:4972980


neuraminidase (NA) mRNA, partial cds
mRNA



289. Influenza A virus
875 bp
AF138714.2


(A/Taiwan/3469/97 (H3N2) ) matrix
linear
GI:4996877


protein M1 (M) mRNA, partial cds
mRNA



290. Influenza A virus
297 bp
AY303744.1


(A/Taiwan/3503/97 (H3N2) ) polymerase
linear
GI:32330977


basic protein 1 (PB1) mRNA, partial
mRNA



cds




291. Influenza A virus
844 bp
AY303745.1


(A/Taiwan/3503/97 (H3N2) )
linear
GI:32330979


hemagglutinin (HA) mRNA, partial cds
mRNA



292. Influenza A virus
919 bp
AF138712.1


(A/Taiwan/3513/96 (H3N2) ) matrix
linear
GI:4928900


protein M1 (M) mRNA, partial cds
mRNA



293. Influenza A virus
861 bp
AF139931.1


(A/Taiwan/3513/97 (H3N2) ) H3
linear
GI:4972926


hemagglutinin (HA) MRNA, partial cds
mRNA



294. Influenza A virus
392 bp
AF140621.1


(A/Taiwan/3513/97 (H3N2) ) N2
linear
GI:4972976


neuraminidase (NA) mRNA, partial cds
mRNA



295. Influenza A virus
791 bp
AY604814.1


(A/Taiwan/3744/2002 (H3N2) )
linear
GI:50727508


hemagglutinin mRNA, partial cds
mRNA



296. Influenza A virus
940 bp
AF362804.1


(A/human/Taiwan/3760/00 (H3N2) )
linear
GI:15055108


hemagglutinin (HA) mRNA, partial cds
mRNA



297. Influenza A virus
561 bp
AY303747.1


(A/Taiwan/3896/2001 (H1N1) )
linear
GI:32330983


hemagglutinin (HA) MRNA, partial cds
mRNA



298. Influenza A virus
791 bp
AY604825.1


(A/Taiwan/4050/2003(H3N2) )
linear
GI:50727530


hemagglutinin mRNA, partial cds
mRNA



299. Influenza A virus
791 bp
AY604824.1


(A/Taiwan/4063/2003 (H3N2) )
linear
GI:50727528


hemagglutinin mRNA, partial cds
mRNA



300. Influenza A virus
750 bp
EU068137.1


(A/Taiwan/41/2004 (H3N2) )
linear
GI:158452147


hemagglutinin (HA) MRNA, partial cds
mRNA



301. Influenza A virus
861 bp
AF139939.1


(A/Taiwan/45/98 (H3N2) ) H3
linear
GI:4972942


hemagglutinin (HA) mRNA, partial cds
mRNA



302. Influenza A virus
392 bp
AF140628.1


(A/Taiwan/45/98 (H3N2) ) N2
linear
GI:4972990


neuraminidase (NA) mRNA, partial cds
mRNA



303. Influenza A virus
875 bp
AF138717.2


(A/Taiwan/45/98 (H3N2) ) matrix
linear
GI:4996883


protein Ml (M) mRNA, partial cds
mRNA



304. Influenza A virus
750 bp
EU068114.1


(A/Taiwan/4548/2003 (H3N2) )
linear
GI:158452101


hemagglutinin (HA) mRNA, partial cds
mRNA



305. Influenza A virus
791 bp
AY604813.1


(A/Taiwan/4673/2002 (H3N2) )
linear
GI:50727506


hemagglutinin mRNA, partial cds
mRNA



306. Influenza A virus
791 bp
AY604812.1


(A/Taiwan/4680/2002(H3N2) )
linear
GI:50727504


hemagglutinin mRNA, partial cds
mRNA



307. Influenza A virus
750 bp
EU068136.1


(A/Taiwan/4735/2004 (H3N2) )
linear
GI:158452145


hemagglutinin (HA) MRNA, partial cds
mRNA



308. Influenza A virus
750 bp
EU068142.1


(A/Taiwan/4829/2005 (H3N2) )
linear
GI:158452157


hemagglutinin (HA) mRNA, partial cds
mRNA



309. Influenza A virus
750 bp
EU068130.1


(A/Taiwan/4836/2005 (H3N2) )
linear
GI:158452133


hemagglutinin (HA) mRNA, partial cds
mRNA



310. Influenza A virus
750 bp
EU068143.1


(A/Taiwan/4865/2005(H3N2) )
linear
GI:158452159


hemagglutinin (HA) mRNA, partial cds
mRNA



311. Influenza A virus
750 bp
EU068121.1


(A/Taiwan/4883/2005 (H3N2) )
linear
GI:158452115


hemagglutinin (HA) mRNA, partial cds
mRNA



312. Influenza A virus
791 bp
AY604809.1


(A/Taiwan/4938/2002 (H3N2) )
linear
GI:50727498


hemagglutinin mRNA, partial cds
mRNA



313. Influenza A virus
791 bp
AY604815.1


(A/Taiwan/4954/2002 (H3N2) )
linear
GI:50727510


hemagglutinin mRNA, partial cds
mRNA



314. Influenza A virus
791 bp
AY604810.1


(A/Taiwan/4963/2002 (H3N2) )
linear
GI:50727500


hemagglutinin mRNA, partial cds
mRNA



315. Influenza A virus
750 bp
EU068122.1


(A/Taiwan/4987/2005 (H3N2) )
linear
GI:158452117


hemagglutinin (HA) mRNA, partial cds
mRNA



316. Influenza A virus
750 bp
EU068127.1


(A/Taiwan/4990/2005 (H3N2) )
linear
GI:158452127


hemagglutinin (HA) mRNA, partial cds
mRNA



317. Influenza A virus
750 bp
EU068118.1


(A/Taiwan/5/2003 (H3N2) )
linear
GI:158452109


hemagglutinin (HA) mRNA, partial cds
mRNA



318. Influenza A virus
791 bp
AY604816.1


(A/Taiwan/5153/2002 (H3N2) )
linear
GI:50727512


hemagglutinin mRNA, partial cds
MRNA



319. Influenza A virus
750 bp
EU068128.1


(A/Taiwan/5267/2005 (H3N2) )
linear
GI:158452129


hemagglutinin (HA) mRNA, partial cds
mRNA



320. Influenza A virus
750 bp
EU068146.1


(A/Taiwan/556/2004 (H3N2) )
linear
GI:158452165


hemagglutinin (HA) MRNA, partial cds
mRNA



321. Influenza A virus
750 bp
EU068126.1


(A/Taiwan/5694/2005(H3N2) )
linear
GI:158452125


hemagglutinin (HA) mRNA, partial cds
mRNA



322. Influenza A virus
750 bp
EU068147.1


(A/Taiwan/587/2004 (H3N2) )
linear
GI:158452167


hemagglutinin (HA) mRNA, partial cds
mRNA



323. Influenza A virus
750 bp
EU068151.1


(A/Taiwan/592/2004 (H3N2) )
linear
GI:158452175


hemagglutinin (HA) MRNA, partial cds
mRNA



324. Influenza A virus
791 bp
AY604829.1


(A/Taiwan/7099/2003 (H3N2) )
linear
GI:50727538


hemagglutinin mRNA, partial cds
mRNA



325. Influenza A virus
791 bp
AY604830.1


(A/Taiwan/7100/2003(H3N2) )
linear
GI:50727540


hemagglutinin mRNA, partial cds
mRNA



326. Influenza A virus
750 bp
EU068150.1


(A/Taiwan/7196/2003 (H3N2) )
linear
GI:158452173


hemagglutinin (HA) MRNA, partial cds
mRNA



327. Influenza A virus
750 bp
EU068135.1


(A/Taiwan/7568/2004 (H3N2) )
linear
GI:158452143


hemagglutinin (HA) mRNA, partial cds
mRNA



328. Influenza A virus
750 bp
EU068144.1


(A/Taiwan/7601/2005 (H3N2) )
linear



hemagglutinin (HA) mRNA, partial cds
mRNA
GI:158452161


329. Influenza A virus
750 bp
EU068124.1


(A/Taiwan/7681/2005(H3N2) )
linear
GI:158452121


hemagglutinin (HA) mRNA, partial cds
mRNA



330. Influenza A virus
750 bp
E0068123.1


(A/Taiwan/7702/2005 (H3N2) )
linear
GI:158452119


hemagglutinin (HA) mRNA, partial cds
mRNA



331. Influenza A virus (A/Taiwan/7873/2005 (H3N2) )
750 bp
EU068129.1


hemagglutinin (HA) mRNA, partial cds
linear
GI:158452131



mRNA



332. Influenza A virus
750 bp
EU068115.1


(A/Taiwan/8/2003 (H3N2) )
linear
GI:158452103


hemagglutinin (HA) mRNA, partial cds
mRNA



333. Influenza A virus
750 bp
EU068140.1


(A/Taiwan/93/2004 (H3N2) )
linear
GI:158452153


hemagglutinin (HA) mRNA, partial cds
mRNA



334. Influenza A virus
528 bp
AY962016.1


(A/Taoyuan/108/02 (H3N2) )
linear
GI:68138189


hemagglutinin (HA) mRNA partial cds
mRNA



335. Influenza A virus
754 bp
AY973338.1


(A/Taoyuan/108/02 (H3N2) )
linear
GI:70673232


neuraminidase (NA) mRNA, partial cds
mRNA



336. Influenza A virus
882 bp
AY986998.1


(A/Taoyuan/108/02 (H3N2) )
linear
GI:70728123


nucleoprotein (NP) mRNA, partial cds
mRNA



337. Influenza A virus
1,410 bp
EU021285.1


(A/Thailand/CU124/2006 (H3N2) )
linear
GI:154224724


neuraminidase (NA) MRNA, complete
mRNA



cds




338. Influenza A virus
1,701 bp
EU021284.1


(A/Thailand/CU124/2006 (H3N2) )
linear
GI:154224795


hemagglutinin (HA) MRNA, complete
mRNA



cds




339. Influenza A virus
1,410 bp
EU021275.1


(A/Thailand/CU228/2006 (H3N2) )
linear
GI:154224714


neuraminidase (NA) mRNA, complete
mRNA



cds




340. Influenza A virus
1,701 bp
EU021274.1


(A/Thailand/CU228/2006 (H3N2) )
linear
GI:154224785


hemagglutinin (HA) mRNA, complete
mRNA



cds




341. Influenza A virus
1,347 bp
EU021267.1


(A/Thailand/CU23/2006 (H3N2) )
linear
GI:154224706


neuraminidase (NA) MRNA, partial cds
mRNA



342. Influenza A virus
1,701 bp
EU021266.1


(A/Thailand/CU23/2006 (H3N2) )
linear
GI:154224777


hemagglutinin (HA) mRNA, complete
mRNA



cds




343. Influenza A virus
1,410 bp
E0021283.1


(A/Thailand/CU231/2006 (H3N2) )
linear
GI:154224722


neuraminidase (NA) MRNA, complete
mRNA



cds




344. Influenza A virus
1,701 bp
EU021282.1


(A/Thailand/CU231/2006 (H3N2) )
linear
GI:154224793


hemagglutinin (HA) mRNA, complete
mRNA



cas




345. Influenza A virus
1,410 bp
EU021279.1


(A/Thailand/CU259/2006 (H3N2) )
linear
GI:154224718


neuraminidase (NA) MRNA, complete
mRNA



cds




346. Influenza A virus
1,701 bp
EU021278.1


(A/Thailand/CU259/2006 (H3N2) )
linear
GI:154224789


hemagglutinin (HA) mRNA, complete
mRNA



cds




347. Influenza A virus
1, 410 bp
EU021281.1


(A/Thailand/CU260/2006 (H3N2) )
linear
GI:154224720


neuraminidase (NA) mRNA, complete
mRNA



cds




348. Influenza A virus
1,129 bp
EU021280.1


(A/Thailand/CU260/2006 (H3N2) )
linear
GI:154224791


hemagglutinin (HA) mRNA, partial cds
mRNA



349. Influenza A virus
1,410 bp
EU021271.1


(A/Thailand/CU272/2007 (H3N2) )
linear
GI:154224710


neuraminidase (NA) MRNA, complete
mRNA



cds




350. Influenza A virus
1,701 bp
EU021270.1


(A/Thailand/CU272/2007 (H3N2) )
linear
GI:154224781


hemagglutinin (HA) MRNA, complete
mRNA



cds




351. Influenza A virus
1,410 bp
EU021273.1


(A/Thailand/CU280/2007 (H3N2) )
linear
GI:154224712


neuraminidase (NA) mRNA, complete
mRNA



cds




352. Influenza A virus
1,701 bp
EU021272.1


(A/Thailand/CU280/2007 (H3N2) )
linear
GI:154224783


hemagglutinin (HA) mRNA, complete
mRNA



cds




353. Influenza A virus
1,410 bp
EU021277.1


(A/Thailand/CU282/2007 (H3N2) )
linear
GI:154224716


neuraminidase (NA) MRNA, complete
mRNA



cds




354. Influenza A virus
1,701 bp
EU021276.1


(A/Thailand/CU282/2007 (H3N2) )
linear
GI:154224787


hemagglutinin (HA) mRNA, complete
mRNA



cds




355. Influenza A virus
1,413 bp
EU021265.1


(A/Thailand/CU32/2006 (H1N1) )
linear
GI:154224704


neuraminidase (NA) mRNA, complete
mRNA



cds




361. Influenza A virus
1,410 bp
EU021269.1


(A/Thailand/CU46/2006 (H3N2} )
linear
GI:154224708


neuraminidase (NA) mRNA, complete
mRNA



cds




362. Influenza A virus
1,701 bp
EU021268.1


(A/Thailand/CU46/2006 (H3N2) )
linear
GI:154224779


hemagglutinin (HA) mRNA, complete
mRNA



cds




377. Influenza A virus
987 bp
U77837.1


(A/Tottori/849AM1AL3/1994 (H3N2) )
linear
GI:2992515


hemagglutinin (HA) mRNA, partial cds
mRNA



378. Influenza A virus
987 bp
U77833.1


(A/Tottori/849AM2/1994 (H3N2) )
linear
GI:2992507


hemagglutinin (HA) mRNA, partial cds
mRNA



379. Influenza A virus
987 bp
U77839.1


(A/Tottori/849AM2AL3/1994 (H3N2) )
linear
GI:2992519


hemagglutinin (HA) mRNA, partial cds
mRNA



380. Influenza A virus
987 bp
U77835.1


(A/Tottori/849AM4/1994 (H3N2) )
linear
GI:2992511


hemagglutinin (HA) MRNA, partial cds
mRNA



382. Influenza A virus
987 bp
U77834.1


(A/Tottori/872AM2/1994 (H3N2) )
linear
GI:2992509


hemagglutinin (HA) mRNA, partial cds
mRNA



383. Influenza A virus
987 bp
U77840.1


(A/Tottori/872AM2AL3/1994 (H3N2) )
linear
GI:2992521


hemagglutinin (HA) MRNA, partial cds
mRNA



384. Influenza A virus
987 bp
U77836.1


(A/Tottori/872AM4/1994 (H3N2) )
linear
GI:2992513


hemagglutinin (HA) MRNA, partial cds
mRNA



385. Influenza A virus
987 bp
U77832.1


(A/Tottori/872K4/1994 (H3N2) )
linear
GI:2992505


hemagglutinin (HA) mRNA, partial cds
mRNA



386. Influenza A virus (A/United
987 bp
AF501529.1


Kingdom/26554/99 (H3N2) )
linear
GI:21314314


hemagglutinin (HA) mRNA, partial cds
mRNA



387. Influenza A virus (A/United
987 bp
AF501527.1


Kingdom/34300/99 (H3N2) )
linear
GI:21314310


hemagglutinin (HA) mRNA, partial cds
mRNA



388. Influenza A virus
987 bp
AF501533.1


(A/Utah/20997/99 (H3N2) )
linear
GI:21314322


hemagglutinin (HA) mRNA, partial cds
mRNA



389. Influenza A virus
1,565 bp
AF072545.1


(A/Victoria/3/75) segment 5
linear
GI:4218933


nucleoprotein mRNA, complete cds
mRNA



390. Influenza A virus
1,762 bp
AF017270.2


(A/Vienna/47/96M (H3N2) )
linear
GI:14286338


hemagglutinin (HA) MRNA, complete
mRNA



cds




391. Influenza A virus
1,762 bp
AF017272.2


(A/Vienna/47/96V (H3N2) )
linear
GI:15004991


hemagglutinin (HA) mRNA, complete
mRNA



cds




392. Influenza A virus
1,069 bp
AF017271.1


(A/Vienna/81/96V (H3N2) )
linear
GI:2407251


hemagglutinin (HA) MRNA, partial cds
mRNA



393. Influenza A virus
987 bp
AF501532.1


(A/Virginia/21712/99 (H3N2) }
linear
GI:21314320


hemagglutinin (HA) mRNA, partial cds
mRNA



394. Influenza A virus
987 bp
AF501515.1


(A/Virginia/21716/99 (H3N2) )
linear
GI:21314286


hemagglutinin (HA) mRNA, partial cds
mRNA



395. Influenza A virus
987 bp
AF501530.1


(A/Virginia/21735/99 (H3N2) )
linear
GI:21314316


hemagglutinin (HA) mRNA, partial cds
mRNA



396. Influenza A virus
987 bp
AF501524.1


(A/Virginia/21743/99 (H3N2) )
linear
GI:21314304


hemagglutinin (HA) MRNA, partial cds
mRNA



397. Influenza A virus
987 bp
AF501519.1


(A/Virginia/21754/99 (H3N2) )
linear
GI:21314294


hemagglutinin (HA) mRNA, partial cds
mRNA



398. Influenza A virus
987 bp
AF501523.1


(A/Virginia/21799/99 (H3N2) )
linear
GI:21314302


hemagglutinin (HA) MRNA, partial cds
mRNA



399. Influenza A virus
987 bp
AF501525.1


(A/Virginia/21817/99 (H3N2) )
linear
GI:21314306


hemagglutinin (HA) mRNA, partial cds
mRNA



400. Influenza A virus
987 bp
AF501520.1


(A/Virginia/21822/99 (H3N2) )
linear
GI:21314296


hemagglutinin (HA) MRNA, partial cds
mRNA



401. Influenza A virus
987 bp
AF501528.1


(A/Virginia/21828/99 (H3N2) }
linear
GI:21314312


hemagglutinin (HA) mRNA, partial cds
mRNA



402. Influenza A virus
987 bp
AF501517.1


(A/Virginia/21833/99 (H3N2) )
linear
GI:21314290


hemagglutinin (HA) mRNA, partial cds
mRNA



403. Influenza A virus
987 bp
AF501522.1


(A/Virginia/21845/99 (H3N2) )
linear
GI:21314300


hemagglutinin (HA) MRNA, partial cds
mRNA



404. Influenza A virus
987 bp
AF501535.1


(A/Virginia/21847/99 (H3N2) )
linear
GI:21314326


hemagglutinin (HA) mRNA, partial cds
mRNA



405. Influenza A virus
987 bp
AF501521.1


(A/Virginia/G1/99 (H3N2) )
linear
GI:21314298


hemagglutinin (HA) mRNA, partial cds
mRNA



406. Influenza A virus
755 bp
AY973339.1


(A/Yilan/508/03 (H3N2) ) neuraminidase
linear
GI:70673234


(NA) mRNA, partial cds
mRNA



407. Influenza A virus
882 bp
AY986999.1


(A/Yilan/508/03 (H3N2) ) nucleoprotein
linear
GI:70728125


(NP) mRNA, partial cds
mRNA



408. Influenza A virus
740 bp
AY962015.1


(A/Yilan/513/03 (H3N2) ) hemagglutinin
linear
GI:68138187


(HA) mRNA, partial cds
mRNA



409. Influenza A virus
396 bp
AY973340.1


(A/Yilan/513/03 (H3N2) ) neuraminidase
linear
GI:70673236


(NA) mRNA, partial cds
mRNA



410. Influenza A virus
882 bp
AY987000.1


(A/Yilan/513/03 (H3N2) ) nucleoprotein
linear
GI:70728127


(NP) mRNA, partial cds
mRNA



411. Influenza A virus
511 bp
AY962010.1


(A/Yilan/515/03 (H3N2) ) hemagglutinin
linear
GI:68138177


(HA) MRNA, partial cds
mRNA



412. Influenza A virus
394 bp
AY973341.1


(A/Yilan/515/03 (H3N2) ) neuraminidase
linear
GI:70673238


(NA) mRNA, partial cds
mRNA



413. Influenza A virus
882 bp
AY987001.1


(A/Yilan/516/03 (H3N2) ) nucleoprotein
linear
GI:70728129


(NP) MRNA, partial cds
mRNA



414. Influenza A virus
530 bp
AY962006.1


(A/Yilan/518/03 (H3N2} ) hemagglutinin
linear
GI:68138169


(HA) mRNA, partial cds
mRNA



415. Influenza A virus
397 bp
AY973342.1


(A/Yilan/518/03 (H3N2) ) neuraminidase
linear
GI:70673240


(NA) mRNA, partial cds
mRNA



416. Influenza A virus
882 bp
AY987002.1


(A/Yilan/518/03 (H3N2) ) nucleoprotein
linear
GI:70728131


(NP) mRNA, partial cds
mRNA



417. Influenza A virus
777 bp
AY962002.1


(A/Yilan/538/04 (H3N2) ) hemagglutinin
linear
GI:68138161


(HA) mRNA, partial cds
mRNA



418. Influenza A virus
783 bp
AY973343.1


(A/Yilan/538/04 (H3N2) ) neuraminidase
linear
GI:70673242


(NA) mRNA, partial cds
mRNA



419. Influenza A virus
882 bp
AY987003.1


(A/Yilan/538/04 (H3N2) ) nucleoprotein
linear
GI:70728133


(NP) mRNA, partial cds
mRNA



420. Influenza A virus
788 bp
AY962003.1


(A/Yilan/549/04 (H3N2) ) hemagglutinin
linear
GI:68138163


(HA) mRNA, partial cds
mRNA



421. Influenza A virus
779 bp
AY973344.1


(A/Yilan/549/04 (H3N2) ) neuraminidase
linear
GI:70673244


(NA) mRNA, partial cds
mRNA



422. Influenza A virus
882 bp
AY987004.1


(A/Yilan/549/04 (H3N2) ) nucleoprotein
linear
GI:70728135


(NP) MRNA, partial cds
mRNA



423. Influenza A virus
776 bp
AY962013.1


(A/Yilan/557/04 (H3N2) ) hemagglutinin
linear
GI:68138183


(HA) mRNA, partial cds
mRNA



424. Influenza A virus
796 bp
AY973345.1


(A/Yilan/557/04 (H3N2) ) neuraminidase
linear
GI:70673246


(NA) mRNA, partial cds
mRNA



425. Influenza A virus
882 bp
AY987005.1


(A/Yilan/557/04 (H3N2) ) nucleoprotein
linear
GI:70728137


(NP) mRNA, partial cds
mRNA



426. Influenza A virus
753 bp
AY962014.1


(A/Yilan/566/04 (H3N2) ) hemagglutinin
linear
GI:68138185


(HA) MRNA, partial cds
mRNA



427. Influenza A virus
808 bp
AY973346.1


(A/Yilan/566/04 (H3N2) ) neuraminidase
linear
GI:70673248


(NA) mRNA, partial cds
mRNA



428. Influenza A virus
882 bp
AY987006.1


(A/Yilan/566/04 (H3N2) ) nucleoprotein
linear
GI:70728139


(NP) mRNA, partial cds
mRNA



429. Influenza A virus
987 bp
AY138513.1


(A/zhe jiang/06/99 (H3N2) )
linear
GI:24895131


hemagglutinin (HA) mRNA, partial cds
mRNA



430. Influenza A virus
987 bp
AY138515.1


(A/zhejiang/10/98 (H3N2) )
linear
GI:24895149


hemagglutinin (HA) MRNA, partial cds
mRNA



431. Influenza A virus
987 bp
AY138516.1


(A/zhejiang/11/2002 (H3N2) )
linear
GI:24895159


hemagglutinin (HA) mRNA, partial cds
mRNA



432. Influenza A virus
987 bp
AY138514.1


(A/zhejiang/12/99 (H3N2) )
linear
GI:24895141


hemagglutinin-like (HA) mRNA,
mRNA



partial sequence




433. Influenza A virus
987 bp
AY138519.1


(A/zhejiang/8/2002 (H3N2) )
linear
GI:24895188


hemagglutinin (HA) MRNA, partial cds
mRNA



434. Influenza A virus H3N2 strain
840 bp
U65670.1


A/Akita/1/94 nonstructural protein 1
linear
GI:3929405


and nonstructural protein 2 mRNAs,
mRNA



complete cds




435. Influenza A virus H3N2 strain
840 bp
U65671.1


A/Akita/1/95 nonstructural protein 1
linear
GI:3929408


and nonstructural protein 2 mRNAS,
mRNA



complete cds




436. Influenza A virus H3N2 strain
840 bp
U65673.1


A/Shiga/20/95 nonstructural protein
linear
GI:3929411


1 and nonstructural protein 2 mRNAs,
mRNA



complete cds




437. Influenza A virus H3N2 strain
840 bp
U65674.1


A/Miyagi/69/95 nonstructural protein
linear
GI:3929414


1 and nonstructural protein 2 mRNAs,
mRNA



complete cds




438. Influenza A virus H3N2 strain
840 bp
U65672.1


A/Hebei/19/95 nonstructural protein
linear
GI:6468319


1 and nonstructural protein 2 mRNAs,
mRNA



complete cds




A/Aichi/69/1994 (H3N2) haemagglutinin

U48446.1


A/Bangkok/1/1979 (H3N2)

AF201843.1


hemagglutinin (HA)




A/Beijing/353/89 (H3) hemagglutinin

U97740.1


(HA)




A/Beijing/353/1989 (H3N2)

Z46391.1


haemagglutinin




A/chicken/Singapore/2002 (H3N2) M2

EU014143.1


protein




A/Christ Hospital/231/82 (H3N2) )

U77830.1


hemagglutinin (HA)




A/duck/Eastern China/36/2002 (H3N2)

EU429701.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/160/2003 (H3N2)

EU429732.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/848/2003 (H3N2)

EU429721.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/770/2003 (H3N2)

EU429736.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/855/2003 (H3N2)

EU429737.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/875/2003 (H3N2)

EU429738.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/901/2003 (H3N2)

EU429739.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/866/2003 (H3N2)

EU429756.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/857/2003 (H3N2)

EU429761.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/852/2003 (H3N2)

EU429767.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/838/2003 (H3N2)

EU429720.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/6/2004 (H3N2)

EU429745.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/03/2005 (H3N2)

EU429781.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/02/2006 (H3N2)

EU429769.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/04/2006 (H3N2)

EU429770.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/21/2006 (H3N2)

EU429771.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/23/2006 (H3N2)

EU429772.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/31/2006 (H3N2)

EU429773.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/35/2006 (H3N2)

EU429768.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/42/2006 (H3N2)

EU429774.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/53/2006 (H3N2)

EU429775.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/60/2006 (H3N2)

EU429776.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/62/2006 (H3N2)

EU429784.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/63/2006 (H3N2)

EU429777.1


segment 6 neuraminidase (NA)




A/duck/Eastern China/142/2006 (H3N2)

EU429742.1


segment 6 neuraminidase (NA)




A/Dunedin/4/1973 (H3N2)

AF201842.1


hemagglutinin (HA)
















TABLE 8





Influenza H5N1 Antigens

















1. Influenza A virus
827 bp
AM503036.1


(A/chicken/Burkina
linear
GI: 147846308


Faso/01.03/2006(H5N1)) mRNA for non-
mRNA


structural protein (ns gene)


2. Influenza A virus
990 bp
AM503007.1


(A/chicken/Burkina
linear
GI: 147846250


Faso/13.1/2006(H5N1)) partial mRNA
mRNA


for matrix protein 1 (m1 gene)


3. Influenza A virus
1,529 bp
AM503029.1


(A/chicken/Burkina
linear
GI: 147846294


Faso/13.1/2006(H5N1)) mRNA for
mRNA


nucleoprotein (np gene)


4. Influenza A virus
827 bp
AM503037.1


(A/chicken/Burkina
linear
GI: 147846310


Faso/13.1/2006(H5N1)) mRNA for non-
mRNA


structural protein (ns gene)


5. Influenza A virus
2,169 bp
AM503046.1


(A/chicken/Burkina
linear
GI: 147846328


Faso/13.1/2006(H5N1)) partial mRNA
mRNA


for polymerase (pa gene)


6. Influenza A virus
2,259 bp
AM503056.1


(A/chicken/Burkina
linear
GI: 147846348


Faso/13.1/2006(H5N1)) partial mRNA
mRNA


for polymerase basic protein 1 (pb1


gene)


7. Influenza A virus
2,315 bp
AM503067.1


(A/chicken/Burkina
linear
GI: 147846859


Faso/13.1/2006(H5N1)) partial mRNA
mRNA


for polymerase basic protein 2 (pb2


gene)


8. Influenza A virus
1,736 bp
DQ023145.1


(A/chicken/China/1/02(H5N1))
linear
GI: 66775624


hemagglutinin (HA) mRNA, complete cds
mRNA


9. Influenza A virus
1,509 bp
DQ023146.1


(A/chicken/China/1/02(H5N1))
linear
GI: 66775626


nucleoprotein (NP) mRNA, complete cds
mRNA


10. Influenza A virus
1,379 bp
DQ023147.1


(A/chicken/China/1/02(H5N1))
linear
GI: 66775628


neuraminidase (NA) mRNA, complete cds
mRNA


11. Influenza A virus
999 bp
DQ650660.1


(A/chicken/Crimea/04/2005(H5N1))
linear
GI: 109692767


matrix protein (M) mRNA, complete cds
mRNA


12. Influenza A virus
850 bp
DQ650662.1


(A/chicken/Crimea/04/2005(H5N1))
linear
GI: 109692771


nonstructural protein (NS) mRNA,
mRNA


complete cds


13. Influenza A virus
994 bp
DQ650664.1


(A/chicken/Crimea/08/2005(H5N1))
linear
GI: 109692775


matrix protein (M) mRNA, complete cds
mRNA


14. Influenza A virus
1,532 bp
DQ650666.1


(A/chicken/Crimea/08/2005(H5N1))
linear
GI: 109692779


nucleoprotein (NP) mRNA, complete cds
mRNA


15. Influenza A virus
850 bp
DQ650667.1


(A/chicken/Crimea/08/2005(H5N1))
linear
GI: 109692781


nonstructural protein (NS) mRNA,
mRNA


complete cds


16. Influenza A virus
2,208 bp
DQ650668.1


(A/chicken/Crimea/08/2005(H5N1))
linear
GI: 109692783


polymerase acidic protein (PA) mRNA,
mRNA


complete cds


17. Influenza A virus
2,305 bp
DQ650670.1


(A/chicken/Crimea/08/2005(H5N1))
linear
GI: 109692787


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


18. Influenza A virus
1,015 bp
DQ676838.1


(A/chicken/Dovolnoe/03/2005(H5N1))
linear
GI: 108782527


hemagglutinin (HA) mRNA, partial cds
mRNA


20. Influenza A virus
2,341 bp
DQ366327.1


(A/chicken/Guangxi/12/2004(H5N1))
linear
GI: 86753731


polymerase PB2 mRNA, complete cds
mRNA


21. Influenza A virus
2,341 bp
DQ366328.1


(A/chicken/Guangxi/12/2004(H5N1))
linear
GI: 86753741


polymerase PB1 mRNA, complete cds
mRNA


22. Influenza A virus
2,233 bp
DQ366329.1


(A/chicken/Guangxi/12/2004(H5N1)) PA
linear
GI: 86753751


protein mRNA, complete cds
mRNA


23. Influenza A virus
1,565 bp
DQ366331.1


(A/chicken/Guangxi/12/2004(H5N1))
linear
GI: 86753771


nucleocapsid mRNA, complete cds
mRNA


24. Influenza A virus
1,027 bp
DQ366333.1


(A/chicken/Guangxi/12/2004(H5N1))
linear
GI: 86753791


matrix protein mRNA, complete cds
mRNA


25. Influenza A virus (A/chicken/Hong
1,718 bp
AF057291.1


Kong/258/97(H5N1)) hemagglutinin
linear
GI: 3068720


mRNA, complete cds
mRNA


26. Influenza A virus (A/chicken/Hong
1,318 bp
AF057292.1


Kong/258/97(H5N1)) neuraminidase
linear
GI: 3068722


mRNA, partial cds
mRNA


27. Influenza A virus (A/chicken/Hong
1,508 bp
AF057293.1


Kong/258/97(H5N1)) nucleoprotein
linear
GI: 3068724


mRNA, complete cds
mRNA


28. Influenza A virus (A/Chicken/Hong
1,726 bp
AF082034.1


Kong/728/97(H5N1)) hemagglutinin H5
linear
GI: 4240435


mRNA, complete cds
mRNA


29. Influenza A virus (A/Chicken/Hong
1,726 bp
AF082035.1


Kong/786/97(H5N1)) hemagglutinin H5
linear
GI: 4240437


mRNA, complete cds
mRNA


30. Influenza A virus (A/chicken/Hong
1,726 bp
AF082036.1


Kong/915/97(H5N1)) hemagglutinin H5
linear
GI: 4240439


mRNA, complete cds
mRNA


31. Influenza A virus (A/chicken/Hong
1,091 bp
AF082037.1


Kong/990/97(H5N1)) hemagglutinin H5
linear
GI: 4240441


mRNA, partial cds
mRNA


32. Influenza A virus
1,002 bp
DQ676835.1


(A/chicken/Krasnodar/01/2006(H5N1))
linear
GI: 108782521


matrix protein 1 (M) mRNA, complete
mRNA


cds


33. Influenza A virus
850 bp
DQ676837.1


(A/chicken/Krasnodar/01/2006(H5N1))
linear
GI: 108782525


nonstructural protein (NS) mRNA,
mRNA


complete cds


34. Influenza A virus
1,754 bp
DQ449632.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289625


hemagglutinin (HA) mRNA, complete cds
mRNA


35. Influenza A virus
1,002 bp
DQ449633.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289627


matrix protein 1 (M) mRNA, complete
mRNA


cds


36. Influenza A virus
1,373 bp
DQ449634.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289629


neuraminidase (NA) mRNA, complete cds
mRNA


37. Influenza A virus
1,540 bp
DQ449635.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289631


nucleoprotein (NP) mRNA, complete cds
mRNA


38. Influenza A virus
850 bp
DQ449636.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289633


nonstructural protein (NS) mRNA,
mRNA


complete cds


39. Influenza A virus
2,208 bp
DQ449637.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289635


polymerase acidic protein (PA) mRNA,
mRNA


complete cds


40. Influenza A virus
2,316 bp
DQ449638.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289637


polymerase basic protein 1 (PB1)
mRNA


mRNA, complete cds


41. Influenza A virus
2,316 bp
DQ449639.1


(A/chicken/Kurgan/05/2005(H5N1))
linear
GI: 90289646


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


42. Influenza A virus
184 bp
EU447276.1


(A/chicken/Lobzenko/01/2008(H5N1))
linear
GI: 168998217


hemagglutinin (HA) mRNA, partial cds
mRNA


43. Influenza A virus
1,002 bp
DQ676831.1


(A/chicken/Mahachkala/05/2006(H5N1))
linear
GI: 108782513


matrix protein 1 (M) mRNA, complete
mRNA


cds


44. Influenza A virus
850 bp
DQ676833.1


(A/chicken/Mahachkala/05/2006(H5N1))
linear
GI: 108782517


nonstructural protein (NS) mRNA,
mRNA


complete cds


45. Influenza A virus
1,531 bp
AM503030.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846296


mRNA for nucleoprotein (np gene)
mRNA


46. Influenza A virus
827 bp
AM503040.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846316


mRNA for non-structural protein (ns
mRNA


gene)


47. Influenza A virus
2,169 bp
AM503051.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846338


partial mRNA for polymerase (pa gene)
mRNA


48. Influenza A virus
2,259 bp
AM503060.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846845


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


49. Influenza A virus
2,315 bp
AM503071.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846867


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


70. Influenza A virus (A/chicken/Hong
1,055 bp
DQ250158.1


Kong/3123.1/2002(H5N1)) neuraminidase
linear
GI: 82412012


(NA) mRNA, partial cds
mRNA


75. Influenza A virus
1,754 bp
DQ676834.1


(A/chicken/Krasnodar/01/2006(H5N1))
linear
GI: 108782519


hemagglutinin (HA) mRNA, complete cds
mRNA


78. Influenza A virus
1,373 bp
DQ676836.2


(A/chicken/Krasnodar/01/2006(H5N1))
linear
GI: 115520953


neuraminidase (NA) mRNA, complete cds
mRNA


91. Influenza A virus
184 bp
EU447276.1


(A/chicken/Lobzenko/01/2008(H5N1))
linear
GI: 168998217


hemagglutinin (HA) mRNA, partial cds
mRNA


92. Influenza A virus
1,683 bp
DQ676830.1


(A/chicken/Mahachkala/05/2006(H5N1))
linear
GI: 108782511


hemagglutinin (HA) mRNA, complete cds
mRNA


94. Influenza A virus
1,373 bp
DQ676832.1


(A/chicken/Mahachkala/05/2006(H5N1))
linear
GI: 108782515


neuraminidase (NA) mRNA, complete cds
mRNA


96. Influenza A virus
433 bp
DQ096567.1


(A/chicken/Malaysia/01/2004(H5N1))
linear
GI: 69145364


neuramidase (NA) mRNA, partial cds
mRNA


97. Influenza A virus
1,722 bp
AM503002.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846240


partial mRNA for hemagglutinin (ha
mRNA


gene)


98. Influenza A virus
1,329 bp
AM503020.1


(A/chicken/Nigeria/AB13/2006(H5N1))
linear
GI: 147846276


partial mRNA for neuraminidase (na
mRNA


gene)


105. Influenza A virus
1,719 bp
AM503003.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846242


partial mRNA for hemagglutinin (ha
mRNA


gene)


106. Influenza A virus
953 bp
AM503011.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846258


partial mRNA for matrix protein 1 (m1
mRNA


gene)


107. Influenza A virus
1,343 bp
AM503025.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846286


partial mRNA for neuraminidase (na
mRNA


gene)


108. Influenza A virus
827 bp
AM503041.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846318


mRNA for non-structural protein (ns
mRNA


gene)


109. Influenza A virus
2,169 bp
AM503054.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846344


partial mRNA for polymerase (pa gene)
mRNA


110. Influenza A virus
2,259 bp
AM503061.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846847


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


111. Influenza A virus
2,315 bp
AM503072.1


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 147846869


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


112. Influenza A virus
1,548 bp
AM503034.2


(A/chicken/Nigeria/AB14/2006(H5N1))
linear
GI: 149773117


mRNA for nucleoprotein (np gene)
mRNA


113. Influenza A virus
1,342 bp
AM503022.1


(A/chicken/Nigeria/BA210/2006(H5N1))
linear
GI: 147846280


partial mRNA for neuraminidase (na
mRNA


gene)


114. Influenza A virus
1,321 bp
AM503021.1


(A/chicken/Nigeria/BA211/2006(H5N1))
linear
GI: 147846278


partial mRNA for neuraminidase (na
mRNA


gene)


115. Influenza A virus
2,315 bp
AM503073.1


(A/chicken/Nigeria/BA211/2006(H5N1))
linear
GI: 147846871


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


116. Influenza A virus
1,717 bp
AM503004.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846244


partial mRNA for hemagglutinin (ha
mRNA


gene)


117. Influenza A virus
989 bp
AM503013.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846262


partial mRNA for matrix protein 1 (m1
mRNA


gene)


118. Influenza A virus
1,321 bp
AM503026.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846288


partial mRNA for neuraminidase (na
mRNA


gene)


119. Influenza A virus
827 bp
AM503045.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846326


mRNA for non-structural protein (ns
mRNA


gene)


120. Influenza A virus
2,169 bp
AM503055.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846346


partial mRNA for polymerase (pa gene)
mRNA


121. Influenza A virus
2,259 bp
AM503064.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846853


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


122. Influenza A virus
2,224 bp
AM503074.1


(A/chicken/Nigeria/FA4/2006(H5N1))
linear
GI: 147846873


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


123. Influenza A virus
1,717 bp
AM502998.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846232


partial mRNA for hemagglutinin (ha
mRNA


gene)


124. Influenza A virus
965 bp
AM503012.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846260


partial mRNA for matrix protein 1 (m1
mRNA


gene)


125. Influenza A virus
1,327 bp
AM503023.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846282


partial mRNA for neuraminidase (na
mRNA


gene)


126. Influenza A virus
1,543 bp
AM503031.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846298


mRNA for nucleoprotein (np gene)
mRNA


127. Influenza A virus
2,169 bp
AM503052.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846340


partial mRNA for polymerase (pa gene)
mRNA


128. Influenza A virus
2,259 bp
AM503063.1


(A/chicken/Nigeria/FA6/2006(H5N1))
linear
GI: 147846851


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


129. Influenza A virus
1,710 bp
AM502999.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846234


partial mRNA for hemagglutinin (ha
mRNA


gene)


130. Influenza A virus
1,001 bp
AM503009.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846254


partial mRNA for matrix protein 1 (m1
mRNA


gene)


131. Influenza A virus
1,331 bp
AM503018.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846272


partial mRNA for neuraminidase (na
mRNA


gene)


132. Influenza A virus
1,531 bp
AM503035.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846306


mRNA for nucleoprotein (np gene)
mRNA


133. Influenza A virus
827 bp
AM503042.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846320


mRNA for non-structural protein (ns
mRNA


gene)


134. Influenza A virus
2,169 bp
AM503049.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846334


partial mRNA for polymerase (pa gene)
mRNA


135. Influenza A virus
2,259 bp
AM503057.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846350


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


136. Influenza A virus
2,315 bp
AM503068.1


(A/chicken/Nigeria/FA7/2006(H5N1))
linear
GI: 147846861


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


137. Influenza A virus
1,714 bp
AM503001.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846238


partial mRNA for hemagglutinin (ha
mRNA


gene)


138. Influenza A virus
990 bp
AM503010.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846256


partial mRNA for matrix protein 1 (m1
mRNA


gene)


139. Influenza A virus
1,332 bp
AM503024.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846284


partial mRNA for neuraminidase (na
mRNA


gene)


140. Influenza A virus
827 bp
AM503044.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846324


mRNA for non-structural protein (ns
mRNA


gene)


141. Influenza A virus
2,169 bp
AM503053.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846342


partial mRNA for polymerase (pa gene)
mRNA


142. Influenza A virus
2,259 bp
AM503059.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846843


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


143. Influenza A virus
2,315 bp
AM503069.1


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 147846863


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


144. Influenza A virus
1,550 bp
AM503033.2


(A/chicken/Nigeria/IF10/2006(H5N1))
linear
GI: 149773115


mRNA for nucleoprotein (np gene)
mRNA


145. Influenza A virus
1,719 bp
AM503005.1


(A/chicken/Nigeria/OD8/2006(H5N1))
linear
GI: 147846246


partial mRNA for hemagglutinin (ha
mRNA


gene)


146. Influenza A virus
989 bp
AM503014.1


(A/chicken/Nigeria/OD8/2006(H5N1))
linear
GI: 147846264


partial mRNA for matrix protein 1 (m1
mRNA


gene)


147. Influenza A virus
1,720 bp
AM503000.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846236


partial mRNA for hemagglutinin (ha
mRNA


gene)


148. Influenza A virus
988 bp
AM503015.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846266


partial mRNA for matrix protein 1 (m1
mRNA


gene)


149. Influenza A virus
1,330 bp
AM503019.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846274


partial mRNA for neuraminidase (na
mRNA


gene)


150. Influenza A virus
1,531 bp
AM503032.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846300


mRNA for nucleoprotein (np gene)
mRNA


151. Influenza A virus
827 bp
AM503043.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846322


mRNA for non-structural protein (ns
mRNA


gene)


152. Influenza A virus
2,169 bp
AM503050.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846336


partial mRNA for polymerase (pa gene)
mRNA


153. Influenza A virus
2,259 bp
AM503058.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846841


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


154. Influenza A virus
2,315 bp
AM503070.1


(A/chicken/Nigeria/OD9/2006(H5N1))
linear
GI: 147846865


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


155. Influenza A virus
1,768 bp
X07869.1


(A/chicken/Scotland/59(H5N1)) mRNA
linear
GI: 60482


for haemagglutinin precursor
mRNA


156. Influenza A virus
1,445 bp
AJ416625.1


(A/chicken/Scotland/59(H5N1)) N1 gene
linear
GI: 39840717


for neuraminidase, genomic RNA
mRNA


161. Influenza A virus
1,497 bp
DQ208502.1


(A/chicken/zz/02/2004(H5N1))
linear
GI: 77158587


nucleoprotein mRNA, complete cds
mRNA


162. Influenza A virus (A/common
1,707 bp
EF110519.1


coot/Switzerland/V544/2006(H5N1))
linear
GI: 119394676


hemagglutinin (HA) gene, complete cds
mRNA


163. Influenza A virus (A/domestic
1,735 bp
EU190482.1


goose/Pavlodar/1/2005(H5N1))
linear
GI: 158516739


hemagglutinin (HA) mRNA, complete cds
mRNA


164. Influenza A virus
1,401 bp
EU429750.1


(A/duck/Eastern China/145/2003(H5N1))
linear
GI: 167859465


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


165. Influenza A virus
1,407 bp
EU429731.1


(A/duck/Eastern China/150/2003(H5N1))
linear
GI: 167859427


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


166. Influenza A virus
1,398 bp
EU429783.1


(A/duck/Eastern China/22/2005(H5N1))
linear
GI: 167859531


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


167. Influenza A virus
1,398 bp
60429747.1


(A/duck/Eastern China/304/2002(H5N1))
linear
GI: 167859459


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


168. Influenza A virus
1,401 bp
EU429727.1


(A/duck/Eastern China/318/2002(H5N1))
linear
GI: 167859419


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


169. Influenza A virus
1,399 bp
EU429778.1


(A/duck/Eastern China/37/2006(H5N1))
linear
GI: 167859521


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


170. Influenza A virus
1,398 bp
EU429757.1


(A/duck/Eastern China/40/2005(H5N1))
linear
GI: 167859479


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


171. Influenza A virus
1,398 bp
EU429779.1


(A/duck/Eastern China/48/2006(H5N1))
linear
GI: 167859523


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


172. Influenza A virus
1,398 bp
EU429763.1


(A/duck/Eastern China/51/2005(H5N1))
linear
GI: 167859491


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


173. Influenza A virus
1,398 bp
EU429758.1


(A/duck/Eastern China/54/2005(H5N1))
linear
GI: 167859481


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


174. Influenza A virus
1,398 bp
EU429764.1


(A/duck/Eastern China/58/2005(H5N1))
linear
GI: 167859493


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


175. Influenza A virus
1,398 bp
EU429759.1


(A/duck/Eastern China/59/2005(H5N1))
linear
GI: 167859483


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


176. Influenza A virus
1,398 bp
EU429765.1


(A/duck/Eastern China/89/2005(H5N1))
linear
GI: 167859495


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


177. Influenza A virus
1,399 bp
EU429785.1


(A/duck/Eastern China/89/2006(H5N1))
linear
GI: 167859535


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


178. Influenza A virus
1,398 bp
EU429717.1


(A/duck/Eastern China/97/2001(H5N1))
linear
GI: 167859399


segment 6 neuraminidase (NA) mRNA,
mRNA


complete cds


179. Influenza A virus
2,281 bp
AY585504.1


(A/duck/Fujian/01/2002(H5N1))
linear
GI: 47156226


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


180. Influenza A virus
760 bp
AY585378.1


(A/duck/Fujian/01/2002(H5N1)) matrix
linear
GI: 47156310


protein mRNA, complete cds
mRNA


181. Influenza A virus
1,357 bp
AY585399.1


(A/duck/Fujian/01/2002(H5N1))
linear
GI: 47156352


neuraminidase (NA) mRNA, complete cds
mRNA


182. Influenza A virus
1,497 bp
AY585420.1


(A/duck/Fujian/01/2002(H5N1))
linear
GI: 47156394


nucleoprotein (NP) mRNA, complete cds
mRNA


183. Influenza A virus
686 bp
AY585441.1


(A/duck/Fujian/01/2002(H5N1))
linear
GI: 47156436


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


184. Influenza A virus
2,281 bp
AY585505.1


(A/duck/Fujian/13/2002(H5N1))
linear
GI: 47156228


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


185. Influenza A virus
761 bp
AY585379.1


(A/duck/Fujian/13/2002(H5N1)) matrix
linear
GI: 47156312


protein mRNA, complete cds
mRNA


186. Influenza A virus
1,357 bp
AY585400.1


(A/duck/Fujian/13/2002(H5N1))
linear
GI: 47156354


neuraminidase (NA) mRNA, complete cds
mRNA


187. Influenza A virus
1,499 bp
AY585421.1


(A/duck/Fujian/13/2002(H5N1))
linear
GI: 47156396


nucleoprotein (NP) mRNA, complete cds
mRNA


188. Influenza A virus
685 bp
AY585442.1


(A/duck/Fujian/13/2002(H5N1))
linear
GI: 47156438


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


189. Influenza A virus
2,281 bp
AY585506.1


(A/duck/Fujian/17/2001(H5N1))
linear
GI: 47156230


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


190. Influenza A virus
759 bp
AY585380.1


(A/duck/Fujian/17/2001(H5N1)) matrix
linear
GI: 47156314


protein mRNA, complete cds
mRNA


191. Influenza A virus
1,418 bp
AY585401.1


(A/duck/Fujian/17/2001(H5N1))
linear
GI: 47156356


neuraminidase (NA) mRNA, complete cds
mRNA


192. Influenza A virus
1,498 bp
AY585422.1


(A/duck/Fujian/17/2001(H5N1))
linear
GI: 47156398


nucleoprotein (NP) mRNA, complete cds
mRNA


193. Influenza A virus
686 bp
AY585443.1


(A/duck/Fujian/17/2001(H5N1))
linear
GI: 47156440


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


194. Influenza A virus
2,281 bp
AY585507.1


(A/duck/Fujian/19/2000(H5N1))
linear
GI: 47156232


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


195. Influenza A virus
760 bp
AY585381.1


(A/duck/Fujian/19/2000(H5N1)) matrix
linear
GI: 47156316


protein mRNA, complete cds
mRNA


196. Influenza A virus
1,355 bp
AY585402.1


(A/duck/Fujian/19/2000(H5N1))
linear
GI: 47156358


neuraminidase (NA) mRNA, complete cds
mRNA


197. Influenza A virus
1,498 bp
AY585423.1


(A/duck/Fujian/19/2000(H5N1))
linear
GI: 47156400


nucleoprotein (NP) mRNA, complete cds
mRNA


198. Influenza A virus
687 bp
AY585444.1


(A/duck/Fujian/19/2000(H5N1))
linear
GI: 47156442


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


199. Influenza A virus
2,281 bp
AY585508.1


(A/duck/Guangdong/01/2001(H5N1))
linear
GI: 47156234


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


200. Influenza A virus
760 bp
AY585382.1


(A/duck/Guangdong/01/2001(H5N1))
linear
GI: 47156318


matrix protein mRNA, complete cds
mRNA


201. Influenza A virus
1,414 bp
AY585403.1


(A/duck/Guangdong/01/2001(H5N1))
linear
GI: 47156360


neuraminidase (NA) mRNA, complete cds
mRNA


202. Influenza A virus
1,497 bp
AY585424.1


(A/duck/Guangdong/01/2001(H5N1))
linear
GI: 47156402


nucleoprotein (NP) mRNA, complete cds
mRNA


203. Influenza A virus
687 bp
AY585445.1


(A/duck/Guangdong/01/2001(H5N1))
linear
GI: 47156444


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


204. Influenza A virus
2,280 bp
AY585509.1


(A/duck/Guangdong/07/2000(H5N1))
linear
GI: 47156236


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


205. Influenza A virus
759 bp
AY585383.1


(A/duck/Guangdong/07/2000(H5N1))
linear
GI: 47156320


matrix protein mRNA, complete cds
mRNA


206. Influenza A virus
1.,417 bp
AY585404.1


(A/duck/Guangdong/07/2000(H5N1))
linear
GI: 47156362


neuraminidase (NA) mRNA, complete cds
mRNA


207. Influenza A virus
1,497 bp
AY585425.1


(A/duck/Guangdong/07/2000(H5N1))
linear
GI: 47156404


nucleoprotein (NP) mRNA, complete cds
mRNA


208. Influenza A virus
690 bp
AY585446.1


(A/duck/Guangdong/07/2000(H5N1))
linear
GI: 47156446


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


209. Influenza A virus
2,281 bp
AY585510.1


(A/duck/Guangdong/12/2000(H5N1))
linear
GI: 47156238


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


210. Influenza A virus
760 bp
AY585384.1


(A/duck/Guangdong/12/2000(H5N1))
linear
GI: 47156322


matrix protein mRNA, complete cds
mRNA


211. Influenza A virus
1,359 bp
AY585405.1


(A/duck/Guangdong/12/2000(H5N1))
linear
GI: 47156364


neuraminidase (NA) mRNA, complete cds
mRNA


212. Influenza A virus
1,498 bp
AY585426.1


(A/duck/Guangdong/12/2000(H5N1))
linear
GI: 47156406


nucleoprotein (NP) mRNA, complete cds
mRNA


213. Influenza A virus
685 bp
AY585447.1


(A/duck/Guangdong/12/2000(H5N1))
linear
GI: 47156448


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


214. Influenza A virus
2,281 bp
AY585511.1


(A/duck/Guangdong/22/2002(H5N1))
linear
GI: 47156240


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


215. Influenza A virus
760 bp
AY585385.1


(A/duck/Guangdong/22/2002(H5N1))
linear
GI: 47156324


matrix protein mRNA, complete cds
mRNA


216. Influenza A virus
1,412 bp
AY585406.1


(A/duck/Guangdong/22/2002(H5N1))
linear
GI: 47156366


neuraminidase (NA) mRNA, complete cds
mRNA


217. Influenza A virus
1,499 bp
AY585427.1


(A/duck/Guangdong/22/2002(H5N1))
linear
GI: 47156408


nucleoprotein (NP) mRNA, complete cds
mRNA


218. Influenza A virus
682 bp
AY585448.1


(A/duck/Guangdong/22/2002(H5N1))
linear
GI: 47156450


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


219. Influenza A virus
2,281 bp
AY585512.1


(A/duck/Guangdong/40/2000(H5N1))
linear
GI: 47156242


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


220. Influenza A virus
760 bp
AY585386.1


(A/duck/Guangdong/40/2000(H5N1))
linear
GI: 47156326


matrix protein mRNA, complete cds
mRNA


221. Influenza A virus
1,401 bp
AY585407.1


(A/duck/Guangdong/40/2000(H5N1))
linear
GI: 47156368


neuraminidase (NA) mRNA, partial cds
mRNA


222. Influenza A virus
1,499 bp
AY585428.1


(A/duck/Guangdong/40/2000(H5N1))
linear
GI: 47156410


nucleoprotein (NP) mRNA, complete cds
mRNA


223. Influenza A virus
689 bp
AY585449.1


(A/duck/Guangdong/40/2000(H5N1))
linear
GI: 47156452


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


224. Influenza A virus
2,281 bp
AY585513.1


(A/duck/Guangxi/07/1999(H5N1))
linear
GI: 47156244


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


225. Influenza A virus
760 bp
AY585387.1


(A/duck/Guangxi/07/1999(H5N1)) matrix
linear
GI: 47156328


protein mRNA, complete cds
mRNA


226. Influenza A virus
1,421 bp
AY585408.1


(A/duck/Guangxi/07/1999(H5N1))
linear
GI: 47156370


neuraminidase (NA) mRNA, complete cds
mRNA


227. Influenza A virus
1,501 bp
AY585429.1


(A/duck/Guangxi/07/1999(H5N1))
linear
GI: 47156412


nucleoprotein (NP) mRNA, complete cds
mRNA


228. Influenza A virus
687 bp
AY585450.1


(A/duck/Guangxi/07/1999(H5N1))
linear
GI: 47156454


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


229. Influenza A virus
875 bp
DQ366342.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753723


nonstructural protein 1 mRNA,
mRNA


complete cds


230. Influenza A virus
2,341 bp
DQ366335.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753733


polymerase PB2 mRNA, complete cds
mRNA


231. Influenza A virus
2,341 bp
DQ366336.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753743


polymerase PB1 mRNA, complete cds
mRNA


232. Influenza A virus
2,233 bp
DQ366337.1


(A/duck/Guangxi/13/2004(H5N1)) PA
linear
GI: 86753753


protein mRNA, complete cds
mRNA


233. Influenza A virus
1,776 bp
DQ366338.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753763


hemagglutinin mRNA, complete cds
mRNA


234. Influenza A virus
1,565 bp
DQ366339.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753773


nucleocapsid mRNA, complete cds
mRNA


235. Influenza A virus
1,378 bp
DQ366340.1


(A/duck/Guangxi/13/2004(H5N1))
linear
GI: 86753783


neuraminidase mRNA, complete cds
mRNA


236. Influenza A virus
1,027 bp
DQ366341.1


(A/duck/Guangxi/13/2004(H5N1)) matrix
linear
GI: 86753793


protein mRNA, complete cds
mRNA


237. Influenza A virus
2,281 bp
AY585514.1


(A/duck/Guangxi/22/2001(H5N1))
linear
GI: 47156246


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


238. Influenza A virus
757 bp
AY585388.1


(A/duck/Guangxi/22/2001(H5N1)) matrix
linear
GI: 47156330


protein mRNA, partial cds
mRNA


239. Influenza A virus
1,414 bp
AY585409.1


(A/duck/Guangxi/22/2001(H5N1))
linear
GI: 47156372


neuraminidase (NA) mRNA, complete cds
mRNA


240. Influenza A virus
1,498 bp
AY585430.1


(A/duck/Guangxi/22/2001(H5N1))
linear
GI: 47156414


nucleoprotein (NP) mRNA, complete cds
mRNA


241. Influenza A virus
687 bp
AY585451.1


(A/duck/Guangxi/22/2001(H5N1))
linear
GI: 47156456


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


242. Influenza A virus
2,281 bp
AY585515.1


(A/duck/Guangxi/35/2001(H5N1))
linear
GI: 47156248


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


243. Influenza A virus
760 bp
AY585389.1


(A/duck/Guangxi/35/2001(H5N1)) matrix
linear
GI: 47156332


protein mRNA, complete cds
mRNA


244. Influenza A virus
1,414 bp
AY585410.1


(A/duck/Guangxi/35/2001(H5N1))
linear
GI: 47156374


neuraminidase (NA) mRNA, complete cds
mRNA


245. Influenza A virus
1,498 bp
AY585431.1


(A/duck/Guangxi/35/2001(H5N1))
linear
GI: 47156416


nucleoprotein (NP) mRNA, complete cds
mRNA


246. Influenza A virus
685 bp
AY585452.1


(A/duck/Guangxi/35/2001(H5N1))
linear
GI: 47156458


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


247. Influenza A virus
2,281 bp
AY585516.1


(A/duck/Guangxi/50/2001(H5N1))
linear
GI: 47156250


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


248. Influenza A virus
760 bp
AY585398.1


(A/duck/Guangxi/50/2001(H5N1)) matrix
linear
GI: 47156350


protein mRNA, complete cds
mRNA


249. Influenza A virus
1,354 bp
AY585411.1


(A/duck/Guangxi/50/2001(H5N1))
linear
GI: 47156376


neuraminidase (NA) mRNA, complete cds
mRNA


250. Influenza A virus
1,498 bp
AY585432.1


(A/duck/Guangxi/50/2001(H5N1))
linear
GI: 47156418


nucleoprotein (NP) mRNA, complete cds
mRNA


251. Influenza A virus
686 bp
AY585453.1


(A/duck/Guangxi/50/2001(H5N1))
linear
GI: 47156460


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


252. Influenza A virus
2,281 bp
AY585517.1


(A/duck/Guangxi/53/2002(H5N1))
linear
GI: 47156252


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


253. Influenza A virus
760 bp
AY585390.1


(A/duck/Guangxi/53/2002(H5N1)) matrix
linear
GI: 47156334


protein mRNA, complete cds
mRNA


254. Influenza A virus
1,361 bp
AY585412.1


(A/duck/Guangxi/53/2002(H5N1))
linear
GI: 47156378


neuraminidase (NA) mRNA, complete cds
mRNA


255. Influenza A virus
1,498 bp
AY585433.1


(A/duck/Guangxi/53/2002(H5N1))
linear
GI: 47156420


nucleoprotein (NP) mRNA, complete cds
mRNA


256. Influenza A virus
687 bp
AY585454.1


(A/duck/Guangxi/53/2002(H5N1))
linear
GI: 47156462


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


257. Influenza A virus
1,754 bp
DQ449640.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289674


hemagglutinin (HA) mRNA, complete cds
mRNA


258. Influenza A virus
1,002 bp
DQ449641.1


(A/duck/Kurgan/08/2005(H5N1)) matrix
linear
GI: 90289689


protein 1 (M) mRNA, complete cds
mRNA


259. Influenza A virus
1,373 bp
DQ449642.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289708


neuraminidase (NA) mRNA, complete cds
mRNA


260. Influenza A virus
1,540 bp
DQ449643.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289731


nucleoprotein (NP) mRNA, complete cds
mRNA


261. Influenza A virus
850 bp
DQ449644.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289739


nonstructural protein (NS) mRNA,
mRNA


complete cds


262. Influenza A virus
2,208 bp
DQ449645.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289756


polymerase acidic protein (PA) mRNA,
mRNA


complete cds


263. Influenza A virus
2,316 bp
DQ449646.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289774


polymerase basic protein 1 (PB1)
mRNA


mRNA, complete cds


264. Influenza A virus
2,316 bp
DQ449647.1


(A/duck/Kurgan/08/2005(H5N1))
linear
GI: 90289783


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


266. Influenza A virus
2,281 bp
AY585518.1


(A/duck/Shanghai/08/2001(H5N1))
linear
GI: 47156254


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


267. Influenza A virus
760 bp
AY585391.1


(A/duck/Shanghai/08/2001(H5N1))
linear
GI: 47156336


matrix protein mRNA, complete cds
mRNA


268. Influenza A virus
1,357 bp
AY585413.1


(A/duck/Shanghai/08/2001(H5N1))
linear
GI: 47156380


neuraminidase (NA) mRNA, complete cds
mRNA


269. Influenza A virus
1,498 bp
AY585434.1


(A/duck/Shanghai/08/2001(H5N1))
linear
GI: 47156422


nucleoprotein (NP) mRNA, complete cds
mRNA


270. Influenza A virus
685 bp
AY585455.1


(A/duck/Shanghai/08/2001(H5N1))
linear
GI: 47156464


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


271. Influenza A virus
2,281 bp
AY585519.1


(A/duck/Shanghai/13/2001(H5N1))
linear
GI: 47156256


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


272. Influenza A virus
760 bp
AY585392.1


(A/duck/Shanghai/13/2001(H5N1))
linear
GI: 47156338


matrix protein mRNA, complete cds
mRNA


273. Influenza A virus
1,417 bp
AY585414.1


(A/duck/Shanghai/13/2001(H5N1))
linear
GI: 47156382


neuraminidase (NA) mRNA, complete cds
mRNA


274. Influenza A virus
1,499 bp
AY585435.1


(A/duck/Shanghai/13/2001(H5N1))
linear
GI: 47156424


nucleoprotein (NP) mRNA, complete cds
mRNA


275. Influenza A virus
685 bp
AY585456.1


(A/duck/Shanghai/13/2001(H5N1))
linear
GI: 47156466


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


276. Influenza A virus
2,281 bp
AY585520.1


(A/duck/Shanghai/35/2002(H5N1))
linear
GI: 47156258


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


277. Influenza A virus
760 bp
AY585393.1


(A/duck/Shanghai/35/2002(H5N1))
linear
GI: 47156340


matrix protein mRNA, complete cds
mRNA


278. Influenza A virus
1,363 bp
AY585415.1


(A/duck/Shanghai/35/2002(H5N1))
linear
GI: 47156384


neuraminidase (NA) mRNA, complete cds
mRNA


279. Influenza A virus
1,498 bp
AY585436.1


(A/duck/Shanghai/35/2002(H5N1))
linear
GI: 47156426


nucleoprotein (NP) mRNA, complete cds
mRNA


280. Influenza A virus
685 bp
AY585457.1


(A/duck/Shanghai/35/2002(H5N1))
linear
GI: 47156468


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


281. Influenza A virus
2,281 bp
AY585521.1


(A/duck/Shanghai/37/2002(H5N1))
linear
GI: 47156260


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


282. Influenza A virus
760 bp
AY585394.1


(A/duck/Shanghai/37/2002(H5N1))
linear
GI: 47156342


matrix protein mRNA, complete cds
mRNA


283. Influenza A virus
1,361 bp
AY585416.1


(A/duck/Shanghai/37/2002(H5N1))
linear
GI: 47156386


neuraminidase (NA) mRNA, complete cds
mRNA


284. Influenza A virus
1,497 bp
AY585437.1


(A/duck/Shanghai/37/2002(H5N1))
linear
GI: 47156428


nucleoprotein (NP) mRNA, complete cds
mRNA


285. Influenza A virus
685 bp
AY585458.1


(A/duck/Shanghai/37/2002(H5N1))
linear
GI: 47156470


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


286. Influenza A virus
2,282 bp
AY585522.1


(A/duck/Shanghai/38/2001(H5N1))
linear
GI: 47156262


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


287. Influenza A virus
760 bp
AY585395.1


(A/duck/Shanghai/38/2001(H5N1))
linear
GI: 47156344


matrix protein mRNA, complete cds
mRNA


288. Influenza A virus
1,355 bp
AY585417.1


(A/duck/Shanghai/38/2001(H5N1))
linear
GI: 47156388


neuraminidase (NA) mRNA, complete cds
mRNA


289. Influenza A virus
1,499 bp
AY585438.1


(A/duck/Shanghai/38/2001(H5N1))
linear
GI: 47156430


nucleoprotein (NP) mRNA, complete cds
mRNA


290. Influenza A virus
692 bp
AY585459.1


(A/duck/Shanghai/38/2001(H5N1))
linear
GI: 47156472


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


291. Influenza A virus
875 bp
DQ354059.1


(A/duck/Sheyang/1/2005(H5N1))
linear
GI: 87128643


nonstructural protein (NS) mRNA,
mRNA


complete cds


292. Influenza A virus
1,748 bp
DQ861291.1


(A/duck/Tuva/01/2006(H5N1))
linear
GI: 112820195


hemagglutinin (HA) mRNA, complete cds
mRNA


293. Influenza A virus
991 bp
DQ861292.1


(A/duck/Tuva/01/2006(H5N1)) matrix
linear
GI: 112820197


protein 1 (M1) mRNA, complete cds
mRNA


294. Influenza A virus
1,364 bp
DQ861293.1


(A/duck/Tuva/01/2006(H5N1))
linear
GI: 112820199


neuraminidase (NA) mRNA, complete cds
mRNA


295. Influenza A virus
1,531 bp
DQ861294.1


(A/duck/Tuva/01/2006(H5N1))
linear
GI: 112820201


nucleoprotein (NP) mRNA, complete cds
mRNA


296. Influenza A virus
842 bp
DQ861295.1


(A/duck/Tuva/01/2006(H5N1))
linear
GI: 112820203


nonstructural protein (NS) mRNA,
mRNA


complete cds


297. Influenza A virus
890 bp
DQ366310.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753715


nonstructural protein 1 mRNA,
mRNA


complete cds


298. Influenza A virus
2,341 bp
DQ366303.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753725


polymerase PB2 mRNA, complete cds
mRNA


299. Influenza A virus
2,341 bp
DQ366304.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753735


polymerase PB1 mRNA, complete cds
mRNA


300. Influenza A virus
2,233 bp
DQ366305.1


(A/duck/Vietnam/1/2005(H5N1)) PA
linear
GI: 86753745


protein mRNA, complete cds
mRNA


301. Influenza A virus
1,779 bp
DQ366306.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753755


hemagglutinin mRNA, complete cds
mRNA


302. Influenza A virus
1,565 bp
DQ366307.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753765


nucleocapsid mRNA, complete cds
mRNA


303. Influenza A virus
1,401 bp
DQ366308.1


(A/duck/Vietnam/1/2005(H5N1))
linear
GI: 86753775


neuraminidase mRNA, complete cds
mRNA


304. Influenza A virus
1,027 bp
DQ366309.1


(A/duck/Vietnam/1/2005(H5N1)) matrix
linear
GI: 86753785


protein mRNA, complete cds
mRNA


305. Influenza A virus
890 bp
DQ366326.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753719


nonstructural protein 1 mRNA,
mRNA


complete cds


306. Influenza A virus
2,341 bp
DQ366319.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753729


polymerase PB2 mRNA, complete cds
mRNA


307. Influenza A virus
2,341 bp
DQ366320.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753739


polymerase PB1 mRNA, complete cds
mRNA


308. Influenza A virus
2,233 bp
DQ366321.1


(A/duck/Vietnam/8/05(H5N1)) PA
linear
GI: 86753749


protein mRNA, complete cds
mRNA


309. Influenza A virus
1,779 bp
DQ366322.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753759


hemagglutinin mRNA, complete cds
mRNA


310. Influenza A virus
1,565 bp
DQ366323.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753769


nucleocapsid mRNA, complete cds
mRNA


311. Influenza A virus
1,401 bp
DQ366324.1


(A/duck/Vietnam/8/05(H5N1))
linear
GI: 86753779


neuraminidase mRNA, complete cds
mRNA


312. Influenza A virus
1,027 bp
DQ366325.1


(A/duck/Vietnam/8/05(H5N1)) matrix
linear
GI: 86753789


protein mRNA, complete cds
mRNA


313. Influenza A virus
876 bp
DQ354060.1


(A/duck/Yangzhou/232/2004(H5N1))
linear
GI: 87128645


nonfunctional nonstructural protein
mRNA


(NS) mRNA, complete sequence


314. Influenza A virus
2,281 bp
AY585523.1


(A/duck/Zhejiang/11/2000(H5N1))
linear
GI: 47156264


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


315. Influenza A virus
760 bp
AY585396.1


(A/duck/Zhejiang/11/2000(H5N1))
linear
GI: 47156346


matrix protein mRNA, complete cds
mRNA


316. Influenza A virus
1,352 bp
AY585418.1


(A/duck/Zhejiang/11/2000(H5N1))
linear
GI: 47156390


neuraminidase (NA) mRNA, complete cds
mRNA


317. Influenza A virus
1,498 bp
AY585439.1


(A/duck/Zhejiang/11/2000(H5N1))
linear
GI: 47156432


nucleoprotein (NP) mRNA, complete cds
mRNA


318. Influenza A virus
687 bp
AY585460.1


(A/duck/Zhejiang/11/2000(H5N1))
linear
GI: 47156474


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


319. Influenza A virus
2,281 bp
AY585524.1


(A/duck/Zhejiang/52/2000(H5N1))
linear
GI: 47156266


polymerase basic protein 2 (PB2)
mRNA


mRNA, complete cds


320. Influenza A virus
760 bp
AY585397.1


(A/duck/Zhejiang/52/2000(H5N1))
linear
GI: 47156348


matrix protein mRNA, complete cds
mRNA


321. Influenza A virus
1,423 bp
AY585419.1


(A/duck/Zhejiang/52/2000(H5N1))
linear
GI: 47156392


neuraminidase (NA) mRNA, complete cds
mRNA


322. Influenza A virus
1,499 bp
AY585440.1


(A/duck/Zhejiang/52/2000(H5N1))
linear
GI: 47156434


nucleoprotein (NP) mRNA, complete cds
mRNA


323. Influenza A virus
686 bp
AY585461.1


(A/duck/Zhejiang/52/2000(H5N1))
linear
GI: 47156476


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


324. Influenza A virus (A/Egypt/0636-
1,749 bp
EF382359.1


NAMRU3/2007(H5N1)) hemagglutinin
linear
GI: 124244205


(HA) mRNA, complete cds
mRNA


325. Influenza A virus
1,707 bp
EF110518.1


(A/goosander/Switzerland/V82/06
linear
GI: 119394674


(H5N1)) hemagglutinin (HA) gene,
mRNA


complete cds


326. Influenza A virus
1,707 bp
AF148678.1


(A/goose/Guangdong/1/96/(H5N1))
linear
GI: 5007022


hemagglutinin mRNA, complete cds
mRNA


327. Influenza A virus
1,779 bp
DQ201829.1


(A/Goose/Huadong/1/2000(H5N1))
linear
GI: 76786306


hemagglutinin (HA) mRNA, complete cds
mRNA


328. Influenza A virus
1,458 bp
DQ201830.1


(A/Goose/Huadong/1/2000(H5N1))
linear
GI: 76786308


neuraminidase (NA) mRNA, complete cds
mRNA


329. Influenza A virus
2,287 bp
EF446768.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428373


polymerase PB1 (PB1) mRNA, partial
mRNA


cds


330. Influenza A virus
2,274 bp
EF446769.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428375


polymerase PB2 (PB2) mRNA, partial
mRNA


cds


331. Influenza A virus
2,175 bp
EF446770.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428377


polymerase PA (PA) mRNA, complete cds
mRNA


332. Influenza A virus
1,735 bp
EF446771.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428379


hemagglutinin (HA) mRNA, complete cds
mRNA


333. Influenza A virus
1,473 bp
EF446772.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428381


nucleocapsid protein (NP) mRNA,
mRNA


partial cds


334. Influenza A virus
1,311 bp
EF446773.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428383


neuraminidase (NA) mRNA, partial cds
mRNA


335. Influenza A virus
971 bp
EF446774.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428385


matrix protein 1 (M1) mRNA, partial
mRNA


cds


336. Influenza A virus
795 bp
EF446775.1


(A/goose/Hungary/2823/2/2007(H5N1))
linear
GI: 126428387


nonstructural protein 1 (NS1) mRNA,
mRNA


partial cds


337. Influenza A virus
2,277 bp
EF446776.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428389


polymerase PB1 (PB1) mRNA, partial
mRNA


cds


338. Influenza A virus
2,274 bp
EF446777.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428391


polymerase PB2 (PB2) mRNA, partial
mRNA


cds


339. Influenza A virus
2,163 bp
EF446778.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428393


polymerase PA (PA) mRNA, partial cds
mRNA


340. Influenza A virus
1,722 bp
EF446779.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428395


hemagglutinin (HA) mRNA, complete cds
mRNA


341. Influenza A virus
1,463 bp
EF446780.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428397


nucleocapsid protein (NP) mRNA,
mRNA


partial cds


342. Influenza A virus
1,289 bp
EF446781.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428399


neuraminidase (NA) mRNA, partial cds
mRNA


343. Influenza A virus
955 bp
EF446782.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428401


matrix protein 1 (M1) mRNA, partial
mRNA


cds


344. Influenza A virus
805 bp
EF446783.1


(A/goose/Hungary/3413/2007(H5N1))
linear
GI: 126428403


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


345. Influenza A virus
877 bp
DQ354061.1


(A/goose/jiangsu/131/2002(H5N1))
linear
GI: 87128646


nonfunctional nonstructural protein
mRNA


(NS) mRNA, complete sequence


346. Influenza A virus
875 bp
DQ354062.1


(A/goose/Jiangsu/220/2003(H5N1))
linear
GI: 87128647


nonstructural protein (NS) mRNA,
mRNA


complete cds


347. Influenza A virus
1,754 bp
DQ676840.1


(A/goose/Krasnoozerka/627/2005(H5N1))
linear
GI: 108782531


hemagglutinin (HA) mRNA, complete cds
mRNA


348. Influenza A virus
1,530 bp
DQ676841.1


(A/goose/Krasnoozerka/627/2005(H5N1))
linear
GI: 108782533


nucleoprotein (NP) mRNA, complete cds
mRNA


349. Influenza A virus
850 bp
DQ676842.1


(A/goose/Krasnoozerka/627/2005(H5N1))
linear
GI: 108782535


nonstructural protein (NS) mRNA,
mRNA


complete cds


350. Influenza A virus
890 bp
DQ366318.1


(A/goose/Vietnam/3/05(H5N1))
linear
GI: 86753717


nonstructural protein 1 mRNA,
mRNA


complete cds


351. Influenza A virus
2,341 bp
DQ366311.1


(A/goose/Vietnam/3/05(H5N1))
linear


polymerase PB2 mRNA, complete cds
mRNA
GI: 86753727


352. Influenza A virus
2,341 bp
DQ366312.1


(A/goose/Vietnam/3/05(H5N1))
linear
GI: 86753737


polymerase PB1 mRNA, complete cds
mRNA


353. Influenza A virus
2,233 bp
DQ366313.1


(A/goose/Vietnam/3/05(H5N1)) PA
linear
GI: 86753747


protein mRNA, complete cds
mRNA


354. Influenza A virus
1,779 bp
DQ366314.1


(A/goose/Vietnam/3/05(H5N1))
linear
GI: 86753757


hemagglutinin mRNA, complete cds
mRNA


355. Influenza A virus
1,565 bp
DQ366315.1


(A/goose/Vietnam/3/05(H5N1))
linear
GI: 86753767


nucleocapsid mRNA, complete cds
mRNA


356. Influenza A virus
1,401 bp
DQ366316.1


(A/goose/Vietnam/3/05(H5N1))
linear
GI: 86753777


neuraminidase mRNA, complete cds
mRNA


357. Influenza A virus
1,027 bp
DQ366317.1


(A/goose/Vietnam/3/05(H5N1)) matrix
linear
GI: 86753787


protein mRNA, complete cds
mRNA


358. Influenza A virus
1,700 bp
AF082043.1


(A/gull/Pennsylvania/4175/83(H5N1))
linear
GI: 4240453


hemagglutinin H5 mRNA, partial cds
mRNA


360. Influenza A virus
1,388 bp
AF028708.1


(A/HongKong/156/97(H5N1))
linear
GI: 2865377


neuraminidase mRNA, complete cds
mRNA


361. Influenza A virus
1,741 bp
AF028709.1


(A/HongKong/156/97(H5N1))
linear
GI: 2865379


hemagglutinin mRNA, complete cds
mRNA


362. Influenza A virus
1,549 bp
AF028710.1


(A/HongKong/156/97(H5N1))
linear
GI: 2865381


nucleoprotein mRNA, complete cds
mRNA


363. Influenza A virus (A/hooded
1,451 bp
AM503028.1


vulture/Burkina Faso/1/2006(H5N1))
linear
GI: 147846292


partial mRNA for nucleoprotein (np
mRNA


gene)


364. Influenza A virus (A/hooded
827 bp
AM503038.1


vulture/Burkina Faso/1/2006(H5N1))
linear
GI: 147846312


mRNA for non-structural protein (ns
mRNA


gene)


365. Influenza A virus (A/hooded
2,169 bp
AM503047.1


vulture/Burkina Faso/1/2006(H5N1))
linear
GI: 147846330


partial mRNA for polymerase (pa gene)
mRNA


366. Influenza A virus (A/hooded
1,686 bp
AM503065.1


vulture/Burkina Faso/1/2006(H5N1))
linear
GI: 147846855


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


367. Influenza A virus (A/hooded
977 bp
AM503006.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846248


partial mRNA for matrix protein 1 (m1
mRNA


gene)


368. Influenza A virus (A/hooded
1,336 bp
AM503017.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846270


partial mRNA for neuraminidase (na
mRNA


gene)


369. Influenza A virus (A/hooded
1,499 bp
AM503027.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846290


partial mRNA for nucleoprotein (np
mRNA


gene)


370. Influenza A virus (A/hooded
827 bp
AM503039.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846314


mRNA for non-structural protein (ns
mRNA


gene)


371. Influenza A virus (A/hooded
2,169 bp
AM503048.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846332


partial mRNA for polymerase (pa gene)
mRNA


372. Influenza A virus (A/hooded
2,259 bp
AM503062.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846849


partial mRNA for polymerase basic
mRNA


protein 1 (pb1 gene)


373. Influenza A virus (A/hooded
2,315 bp
AM503066.1


vulture/Burkina Faso/2/2006(H5N1))
linear
GI: 147846857


partial mRNA for polymerase basic
mRNA


protein 2 (pb2 gene)


374. Influenza A virus
294 bp
EU014135.1


(A/Indonesia/CDC177/2005(H5N1)) M2
linear
GI: 151336850


protein mRNA, complete cds
mRNA


375. Influenza A virus
294 bp
EU014138.1


(A/Indonesia/CDC298/2005(H5N1)) M2
linear
GI: 151336856


protein mRNA, complete cds
mRNA


376. Influenza A virus
294 bp
EU014136.1


(A/Indonesia/CDC485/2006(H5N1)) M2
linear
GI: 151336852


protein mRNA, complete cds
mRNA


377. Influenza A virus
294 bp
EU014134.1


(A/Indonesia/CDC530/2006(H5N1)) M2
linear
GI: 151336848


protein mRNA, complete cds
mRNA


378. Influenza A virus
294 bp
EU014133.1


(A/Indonesia/CDC535/2006(H5N1)) M2
linear
GI: 151336846


protein mRNA, complete cds
mRNA


379. Influenza A virus
294 bp
EU014132.1


(A/Indonesia/CDC540/2006(H5N1)) M2
linear
GI: 151336844


protein mRNA, complete cds
mRNA


380. Influenza A virus
294 bp
EU014137.1


(A/Indonesia/CDC561/2006(H5N1)) M2
linear
GI: 151336854


protein mRNA, complete cds
mRNA


381. Influenza A virus
294 bp
EU014139.1


(A/Indonesia/CDC60/2005(H5N1)) M2
linear
GI: 151336858


protein mRNA, complete cds
mRNA


382. Influenza A virus
996 bp
U79453.1


(A/mallard/Wisconsin/428/75(H5N1))
linear
GI: 1840071


hemagglutinin mRNA, partial cds
mRNA


383. Influenza A virus
441 bp
JN157759.1


(A/ostrich/VRLCU/Egypt/2011(H5N1))
linear
GI: 338223304


segment 4 hemagglutinin (HA) mRNA,
mRNA


partial cds


384. Influenza A virus
875 bp
DQ354063.1


(A/quail/yunnan/092/2002(H5N1))
linear
GI: 87128649


nonstructural protein (NS) mRNA,
mRNA


complete cds


385. Influenza A virus
1,472 bp
AB241613.1


(A/R(Turkey/Ontario/7732/66-
linear
GI: 82581222


Bellamy/42)(H5N1)) HA mRNA for
mRNA


hemagglutinin, partial cds


386. Influenza A virus
1,350 bp
AY679513.1


(A/Thailand/LFPN-2004/2004(H5N1))
linear
GI: 50843945


neuraminidase mRNA, complete cds
mRNA


387. Influenza A virus
1,704 bp
AY679514.1


(A/Thailand/LFPN-2004/2004(H5N1))
linear
GI: 50843949


hemagglutinin mRNA, complete cds
mRNA


388. Influenza A virus
534 bp
DQ017251.1


(A/tiger/Thailand/CU-T4/04(H5N1))
linear
GI: 65329524


polymerase basic protein 2 (PB2)
mRNA


mRNA, partial cds


389. Influenza A virus
582 bp
DQ017252.1


(A/tiger/Thailand/CU-T5/04(H5N1))
linear
GI: 65329536


polymerase basic protein 2 (PB2)
mRNA


mRNA, partial cds


390. Influenza A virus
564 bp
DQ017253.1


(A/tiger/Thailand/CU-T6/04(H5N1))
linear
GI: 65329553


polymerase basic protein 2 (PB2)
mRNA


mRNA, partial cds


391. Influenza A virus
582 bp
DQ017254.1


(A/tiger/Thailand/CU-T8/04(H5N1))
linear
GI: 65329568


polymerase basic protein 2 (PB2)
mRNA


mRNA, partial cds


392. Influenza A virus
1,695 bp
EF441263.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307104


hemagglutinin (HA) mRNA, partial cds
mRNA


393. Influenza A virus
943 bp
EF441264.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307106


matrix protein (M) mRNA, partial cds
mRNA


394. Influenza A virus
812 bp
EF441265.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307109


nonstructural protein 1 (NS1) mRNA,
mRNA


complete cds


395. Influenza A virus
2,185 bp
EF441266.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307111


polymerase PA (PA) mRNA, complete cds
mRNA


396. Influenza A virus
2,272 bp
EF441267.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307113


polymerase PB2 (PB2) mRNA, partial
mRNA


cds


397. Influenza A virus
1,396 bp
EF441268.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307115


nucleocapsid (NP) mRNA, partial cds
mRNA


398. Influenza A virus
2,288 bp
EF441269.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307117


polymerase PB1 (PB1) mRNA, partial
mRNA


cds


399. Influenza A virus
1,276 bp
EF441270.1


(A/turkey/England/250/2007(H5N1))
linear
GI: 129307119


neuraminidase (NA) mRNA, partial cds
mRNA


A/chicken/Burkina

AM503016.1


Faso/13.1/2006(H5N1) neuraminidase


(NA)


A/chicken/Crimea/04/2005(H5N1)

DQ650661.1


neuraminidase (NA)


A/chicken/Crimea/04/2005(H5N1)

DQ650659.1


hemagglutinin


A/chicken/Crimea/08/2005(H5N1)

DQ650669.1


polymerase basic protein 1 (PB1)


A/chicken/Crimea/08/2005(H5N1)

DQ650665.1


neuraminidase (NA)


A/chicken/Crimea/08/2005(H5N1)

DQ650663.1


hemagglutinin (HA)


A/chicken/Guangxi/12/2004(H5N1)

DQ366334.1


nonstructural protein 1


A/chicken/Guangxi/12/2004(H5N1)

DQ366332.1


neuraminidase


A/chicken/Guangxi/12/2004(H5N1)

DQ366330.1


hemagglutinin


A/duck/Kurgan/08/2005(H5N1)

DQ449643.1


nucleoprotein (NP)
















TABLE 9







Other Influenza A Antigens(H1N*, H2N*, H3N*)











GenBank/GI




Accession


Strain/Protein
Length
Nos.





H1N*




Influenza A virus (A/duck/Hong
1,402 bp
U49097.1


Kong/193/1977(H1N2)) nucleoprotein (NP)
linear mRNA
GI: 1912392


mRNA, partial cds


Influenza A virus (A/duck/Hong
258 bp
U48285.1


Kong/193/1977(H1N2)) polymerase (PB1)
linear mRNA
GI: 1912374


mRNA, partial cds


Influenza A virus
795 bp
AJ519455.1


(A/England/2/2002(H1N2)) partial NS1 gene
linear mRNA
GI: 31096426


for non structural protein 1 and partial


NS2 gene for non structural protein 2,


genomic RNA


Influenza A virus (A/England/3/02(H1N2))
384 bp
AJ489497.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526856


Influenza A virus (A/England/3/02(H1N2))
442 bp
AJ489488.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526838


(pb2 gene)


Influenza A virus (A/England/5/02(H1N2))
384 bp
AJ489498.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526858


Influenza A virus (A/England/5/02(H1N2))
442 bp
AJ489489.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526840


(pb2 gene)


Influenza A virus (A/England/57/02(H1N2))
384 bp
AJ489499.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526860


Influenza A virus (A/England/57/02(H1N2))
442 bp
AJ489492.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526846


(pb2 gene)


Influenza A virus
384 bp
AJ489496.1


(A/England/691/01(H1N2)) partial mRNA for
linear mRNA
GI: 27526854


nucleoprotein (np gene)


Influenza A virus (A/England/73/02(H1N2))
384 bp
AJ489500.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526862


Influenza A virus (A/England/73/02(H1N2))
442 bp
AJ489493.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526848


(pb2 gene)


Influenza A virus (A/England/90/02(H1N2))
384 bp
AJ489501.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526864


Influenza A virus (A/England/90/02(H1N2))
442 bp
AJ489490.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526842


(pb2 gene)


Influenza A virus (A/England/97/02(H1N2))
384 bp
AJ489502.1


partial mRNA for nucleoprotein (np gene)
linear mRNA
GI: 27526866


Influenza A virus (A/England/97/02(H1N2))
442 bp
AJ489491.1


partial mRNA for polymerase subunit 2
linear mRNA
GI: 27526844


(pb2 gene)


Influenza A virus
384 bp
AJ489494.1


(A/England/627/01(H1N2)) partial mRNA for
linear mRNA
GI: 27526850


nucleoprotein (np gene)


Influenza A virus
442 bp
AJ489485.1


(A/England/627/01(H1N2)) partial mRNA for
linear mRNA
GI: 27526832


polymerase subunit 2 (pb2 gene)


Influenza A virus
442 bp
AJ489487.1


(A/England/691/01(H1N2)) partial mRNA for
linear mRNA
GI: 27526836


polymerase subunit 2 (pb2 gene)


Influenza A virus (A/Egypt/96/2002(H1N2))
747 bp
AJ519457.1


partial NS1 gene for non structural
linear mRNA
GI: 31096432


protein 1 and partial NS2 gene for non


structural protein 2, genomic RNA


Influenza A virus (A/Israel/6/2002(H1N2))
773 bp
AJ519456.1


partial NS1 gene for non structural
linear mRNA
GI: 31096429


protein 1 and partial NS2 gene for non


structural protein 2, genomic RNA


Influenza A virus (A/Saudi
772 bp
AJ519453.1


Arabia/2231/2001(H1N2)) partial NS1 gene
linear mRNA
GI: 31096420


for non structural protein 1 and partial


NS2 gene for non structural protein 2,


genomic RNA


Influenza A virus
384 bp
AJ489495.1


(A/Scotland/122/01(H1N2)) partial mRNA
linear mRNA
GI: 27526852


for nucleoprotein (np gene)


Influenza A virus
442 bp
AJ489486.1


(A/Scotland/122/01(H1N2)) partial mRNA
linear mRNA
GI: 27526834


for polymerase subunit 2 (pb2 gene)


Influenza A virus
832 bp
AY861443.1


(A/swine/Bakum/1832/2000(H1N2))
linear mRNA
GI: 57791765


hemagglutinin (HA) mRNA, partial cds


Influenza A virus
467 bp
AY870645.1


(A/swine/Bakum/1832/2000(H1N2))
linear mRNA
GI: 58042754


neuraminidase mRNA, partial cds


Influenza A virus (A/swine/Cotes
1,039 bp
AM503547.1


d'Armor/0040/2007(H1N2)) segment 4
linear mRNA
GI: 225578611


partial mRNA


Influenza A virus (A/swine/Cotes
1,136 bp
AM490224.3


d'Armor/0136_17/2006(H1N2)) partial mRNA
linear mRNA
GI: 222062921


for haemagglutinin precursor (HA1 gene)


Influenza A virus
1,778 bp
AF085417.1


(A/swine/England/72685/96(H1N2))
linear mRNA
GI: 3831770


haemagglutinin precursor, mRNA, complete


cds


Influenza A virus
1,778 bp
AF085416.1


(A/swine/England/17394/96(H1N2))
linear mRNA
GI: 3831768


haemagglutinin precursor, mRNA, complete


cds


Influenza A virus
1,778 bp
AF085415.1


(A/swine/England/690421/95(H1N2))
linear mRNA
GI: 3831766


haemagglutinin precursor, mRNA, complete


cds


Influenza A virus
1,778 bp
AF085414.1


(A/swine/England/438207/94(H1N2))
linear mRNA
GI: 3831764


haemagglutinin precursor, mRNA, complete


cds


Influenza A virus
1,427 bp
AY129157.1


(A/Swine/Korea/CY02/02(H1N2))
linear mRNA
GI: 24286064


neuraminidase (NA) mRNA, complete cds


Influenza A virus
952 bp
AY129158.1


(A/Swine/Korea/CY02/02(H1N2)) matrix
linear mRNA
GI: 24286066


protein (M) mRNA, complete cds


Influenza A virus
1,542 bp
AY129159.1


(A/Swine/Korea/CY02/02(H1N2))
linear mRNA
GI: 24286069


nucleoprotein (NP) mRNA, complete cds


Influenza A virus
842 bp
AY129160.1


(A/Swine/Korea/CY02/02(H1N2))
linear mRNA
GI: 24286081


nonstructural protein (NS) mRNA, complete


cds


Influenza A virus
2,165 bp
AY129161.1


(A/Swine/Korea/CY02/02(H1N2)) polymerase
linear mRNA
GI: 24286087


acidic protein 2 (PA) mRNA, complete cds


Influenza A virus
2,274 bp
AY129162.1


(A/Swine/Korea/CY02/02(H1N2)) polymerase
linear mRNA
GI: 24286096


subunit 1 (PB1) mRNA, complete cds


Influenza A virus
2,334 bp
AY129163.1


(A/Swine/Korea/CY02/02(H1N2)) polymerase
linear mRNA
GI: 24286100


subunit 2 (PB2) mRNA, complete cds


Influenza A virus
1,778 bp
AF085413.1


(A/swine/Scotland/410440/94(H1N2))
linear mRNA
GI: 3831762


haemagglutinin precursor, mRNA, complete


cds


Influenza A virus (A/swine/Spain/80598-
291 bp
EU305436.1


LP4/2007(H1N2)) matrix protein 2 (M2)
linear mRNA
GI: 168830657


mRNA, partial cds


Influenza A virus
975 bp
AJ517813.1


(A/Switzerland/3100/2002(H1N2)) partial
linear mRNA
GI: 38422519


HA gene for Haemagglutinin, genomic RNA


Influenza A virus (A/duck/Hong
1,387 bp
U49095.1


Kong/717/1979(H1N3)) nucleoprotein (NP)
linear mRNA
GI: 1912388


mRNA, partial cds


Influenza A virus (A/duck/Hong
265 bp
U48281.1


Kong/717/1979(H1N3)) polymerase (PB1)
linear mRNA
GI: 1912366


mRNA, partial cds


Influenza A virus (A/herring gull/New
971 bp
AY664422.1


Jersey/780/86(H1N3)) nonfunctional
linear mRNA
GI: 51011826


matrix protein mRNA, partial sequence


Influenza A virus
997 bp
AY664426.1


(A/mallard/Alberta/42/77(H1N6))
linear mRNA
GI: 51011830


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
1,020 bp
U85985.1


(A/swine/England/191973/92(H1N7)) matrix
linear mRNA
GI: 1835733


protein M1 mRNA, complete cds


Influenza A virus
1,524 bp
U85987.1


(A/swine/England/191973/92(H1N7))
linear mRNA
GI: 1835737


nucleoprotein mRNA, complete cds


Influenza A virus
1,458 bp
085988.1


(A/swine/England/191973/92(H1N7))
linear mRNA
GI: 1835739


neuraminidase mRNA, complete cds


Influenza A virus
1,698 bp
U85986.1


(A/swine/England/191973/92(H1N7))
linear mRNA
GI: 1835735


haemagglutinin HA mRNA, partial cds


H2N*


Influenza A virus (A/ruddy
917 bp
AY664465.1


turnstone/Delaware/81/93(H2N1))
linear mRNA
GI: 51011869


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus (A/ruddy
968 bp
AY664429.1


turnstone/Delaware/34/93(H2N1))
linear mRNA
GI: 51011833


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
925 bp
AY664466.1


(A/Shorebird/Delaware/122/97(H2N1))
linear mRNA
GI: 51011870


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
958 bp
AY664454.1


(A/shorebird/Delaware/138/97(H2N1))
linear mRNA
GI: 51011858


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
958 bp
AY664457.1


(A/shorebird/Delaware/111/97(H2N1))
linear mRNA
GI: 51011861


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
979 bp
AY664442.1


(A/shorebird/Delaware/24/98(H2N1))
linear mRNA
GI: 51011846


nonfunctional matrix protein mRNA,


partial sequence


Influenza virus type
2,233 bp
M81579.1


A/Leningrad/134/17/57(H2N2) PA RNA,
linear mRNA
GI: 324935


complete cds


Influenza A virus (STRAIN A/MALLARD/NEW
2,151 bp
AJ243994.1


YORK/6750/78) partial mRNA for PA protein
linear mRNA
GI: 5918195


Influenza A virus (A/X-7 (F1)/(H2N2))
1,467 bp
M11205.1


neuraminidase mRNA, complete cds
linear mRNA
GI: 323969


Influenza A virus
1,009 bp
AY664425.1


(A/mallard/Alberta/77/77(H2N3))
linear mRNA
GI: 51011829


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
968 bp
AY664447.1


(A/mallard/Alberta/226/98(H2N3))
linear mRNA
GI: 51011851


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus (A/sanderling/New
846 bp
AY664477.1


Jersey/766/86(H2N7)) nonfunctional
linear mRNA
GI: 51011881


matrix protein mRNA, partial sequence


Influenza A virus (A/laughing gull/New
907 bp
AY664471.1


Jersey/798/86(H2N7)) nonfunctional
linear mRNA
GI: 51011875


matrix protein mRNA, partial sequence


Influenza A virus (A/herring
960 bp
AY664440.1


gull/Delaware/471/1986(H2N7))
linear mRNA
GI: 51011844


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus (A/ruddy
1,011 bp
AY664423.1


turnstone/Delaware/142/98(H2N8))
linear mRNA
GI: 51011827


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
906 bp
AY664473.1


(A/pintail/Alberta/293/77(H2N9))
linear mRNA
GI: 51011877


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus (A/blue-winged
961 bp
AY664449.1


teal/Alberta/16/97(H2N9)) nonfunctional
linear mRNA
GI: 51011853


matrix protein mRNA, partial sequence


Influenza A virus (A/Laughing gull/New
952 bp
AY664437.1


Jersey/75/85(H2N9)) nonfunctional matrix
linear mRNA
GI: 51011841


protein mRNA, partial sequence


Influenza A virus
959 bp
AY664450.1


(A/mallard/Alberta/205/98(H2N9))
linear mRNA
GI: 51011854


nonfunctional matrix protein mRNA,


partial sequence


H3N*


Influenza A virus (A/duck/Eastern
1,458 bp
EU429755.1


China/267/2003(H3N1)) segment 6
linear mRNA
GI: 167859475


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429754.1


China/253/2003(H3N1)) segment 6
linear mRNA
GI: 167859473


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
E0429753.1


China/252/2003(H3N1)) segment 6
linear mRNA
GI: 167859471


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429752.1


China/243/2003(H3N1)) segment 6
linear mRNA
GI: 167859469


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429734.1


China/262/2003(H3N1)) segment 6
linear mRNA
GI: 167859433


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,459 bp
EU429733.1


China/233/2003(H3N1)) segment 6
linear mRNA
GI: 167859431


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429723.1


China/213/2003(H3N1)) segment 6
linear mRNA
GI: 167859411


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429719.1


China/341/2003(H3N1)) segment 6
linear mRNA
GI: 167859403


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,458 bp
EU429718.1


China/01/2002(H3N1)) segment 6
linear mRNA
GI: 167859401


neuraminidase (NA) mRNA, complete cds


Influenza A virus
1,013 bp
AY664434.1


(A/mallard/Alberta/22/76(H3N6))
linear mRNA
GI: 51011838


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
970 bp
AY664443.1


(A/mallard/Alberta/199/99(H3N6))
linear mRNA
GI: 51011847


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
922 bp
AY664461.1


(A/shorebird/Delaware/222/97(H3N6))
linear mRNA
GI: 51011865


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus (A/Duck/Hokkaido/8/80
984 bp
AF079570.1


(H3N8)) hemagglutinin precursor, mRNA,
linear mRNA
GI: 3414978


partial cds


Influenza A virus (A/Duck/Hokkaido/8/80
1,497 bp
AF079571.1


(H3N8)) nucleoprotein mRNA, complete cds
linear mRNA
GI: 3414980


Influenza A virus
1,461 bp
EU429797.1


(A/duck/Ukraine/1/1963(H3N8)) segment 6
linear mRNA
GI: 167859559


neuraminidase (NA) mRNA, complete cds


(A/duck/Eastern


Influenza A virus (A/duck/Eastern
1,460 bp
EU429698.1


China/19/2004(H3N8)) segment 6
linear mRNA
GI: 167859361


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,460 bp
EU429700.1


China/90/2004(H3N8)) segment 6
linear mRNA
GI: 167859365


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,460 bp
EU429787.1


China/18/2005(H3N8)) segment 6
linear mRNA
GI: 167859539


neuraminidase (NA) mRNA, complete cds


Influenza A virus (A/duck/Eastern
1,460 bp
EU429788.1


China/119/2005(H3N8)) segment 6
linear mRNA
GI: 167859541


neuraminidase (NA) mRNA, complete cds


Influenza A virus
1,061 bp
AF197246.1


(A/equine/Argentina/1/96(H3N8))
linear mRNA
GI: 6651512


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,061 bp
AF197245.1


(A/equine/Argentina/2/94(H3N8))
linear mRNA
GI: 6651510


hemagglutinin precursor (HA1) mRNA


partial cds


Influenza A virus
1,061 bp
AF197244.1


(A/equine/Argentina/1/95(H3N8))
linear mRNA
GI: 6651508


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus HA partial gene for
1,026 bp
AJ223194.1


haemagglutinin, genomic RNA, strain
linear mRNA
GI: 2780201


A/equine/Berlin/3/89(H3N8)


Influenza A virus HA partial gene for
1,006 bp
AJ223195.1


haemagglutinin, genomic RNA, strain
linear mRNA
GI: 2780203


A/equine/Berlin/4/89(H3N8)


Influenza A virus
1,061 bp
AF197242.1


(A/equine/Florida/1/94(H3N8))
linear mRNA
GI: 6651504


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
695 bp
AY328471.1


(A/equine/Grobois/1/98(H3N8))
linear mRNA
GI: 32966577


nonstructural protein NS1 mRNA, complete


cds


Influenza A virus (A/equi
473 bp
AY919314.1


2/Gotland/01(H3N8)) hemagglutinin HA1
linear mRNA
GI: 60250543


subunit mRNA, partial cds


Influenza A virus
1,763 bp
U58195.1


(A/eq/Kentucky/81(H3N8)) hemagglutinin
linear mRNA
GI: 1377873


mRNA, complete cds


Influenza A virus
1,061 bp
AF197247.1


(A/equine/Kentucky/9/95(H3N8))
linear mRNA
GI: 6651514


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,061 bp
AF197248.1


(A/equine/Kentucky/1/96(H3N8))
linear mRNA
GI: 6651516


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,061 bp
AF197249.1


(A/equine/Kentucky/1/97(H3N8))
linear mRNA
GI: 6651518


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,061 bp
AF197241.1


(A/equine/Kentucky/1/98(H3N8))
linear mRNA
GI: 6651502


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,497 bp
AY383753.1


(A/equine/Santiago/85(H3N8))
linear mRNA
GI: 37223511


nucleoprotein mRNA, complete cds


Influenza A virus
1,698 bp
AY383755.1


(A/equine/Santiago/85(H3N8))
linear mRNA
GI: 37223515


hemagglutinin mRNA, complete cds


Influenza A virus
1,413 bp
AY383754.1


(A/equine/Santiago/85(H3N8))
linear mRNA
GI: 37223513


neuraminidase mRNA, complete cds


Influenza A virus
1,061 bp
AF197243.1


(A/equine/Saskatoon/1/90(H3N8))
linear mRNA
GI: 6651506


hemagglutinin precursor (HA1) mRNA,


partial cds


Influenza A virus
1,010 bp
AY664432.1


(A/mallard/Alberta/114/97(H3N8))
linear mRNA
GI: 51011836


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
961 bp
AY664489.1


(A/mallard/Alberta/167/98(H3N8))
linear mRNA
GI: 51011893


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
970 bp
AY664445.1


(A/pintail/Alberta/37/99(H3N8))
linear mRNA
GI: 51011849


nonfunctional matrix protein mRNA,


partial sequence


Influenza A virus
922 bp
AY664455.1


(A/sanderling/Delaware/65/99(H3N8))
linear mRNA
GI: 51011859


nonfunctional matrix protein mRNA,


partial sequence
















TABLE 10







Other Influenza A Antigens (H4N*-H13N*)









GenBank


Strain/Protein
Access No.





H4N*



A/chicken/Singapore/1992(H4N1) M2 protein
EU014144.1


A/mallard/Alberta/47/98(H4N1) nonfunctional matrix protein
AY664488.1


A/duck/Hong Kong/412/1978(H4N2) polymerase (PB1)
U48279.1


A/mallard/Alberta/300/77 (H4N3) nonfunctional matrix protein
AY664480.1


A/Duck/Czechoslovakia/56(H4N6) segment 4 hemagglutinin
AF290436.1


A/duck/Eastern China/376/2004(H4N6) segment 6neuraminidase (NA)
EU429792.1


A/duck/Eastern China/01/2007(H4N6) segment 6 neuraminidase (NA)
EU429790.1


A/duck/Eastern China/216/2007(H4N6) segment 6 neuraminidase (NA)
EU429789.1


A/duck/Eastern China/166/2004(H4N6) segment 6 neuraminidase (NA)
EU429746.1


A/duck/Eastern China/02/2003(H4N6) segment 6 neuraminidase (NA)
EU429713.1


A/duck/Eastern China/160/2002(H4N6) segment 6 neuraminidase (NA)
EU429706.1


A/mallard/Alberta/111/99(H4N6) nonfunctional matrix protein
AY664482.1


A/mallard/Alberta/213/99 (H4N6) nonfunctional matrix protein
AY664460.1


A/mallard/Alberta/30/98 (H4N6) nonfunctional matrix protein
AY664484.1


A/blue-winged teal/Alberta/96/76 (H4N8) nonfunctional matrix protein
AY664420.1


H5N*



A/chicken/Florida/25717/1993(H5N2) hemagglutinin
U05332.1


A/chicken/Hidalgo/26654-1368/1994(H5N2) hemagglutinin (HA)
U37172.1


A/chicken/Jalisco/14585-660/1994(H5N2) hemagglutinin (HA)
U37181.1


A/chicken/Mexico/26654-1374/1994(H5N2) hemagglutinin (HA)
U37173.1


A/chicken/Mexico/31381-3/1994(H5N2) hemagglutinin (HA)
U37176.1


A/chicken/Mexico/31381-6/1994(H5N2) hemagglutinin (HA)
U37175.1


A/chicken/Mexico/31381-4/1994(H5N2) hemagglutinin (HA)
U37174.1


A/chicken/Mexico/31381-5/1994(H5N2) hemagglutinin (HA)
U37169.1


A/chicken/Mexico/31381-8/1994(H5N2) hemagglutinin (HA)
U37170.1


A/Chicken/Mexico/31381-Avilab/94(H5N2)hemagglutinin (HA)
L46585.1


A/chicken/Mexico/31382-1/1994(H5N2)hemagglutinin (HA)
U37168.1


A/chicken/Mexico/31381-2/1994(H5N2) hemagglutinin (HA)
U37167.1


A/chicken/Mexico/31381-1/1994(H5N2) hemagglutinin (HA)
U37166.1


A/chicken/Mexico/31381-7/1994(H5N2) hemagglutinin (HA)
U37165.1


A/chicken/Pennsylvania/13609/1993(H5N2) hemagglutinin
U05331.1


A/chicken/Pennsylvania/1/1983(H5N2) hemagglutinin esterase precursor
M18001.1


A/chicken/Pennsylvania/1370/1983(H5N2) hemagglutinin esterase precursor
M10243.1


A/Chicken/Puebla/8623-607/94(H5N2) hemagglutinin (HA)
L46586.1


A/chicken/Puebla/14586-654/1994(H5N2) hemagglutinin (HA)
U37180.1


A/chicken/Puebla/14585-622/1994(H5N2) hemagglutinin (HA)
U37179.1


A/chicken/Puebla/8623-607/1994(H5N2)hemagglutinin (HA)
U37178.1


A/chicken/Puebla/8624-604/1994(H5N2) hemagglutinin (HA)
U37177.1


A/Chicken/Queretaro/14588-19/95(H5N2) hemagglutinin (HA)
L46587.1


A/chicken/Queretaro/7653-20/95(H5N2) hemagglutinin (HA)
U79448.1


A/chicken/Queretaro/26654-1373/1994(H5N2) hemagglutinin (HA)
U37171.1


A/chicken/Queretaro/14588-19/1994(H5N2)hemagglutinin (HA)
U37182.1


A/chicken/Singapore/98(H5N2) matrix protein 2 (M2)
EF682127.1


A/chicken/Taiwan/1209/03(H5N2) hemagglutinin protein (HA)
AY573917.1


A/chicken/Taiwan/1209/03(H5N2) neuraminidase
AY573918.1


A/duck/Eastern China/64/2004(H5N2) segment 6 neuraminidase (NA)
EU429791.1


A/duck/Eastern China/264/2002(H5N2) segment 6 neuraminidase (NA)
EU429744.1


A/duck/Eastern China/01/2001(H5N2) segment 6 neuraminidase (NA)
EU429728.1


A/duck/Eastern China/06/2000(H5N2) segment 6 neuraminidase (NA)
EU429722.1


A/duck/Hong Kong/342/78(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107452.1


A/duck/Hong Kong/342/78(H5N2) hemagglutinin precursor
U20475.1


A/duck/Michigan/80(H5N2) hemagglutinin 1 chain
U20474.1


A/duck/Michigan/80(H5N2) hemagglutinin
U79449.1


A/duck/MN/1564/81(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107467.1


A/duck/Mongolia/54/2001(H5N2) hemagglutinin (HA)
AB241614.2


A/duck/Primorie/2621/01(H5N2) hemagglutinin (HA)
AJ621811.3


A/duck/Primorie/2621/01(H5N2)nucleoprotein (NP )
AJ621812.1


A/duck/Primorie/2621/01(H5N2) nonstructural protein (NS)
AJ621813.1


A/duck/Pennsylvania/84(H5N2) hemagglutinin 1chain
U20473.1


A/duck/Potsdam/1402-6/86(H5N2) hemagglutinin H5
AF082042.1


A/emu/Texas/39442/93(H5N2) hemaglutinin
U28920.1


A/emu/Texas/39442/93(H5N2) hemaglutinin
U28919.1


A/mallard/Alberta/645/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107471.1


A/mallard/AR/1C/2001(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107463.1


A/mallard/NY/189/82(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107465.1


A/mallard/MN/25/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107473.1


A/mallard/MI/18/80(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107470.1


A/mallard/Ohio/345/88(H5N2) hemagglutinin
U79450.1


A/parrot/CA/6032/04(H5N2) polymerase basic protein 2 (PB2)
DQ256390.1


A/parrot/CA/6032/04(H5N2) polymerase basic protein 1 (PB1)
DQ256389.1


A/parrot/CA/6032/04(H5N2) matrix protein (M)
DQ256384.2


A/parrot/CA/6032/04(H5N2) hemagglutinin (HA)
DQ256383.1


A/parrot/CA/6032/04(H5N2) neuraminidase (NA)
DQ256385.1


A/parrot/CA/6032/04(H5N2) polymerase basic protein 2 (PB2)
DQ256390.1


A/parrot/CA/6032/04(H5N2) nucleoprotein (NP)
DQ256386.1


A/parrot/CA/6032/04(H5N2)) polymerase (PA)
DQ256388.1


A/ruddy turnstone/Delaware/244/91 (H5N2) nonfunctional matrix protein
AY664474.1


A/ruddy turnstone/Delaware/244/91 (H5N2)
U05330.1


A/turkey/Colorado/72(H5N2) hemagglutinin 1 chain (HA)
U20472.1


A/turkey/England/N28/73 (H5N2) hemagglutinin
AY500365.1


A/turkey/TX/14082/81(H5N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107464.1


A/turkey/MN/1704/82(H5N2)) matrix protein 1 (M) and matrix protein 2 (M)
DQ107472.1


A/turkey/Minnesota/10734/95(H5N2)) hemagglutinin
U79455.1


A/turkey/Minnesota/3689-1551/81(H5N2) hemagglutinin
U79454.1


A/chicken/Singapore/1997(H5N3) M2 protein
EU014141.1


A/duck/Hokkaido/299/04(H5N3) hemagglutinin (HA)
AB241626.1


A/duck/Hokkaido/193/04(H5N3) hemagglutinin (HA)
AB241625.1


A/duck/Hokkaido/101/04(H5N3) hemagglutinin (HA)
AB241624.1


A/duck/Hokkaido/447/00(H5N3) hemagglutinin (HA)
AB241620.1


A/duck/Hokkaido/69/00(H5N3) hemagglutinin (HA)
AB241619.1


A/duck/Hong Kong/205/77(H5N3) hemagglutinin H5
AF082038.1


A/duck/Hong Kong/698/79(H5N3) hemagglutinin H5
AF082039.1


A/duck/Hong Kong/308/78(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107457.1


A/duck/Hong Kong/825/80(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107455.1


A/duck/Hong Kong/820/80(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107453.1


A/duck/Hong Kong/205/77(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107456.1


A/Duck/Ho Chi Minh/014/78(H5N3) segment 4 hemagglutinin
AF290443.1


A/duck/Jiangxi/6151/2003(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107451.1


A/duck/Malaysia/F119-3/97(H5N3) hemagglutinin
AF303057.1


A/duck/Miyagi/54/76(H5N3)hemagglutinin (HA)
AB241615.1


A/duck/Mongolia/596/01(H5N3) hemagglutinin HA)
AB241622.1


A/duck/Mongolia/500/01(H5N3)hemagglutinin (HA)
AB241621.1


A/duck/Primorie/2633/01(H5N3) matrix protein (M1)
AJ621810.1


A/duck/Primorie/2633/01(H5N3)nucleoprotein (NP)
AJ621808.1


A/duck/Primorie/2633/01(H5N3)hemagglutinin (HA )
AJ621807.1


A/duck/Primorie/2633/01(H5N3)nucleoprotein (NP)
AJ621809.1


A/goose/Hong Kong/23/78(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107454.1


A/mallard/Wisconsin/169/75(H5N3) hemagglutinin
U79452.1


A/swan/Hokkaido/51/96(H5N3)hemagglutinin (HA)
AB241617.1


A/swan/Hokkaido/4/96(H5N3) hemagglutinin (HA)
AB241616.1


A/turkey/CA/6878/79(H5N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107469.1


A/tern/South Africa/61(H5N3) hemagglutinin precursor (HA)
U20460.1


A/gull/Delaware/5/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M)
DQ107459.1


A/gull/Delaware/4/2000(H5N4) matrix protein 1 (M) and matrix protein 2 (M)
DQ107458.1


A/shorebird/Delaware/109/2000(H5N4) matrix protein 1 (M)
DQ107460.1


A/shorebird/Delaware/243/2000(H5N4) matrix protein 1 (M) and matrix protein 2
DQ107462.1


(M)



A/shorebird/Delaware/230/2000(H5N4) matrix protein 1 (M) and matrix protein 2
DQ107461.1


(M)



A/mallard/Wisconsin/34/75(H5N6) hemagglutinin
U79451.1


A/duck/Potsdam/2216-4/1984(H5N6) hemagglutinin H5
AF082041.1


A/shorebird/Delaware/207/98 (H5N8) nonfunctional matrix protein
AY664456.1


A/shorebird/Delaware/27/98 (H5N8) nonfunctional matrix protein
AY664453.1


A/herring gull/Delaware/281/98 (H5N8) nonfunctional matrix protein
AY664452.1


A/mallard/Ohio/556/1987(H5N9) hemagglutinin (HA)
U67783.2


A/turkey/Wisconsin/68(H5N9) hemagglutinin
U79456.1


H6N*



A/blue-winged teal/Alberta/685/82(H6N1) matrix protein 1 (M) and matrix protein
DQ107448.1


2 (M)



A/chicken/Taiwan/7-5/99(H6N1) nucleocapsid protein (NP)
AF261750.1


A/chicken/Taiwan/7-5/99(H6N1) matrix protein
AF262213.1


A/chicken/Taiwan/7-5/99(H6N1) nonstructural protein
AF262212.1


A/chicken/Taiwan/7-5/99(H6N1) polymerase (PA)
AF262211.1


A/chicken/Taiwan/7-5/99(H6N1) polymerase subunit PB1
AF262210.1


A/chicken/Taiwan/7-5/99(H6N1) nucleocapsid protein (NP)
AF261750.1


A/chicken/Taiwan/ns2/99(H6N1) segment 4 hemagglutinin (HA1)
AF310985.1


A/chicken/Taiwan/na3/98(H6N1) segment 4 hemagglutinin (HA1)
AF310984.1


A/chicken/Taiwan/7-5/99(H6N1) segment 4 hemagglutinin (HA1)
AF310983.1


A/duck/Hong Kong/D73/76(H6N1) matrix protein 1 (M) and matrix protein 2 (M)
DQ107432.1


A/duck/Taiwan/9/23-3/2000(H6N1) matrix protein 1 (M) and matrix protein 2 (M)
DQ107407.1


A/pheasant/Hong Kong/FY479/2000(H6N1) matrix protein 1 (M) and matrix
DQ107409.1


protein 2 (M)



A/pheasant/Hong Kong/SSP44/2002(H6N1) matrix protein 1 (M) and matrix
DQ107412.1


protein 2 (M)



A/quail/Hong Kong/YU421/2002(H6N1) matrix protein 1 (M) and matrix protein 2
DQ107414.1


(M)



A/avian/NY/17150-7/2000(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107423.1


A/chicken/CA/285/2003(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107429.1


A/chicken/CA/375TR/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107428.1


A/chicken/CA/203/2003(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107426.1


A/chicken/NY/101250-7/2001(H6N2) matrix protein 1 (M) and matrix protein 2
DQ107419.1


(M)



A/chicken/CA/625/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107418.1


A/Chicken/California/0139/2001(H6N2)nucleoprotein (NP)
AF474070.1


A/Chicken/California/650/2000(H6N2) nucleoprotein (NP)
AF474069.1


A/Chicken/California/9420/2001(H6N2) neuraminidase N2 (N2)
AF474048.1


A/Chicken/California/9174/2001 (H6N2) neuraminidase N2 (N2)
AF474047.1


A/Chicken/California/8892/2001(H6N2)neuraminidase N2 (N2)
AF474046.1


A/Chicken/California/6643/2001(H6N2) neuraminidase N2 (N2)
AF474045.1


A/Chicken/California/1316/2001(H6N2)neuraminidase N2 (N2)
AF474044.1


A/Chicken/California/0139/2001(H6N2) neuraminidase N2 (N2)
AR474043.1


A/Chicken/California/1002/2000(H6N2) neuraminidase N2 (N2)
AF474042.1


A/Chicken/California/650/2000(H6N2) neuraminidase N2 (N2)
AF474041.1


A/Chicken/California/465/2000(H6N2) neuraminidase N2 (N2)
AF474040.1


A/Chicken/California/431/2000(H6N2) neuraminidase N2 (N2)
AF474039.1


A/Chicken/California/6643/2001 (H6N2) hemagglutinin H6 (H6)
AF474035.1


A/Chicken/California/431/2000(H6N2) hemagglutinin H6 (H6)
AF474029.1


A/Chicken/California/9420/2001(H6N2) hemagglutinin H6 (H6)
AF474038.1


A/Chicken/California/9174/2001 (H6N2) hemagglutinin H6 (H6)
AF474037.1


A/Chicken/California/8892/2001(H6N2) hemagglutinin H6 (H6)
AF474036.1


A/Chicken/California/1316/2001 (H6N2) hemagglutinin H6 (H6)
AF474034.1


A/Chicken/California/0139/2001(H6N2) hemagglutinin H6 (H6)
AF474033.1


A/Chicken/California/1002/2000(H6N2) hemagglutinin H6 (H6)
AF474032.1


A/Chicken/California/650/2000(H6N2) hemagglutinin H6 (H6)
AF474031.1


A/Chicken/California/465/2000(H6N2) hemagglutinin H6 (H6)
AF474030.1


A/cornish cross/CA/139/2001(H6N2) matrix protein 1 (M) and matrix protein 2
DQ107424.1


(M)



A/duck/Eastern China/164/2002(H6N2) segment 6 neuraminidase (NA)
EU429762.1


A/duck/Eastern China/729/2003(H6N2) segment 6 neuraminidase (NA)
EU429760.1


A/duck/Eastern China/262/2002(H6N2) segment 6 neuraminidase (NA)
EU429743.1


A/duck/Eastern China/74/2006(H6N2) segment 6 neuraminidase (NA)
EU429741.1


A/duck/Eastern China/161/2002(H6N2) segment 6 neuraminidase (NA)
EU429740.1


A/duck/Hong Kong/960/80(H6N2)) matrix protein 1 (M) and matrix protein 2 (M)
DQ107435.1


A/duck/Hong Kong/D134/77(H6N2)) matrix protein 1 (M) and matrix protein 2
DQ107433.1


(M)



A/duck/CA/10221/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107421.1


A/duck/Shantou/5540/2001(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107431.1


A/guinea fowl/Hong Kong/SSP99/2002(H6N2) matrix protein 1 (M) and matrix
DQ107413.1


protein 2 (M)



A/mallard/NY/016/83(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107449.1


A/mallard/NY/046/83(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107450.1


A/pintail/Alberta/644/81(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107445.1


A/quail/Hong Kong/SF792/2000(H6N2) matrix protein 1 (M) and matrix protein 2
DQ107410.1


(M)



A/ruddy turnstone/Delaware/106/98 (H6N2) nonfunctional matrix protein
AY664439.1


A/Shorebird/Delaware/127/97(H6N2) nonfunctional matrix protein
AY664467.1


A/shorebird/Delaware/124/2001(H6N2) matrix protein 1 (M) and matrix protein 2
DQ107417.1


(M)



A/shorebird/Delaware/208/2001(H6N2) matrix protein 1 (M) and matrix protein 2
DQ107427.1


(M)



A/turkey/CA/527/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107420.1


A/turkey/CA/1623CT/2002(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107425.1


A/turkey/MN/836/80(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107440.1


A/turkey/MN/735/79(H6N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107437.1


A/chicken/Hong Kong/17/77(H6N4)) matrix protein 1 (M) and matrix protein 2
DQ107436.1


(M)



A/chicken/Hong Kong/CSW106/2001(H6N4) matrix protein 1 (M) and matrix
DQ107406.1


protein 2 (M)



A/gull/Delaware/18/2000(H6N4) matrix protein 1 (M) and matrix protein 2 (M)
DQ107415.1


A/pheasant/Hong Kong/CSW2573/2001(H6N4) matrix protein 1 (M) and matrix
DQ107411.1


protein 2 (M)



A/quail/Hong Kong/CSW106/2001(H6N4) matrix protein 1 (M) and matrix protein
DQ107430.1


2 (M)



A/Shorebird/Delaware/194/98(H6N4) nonfunctional matrix protein
AY664424.1


A/shorebird/Delaware/259/2000(H6N4) matrix protein 1 (M) and matrix protein 2
DQ107416.1


(M)



A/shearwater/Australia/1/1972(H6N5) segment 6 neuraminidase (NA)
EU429794.1


A/shearwater/Australia/1/1972(H6N5) polymerase A (PA)
L25832.1


A/pintail/Alberta/1040/79(H6N5) matrix protein 1 (M) and matrix protein 2 (M)
DQ107439.1


A/blue-winged teal/MN/993/80(H6N6)) matrix protein 1 (M) and matrix protein 2
DQ107441.1


(M)



A/duck/NY/83779/2002(H6N6) matrix protein 1 (M) and matrix protein 2 (M)
DQ107422.1


A/duck/MN/1414/81(H6N6) matrix protein 1 (M) and matrix protein 2 (M)
DQ107444.1


A/mallard/Alberta/289/82(H6N6) matrix protein 1 (M) and matrix protein 2 (M)
DQ107447.1


A/mallard duck/MN/1041/80(H6N6) matrix protein 1 (M) and matrix protein 2 (M)
DQ107442.1


A/pintail/Alberta/189/82(H6N6) matrix protein 1 (M) and matrix protein 2 (M)
DQ107446.1


A/sanderling/Delaware/1258/86(H6N6) nonfunctional matrix protein
AY664436.1


A/blue-winged teal/Alberta/368/78(H6N8)) matrix protein 1 (M) and matrix
DQ107438.1


protein 2 (M)



A/ruddy turnstone/Delaware/105/98 (H6N8) nonfunctional matrix protein
AY664428.1


A/domestic duck/NY/81(H6N8)) matrix protein (M)
DQ107443.1


A/duck/Eastern China/163/2002(H6N8) segment 6 neuraminidase (NA)
EU429786.1


A/duck/Hong Kong/D182/77(H6N9) matrix protein 1 (M) and matrix protein 2 (M)
DQ107434.1


A/chicken/Hong Kong/SF3/2001(H6) matrix protein 1 (M) and matrix protein 2
DQ107408.1


(M)



H7N*



A/African starling/England/983/79(H7N1) neuraminidase (N1)
AJ416629.1


A/Afri.Star./Eng-Q/938/79(H7N1) hemagglutinin precurosr
AF149295.1


A/chicken/Italy/1067/99(H7N1) matrix protein 1 (M1)
AJ416630.1


A/chicken/Italy/1067/99(H7N1) neuraminidase (N1)
AJ416627.1


A/chicken/Italy/4575/99 (H7N1) hemagglutinin (HA)
AJ493469.1


A/chicken/Italy/13474/99(H7N1) haemagglutinin (HA)
AJ491720.1


A/chicken/Italy/445/1999(H7N1)
AX537385.1


A/Chicken/Italy/267/00(H7N1) hemagglutinin (HA)
AJ493215.1


A/Chicken/Italy/13489/99(H7N1) hemagglutinin (HA)
AJ493214.1


A/Chicken/Italy/13307/99(H7N1) hemagglutinin (HA)
AJ493212.1


A/chicken/Singapore/1994(H7N1) M2 protein
EU014140.1


A/duck/Hong Kong/301/78(H7N1) matrix protein 1 (M) and matrix protein 2 (M)
DQ107475.1


A/Hong Kong/301/78(H7N1) hemagglutinin (HA)
AY672090.1


A/fowl plaguq virus/Rostock/34 (H7N1) NP protein
AJ243993.1


A/fowl plaguq virus/Rostock/34 (H7N1) PA protein
AJ243992.1


A/fowl plaguq virus/Rostock/34 (H7N1) PB2 protein
AJ243991.1


A/fowl plaguq virus/Rostock/34 (H7N1) PB1 protein
AJ243990.1


A/ostrich/South Africa/5352/92(H7N1) hemagglutinin precursor (HA)
U20458.1


A/rhea/North Carolina/39482/93(H7N1) hemagglutinin precursor (HA)
U20468.1


A/turkey/Italy/3775/99 (H7N1) hemagglutinin (HA)
AJ493472.1


A/turkey/Italy/4603/99 (H7N1) hemagglutinin (HA)
AJ493471.1


A/turkey/Italy/4602/99 (H7N1) hemagglutinin (HA)
AJ493470.1


A/turkey/Italy/4169/99 (H7N1) hemagglutinin (HA)
AJ493468.1


A/turkey/Italy/4073/99 (H7N1) hemagglutinin (HA)
AJ493467.1


A/turkey/Italy/3889/99 (H7N1) hemagglutinin (HA)
AJ493466.1


A/turkey/Italy/12598/99(H7N1) haemagglutinin (HA)
AJ489520.1


A/turkey/Italy/4580/99(H7N1) haemagglutinin (HA)
AJ416628.1


A/Turkey/Italy/335/00(H7N1) haemagglutinin (HA)
AJ493217.1


A/Turkey/Italy/13468/99(H7N1) haemagglutinin (HA)
AJ493216.1


A/Turkey/Italy/13467/99(H7N1) haemagglutinin (HA)
AJ493213.1


A/chicken/CT/9407/2003(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107478.1


A/chicken/NY/116124/2003(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107479.1


A/chicken/PA/143586/2002(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107477.1


A/duck/Hong Kong/293/78(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107474.1


A/duck/Hong Kong/293/78(H7N2) hemagglutinin precursor (HA)
U20461.1


A/laughing gull/Delaware/2838/87 (H7N2) nonfunctional matrix protein
AY664427.1


A/pheasant/NJ/30739-9/2000(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107481.1


A/ruddy turnstone/Delaware/130/99 (H7N2) onfunctional matrix protein
AY664451.1


A/unknown/149717-12/2002(H7N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107480.1


A/unknown/NY/74211-5/2001(H7N2) matrix protein 1 (M) and matrix protein 2
DQ107476.1


(M)



A/unknown/149717-12/2002(H7N2) matrix protein 1 (M) and matrix protein 2(M)
DQ107480.1


A/unknown/NY/74211-5/2001(H7N2) matrix protein 1(M) and matrix protein 2
DQ107476.1


(M)



A/chicken/British Columbia/CN7-3/04 (H7N3) hemagglutinin (HA)
AY644402.1


A/chicken/British Columbia/CN7-3/04 (H7N3) matrix protein (M1)
AY677732.1


A/chicken/Italy/270638/02(H7N3) hemagglutinin (HA)
EU158111.1


A/gadwall/MD/3495/83(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107488.1


A/mallard/Alberta/22/2001(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107482.1


A/mallard/Alberta/699/81(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107487.1


A/pintail/Alberta/25/2001(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107483.1


A/Quail/Arkansas/16309-7/94 (H7N3) hemagglutinin protein subunit 1 precursor
AF072401.1


(HA1)



A/ruddy turnstone/New Jersey/65/85(H7N3) nonfunctional matrix protein
AY664433.1


A/turkey/England/63(H7N3) hemagglutinin precursor (HA)
U20462.1


A/Turkey/Colorado/13356/91 (H7N3) hemagglutinin protein subunit 1 precursor
AF072400.1


(HAI)



A/turkey/MN/1200/80(H7N3)) matrix protein 1 (M) and matrix protein 2 (M)
DQ107486.1


A/turkey/MN/1818/82(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107489.1


A/turkey/Minnesota/1237/80(H7N3) hemagglutinin precursor (HA)
U20466.1


A/turkey/TX/1/79(H7N3) matrix protein 1 (M) and matrix protein 2 (M)
DQ107484.1


A/Turkey/Oregon/71(H7N3) hemagglutinin
AF497557.1


A/Turkey/Utah/24721-10/95 (H7N3) hemagglutinin protein subunit 1 precursor
AF072402.1


(HA1)



A/softbill/South Africa/142/92(H7N4) hemagglutinin precursor (HA)
U20464.1


A/ruddy turnstone/Delaware/2770/87 (H7N5) nonfunctional matrix protein
AY664476.1


A/chicken/Brescia/1902(H7N7) hemagglutinin 1 chain (HA)
U20471.1


A/chicken/Jena/1816/87(H7N7) hemagglutinin precursor (HA)
U20469.1


A/chicken/Leipzig/79(H7N7) hemagglutinin precursor (HA)
U20459.1


A/duck/Heinersdorf/S495/6/86(H7N7) hemagglutinin precursor (HA)
U20465.1


A/equine/Prague/1/56 (H7N7) neuraminidase
U85989.1


A/equine/Santiago/77(H7N7) nucleoprotein
AY383752.1


A/equine/Santiago/77(H7N7) neuraminidase
AY383757.1


A/equine/Santiago/77(H7N7) hemagglutinin
AY383756.1


A/FPV/Weybridge(H7N7) matrix protein
M38299.1


A/goose/Leipzig/187/7/1979(H7N7) hemagglutinin
L43914.1


A/goose/Leipzig/192/7/1979(H7N7) hemagglutinin
L43915.1


A/goose/Leipzig/137/8/1979(H7N7) hemagglutinin
L43913.1


A/ruddy turnstone/Delaware/134/99 (H7N7) nonfunctional matrix protein
AY664468.1


A/seal/Mass/1/80 H7N7 recombinant
S73497.1


A/swan/Potsdam/63/6/81(H7N7) hemagglutinin precursor (HA)
U20467.1


A/tern/Potsdam/342/6/79(H7N7) hemagglutinin precursor (HA)
U20470.1


A/pintail/Alberta/121/79(H7N8) matrix protein 1 (M) and matrix protein 2 (M)
DQ107485.1


A/Turkey/Minnesota/38429/88(H7N9) hemagglutinin
AF497551.1


H8N*



A/turkey/Ontario/6118/1968(H8N4) segment 6 neuraminidase (NA)
EU429793.1


A/Mallard Duck/Alberta/357/84(H8N4) segment 4 hemagglutinin (HA1)
AF310988.1


A/Pintail Duck/Alberta/114/79(H8N4) segment 4 hemagglutinin (HA1)
AF310987.1


A/duck/Eastern China/01/2005(H8N4) segment 6 neuraminidase (NA)
EU429780.1


A/Red Kont/Delaware/254/94(H8N4) segment 4 hemagglutinin (HA1)
AF310989.1


H9N*



A/chicken/Amioz/1527/03(H9N2) nucleoprotein
DQ116511.1


A/chicken/Amioz/1527/03(H9N2) neuraminidase
DQ116081.1


A/chicken/Amioz/1527/03(H9N2) hemagglutinin
DQ108911.1


A/chicken/Alonim/1953/104(H9N2) hemagglutinin
DQ108928.1


A/chicken/Alonim/1552/03(H9N2) hemagglutinin
DQ108914.1


A/chicken/Alonim/1552/03(H9N2) nucleoprotein
DQ116514.1


A/chicken/Alonim/1965/04(H9N2) hemagglutinin
DQ108929.1


A/Chicken/Anhui/1/98(H9N2) hemagglutinin (HA)
AF461511.1


A/Chicken/Beijing/1/95(H9N2) nonfunctional matrix protein
AF536719.1


A/Chicken/Beijing/1/95(H9N2) nucleoprotein (NP)
AF536699.1


A/Chicken/Beijing/1/95(H9N2) nonfunctional nonstructural protein
AF536729.1


A/Chicken/Beijing/1/95(H9N2) segment 6 neuraminidase (NA)
AF536709.1


A/Chicken/Beijing/2/97(H9N2) nucleoprotein (NP)
AF536700.1


A/Chicken/Beijing/2/97(H9N2) nonfunctional matrix protein
AF536720.1


A/Chicken/Beijing/2/97(H9N2) nonfunctional nonstructural protein
AF536730.1


A/Chicken/Beijing/2/97(H9N2) segment 6 neuraminidase (NA)
AF536710.1


A/Chicken/Beijing/1/97(H9N2) hemagglutinin (HA)
AF461530.1


A/Chicken/Beijing/3/99(H9N2) nonfunctional matrix protein
AF536721.1


A/Chicken/Beijing/3/99(H9N2) nucleoprotein (NP)
AF536701.1


A/Chicken/Beijing/3/99(H9N2) nonfunctional nonstructural protein
AF536731.1


A/Chicken/Beijing/3/99(H9N2) segment 6 neuraminidase (NA)
AF536711.1


A/chicken/Beit Alfa/1282/03(H9N2)hemagglutinin
DQ104476.1


A/chicken/Beit-Aran/29/05(H9N2) hemagglutinin
DQ108931.1


A/chicken/Bnei Darom/1557/03(H9N2) hemagglutinin
DQ108915.1


A/chicken/Ein Habsor/1808/04(H9N2) hemagglutinin
DQ108925.1


A/Chicken/Gangxi/2/00(H9N2) hemagglutinin (HA)
AF461514.1


A/Chicken/Gangxi/1/00(H9N2) hemagglutinin (HA)
AF461513.1


A/chicken/Gan Shomron/1465/03(H9N2) hemagglutinin
DQ104480.1


A/chicken/Gan Shomron/1292/03(H9N2) hemagglutinin
DQ104478.1


A/chicken/Gan_Shomron/1465/03(H9N2) nucleoprotein
DQ116506.1


A/chicken/Gan_Shomron/1465/03(H9N2) neuraminidase
DQ116077.1


A/chicken/Gan Shomron/1543/04(H9N2) nucleoprotein
DQ116512.1


A/chicken/Gan Shomron/1543/04(H9N2) hemagglutinin
DQ108912.1


A/Chicken/Guangdong/97(H9N2) nonfunctional matrix protein
AF536722.1


A/Chicken/Guangdong/97(H9N2) nucleoprotein (NP)
AF536702.1


A/Chicken/Guangdong/97(H9N2) nonfunctional nonstructural protein
AF536732.1


A/Chicken/Guangdong/97(H9N2) segment 6 neuraminidase (NA)
AF536712.1


A/Chicken/Gansu/1/99(H9N2) hemagglutinin (HA)
AF461512.1


A/chicken/Gujrat/India/3697/2004(H9N2) polymerase basic 2 (PB2)
DQ979865.1


A/chicken/Haryana/India/2424/2004(H9N2) polymerase basic 2 (PB2)
DQ979862.1


A/Chicken/Henan/98(H9N2) nonfunctional matrix protein
AF536726.1


A/Chicken/Henan/98(H9N2) nucleoprotein (NP)
AF536706.1


A/Chicken/Henan/98(H9N2) nonfunctional nonstructural protein
AF536736.1


A/Chicken/Henan/2/98(H9N2) hemagglutinin (HA)
AF461517.1


A/Chicken/Henan/1/99(H9N2) hemagglutinin (HA)
AF461516.1


A/Chicken/Henan/98(H9N2) segment 6 neuraminidase (NA)
AF536716.1


A/Chicken/Hebei/1/96(H9N2) nonfunctional matrix protein
AF536723.1


A/Chicken/Hebei/1/96(H9N2) segment 6 nonfunctional neuraminidase protein
AF536713.1


A/Chicken/Hebei/1/96(H9N2) nucleoprotein (NP)
AF536703.1


A/Chicken/Hebei/1/96(H9N2) nonfunctional nonstructural protein
AF536733.1


A/Chicken/Hebei/1/96(H9N2) segment 6 nonfunctional neuraminidase protein
AF536713.1


A/Chicken/Hebei/2/00(H9N2) hemagglutinin (HA)
AF461531.1


A/Chicken/Hebei/2/98(H9N2) nonfunctional matrix protein
AF536724.1


A/Chicken/Hebei/2/98(H9N2) nucleoprotein (NP)
AF536704.1


A/Chicken/Hebei/2/98(H9N2) nonfunctional nonstructural protein
AF536734.1


A/Chicken/Hebei/2/98(H9N2) segment 6 neuraminidase (NA)
AF536714.1


A/Chicken/Hebei/1/00(H9N2) hemagglutinin (HA)
AF461515.1


A/Chicken/Hebei/3/98(H9N2) nucleoprotein (NP)
AF536705.1


A/Chicken/Hebei/3/98(H9N2) nonfunctional matrix protein
AF536725.1


A/Chicken/Hebei/3/98(H9N2) nonfunctional onstructural protein
AF536735.1


A/Chicken/Hebei/3/98(H9N)) segment 6 neuraminidase (NA)
AF536715.1


A/chicken/Hong Kong/FY313/2000(H9N2) matrix protein 1 (M) and matrix
DQ107508.1


protein 2 (M)



A/chicken/Hong Kong/WF208/2001(H9N2) matrix protein 1 (M) and matrix
DQ107513.1


protein 2 (M)



A/chicken/Hong Kong/NT471/2002(H9N2) matrix protein 1 (M) and matrix
DQ107514.1


protein 2 (M)



A/chicken/Hong Kong/WF2/99(H9N2) hemagglutinin
AY206677.1


A/chicken/Iarah/1376/03(H9N2) nucleoprotein
DQ116504.1


A/chicken/Iarah/1376/03(H9N2) neuraminidase
DQ116075.1


A/chicken/Iarah/1376/03(H9N2) hemagglutinin
DQ108910.1


A/chicken/India/2793/2003(H9N2) hemagglutinin (HA)
AY336597.1


A/chicken/Iran/101/1998(H9N2) matrix protein 2 (M2)
EU477375.1


A/Chicken/Jiangsu/1/99(H9N)) hemagglutinin (HA)
AF461509.1


A/Chicken/Jiangsu/2/98(H9N2) hemagglutinin (HA)
AF461510.1


A/chicken/Kfar Monash/636/02(H9N2) hemagglutinin
DQ104464.1


A/chicken/Kalanit/1966/06.12.04(H9N2) hemagglutinin
DQ108930.1


A/chicken/Kalanit/1946/04(H9N2) hemagglutinin
DQ108927.1


A/chicken/Korea/S4/2003(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107517.1


A/Chicken/Korea/MS96/96(H9N2) matrix protein 1 and 2 (M)
AF203788.1


A/Chicken/Korea/MS96/96(H9N2) neuraminidase subtype 2
AF203786.1


A/Chicken/Korea/MS96/96(H9N2) nucleoprotein
AF203787.1


A/Chicken/Liaoning/99(H9N2) nonfunctional matrix protein
AF536727.1


A/Chicken/Liaoning/1/00(H9N2) hemagglutinin (HA)
AF461518.1


A/Chicken/Liaoning/99(H9N2) nucleoprotein (NP)
AF536707.1


A/Chicken/Liaoning/99(H9N2) nonfunctional matrix protein
AF536727.1


A/Chicken/Liaoning/99(H9N2) nonfunctional onstructural protein
AF536737.1


A/Chicken/Liaoning/2/00(H9N2) hemagglutinin (HA)
AF461519.1


A/chicken/Liaoning/99(H9N2) segment 6 neuraminidase (NA)
AF536717.1


A/chicken/Mudanjiang/0823/2000(H9N2) nucleoprotein (NP)
AY496851.1


A/Chicken/Mudanjiang/0823/2000 (H9N2) nonstructural protein
AY631868.1


A/Chicken/Mudanjiang/0823/00 (H9N2) hemagglutinin (HA)
AY513715.1


A/chicken/Mudanjiang/0823/2000(H9N2) matrix protein (M1)
AY496852.1


A/chicken/Mudanjiang/0823/2000(H9N2) nucleoprotein (np)
AY496851.1


A/chicken/Maale HaHamisha/90658/00(H9N2) hemagglutinin
DQ104472.1


A/chicken/Maanit/1477/03(H9N2) hemagglutinin
DQ104483.1


A/chicken/Maanit/1291/03(H9N2) hemagglutinin
DQ104477.1


A/chicken/Maanit/1275/03(H9N2) hemagglutinin
DQ104457.1


A/chicken/Maanit/1477/03(H9N2) nucleoprotein
DQ116508.1


A/chicken/Netohah/1373/03 (H9N2) nucleoprotein
DQ116503.1


A/chicken/Netohah/1373/03 (H9N2) neuraminidase
DQ116074.1


A/chicken/Netobah/1373/03 (H9N2) hemagglutinin
DQ108909.1


A/chicken/Neve Ilan/1504/03(H9N2) hemagglutinin
DQ104484.1


A/chicken/Neve_Ilan/1504/03(H9N2) nucleoprotein
DQ116509.1


A/chicken/Neve_Ilan/1504/03(H9N2) neuraminidase
DQ116079.1


A/chicken/Orissa/India/2317/2004(H9N2) polymerase basic 2 (PB2)
DQ979861.1


A/chicken/Pardes-Hana-Carcur/1475/03(H9N2) hemagglutinin
DQ104482.1


A/chicken/Pardes-Hana-Carcur/1475/03(H9N2) neuraminidase
DQ116078.1


A/chicken/Saar/1456/03(H9N2) hemagglutinin
DQ104479.1


A/chicken/Sde_Uziahu/1747/04(H9N2) neuraminidase
DQ116068.1


A/chicken/Sede Uzziyyahu/1651/04(H9N2) hemagglutinin
DQ108923.1


A/chicken/Sde Uziahu/1747/04(H9N2)
DQ108905.1


A/chicken/Singapore/1998(H9N2) M2 protein
EU014142.1


A/chicken/Singapore/1998(H9N2) M2 protein
EU014142.1


A/Chicken/Shandong/98(H9N2) nonfunctional matrix protein
AF536728.1


A/Chicken/Shandong/1/98(H9N2) hemagglutinin (HA)
AF461520.1


A/Chicken/Shandong/98(H9N2) nucleoprotein (NP)
AF536708.1


A/Chicken/Shandong/98(H9N2) nonfunctional nonstructural protein
AF536738.1


A/Chicken/Shandong/98(H9N2) segment 6 neuraminidase (NA)
AF536718.1


A/Chicken/Shandong/2/99(H9N2) hemagglutinin (HA)
AF461521.1


A/chicken/Shandong/1/02(H9N2) neuraminidase (NA)
AY295761.1


A/Chicken/Shanghai/F/98(H9N2) hemagglutinin
AF461532.1


A/Chicken/Shanghai/1/02(H9N2) hemagglutinin
AY281745.1


A/Chicken/Shanghai/2/99(H9N2)) hemagglutinin (HA)
AF461522.1


A/Chicken/Shanghai/3/00(H9N2)) hemagglutinin (HA)
AF461523.1


A/Chicken/Shanghai/F/98(H9N2) hemagglutinin (HA)
AY743216.1


A/Chicken/Shanghai/4-2/01(H9N2) hemagglutinin (HA)
AF461525.1


A/Chicken/Shanghai/4-1/01(H9N2) hemagglutinin (HA)
AF461524.1


A/Chicken/Shanghai/4/01(H9N2) hemagglutinin (HA)
AY083841.1


A/Chicken/Shanghai/3/01(H9N2) hemagglutinin HA)
AY083840.1


A/chicken/Talmei_Elazar/1304/03(H9N2)nucleoprotein
DQ116530.1


A/chicken/Talmei_Elazar/1304/03(H9N2) neuraminidase
DQ116072.1


A/Chicken/Tianjing/2/96(H9N2) hemagglutinin
AF461527.1


A/Chicken/Tianjing/1/96(H9N2) hemagglutinin (HA)
AF461526.1


A/chicken/Tel Adashim/811/01 (H9N2) hemagglutinin
DQ104467.1


A/chicken/Tel Adashim/811/01 (H9N2) nucleoprotein
DQ116527.1


A/ck/Tel_Adashim/811/01(H9N2) neuraminidase
DQ116064.1


A/chicken/Tel Adashim/812/01 (H9N2) nucleoprotein
DQ116528.1


A/chicken/Tel Adashim/812/01 (H9N2) hemagglutinin
DQ104468.1


A/ck/Tel_Adashim/812/01(H9N2) neuraminidase
DQ116065.1


A/chicken/Tel Adashim/786/01 (H9N2) nucleoprotein
DQ116524.1


A/chicken/Tel Adashim/809/01 (H9N2) hemagglutinin
DQ104465.1


A/chicken/Tel Adashim/809/01 (H9N2) nucleoprotein
DQ116525.1


A/chicken/Tel Adashim/1469/03 (H9N2) nucleoprotein
DQ116507.1


A/chicken/Tel Adashim/1469/303(H9N2) hemagglutinin
DQ104481.1


A/chicken/Tel Adashim/1506/03 (H9N2) neuraminidase
DQ116080.1


A/chicken/Tel Adashim/1506/03(H9N2) hemagglutinin
DQ104474.1


A/chicken/Tel Adashim/1506/03 (H9N2) nucleoprotein
DQ116510.1


A/chicken/Tel Adashim/1332/03(H9N2) nucleoprotein
DQ116501.1


A/chicken/Tel Adashim/1321/03(H9N2) nucleoprotein
DQ116500.1


A/chicken/Tel Adashim/1332/03(H9N2) hemagglutinin
DQ108907.1


A/chicken/Tel Adashim/1321/03(H9N2) hemagglutinin
DQ108906.1


A/chicken/Telmond/1308/03(H9N2) nucleoprotein
DQ116499.1


A/chicken/Telmond/1308/03(H9N2) neuraminidase
DQ116073.1


A/chicken/Telmond/1308/03(H9N2) hemagglutinin
DQ108921.1


A/chicken/Tzrofa/1568/04(H9N2) nucleoprotein
DQ116519.1


A/chicken/Tzrofa/1568/04(H9N2) hemagglutinin
DQ108919.1


A/chicken/UP/India/2544/2004(H9N2) polymerase basic 2 (PB2)
DQ979864.1


A/chicken/UP/India/2543/2004(H9N2) polymerase basic 2 (PB2)
DQ979863.1


A/chicken/Wangcheng/4/2001(H9N2) nucleoprotein
AY268949.1


A/chicken/Y sodot/1362/03(H9N2) nucleoprotein
DQ116502.1


A/chicken/Y sodot/1362/03(H9N2) hemagglutinin
DQ108908.1


A/Chicken/Yunnan/2/00(H9N2) hemagglutinin (HA)
AF461529.1


A/Chicken/Yunnan/1/99(H9N2) hemagglutinin (HA)
AF461528.1


A/duck/Eastern China/01/2000(H9N2) segment 6 neuraminidase (NA)
EU429725.1


A/duck/Eastern China/48/2001(H9N2) segment 6 neuraminidase (NA)
EU429707.1


A/duck/Eastern China/66/2003(H9N2) segment 6 neuraminidase (NA)
EU429699.1


A/duck/Eastern China/80/2004(H9N2) segment 6 neuraminidase (NA)
EU429726.1


A/duck/Hong Kong/448/78(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107494.1


A/duck/Hong Kong/448/78(H9N2) hemagglutinin precursor
AY206673.1


A/duck/Hong Kong/366/78(H9N2) hemagglutinin precursor
AY206674.1


A/duck/Hong Kong/784/79(H9N2)) matrix protein 1(M) and matrix protein 2 (M)
DQ107496.1


A/duck/Hong Kong/702/79(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107495.1


/duck/Hong Kong/702/79(H9N2) hemagglutinin precursor
AY206672.1


A/duck/Hong Kong/610/79(H9N2) hemagglutinin precursor
AY206680.1


A/duck/Hong Kong/552/79(H9N2) hemagglutinin precursor
AY206679.1


A/duck/Hong Kong/644/79(H9N2) hemagglutinin precursor
AY206678.1


A/duck/Korea/S13/2003(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107518.1


A/duck/Nanchang/4-361/2001(H9N2) matrix protein 1 (M) and matrix protein 2
DQ107511.1


(M)



A/duck/NY/83793/2002(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107499.1


A/goose/MN/5733-1243/80(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107492.1


A/geese/Tel Adashim/829/01(H9N2) hemagglutinin
DQ104469.1


A/geese/Tel Adasbim/830/01(H9N2 hemagglutinin
DQ104470.1


A/ostrich/Esbkol/1436/03(H9N2) neuraminidase
DQ116076.1


A/ostrich/Eshkol/1436/03(H9N2) nucleoprotein
DQ116505.1


A/pigeon/Hong Kong/WF286/2000(H9N2) matrix protein 1 (M) and matrix protein
DQ107509.1


2 (M)



A/quail/Hong Kong/YU415/2002(H9N2) matrix protein 1 (M) and matrix protein 2
DQ107516.1


(M)



A/quail/Hong Kong/SSP225/2001(H9) matrix protein 1 (M) and matrix protein 2
DQ107512.1


(M)



A/quail/Hong Kong/YU1495/2000(H9N2) matrix protein 1 (M) and matrix protein
DQ107510.1


2 (M)



A/quail/Hong Kong/A28945/88(H9N2) hemagglutinin precursor
AY206675.1


A/shorebird/Delaware/276/99 (H9N2) nonfunctional matrix protein
AY664464.1


A/shorebird/Delaware/113/2001(H9N2) matrix protein 1 (M) and matrix protein 2
DQ107505.1


(M)



A/silky chicken/Hong Kong/WF266/2002(H9N2) matrix protein 2 (M) and matrix
DQ107515.1


protein 1 (M)



A/shorebird/Delaware/77/2001(H9N2) matrix protein 1 (M) and matrix protein 2
DQ107497.1


(M)



A/guinea fowl/Hong Kong/WF10/99(H9N2) hemagglutinin precursor
AY206676.1


A/swine/Hangzhou/1/2006(H9N2) nucleocapsid protein (NP)
DQ907704.1


A/swine/Hangzhou/1/2006(H9N2)) matrix protein 1 (M1)
EF055887.1


A/swine/Hangzhou/1/2006(H9N2)) nonstructural protein 1 (NS1)
DQ823385.1


A/Sw/ShanDong/1/2003(H9N2) hemagglutinin (HA)
AY294658.1


A/turkey/CA/6889/80(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107491.1


A/turkey/TX/28737/81(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107493.1


A/turkey/MN/511/78(H9N2) matrix protein 1 (M) and matrix protein 2 (M)
DQ107490.1


A/turkey/Beit Herut/1267/03(H9N2) hemagglutinin
DQ104485.1


A/turkey/Beit HaLevi/1009/02(H9N2) hemagglutinin
DQ104473.1


A/turkey/Beit Herut/1265/03(H9N2) hemagglutinin
DQ104456.1


A/turkey/Beit_HaLevi/1562/03(H9N2) nucleoprotein
DQ116515.1


A/turkey/Beit_HaLevi/1566/04(H9N2) nucleoprotein
DQ116517.1


A/turkey/Beit_HaLevi/1562/03(H9N2) neuraminidase
DQ116083.1


A/turkey/Beit_HaLevi/1566/04(H9N2) neuraminidase
DQ116084.1


A/turkey/Beit_Herut/1267/03(H9N2) neuraminidase
DQ116070.1


A/turkey/Beit_Herut/1265/03(H9N2) neuraminidase
DQ116069.1


A/turkey/Beit HaLevi/1566/04(H9N2) hemagglutinin
DQ108917.1


A/turkey/Bezat/89/05(H9N2) hemagglutinin
DQ108922.1


A/turkey/Brosh/1276/03(H9N2) hemagglutinin
DQ104458.1


A/turkey/Brosh/1276/03(H9N2) neuraminidase
DQ116071.1


A/turkey/Emek Hefer/1272/03(H9N2) hemagglutinin
DQ104475.1


A/turkey/Ein Habsor/1804/04(H9N2) hemagglutinin
DQ108924.1


A/turkey/Ein Tzurim/1172/02(H9N2) hemagglutinin
DQ104451.1


A/turkey/Ein Tzurim/1738/04(H9N2) hemagglutinin
DQ108920.1


A/turkey/Ein_Tzurim/1738/04(H9N2) neuraminidase
DQ116085.1


A/turkey/Gyvat Haim Ehud/1544/03(H9N2)hemagglutinin
DQ108913.1


A/turkey/Givat Haim/810/01 (H9N2) hemagglutinin
DQ104466.1


A/turkey/Givat Haim/810/01 (H9N2) nucleoprotein
DQ116526.1


A/turkey/Givat Haim/868/02(H9N2) hemagglutinin
DQ104471.1


A/turkey/Givat Haim/622/02(H9N2) hemagglutinin
DQ104462.1


A/turkey/Givat_Haim/965/02(H9N2) nucleoprotein
DQ116498.1


A/turkey/Gyvat_Haim_Ehud/1544/03(H9N2) nucleoprotein
DQ116513.1


A/turkey/Gyvat_Haim_Ehud/1544/03(H9N2) neuraminidase
DQ116082.1


A/tk/Givat_Haim/810/25.12.01(H9N2) neuraminidase
DQ116063.1


A/turkey/Givat_Haim/622/02(H9N2)) neuraminidase
DQ116060.1


A/turkey/Givat_Haim/965/02(H9N2) neuraminidase
DQ116057.1


A/turkey/Hod_Ezyon/699/02(H9N2) neuraminidase
DQ116062.1


A/turkey/Mishmar Hasharon/619/02 (H9N2) hemagglutinin
DQ104461.1


A/turkey/Mishmar_Hasharon/619/02(H9N2) neuraminidase
DQ116059.1


A/turkey/Kfar_Vitkin/616/02(H9N2) neuraminidase
DQ116058.1


A/turkey/Kfar Vitkin/616/02 (H9N2) hemagglutinin
DQ104460.1


A/turkey/Kfar Vitkin/615/02 (H9N2)hemagglutinin
DQ104459.1


A/turkey/Kfar Vitkin/615/02 (H9N2) nucleoprotein
DQ116520.1


A/turkey/Kfar_Vitkin/616/02(H9N2)) nucleoprotein
DQ116521.1


A/turkey/Kfar Warburg/1224/03(H9N2) hemagglutinin
DQ104455.1


A/tk/Kfar_Vitkin/615/02(H9N)) neuraminidase
DQ116067.1


A/turkey/Mishmar_Hasharon/619/02(H9N2) nucleoprotein
DQ116522.1


A/turkey/Naharia/1013/02(H9N2) hemagglutinin
DQ104449.1


A/turkey/Nahalal/1547/04(H9N2) hemagglutinin
DQ108932.1


A/turkey/Neve Ilan/90710/00 (H9N2) nucleoprotein
DQ116529.1


A/tk/Neve_Ilan/90710/00(H9N2) neuraminidase
DQ116066.1


A/turkey/Qevuzat_Yavne/1242/03(H9N2) neuraminidase
DQ116086.1


A/turkey/Sapir/1199/02(H9N2) hemagglutinin
DQ104452.1


A/turkey/Shadmot Dvorah/1567/04(H9N2) nucleoprotein
DQ116518.1


A/turkey/Sbadmot Dvorah/1567/04(H9N2) hemagglutinin
DQ108918.1


A/turkey/Tzur Mosbe/1565/04(H9N2) nucleoprotein
DQ116516.1


A/turkey/Tzur Moshe/1565/04(H9N2) hemagglutinin
DQ108916.1


A/turkey/Yedidia/625/02 (H9N2) hemagglutinin
DQ104463.1


A/turkey/Yedidia/625/02 (H9N2) nucleoprotein
DQ116523.1


A/turkey/Yedidia/625/02 (H9N2) neuraminidase
DQ116061.1


A/turkey/Yedidia/911/02(H9N2) hemagglutinin
DQ104448.1


A/turkey/Avigdor/1215/03(H9N2) hemagglutinin
DQ104454.1


A/turkey/Avigdor/1209/03(H9N2) hemagglutinin
DQ104453.1


A/turkey/Avichail/1075/02(H9N2) hemagglutinin
DQ104450.1


A/turkey/Avigdor/1920/04(H9N2) hemagglutinin
DQ108926.1


A/pintail/Alberta/49/2003(H9N5) matrix protein 1 (M) and matrix protein 2 (M)
DQ107498.1


A/red knot/Delaware/2552/87 (H9N5) nonfunctional matrix protein
AY664472.1


A/duck/Hong Kong/147/77(H9N6) hemagglutinin precursor
AY206671.1


A/shorebird/Delaware/270/2001(H9N7) matrix protein 1 (M) and matrix protein 2
DQ107504.1


(M)



A/shorebird/Delaware/277/2000(H9N7) matrix protein 1 (M) and matrix protein 2
DQ107507.1


(M)



A/shorebird/Delaware/275/2001(H9N7)) matrix protein 2 (M) and matrix protein 1
DQ107506.1


(M)



A/ruddy turnstone/Delaware/116/98 (H9N8) nonfunctional matrix protein
AY664435.1


A/shorebird/Delaware/141/2002(H9N9) matrix protein 1 (M) and matrix protein 2
DQ107503.1


(M)



A/ruddy turnstone/Delaware/103/2002(H9N9) matrix protein 1 (M) and matrix
DQ107502.1


protein 2 (M)



A/shorebird/Delaware/29/2002(H9N9) matrix protein 1 (M) and matrix protein 2
DQ107501.1


(M)



A/shorebird/Delaware/18/2002(H9N9) matrix protein 1 (M) and matrix protein 2
DQ107500.1


(M)



A/ruddy turnstone/Delaware/259/98 (H9N9) nonfunctional matrix protein
AY664469.1


H10N*



A/duck/Eastern China/527/2003(H10N3) segment 6 neuraminidase (NA)
EU429716.1


A/duck/Eastern China/495/2003(H10N3) segment 6 neuraminidase (NA)
EU429715.1


A/duck/Eastern China/372/2003(H10N3) segment 6 neuraminidase (NA)
EU429714.1


A/duck/Eastern China/488/2003(H10N3) segment 6 neuraminidase (NA)
EU429712.1


A/duck/Eastern China/453/2002(H10N3) segment 6 neuraminidase (NA)
EU429711.1


A/duck/Eastern China/412/2003(H10N3) segment 6 neuraminidase (NA)
EU429710.1


A/duck/Eastern China/404/2003(H10N3) segment 6 neuraminidase (NA)
EU429709.1


A/duck/Eastern China/397/2003(H10N3) segment 6 neuraminidase (NA)
EU429708.1


A/duck/Eastern China/502/2003(H10N3) segment 6 neuraminidase (NA)
EU429705.1


A/duck/Eastern China/395/2003(H10N3) segment 6 neuraminidase (NA)
EU429704.1


A/duck/Eastern China/356/2003(H10N3) segment 6 neuraminidase (NA)
EU429703.1


A/duck/Eastern China/368/2003(H10N3) segment 6 neuraminidase (NA)
EU429702.1


A/chicken/Singapore/1993(H10N5) M2 protein
EU014145.1


A/red knot/Delaware/2561/87 (H10N5) nonfunctional matrix protein
AY664441.1


A/chicken/Germany/N/1949(H10N7) segment 6 neuraminidase (NA)
EU429796.1


A/ruddy turnstone/Delaware/2764/87 (H10N7) nonfunctional matrix protein
AY664462.1


A/mallard/Alberta/71/98 (H10N7) nonfunctional matrix protein
AY664485.1


A/mallard/Alberta/90/97 (H10N7) nonfunctional matrix protein
AY664446.1


A/mallard/Alberta/110/99(H10N7) nonfunctional matrix protein
AY664481.1


A/mallard/Alberta/297/77 (H10N7) nonfunctional matrix protein
AY664430.1


A/mallard/Alberta/223/98 (H10N8) nonfunctional matrix protein
AY664486.1


H11N*



A/ruddy turnstone/New Jersey/51/85 (H11N1) nonfunctional matrix protein
AY664479.1


A/duck/Nanchang/1749/1992(H11N2) nucleoprotein (NP)
U49094.1


A/duck/Hong Kong/62/1976(H11N2) polymerase (PB1)
U48280.1


A/duck/Yangzhou/906/2002(H11N2) hemagglutinin
DQ080993.1


A/shorebird/Delaware/86/99 (H11N2) nonfunctional matrix protein
AY664463.1


A/ruddy turnstone/Delaware Bay/2762/1987(H11N2)polymerase PB2 (PB2)
CY126279.1


A/ruddy turnstone/Delaware/2762/87 (H11N2) nonfunctional matrix protein
AY664459.1


A/ruddy turnstone/Delaware Bay/2762/1987(H11N2) polymerase PB1 (PB1) and
CY126278.1


PB1-F2 protein (PB1-F2)



A/ruddy turnstone/Delaware/2589/87 (H11N4) nonfunctional matrix protein
AY664478.1


A/duck/England/1/1956(H11N6) segment 6 neuraminidase (NA)
EU429795.1


A/mallard/Alberta/125/99 (H11N6) nonfunctional matrix protein
AY664483.1


A/duck/Memphis/546/1974(H11N9) segment 6 neuraminidase (NA)
EU429798.1


A/mallard/Alberta/122/99 (H11N9) nonfunctional matrix protein
AY664444.1


H12N*



A/Mallard Duck/Alberta/342/83(H12N1) segment 4 hemagglutinin (HA1)
AF310991.1


A/ruddy turnstone/Delaware/67/98(H12N4) nonfunctional matrix protein
AY664470.1


A/Ruddy Turnstone/Delaware/67/98(H12N4) segment 4 hemagglutinin (HA1)
AF310990.1


A/mallard/Alberta/52/97 (H12N5) nonfunctional matrix protein
AY664448.1


A/mallard/Alberta/223/77 (H12N5) nonfunctional matrix protein
AY664431.1


A/Laughing Gull/New Jersey/171/92(H12N5) segment 4 hemagglutinin (HA1)
AF310992.1


A/ruddy turnstone/Delaware/265/98 (H12N8) nonfunctional matrix protein
AY664438.1


H13N*



A/herring gull/New Jersey/782/86 (H13N2) nonfunctional matrix protein
AY664475.1


A/shorebird/Delaware/224/97 (H13N6) nonfunctional matrix protein
AY664421.1


Other



A/PR/8/34 (H1N1) x A/England/939/69 (H3N2) PB1 protein
AJ564806.1


A/PR/8/34 (H1N1) x A/England/939/69 (H3N2)PB2 protein
AJ564804.1


A/duck/Czechslovakia/56(H4N6) x A/USSR/90/77(H1N1)) neuraminidase (NA)
EU643639.1


A/duck/Czechslovakia/56(H4N6) x A/USSR/90/77(H1N1)) neuraminidase (NA)
EU643638.1


A/duck/Ukraine/63(H3N8) x A/USSR/90/77(H1N1)) neuraminidase (NA)
EU643637.1


A/duck/Ukraine/63(H3N8) x A/USSR/90/77(H1N1)) neuraminidase (NA)
EU643636.1


RCB1-XXI: A/USSR/90/77(H1N1)xA/Duck/Czechoslov 56 (H4N6) segment 4
AF290438.1


hemagglutinin



RCB1: A/USSR/90/77(H1N1)xA/Duck/Czechoslov 56 (H4N6) hemagglutinin
AF290437.1


PX14-XIII (A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3))
AF290442.1


segment 4 hemagglutinin



PX14(A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) segment 4
AF290441.1


hemagglutinin



PX8-XIII(A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3))



segment 4 hemagglutinin



PX8(A/USSR/90/77(H1N1)xA/Pintail Duck/Primorie/695/76(H2N3)) segment 4
AF290439.1


hemagglutinin



A/swine/Schleswig-Holstein/1/93 hemagglutinin (HA)
U72669.1


A/swine/England/283902/93 hemagglutinin (HA)
U72668.1


A/swine/England/195852/92 hemagglutinin (HA)
U72667.1


A/swine/England/117316/86 hemagglutinin (HA)
U72666.1


A/turkey/Germany/2482/90) hemagglutinin (HA)
U96766.1
















TABLE 11







Influenza B Antigens









GenBank Access


Strain/Protein
No.





B/Daeku/47/97 hemagglutinin
AF521237.1


B/Daeku/45/97 hemagglutinin
AF521236.1


B/Daeku/10/97 hemagglutinin
AF521221.1


B/Daeku/9/97 hemagglutinin
AF521220.1


B/Gyeonggi/592/2005 neuraminidase
DQ231543.1


B/Gyeonggi/592/2005 hemagglutinin
DQ231538.1


B/Hong Kong/5/72 neuraminidase
AF305220.1


B/Hong Kong/5/72 hemagglutinin
AF305219.1


B/Hong Kong/157/99 hemagglutinin
AF387503.1


B/Hong Kong/157/99 hemagglutinin
AF387502.1


B/Hong Kong/156/99 hemagglutinin
AF387501.1


B/Hong Kong/156/99 hemagglutinin
AF387500.1


B/Hong Kong/147/99 hemagglutinin
AF387499.1


B/Hong Kong/147/99 hemagglutinin
AF387498.1


B/Hong Kong/110/99 hemagglutinin
AF387497.1


B/Hong Kong/110/99 hemagglutinin
AF387496.1


B/Incheon/297/2005 hemagglutinin
DQ231539.1


B/Incheon/297/2005 neuraminidase
DQ231542.1


B/Lee/40 polymerase protein (PB1)
D00004.1


B/Michigan/22572/99 hemagglutinin
AY129961.1


B/Michigan/22723/99 hemagglutinin (HA)
AY112992.1


B/Michigan/22631/99 hemagglutinin (HA)
AY112991.1


B/Michigan/22587/99 hemagglutinin (HA)
AY112990.1


B/New York/20139/99 hemagglutinin
AY129960.1


B/Panama/45/90 nucleoprotein
AF005739.1


B/Panama/45/90 polymerase (PA)
AF005738.1


B/Panama/45/90 polymerase (PB2)
AF005737.1


B/Panama/45/90 polymerase (PB1)
AF005736.1


B/Pusan/250/99 hemagglutinin
AF521218.1


B/Pusan/255/99 hemagglutinin
AF521226.1


B/Pusan/270/99 hemagglutinin
AF521219.1


B/Pusan/285/99 hemagglutinin
AF521217.1


B/Riyadh/01/2007 segment 8 nuclear export protein
GU135839.1


(NEP) and non structural protein 1 (NS1)



B/Seoul/6/88 hemagglutinin
AF521238.1


B/Seoul/12/88 hemagglutinin
AF521239.1


B/Seoul/1/89 hemagglutinin
AF521230.1


B/Seoul/37/91 hemagglutinin
AF521229.1


B/Seoul/38/91 hemagglutinin
AF521227.1


B/Seoul/40/91 hemagglutinin
AF521235.1


B/Seoul/41/91 hemagglutinin
AF521228.1


B/Seoul/13/95 hemagglutinin
AF521225.1


B/Seoul/12/95 hemagglutinin
AF521223.1


B/Seoul/17/95 hemagglutinin
AF521222.1


B/Seoul/21/95 hemagglutinin
AF521224.1


B/Seoul/16/97 hemagglutinin
AF521233.1


B/Seoul/19/97 hemagglutinin
AF521231.1


B/Scoul/28/97 hemagglutinin
AF521234.1


B/Seoul/31/97 hemagglutinin
AF521232.1


B/Seoul/232/2004 neuraminidase
DQ231541.1


B/Seoul/1163/2004 neuraminidase
DQ231540.1


B/Seoul/1163/2004 hemagglutinin
DQ231537.1


B/Sichuan/379/99 hemagglutinin (HA)
AF319590.1


B/Sichuan/38/2000 hemagglutinin (HA)
AF319589.1


B/South Carolina/25723/99 hemagglutinin
AY129962.1


B/Switzerland/4291/97 hemagglutinin
AF387505.1


B/Switzerland/4291/97 hemagglutinin
AF387504.1


B/Taiwan/21706/97 nonstructural protein 1 (NS1)
AF492479.1


B/Taiwan/21706/97 hemagglutinin (HA)
AF026162.1


B/Taiwan/3143/97 nonstructural protein 1 (NS1)
AF492478.1


B/Taiwan/3143/97 haemagglutinin (HA)
AF026161.1


B/Taiwan/2026/99 nonstructural protein 1 (NS1)
AF492481.1


B/Taiwan/2026/99 hemagglutinin
AY604741.1


B/Taiwan/2027/99 nonstructural protein 1 (NS1)
AF492480.1


B/Taiwan/2027/99 hemagglutinin
AY604742.1


B/Taiwan/1243/99 nonstructural protein NS1(NS1)
AF380504.1


B/Taiwan/1243/99 hemagglutinin
AY604740.1


B/Taiwan/2195/99 hemagglutinin
AY604743.1


B/Taiwan/2195/99 nonstructural protein 1 (NS1)
AF492482.1


B/Taiwan/1293/2000 nonstructural protein NS1(NS1)
AF380509.1


B/Taiwan/1293/00 hemagglutinin
AY604746.1


B/Taiwan/1293/2000 hemagglutinin (HA)
AF492477.1


B/Taiwan/1265/2000 nonstructural protein NS1 (NS1)
AF380508.1


B/Taiwan/1265/00 hemagglutinin
AY604745.1


B/Taiwan/4184/2000 nonstructural protein NS1 (NS1)
AF380507.1


B/Taiwan/4184/00 hemagglutinin (HA)
AY604750.1


B/Taiwan/31511/2000 nonstructural protein NS1 (NS1)
AF380505.1


B/Taiwan/31511/00 hemagglutinin (HA)
AY604748.1


B/Taiwan/12192/2000 hemagglutinin
AY604747.1


B/Taiwan/41010/00 hemagglutinin (HA)
AY604749.1


B/Taiwan/41010/2000 nonstructural protein NS1 (NS1)
AF380506.1


B/Taiwan/0409/00 hemagglutinin (HA)
AY604744.1


B/Taiwan/202/2001 nonstructural protein 1 (NS1)
AF380512.1


B/Taiwan/202/2001 hemagglutinin (HA)
AF366076.1


B/Taiwan/11515/2001 nonstructural protein 1 (NS1)
AF380511.1


B/Taiwan/11515/01 hemagglutinin
AY604754.1


B/Taiwan/11515/2001 hemagglutinin (HA)
AF366075.1


B/Taiwan/1103/2001 nonstructural protein NS1 (NS1)
AF380510.1


B/Taiwan/1103/01 hemagglutinin
AY604755.1


B/Taiwan/114/2001 hemagglutinin (HA), HA-4 allele
AF492476.1


B/Taiwan/2805/2001 hemagglutinin (HA)
AF400581.1


B/Taiwan/2805/01 hemagglutinin (HA)
AY604752.1


B/Taiwan/0114/01 hemagglutinin (HA)
AY604753.1


B/Taiwan/0202/01 hemagglutinin (HA)
AY604751.1


B/Taiwan/4119/02 hemagglutinin (HA)
AY604778.1


B/Taiwan/4602/02 hemagglutinin (HA)
AY604777.1


B/Taiwan/1950/02 hemagglutinin (HA)
AY604776.1


B/Taiwan/1949/02 hemagglutinin (HA)
AY604775.1


B/Taiwan/1584/02 hemagglutinin (HA)
AY604774.1


B/Taiwan/1561/02 hemagglutinin (HA)
AY604773.1


B/Taiwan/1536/02 hemagglutinin (HA)
AY604772.1


B/Taiwan/1534/02 hemagglutinin (HA)
AY604771.1


B/Taiwan/1503/02 hemagglutinin (HA)
AY604770.1


B/Taiwan/1502/02 hemagglutinin (HA)
AY604769.1


B/Taiwan/1013/02 hemagglutinin (HA)
AY604768.1


B/Taiwan/0993/02 hemagglutinin (HA)
AY604766.1


B/Taiwan/0932/02 hemagglutinin (HA)
AY604765.1


B/Taiwan/0927/02 hemagglutinin (HA)
AY604764.1


B/Taiwan/0880/02 hemagglutinin (HA)
AY604763.1


B/Taiwan/0874/02 hemagglutinin (HA)
AY604762.1


B/Taiwan/0730/02 hemagglutinin (HA)
AY604761.1


B/Taiwan/0722/02 hemagglutinin (HA)
AY604760.1


B/Taiwan/0702/02 hemagglutinin (HA)
AY604759.1


B/Taiwan/0654/02 hemagglutinin (HA)
AY604758.1


B/Taiwan/0600/02 hemagglutinin (HA)
AY604757.1


B/Taiwan/0409/02 hemagglutinin (HA)
AY604756.1


B/Taiwan/0879/02 nonfunctional hemagglutinin
AY604767.1


B/Taiwan/3532/03 hemagglutinin (HA)
AY604794.1


B/Taiwan/2551/03 hemagglutinin (HA)
AY604793.1


B/Taiwan/1618/03 hemagglutinin (HA)
AY604792.1


B/Taiwan/1574/03 hemagglutinin (HA)
AY604791.1


B/Taiwan/1013/03 hemagglutinin (HA)
AY604790.1


B/Taiwan/0833/03 hemagglutinin (HA)
AY604789.1


B/Taiwan/0735/03 hemagglutinin (HA)
AY604788.1


B/Taiwan/0699/03 hemagglutinin (HA)
AY604787.1


B/Taiwan/0684/03 hemagglutinin (HA)
AY604786.1


B/Taiwan/0616/03 hemagglutinin (HA)
AY604785.1


B/Taiwan/0615/03 hemagglutinin (HA)
AY604784.1


B/Taiwan/0610/03 hemagglutinin (HA)
AY604783.1


B/Taiwan/0576/03 hemagglutinin (HA)
AY604782.1


B/Taiwan/0569/03 hemagglutinin (HA)
AY604781.1


B/Taiwan/0562/03 hemagglutinin (HA)
AY604780.1


B/Taiwan/0002/03 hemagglutinin (HA)
AY604779.1


B/Taiwan/773/2004 hemagglutinin (HA)
EU068195.1


B/Taiwan/187/2004 hemagglutinin (HA)
EU068194.1


B/Taiwan/3892/2004 hemagglutinin (HA)
EU068193.1


B/Taiwan/562/2004 hemagglutinin (HA)
EU068191.1


B/Taiwan/234/2004 hemagglutinin (HA)
EU068188.1


B/Taiwan/4897/2004 hemagglutinin (HA)
EU068186.1


B/Taiwan/8579/2004 hemagglutinin (HA)
EU068184.1


B/Taiwan/184/2004 hemagglutinin (HA)
EU068183.1


B/Taiwan/647/2005 hemagglutinin (HA)
EU068196.1


B/Taiwan/877/2005 hemagglutinin (HA)
EU068198.1


B/Taiwan/521/2005 hemagglutinin (HA)
EU068189.1


B/Taiwan/1064/2005 hemagglutinin (HA)
EU068192.1


B/Taiwan/3722/2005 hemagglutinin (HA)
EU068197.1


B/Taiwan/5049/2005 hemagglutinin (HA)
EU068190.1


B/Taiwan/5011/2005 hemagglutinin (HA)
EU068187.1


B/Taiwan/4659/2005 hemagglutinin (HA)
EU068185.1


B/Taiwan/25/2005 hemagglutinin (HA)
EU068182.1


B/Taiwan/1037/2005 hemagglutinin (HA)
EU068181.1


B/Taiwan/62/2005 hemagglutinin (HA)
EU068180.1


B/Taiwan/591/2005 hemagglutinin (HA)
EU068179.1


B/Taiwan/649/2005 hemagglutinin (HA)
EU068178.1


B/Taiwan/4554/2005 hemagglutinin (HA)
EU068177.1


B/Taiwan/987/2005 hemagglutinin (HA)
EU068176.1


B/Taiwan/2607/2006 hemagglutinin (HA)
EU068175.1


B/Vienna/1/99 hemagglutinin
AF387495.1


B/Vienna/1/99 hemagglutinin
AF387494.1


B/Vienna/1/99 hemagglutinin
AF387493.1


B/Vienna/1/99 hemagglutinin
AF387492.1
















TABLE 12







Influenza C Antigens









GenBank


Strain/Protein
Access No.





C/JHB/1/66) hemagglutinin-esterase-fusion
AY880247.1


protein (HEF) mRNA, complete cds.



STRAIN C/ANN ARBOR/1/50) persistent variant
AF102027.1


segment 7 non-structural protein 1 (NS1) mRNA, complete cds



(STRAIN C/ANN ARBOR/1/50) wild type segment 7 non-structural protein 1
AF102026.1


(NS1) mRNA, complete cds



(C/JHB/1/66) hemagglutinin-esterase-fusion protein (HEF) mRNA, complete cds
AY880247.1


(STRAIN C/BERLIN/1/85) mRNA for basic polymerase 2 precursor
X55992.1
















TABLE 13







H7 Hemagglutinin Amino Acid Sequences









SEQ
Accession No/



ID NO
Strain/Protein
Amino Acid Sequence












1
AAM19228
ACVLVEAKGDKICLGHHAVVNGTKVNTLTEKGIEVVNAT



A/turkey/
ETVETANIGKICTQGKRPTDLGQCGLLGTLIGPPQCDQFLE



Minnesota/
FESDLIIERREGNDVCYPGKFTNEESLRQILRGSGGIDKESM



38429/1988
GFTYSGIITNGATSACRRSGSSFYAEMKWLLSNSDNAAFP



1988// HA
QMTKSYRNPRNKPALIVWGIHHSGSTTEQTKLYGSGNKLI



20335017
TVESSKYQQSFTPSPGARPQVNGESGRIDFHWMLLDPNDT




VTFTFNGAFIAPDRASFFKGESLGVQSDVPLDSSCGGDCFH




SGGTIVSSLPFQNINPRTVGKCPRYVKQPSLLLATGMRNVP




ENPKTRGLFGAIAGFIEKDGGSHYG





2
AAY46211
MNTQILVFALVAIPINADKICLGHHAVSNGTKVNTLTERG



A/mallard/
VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP



Sweden/91/2002
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2002// HA
GGIDKETMGFTYSGIRTNGAPSACRRSGSSFYAEMKWLLS



66394828
NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA




NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI





3
ABI84694
MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE



A/turkey/
KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG



Minnesota/
PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG



1/1988
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



1988/07/13 HA
SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK



115278573
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHAQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





4
ABS89409
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



teal/Ohio/566/
PQCDQFLEFDTDLIIERREGTDVCYPGKFTNEESLRQILRGS



2006 2006// HA
GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



155016324
NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL




YGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHW




LLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDS




GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL




ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL




IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD




DQCMESIRNNTYDHTQYRTESLQNRIQIDPVRLSSGYKDII




LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





5
ACD03594
MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE



A/ruddy
KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG



turnstone/DE/
PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG



1538/2000 2000//
SGGIDKESMGFTYSGIRTNGATSACRRLGSSFYAEMKWLL



HA 187384848
SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI





6
BAH22785
MNTQILVEALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP



119/2008
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2008// HA
GGIGKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



223717820
NTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





7
CAY39406
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/Anas 
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



crecca/Spain/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



1460/2008
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2008/01/26 HA
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK



254674376
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





8
ACX53683
MNIQILVFALVAHIPTNADKICLGHHAVSNGTKVNTLTERG



A/goose/Czech
VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP



Republic/1848-
PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE



K9/2009
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2009/02/04 HA
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK



260907763
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS




GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





9
ACZ48625
MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE



A/turkey/
KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG



Minnesota/
PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG



38429/1988
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



1988// HA
SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK



269826341
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




L





10
ADC29485
STQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGNVI



A/mallard/Spain/
NWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNKLY



08.00991.3/2005
ERVKRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTYD



2005/11/ HA
HSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFILL



284927336






11
ADK71137
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



teal/Guatemala/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



CIP049-01/2008
SGGIDKESMGFTYSGIRTNGATSACRRSGSSSYAEMKWLL



2008/02/07 HA
SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK



301333785
LYGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLD




SGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLL




LATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQHFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDI




ILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





12
ADK71148
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNXTETVETANIKKICTHGKRPTDLGQCGLLGTLIGP



teal/Guatemala/
PQCDRFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRGS



CIP049-02/2008
GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2008/03/05 HA
NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL



301333804
YGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFHW




LLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLDS




GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL




ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL




IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD




DQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDII




LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





13
ADN34727
MNIQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTERG



A/goose/Czech
VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP



Republic/1848-
PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE



T14/2009
SGGIDKETMGFTYSGIRTNGXTSACRRSGSSFYAEMKWLL



2009/02/04 HA
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK



307141869
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS




GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





14
AEK84760
PAFIAPDRASFLRGKSMGIQSGVQVDASCEGDCYHSGGTII



A/wild
SNLPFQNINSRAVGKCPRYVKQESLMLATGMKNVPELPK



bird/Korea/A14/
GRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQGEGTAAD



2011 2011/02/
YKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGN



HA 341610308
VINWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNK




LYERVRRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTY




DHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFIL




LAIAMGLVFICVKNGNMRCTICI





15
AEK84761
ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEVF



A/wild
NATETVERTNVPRICSKGKKTVDLGQCGLRGTITGPPQCD



bird/Korea/A3/
QFLKFSPDLIIERQKGSDVCYPGKFVNEKPLRQILRESGGID



2011 2011/02/
KETMGFAYNGIKTNGPPIACRKSGSSFYAKMKWLLSNTD



HA 341610310
KAAFPQMTKSYKNTRRNPALIVWGIHHSGSTTKQTKLYGI




GSNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN




PNDTVTFSFNGAFIPPDRASFLRGKSMGIQSGVQVDASCEG




DCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATG




MKNVPELPKGKGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTI




DLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD




CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL




WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





16
AEK84763
ILVFALVAIPTNANKIGLGHHAVSNGTKVNTLTERGVEFF



A/wild
NATETVEPTNVPRICSKGKKTVDLGQCGLLGTITGPPQCD



bird/Korea/A9/
QFLEFSADLIIERREGSDVCYPGKFVNEKALRQILRESGGID



2011 2011/02/
KETMGFAYSGIKTNGPPIACRKSGSSFYAKMKWLLSNTDK



HA 341610314
AAFPQMTKSYKNIRRDPALIVWGIHHSGSTTKQTNLYGIG




SNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNP




NDTVTFIFNGAFIAPDRASFLIGKSMGIQSGVQVDASCEGD




CYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATGM




KNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNA




QGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEF




TEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID




LADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIAMGLVFICVKNGNMRCTICI





17
AEK84765
LVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVV



A/spot-billed
NATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQCD



duck/Korea/447/
QFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGID



2011 2011/04/
KETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD



HA 341610318
NAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTKLYGS




GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN




PNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDASCE




GDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLAT




GMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQ




NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN




EFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHT




IDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD




CMARIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL




WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





18
AEM98291
SILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV



A/wild
VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC



duck/Mongolia/
DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI



1-241/2008
DKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT



2008/04/ HA
DNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYG



344196120
SGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLM




LNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDAN




CEGDCYHSGGSIISNLPFQNINSRAVGKCPRYVKQESLML




ATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI





19
AFM09439
QILAFIACMLIGAKGDKICLGHHAVANGTKVNTLTERGIE



A/emperor
VVNATETVETVNIKKICTQGKRPTDLGQCGLLGTLIGPPQC



goose/Alaska/
DQFLEFDADLIIERRKGTDVCYPGKFTNEESLRQILRGSGGI



44063-061/2006
DKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSD



2006/05/23 HA
NAAFPQMTKSYRNPRNKPALIWGVHHSGSATEQTKLYGS



390535062
GNKLITVGSSKYQQSFVPSPGARPQVNGQSGRIDFHWLLL




DPNDTVTFTFNGAFIAPERASFFRGESLGVQSDVPLDSGCE




GDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATG




MRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNE




FSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID




LADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQC




MESIRNNTYDHTQYRTESLQNRIQINPVKLSSGYKDIILWF




SFGASCFLLLAIAMGLVFICIKNGNMRCTICI





20
AFV33945
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/guinea
RIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



fowl/Nebraska/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



17096-1/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/04/05 HA
SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT



409676820
KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





21
AFV33947
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/goose/Nebraska/
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



17097-
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



4/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/04/05 HA
SNSDNAAFPQMTKSYRNPRNKPALIVWGVHHSASATEQT



409676827
KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





22
AFX85260
MNTQILAFIACMLIGINGDKICLGHHAVANGTKVNTLTER



A/ruddy
GIEVVNATETVETANIKRICTQGKRPIDLGQCGLLGTLIGPP



turnstone/
QCDQFLEFDSDLIERREGTDVCYPGKFTNEESLRQILRGS



Delaware
GGIDKESMGFTYSGIRTNGATSACIRLGSSFYAEMKWLLS



Bay/220/1995
NSDNAAFPQMTKSYRNPRNKPALIWGVHHSGSANEQTK



1995/05/21 HA
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH



423514912
WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGRCPRYVKQTSL




LLATGMKNVPENPKTRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQF




ELIDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





23
AGE08098
MNTQILTLIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/northern
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



shoverl/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



Mississippi/
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



11OS145/2011
SNSDNAAFPQMTKSYRNPRNKPALIWGVHHSGSATEQTK



2011/01/08
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH



HA 444344488
WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHNGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





24
AGI60301
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hangzhou/1/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/03/24
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 475662454
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGISGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





25
AGI60292
MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4664T/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/03/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



476403560
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCHHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





26
AGJ72861
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
GEVVNATETVERTNIPRICSKGKKTVDLGQGGPRGTITGPP



Zhejiang/DTID-
QCDQFLEFSADLIMERREGSDVCYPGKFVNEEALRQILRES



ZJU01/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/04/ HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



479280294
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





27
AGJ73503
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/1/2013
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013/03/28
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 479285761
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





28
BAN16711
MNTQVLVFALMAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Gunma/
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



466/2011 2011//
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



HA 482661571
SGGIDKETMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRRDPALIAWGIHHSGSTTEQTK




LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDDTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





29
AGK84857
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hangzhou/2/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/04/01
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 485649824
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQITKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





30
AGL44438
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/02/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/03/05
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 496493389
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





31
AGL33692
GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR



A/Shanghai/
LIEKTNQQFELIDNEFTEVEKQIGNVINWTRDSITEVWSYN



4655T/2013
AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG



2013/02/26 HA
TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID



491874175
PVKLSSGYKDVILWFSFGASCFILLAIAMGLVFICVKNGN




MRCTICI





32
AGL33693
GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR



A/Shanghai/
LIEKTNQQFELIDNEFNEVEKQIGNVINWTRDSITEVWSYN



4659T/2013
AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG



2013/02/27 HA
TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID



491874186
PVKLSSGYKDVILWFSFGASCFILLAIVMGLVFICVKNGN




MRCTICI





33
AGL95088
VFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN



A/Taiwan/
ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF



S02076/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/22 HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



501485301
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMR





34
AGL95098
LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN



A/Taiwan/
ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF



T02081/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/22 HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



501485319
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMRCT





35
AGM53883
GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ



A/Shanghai/
FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM



5083T/2013
ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH



2013/04/20 HA
KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG



507593986
YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCT





36
AGM53884
AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE



A/Shanghai/
FNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQHTID



5180T/2013
LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC



2013/04/23 HA
MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW



507593988
FSFGASCFILLAIVMGLVFICVKNGNMRCTICI





37
AGM53885
QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID



A/Shanghai/
NEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQH



5240T/2013
TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD



2013/04/25 HA
DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI



507593990
LWFSFGASCFILLAIVMGLVFICVKNGNMRCT





38
AGM53886
NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN



A/Shanghai/
EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI



4842T/2013
DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD



2013/04/13 HA
CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL



507593992
WFSFGASCFILLAIVMGLVFICVKNGNMRCT





39
AGM53887
NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN



A/Shanghai/
EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI



4701T/2013
DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD



2013/04/06 HA
CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL



507593994
WFSFGASCFILLAIVMGLVFICVKNGNMRCTIC





40
AGN69462
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/2/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/03/31 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



511105778
GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





41
AGN69474
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/1/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/03/31 HA
QCDQFLEFSADLHIERREGSDVCYPGKFVNEEALRQILRES



511105798
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLINGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





42
AGO51387
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Jiangsu/2/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013 2013/04/20
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 514390990
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRXEAMXBXIQIDPVKLSSGY




KDVXJWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





43
BAN59726
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP



147/2008
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2008/08/29 HA
GGIGKETMGFTYSGIRTNGATSACRRSRSSFYAEMKWLLS



519661951
NTDNAAFPQMTRSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





44
BAN59727
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERINVPRICSKGKRTVDLGQCGLLGTITG



129/2010
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



2010// HA
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



519661954
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK




LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





45
AGQ80952
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Jiangxi/
GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP



3096/2009
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2009// HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788794
NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





46
AGQ80989
MNTQILVFALVAHIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Jiangxi/
GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP



3257/2009
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2009// HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788868
NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGXSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





47
AGQ81043
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Rizhao/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



515/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEEMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788976
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





48
AGR33894
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Rizhao/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



719b/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



524845213
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDRSKYREEAMQNRXXXXXXXXXXX




XKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





49
AGR49399
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SD001/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2013/05/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338528
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





50
AGR49495
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shanghai/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



S1358/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/03
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



HA 525338689
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIKNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





51
AGR49506
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



S1410/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/03
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



HA 525338708
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





52
AGR49554
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Zhejiang/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SD033/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/11 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338789
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





53
AGR49566
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/duck/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SC702/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338809
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





54
AGR49722
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/homing
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



pigeon/Jiangsu/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



SD184/2013
GGIDKEAMGFTYSEIRTNGATSACRRSGSSFYAEMKWLLS



2013/04/20 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



525339071
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





55
AGR49734
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/pigeon/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



S1069/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/02 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525339091
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTITFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





56
AGR49770
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/wild
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



pigeon/Jiangsu/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



SD001/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/04/17 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



525339151
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





57
AGY41893
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Huizhou/01/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2013 2013/08/08
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 552049496
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





58
AGY42258
FALVAIIPINADKICLGHHAVSNGTKVNTLTERGVEVVNA



A/mallard/Sweden/
TETVERTNVPRICSRGKRTVDLGQCGLLGTIXGPPQCDQFL



91/2002
EFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKET



2002/12/12 HA
MGFTYSGIRTNGAXSACRRSGSSFYAEMKWLLSNTDNAA



552052155
FPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKLYGSGNK




LITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNPND




TVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDANCEGDC




YHSGGTHISNLPFQNINSRAVGKCPRYVKQESLLLATGMK




NVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG




EGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTE




VEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTIDLA




DSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIAMGLVFMCVKNGNMRCTICI





59
AHA11441
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/guinea
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



fowl/Nebraska/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



17096/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/04/10 HA
SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT



557478572
KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





60
AHA11452
MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE



A/turkey/Minnesota/
RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG



32710/2011
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR



2011/07/12 HA
GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL



557478591
LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ




TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FEMIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





61
AHA11461
MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE



A/turkey/Minnesota/
RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG



31900/2011
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR



2011/07/05 HA
GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL



557478606
LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ




TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





62
AHK10585
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Guangdong/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



G1/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/05/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



587680636
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





63
AGG53366
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



CSM42-34/2011
SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK



459252887
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





64
AGG53377
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



CSM42-1/2011
SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK



459252925
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT





65
AGG53399
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



MHC39-26/2011
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253005
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTHISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





66
AGG53432
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



MHC35-41/2011
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253136
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT





67
AGG53476
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



SH19-27/2010
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2010/12/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253257
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI





68
AGG53487
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



SH19-50/2010
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2010/01/ HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253278
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





69
AGG53520
QILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV



A/wild
VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC



duck/Korea/
DQLLEFSADLIIERREGTDVCYPGKFVNEEALRQILRESGGI



SH20-27/2008
EKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD



2008/12/ HA
NAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYGS



459253409
GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLML




NPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANC




EGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLA




TGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFICVKNGNMR





70
AGL43637
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Taiwan/1/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013// HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



496297389
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGPSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIINNLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





71
AGL97639
IACMLVGAKGDKICLGHHAVANGTKVNTLTERGIEVVNA



A/mallard/
TETVETANIKKLCTQGKRPTDLGQCGLLGTLIGPPQCDQFL



Minnesota/AI09-
EFDADLIIERREGTDVCYPGKFTNEESLRQILRGSGGIDKES



3770/2009
MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSDNAA



2009/09/12 HA
FPQMTKSYRNPRNKPALIWGVHHSGSATEQTKLYGSGNK



505555371
LITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHWLLLDPN




DTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDSGCEGDC




FHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATGMRN




VPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG




EGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNEFSEI




EQQIGNVINWTRDSMTELWSYNAELLVAMENQHTIDLAD




SEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQCMESI




RNNTYDHTQYRTESLQNRIQIDPVKLS





72
AGO02477
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Xuzhou/1/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/25
QCDQFLEFSADLIERREGSDVCYPGKFVNEEALRQILRES



HA 512403688
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





73
AGR84942
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Suzhou/5/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/12
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304561
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





74
AGR84954
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/6/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/11
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304594
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNRNMRCTICI





75
AGR84978
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/4/2013
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2013/04/07 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



526304656
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





76
AGR84990
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/3/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/07 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



526304688
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





77
AGR85002
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Zhenjiang/1/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013 2013/04/07
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304708
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPPQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNKRCTICI





78
AGR85026
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/2/2013
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013/04/05
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304762
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





79
AGU02230
LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVN



A/Zhejiang/
ATETVERTNIPRICSKGKRTVDLGQCGLRGTITGPPQCDQF



DTID-ZJU05/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/ HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



532808765
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMRCT





80
AGU02233
FALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVNAT



A/Zhejiang/DTID-
ETVERTNFPRICSKGKRTVDLGQCGLRGTITGPPQCDQFLE



ZJU08/2013
FSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEA



2013/04/ HA
MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNAA



532808788
FPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNK




LVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN




DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD




CYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATGM




KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ




GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN




EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA




DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIVMGLVFICVKNGNMRCT





81
AGW82588
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/tree
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



sparrow/Shanghai/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



01/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/05/09 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



546235348
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTIGI





82
AGW82600
ALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVNATE



A/Shanghai/
TVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQFLEF



CN01/2013
SADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEAM



2013/04/11 HA
GFTYSGIRTNGATSACRRSRSSFYAEMKWLLSNTDNAAFP



546235368
QMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNKL




VTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN




DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD




CYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQRSLLLATGM




KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ




GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN




EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA




DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIVMGLVFICVKNGNMRCTICI





83
AGW82612
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/JS01/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



546235388
NTDNAAFPQMTKSYKNTRKNPALIVWGIHHSGSTAEQTK




LYGSGNKLVTVGSSNYQQSFAPSPGARTQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





84
AHA11472
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



31676/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/12/08 HA
GSGGIDKESMGFTYSGIRTNGETSACRRSGSSFYAEMKWL



557478625
LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITNKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





85
AHA11483
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



14135-2/
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



2009/08/07 HA
LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT



557478644
KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





86
AHA11500
TQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVE



A/Zhejiang/DTID-
VVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQC



ZJU10/2013
DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI



2013/10/14 HA
DKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT



557478676
DNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY




GSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHWL




MLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDA




NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH




TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIVMGLVFICVKN





87
AHA57050
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



14659/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/08/12 HA
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



558484427
LSNSNNAAFPQMTKSYRNPRDKPALIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




NCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





88
AHA57072
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



18421/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/09/09 HA
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



558484465
LSNSNDAAFPQMTKSYRNPRDKPALIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





89
AHD25003
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Guangdong/02/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2013 2013/10/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 568260567
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNM





90
AHF20528
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hong
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Kong/470129/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013 2013/11/30
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



HA 570933555
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





91
AHF20568
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



CN02/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/02 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



570933626
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





92
AHH25185
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Guangdong/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



04/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/16 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



576106234
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





93
AHJ57411
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/PD-
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



01/2014
QCDQFLEFSADLHIERREGSDVCYPGKFVNEEALRQILRES



2014/01/17 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



585478041
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVSSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCKGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





94
AHJ57418
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/PD-
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



02/2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/01/17 HA
GIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSN



585478256
TDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY




GSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWL




MLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQVDA




NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFELID




NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH




TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





95
AHK10800
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/01/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2014 2014/01/03
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 587681014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





96
AHM24224
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Beijing/3/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/04/16
QCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES



HA 594704802
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





97
AHN96472
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shanghai/PD-CN-
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



02/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/01/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



602701641
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





98
AHZ39686
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



DEWH72-01/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632807036
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





99
AHZ39710
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



DEWH72-03/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEAMGFTYSGIRTDGATSACRRSGSSFYAEMKWLLS



632807076
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





100
AHZ39746
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



DEWH72-06/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632807136
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGERPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





101
AHZ41929
MNTQILVFALVAIPINADKICLGHHAVSNGTKVNTLTERG



A/mallard/Sweden/
VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP



1621/2002
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2002/12/12 HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632810949
NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA




NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI





102
AHZ42537
MNTQILAFIACMLVGAKGDKICLGHHAVANGTKVNTLTE



A/mallard/
RGIEVVNATETVETANIKKLCTQGKRPTDLGQCGLLGTLI



Minnesota/A109-
GPPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQIL



3770/2009
RGSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKW



2009/09/12 HA
LLSNSDNAAFPQMTKSYRNPRNKPALIWGVHHSGSATEQ



632811964
TKLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTELWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





103
AHZ42549
MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE



A/ruddy
KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG



turnstone/
PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG



Delaware/AI00-
SGGIDKESMGFTYSGIRTNGATSACRRLGSSSFYAEMKWL



1538/2000
LSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT



2000/05/20 HA
KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF



632811984
HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI





104
AID70634
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Mix1/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



660304650
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQISNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





105
AIN76383
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/Zhejiang/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



LS01/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/08 HA
GGIDKEAMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLLS



684694637
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





106
AIU46619
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Zhejiang/DTID-
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



ZJU06/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/12/ HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



699978931
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVEV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





107
AIU47013
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Suzhou/040201H/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013 2013/04/ HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



699979673
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDMILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





108
AJJ90490
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shenzhen/742/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/10 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178094
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





109
AJJ90526
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shenzhen/898/2013
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2013/12/09 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755178154
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





110
AJJ90538
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Shenzhen/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



918/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/09 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178174
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





111
AJJ90576
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1665/2013
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2013/12/12 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755178238
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





112
AJJ90588
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2110/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/13 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178258
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





113
AJJ90661
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2912/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/18 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178380
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





114
AJJ90673
MNTQILVFALTAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3049/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/18 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178400
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





115
AJJ90795
MNTQILVFALIAIIPTNADKICLGHHAVPNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3281/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/18 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178604
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





116
AJJ90891
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3520/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/19 HA
SNTDNAAFPQMTKSYKNTRKXPALIVWGIHHSVSTAEQT



755178764
KLYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDF




HWLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQ




VDANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





117
AJJ90951
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/3544/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178864
SNTDNAAFPQMTKSYRNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





118
AJJ91035
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shenzhen/3780/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755179004
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





119
AJJ91155
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/4037/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755179204
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





120
AJJ92005
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shenzhen/801/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/09 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180629
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





121
AJJ94254
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1374/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184382
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





122
AJJ94606
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/191/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184968
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





123
AJJ96552
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP



12206/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188219
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





124
AJJ96684
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKINTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13207/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188439
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





125
AJJ96732
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13223/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188519
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





126
AJK00354
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Zhejiang/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



LS02/2014
PQCDQFLEFSADLIVERREGSDVCYPGKFVNEEALRQILRE



2014/01/12 HA
SGGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



755194469
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK




LYGSGNKLITVGSSNYQQSFVPSPGARPLVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQ




QFELIDHEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSS




GYKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





127
AJJ91264
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



4129/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/19 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755179386
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLMEKTNQQ




FELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





128
AJJ91314
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Shaoxing/2417/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179470
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





129
AJJ91402
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Huzhou/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4045/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/24 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179618
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KEVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





130
AJJ91476
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Huzhou/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4076/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2013/10/24 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179743
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





131
AJJ91725
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Shaoxing/5201/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/28 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755180161
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





132
AJJ91885
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP4/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/16 HA
GGIDKEAMGFTYSGIRANGVTSACRRSGSSFYAEMKWLL



755180429
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





133
AJJ91909
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP26/2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/01/20 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755180469
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDGCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





134
AJJ91945
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP38/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/22 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180529
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIGGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





135
AJJ91957
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SP44/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/23 HA
GGIDKEAMGFTYSGIRANGTTSACRRSGSSFYAEMKWLLS



755180549
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





136
AJJ91969
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP48/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/23 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755180569
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





137
AJJ91993
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/4119/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180609
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLLGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFTLLAIVMGLVFICVKNGNMRCTICI





138
AJJ92031
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/4064/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180672
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVESSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





139
AJJ92967
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/silkie
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



chicken/Jiangxi/
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



9469/2014
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



2014/02/16 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755182232
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





140
AJJ93027
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



9558/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES



2014/02/16 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755182332
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





141
AJJ93051
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



10573/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/18 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755182372
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





142
AJJ93845
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



157/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/20 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755183695
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





143
AJJ93857
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



169/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACMRSGSSFYAEMKWLL



755183715
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





144
AJJ93869
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



Dongguan/173/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183735
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





145
AJJ93881
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



Dongguan/189/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183755
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPKYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





146
AJJ93907
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/449/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183799
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





147
AJJ93931
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/536/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755183839
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISKLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





148
AJJ93943
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/568/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755183859
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





149
AJJ93979
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



chicken/Dongguan/
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



656/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/20 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755183919
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




GLIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





150
AJJ94134
MNTQILVLALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1051/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184182
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVXLSXGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





151
AJJ94158
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1075/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184222
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





152
AJJ94182
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1177/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACKRSGSSFYAEMKWLLS



755184262
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSIAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





153
AJJ94194
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP



chicken/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



Dongguan/1264/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755184282
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQQ




FELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





154
AJJ94206
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



1268/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/21 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755184302
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISDLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





155
AJJ94344
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNSTETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



1451/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL



755184532
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRTVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





156
AJJ94356
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1456/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184552
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





157
AJJ94396
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1494/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755184618
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





158
AJJ94754
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/748/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755185215
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSNAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





159
AJJ94838
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/835/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185356
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFGFGASCFILLAIVMGLVFICVKNGNMRCTICI





160
AJJ94862
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/843/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755185396
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





161
AJJ94886
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/851/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185436
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





162
AJJ94910
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/874/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185476
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





163
AJJ94959
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



967/2014
GGIDKEAMGFTYSGIRANGATSACXRSGSSFYAEMKWLL



2014/02/21 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755185558
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





164
AJJ95048
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Dongguan/1009/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185708
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





165
AJJ95171
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1314/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755185913
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFNFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





166
AJJ95227
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1382/2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/02/21 HA
GIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755186006
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





167
AJJ95251
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1401/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186046
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





168
AJJ95346
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1548/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186206
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





169
AJJ95382
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/1690/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186266
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





170
AJJ95464
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Shenzhen/138/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/19 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186404
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





171
AJJ95572
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Dongguan/1100/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755186584
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASELRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





172
AJJ95584
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



1519/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755186604
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





173
AJJ95596
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP58/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/25 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755186624
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





174
AJJ95620
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP75/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/15 HA
GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS



755186664
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAVVMGLVFICVKNGNMRCTICI





175
AJJ95632
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP62/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186684
NTDNATFPQMTKSYKNTRKSPALIIWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





176
AJJ96720
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTTIPRICSKGKKTVDLGQCGLLGTITGPP



13220/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188499
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





177
AJJ96817
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATEIVERTNIPRICSKGKKTVDLGQCGLLGTITGP



9513/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/16 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755188661
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





178
AJJ96841
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



SP139/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/04/02 HA
GGIDKEAMGFTYSGIRTNGATSTCRRSGSSFYAEMKWLLS



755188701
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRACFLRGKSMGIQSGVQ




VDADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVERQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





179
AJJ96889
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTXIPRICSKGKKTVDLGQCGLLGTITGPP



13496/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKXAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



755188781
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





180
AJJ96901
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13502/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188801
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSXGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





181
AJJ96925
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13513/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755188841
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHTVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDLH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





182
AJJ97267
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13252/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189411
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





183
AJJ97291
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13493/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189451
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





184
AJJ97331
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13512/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189517
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





185
AJJ97373
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13521/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189587
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPXRASFLRGKSXGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





186
AJJ97443
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTTIPRICSKGKRTVDLGQCGLLGTITGPP



13530/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189702
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





187
AJJ97582
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



14023/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/13 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189933
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





188
AJJ97697
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



14517/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190125
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCDGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





189
AJJ97709
MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



14518/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755190145
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGNCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





190
AJJ97745
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



14554/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190205
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELMDNEFNEVEKQIGNVINWIRDSITELWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





191
AJJ97757
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shantou/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2537/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/04/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190225
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





192
AJJ97841
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/duck/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



15044/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/27 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190365
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVRLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





193
AJJ97899
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



15524/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/05/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190462
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFMCVKNGNMRCTICI





194
AJJ97925
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Shantou/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2050/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/03/25 HA
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL



755190506
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





195
AJJ97973
MNTQILVFALISIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shantou/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



4325/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/07/01 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755190586
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





196
AJJ97998
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Shantou/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



4816/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/07/22 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190628
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKOKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELVDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI
















TABLE 14







H10 Hemagglutinin Amino Acid Sequences









SEQ ID
Accession No/



NO
Strain/Protein
Amino Acid Sequence





197
AAM19228
ACVLVEAKGDKICLGHHAVVNGTKVNTLTEKGIEVVNAT



A/turkey/Minnesota/
ETVETANIGKICTQGKRPTDLGQCGLLGTLIGPPQCDQFLE



38429/19881988//
FESDLIIERREGNDVCYPGKFTNEESLRQILRGSGGIDKESM



HA
GFTYSGIITNGATSACRRSGSSFYAEMKWLLSNSDNAAFP



20335017
QMTKSYRNPRNKPALIVWGIHHSGSTTEQTKLYGSGNKLI




TVESSKYQQSFTPSPGARPQVNGESGRIDFHWMLLDPNDT




VTFTFNGAFIAPDRASFFKGESLGVQSDVPLDSSCGGDCFH




SGGTIVSSLPFQNINPRTVGKCPRYVKQPSLLLATGMRNVP




ENPKTRGLFGAIAGFIEKDGGSHYG





198
AAY46211
MNTQILVFALVAIIPINADKICLGHHAVSNGTKVNTLTERG



A/mallard/Sweden/
VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP



91/20022002//
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA
GGIDKETMGFTYSGIRTNGAPSACRRSGSSFYAEMKWLLS



66394828
NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA




NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI





199
ABI84694A/
MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE



turkey/Minnesota/
KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG



1/19881988/
PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG



07/13 HA
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



115278573
SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK




LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHAQYRAESLQNRIQIDPVKLSSGYKD




ILWFSFGASCELLLAIAMGLVFICIKNGNMRCTICI





200
ABS89409
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



teal/Ohio/566/
PQCDQFLEFDTDLIIERREGTDVCYPGKFTNEESLRQILRGS



2006 2006//HA
GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



155016324
NSDNAAFPQMTKSYRNPRNKPALIWGVHHSGSATEQTKL




YGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHW




LLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDS




GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL




ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL




IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD




DQCMESIRNNTYDHTQYRTESLQNRIQIDPVRLSSGYKDII




LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





201
ACD03594
MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTB



A/ruddy
KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG



turnstone/DE/
PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG



1538/2000 2000//
SGGIDKESMGFTYSGIRTNGATSACRRLGSSFYAEMKWLL



HA 187384848
SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENABEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI





202
BAH22785
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP



119/2008
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2008//HA
GGIGKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



223717820
NTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTHISNLPFQNINSRTVGKCPRYVKQESLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





203
CAY39406
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/Anas
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



crecca/Spain/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



1460/2008
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2008/01/26 HA
SNTDNAAFPQMTKSYKNTRKDPALIWGIHHSGSTTEQTK



254674376
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





204
ACX53683
MNIQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTERG



A/goose/Czech
VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP



Republic/1848-
PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE



K9/2009
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2009/02/04 HA
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK



260907763
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLKGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS




GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





205
ACZ48625
MNTQILVFIACVLVEAKGDKICLGHHAVVNGTKVNTLTE



A/turkey/Minnesota/
KGIEVVNATETVETANIGKICTQGKRPTDLGQCGLLGTLIG



38429/1988
PPQCDQFLEFESDLIIERREGNDVCYPGKFTNEESLRQILRG



1988//HA
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



269826341
SNSDNAAFPQMTKSYRNPRNKPALIVWGIHHSGSTTEQTK




LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WMLLDPNDTVTFTFNGAFIAPDRASFFKGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQPSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




KHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




L





206
ADC29485
STQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGNVI



A/mallard/Spain/
NWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNKLY



08.00991.3/2005
ERVKRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTYD



2005/11/ HA
HSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFILL



284927336






207
ADK71137
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



teal/Guatemala/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



CIP049-01/2008
SGGIDKESMGFTYSGIRTNGATSACRRSGSSSYAEMKWLL



2008/02/07 HA
SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK



301333785
LYGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLD




SGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLL




LATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQHFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDI




ILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





208
ADK71148
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/blue-winged
GIEVVNXTETVETANIKKICTHGKRPTDLGQCGLLGTLIGP



teal/Guatemala/
PQCDRFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRGS



CIP049-02/2008
GGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2008/03/05 HA
NSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTKL



301333804
YGSGNKLITVGSSKYQQSFTPSPGTRPQVNGQSGRIDFHW




LLLDPNDTVTFTFNGAFIAPDRASFLRGKSLGIQSDVPLDS




GCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLL




ATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFEL




IDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCD




DQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYKDII




LWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





209
ADN34727
MNIQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/goose/Czech
VEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGP



Republic/1848-
PQCDQFLEFSADLIIERRGGSDVCYPGKFVNEEALRQILRE



T14/2009
SGGIDKETMGFTYSGIRTNGXTSACRRSGSSFYAEMKWLL



2009/02/04 HA
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK



307141869
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQES




LMLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSS




GYKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





210
AEK84760
PAFIAPDRASFLRGKSMGIQSGVQVDASCEGDCYHSGGTII



A/wild
SNLPFQNINSRAVGKCPRYVKQESLMLATGMKNVPELPK



bird/Korea/A14/
GRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQGEGTAAD



2011 2011/02/
YKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTEVEKQIGN



HA 341610308
VINWTRDSMTEVWSYNAELLVAMENQHTIDLADSEMNK




LYERVRRQLRENAEEDGTGCFEIFHKCDDDCMASIRNNTY




DHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSFGASCFIL




LAIAMGLVFICVKNGNMRCTICI





211
AEK84761
ILVFALVAUPTNANKIGLGHHAVSNGTKVNTLTERGVEVF



A/wild
NATETVERTNVPRICSKGKKTVDLGQCGLRGTITGPPQCD



bird/Korea/A3/
QFLKFSPDLIIERQKGSDVCYPGKFVNEKPLRQILRESGGID



2011 2011/02/
KETMGFAYNGIKTNGPPIACRKSGSSFYAKMKWLLSNTD



HA 341610310
KAAFPQMTKSYKNTRRNPALIVWGIHHSGSTTKQTKLYGI




GSNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN




PNDTVTFSFNGAFIPPDRASFLRGKSMGIQSGVQVDASCEG




DCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATG




MKNVPELPKGKGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTI




DLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD




CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL




WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





212
AEK84763
ILVFALVAIIPTNANKIGLGHHAVSNGTKVNTLTERGVEFF



A/wild
NATETVEPTNVPRICSKGKKTVDLGQCGLLGTITGPPQCD



bird/Korea/A9/
QFLEFSADLIIERREGSDVCYPGKFVNEKALRQILRESGGID



2011 2011/02/
KETMGFAYSGIKTNGPPIACRKSGSSFYAKMKWLLSNTDK



HA 341610314
AAFPQMTKSYKNIRRDPALIVWGIHHSGSTTKQTNLYGIG




SNLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNP




NDTVTFIFNGAFIAPDRASFLIGKSMGIQSGVQVDASCEGD




CYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLATGM




KNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNA




QGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEF




TEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID




LADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIAMGLVFICVKNGNMRCTICI





213
AEK84765
LVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVV



A/spot-billed
NATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQCD



duck/Korea/447/
QFLEFSADLIERREGSDVCYPGKFVNEEALRQILRESGGID



2011 2011/04/
KETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD



HA 341610318
NAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTKLYGS




GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILN




PNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDASCE




GDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLAT




GMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQ




NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN




EFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHT




IDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDD




CMARIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL




WFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





214
AEM98291
SILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV



A/wild
VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC



duck/Mongolia/
DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI



1-241/2008
DKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT



2008/04/HA
DNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTKLYG



344196120
SGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLM




LNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDAN




CEGDCYHSGGSIISNLPFQNINSRAVGKCPRYVKQESLML




ATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASINNTYDHSKYREEAMQNRIQINPVKLSSGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI





215
AFM09439
QILAFIACMLIGAKGDKICLGHHAVANGTKVNTLTERGIE



A/emperor
VVNATETVETVNIKKICTQGKRPTDLGQCGLLGTLIGPPQC



goose/Alaska/
DQFLEFDADLIIERRKGTDVCYPGKFTNEESLRQILRGSGGI



44063-061/2006
DKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSD



2006/05/23 HA
NAAFPQMTKSYRNPRNKPALIWGVHHSGSATEQTKLYGS



390535062
GNKLITVGSSKYQQSFVPSPGARPQVNGQSGRIDFHWLLL




DPNDTVTFTFNGAFIAPERASFFRGESLGVQSDVPLDSGCE




GDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATG




MRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNE




FSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMENQHTID




LADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQC




MESIRNNTYDHTQYRTESLQNRIQINPVKLSSGYKDIILWF




SFGASCELLLAIAMGLVFICIKNGNMRCTICI





216
AFV33945
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/guinea
RIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



fowl/Nebraska/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



17096-1/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/04/05 HA
SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT



409676820
KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





217
AFV33947
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/goose/Nebraska/
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



17097-4/2011
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



2011/04/05 HA
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



409676827
SNSDNAAFPQMTKSYRNPRNKPALIVWGVHHSASATEQT




KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENABEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCELLLAIAMGLVFICIKNGNMRCTICI





218
AFX85260
MNTQILAFIACMLIGINGDKICLGHHAVANGTKVNTLTER



A/ruddy
GIEVVNATETVETANIKRICTQGKRPIDLGQCGLLGTLIGPP



turnstone/Delaware
QCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRGS



Bay/220/1995
GGIDKESMGFTYSGIRTNGATSACIRLGSSFYAEMKWLLS



1995/05/21 HA
NSDNAAFPQMTKSYRNPRNKPALIWGVHHSGSANEQTK



423514912
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGRCPRYVKQTSL




LLATGMKNVPENPKTRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQF




ELIDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





219
AGB08098
MNTQILTLIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/northern
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



shoverl/Mississippi/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



11OS145/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/01/08
SNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQTK



HA 444344488
LYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHNGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





220
AGI60301
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hangzhou/1/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/03/24
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 475662454
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGISGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





221
AGI60292
MNTQILVEALIAIIPANADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/466
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4T/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/03/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



476403560
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCHHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





222
AGJ72861
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Zhejiang/
GEVVNATETVERTNIPRICSKGKKTVDLGQGGPRGTITGPP



DTID-ZJU01/2013
QCDQFLEFSADLIMERREGSDVCYPGKFVNEEALRQILRES



2013/04/ HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



479280294
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





223
AGJ73503
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/1/2013
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013/03/28
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 479285761
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





224
BAN16711
MNTQVLVFALMAIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Gunma/
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



466/2011 2011//
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



HA 482661571
SGGIDKETMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRRDPALIAWGIHHSGSTTEQTK




LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDDTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





225
AGK84857
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hangzhou/2/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/04/01
QCDQFLEFSADLIHIERREGSDVCYPGKFVNEEALRQILRES



HA 485649824
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQITKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





226
AGL44438
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/02/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/03/05
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 496493389
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





227
AGL33692
GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR



A/Shanghai/465
LIEKTNQQFELIDNEFTEVEKQIGNVINWTRDSITEVWSYN



5T/2013
AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG



2013/02/26 HA
TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID



491874175
PVKLSSGYKDVILWFSFGASCFILLAIAMGLVFICVKNGN




MRCTICI





228
AGL33693
GMIDGWYGFRHQNAQGEGTAADYKSTQSAIDQITGKLNR



A/Shanghai/465
LIEKTNQQFELIDNEFNEVEKQIGNVINWTRDSITEVWSYN



9T/2013
AELLVAMENQHTIDLADSEMDKLYERVKRQLRENAEEDG



2013/02/27 HA
TGCFEIFHKCDDDCMASIRNNTYDHSKYREEAMQNRIQID



491874186
PVKLSSGYKDVILWFSFGASCFILLAIVMGLVFICVKNGN




MRCTICI





229
AGL95088
VFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN



A/Taiwan/S020
ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF



76/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/22 HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



501485301
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMR





230
AGL95098
LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVN



A/Taiwan/T020
ATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQF



81/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/22 HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



501485319
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMRCT





231
AGM53883
GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ



A/Shanghai/508
FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM



3T/2013
ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH



2013/04/20 HA
KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG



507593986
YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCT





232
AGM53884
AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE



A/Shanghai/518
FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID



0T/2013
LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC



2013/04/23 HA
MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW



507593988
FSFGASCFILLAIVMGLVFICVKNGNMRCTICI





233
AGM53885
QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID



A/Shanghai/524
NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH



0T/2013
TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD



2013/04/25 HA
DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI



507593990
LWFSFGASCFILLAIVMGLVFICVKNGNMRCT





234
AGM53886
NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN



A/Shanghai/484
EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI



2T/2013
DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD



2013/04/13 HA
CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL



507593992
WFSFGASCFILLAIVMGLVFICVKNGNMRCT





235
AGM53887
NAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDN



A/Shanghai/470
EFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTI



1T/2013
DLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDD



2013/04/06 HA
CMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVIL



507593994
WFSFGASCFILLAIVMGLVFICVKNGNMRCTIC





236
AGN69462
MNTQILVFALIAUPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/2/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/03/31 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEBALRQILRES



511105778
GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





237
AGN69474
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/1/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/03/31 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEBALRQILRES



511105798
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLINGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





238
AGO51387
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Jiangsu/2/2013
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013/04/20
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 514390990
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRXEAMXBXIQIDPVKLSSGY




KDVXJWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





239
BAN59726
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGP



147/2008
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2008/08/29 HA
GGIGKETMGFTYSGIRTNGATSACRRSRSSFYAEMKWLLS



519661951
NTDNAAFPQMTRSYKNTRKDPALIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRTVGKCPRYVKQESLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIERTNQQFELI




DNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQ




HTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSNGYKD




VILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





240
BAN59727
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Mongolia/
GVEVVNATETVERINVPRICSKGKRTVDLGQCGLLGTITG



129/2010
PPQCDQFLEFSADLHIERREGSDVCYPGKFVNEEALRQILRE



2010//HA
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



519661954
SNTDNAAFPQMTKSYKNTRKDPALIIWGIHHSGSTTEQTK




LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTHISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





241
AGQ80952
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Jiangxi/
GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP



3096/2009
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2009//HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788794
NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTIISNLPFQNINSRAVGKCPRYVKQESL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





242
AGQ80989
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Jiangxi/
GVEVVNATETVERTSIPRICSKGKRAVDLGQCGLLGTITGP



3257/2009
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2009//HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788868
NTDNAAFPQTTKSYKNTRKDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGXSNYQQSFVPSPGARPQVNGQSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHNGGTHISNLPFQNINSRAVGKCPRYVKQESL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFTEVERQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





243
AGQ81043
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Rizhao/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



515/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013//HA
GGIDKEEMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



523788976
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





244
AGR33894
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Rizhao/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



719b/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013// HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



524845213
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDRSKYREEAMQNRXXXXXXXXXXX




XKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





245
AGR49399
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SD001/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2013/05/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338528
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





246
AGR49495
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shanghai/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



S1358/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/03
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



HA 525338689
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIKNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





247
AGR49506
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



S1410/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEBALRQILRES



2013/04/03
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



HA 525338708
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





248
AGR49554
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Zbejiang/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SD033/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/11 HA
GGIDKBAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338789
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVRRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





249
AGR49566
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/duck/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



SC702/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525338809
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





250
AGR49722
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/homing
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



pigeon/Jiangsu/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



SD184/2013
GGIDKEAMGFTYSEIRTNGATSACRRSGSSFYAEMKWLLS



2013/04/20 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



525339071
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFBIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





251
AGR49734
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/pigeon/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



S1069/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/02 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



525339091
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTITFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





252
AGR49770
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/wild
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



pigeon/Jiangsu/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



SD001/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/04/17 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



525339151
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





253
AGY41893
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Huizhou/01/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2013 2013/08/08
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 552049496
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





254
AGY42258
FALVAIIPINADKICLGHHAVSNGTKVNTLTERGVEVVNA



A/mallard/Sweden/
TETVERTNVPRICSRGKRTVDLGQCGLLGTIXGPPQCDQFL



91/2002
EFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKET



2002/12/12 HA
MGFTYSGIRTNGAXSACRRSGSSFYAEMKWLLSNTDNAA



552052155
FPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKLYGSGNK




LITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLILNPND




TVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDANCEGDC




YHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLLATGMK




NVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG




EGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFTE




VEKQIGNVINWTRDSMTEVWSYNAELLVAMENQHTIDLA




DSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIAMGLVFMCVKNGNMRCTICI





255
AHA11441
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/guinea
GIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIGP



fowl/Nebraska/
PQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILRG



17096/2011
SGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/04/10 HA
SNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQT



557478572
KLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDFH




WLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVPL




DSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAMEN




QHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHKC




DDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYKD




IILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





256
AHA11452
MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE



A/turkey/Minnesota/
RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG



32710/2011
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR



2011/07/12 HA
GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL



557478591
LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ




TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FEMIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





257
AHA11461
MNTQILALIACMLVGTKGDKICLGHHAVANGTKVNTLTE



A/turkey/Minne
RGIEVVNATETVETANIKKICTQGKRPTDLGQCGLLGTLIG



sota/31900/2011
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEEPLRQILR



2011/07/05 HA
GSGGIDKESMGFTYSGIRTNGATSTCRRSGSSFYAEMKWL



557478606
LSNSNNAAFPQMTKSYRNPRNKPALIVWGVHHSGSATEQ




TKLYGSGSKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHKGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEIWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRAESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI


258
AHK10585
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Guangdong/G1/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/05/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



587680636
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





259
AGG53366
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



CSM42-34/2011
SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK



459252887
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENABEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





260
AGG53377
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



CSM42-1/2011
SGGIDKETMGLTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSSTEQTK



459252925
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENABEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVRLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT





261
AGG53399
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLHIERREGSDVCYPGKFVNEEALRQILRE



MHC39-26/2011
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253005
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





262
AGG53432
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



MHC35-41/2011
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2011/03/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253136
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPEPPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENABEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCT





263
AGG53476
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



SH19-27/2010
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2010/12/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253257
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTI





264
AGG53487
MNTQILVFALVAIPTNADKICLGHHAVSNGTKVNTLTER



A/wild
GVEVVNATETVERTNVPRICSKGKRTVDLGQCGLLGTITG



duck/Korea/
PPQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRE



SH19-50/2010
SGGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



2010/01/HA
SNTDNAAFPQMTKSYKNTRRDPALIVWGIHHSGSTTEQTK



459253278
LYGSGSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFH




WLILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DASCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESL




MLATGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





265
AGG53520
QILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTERGVEV



A/wild
VNATETVERTNVPRICSKGKRTVDLGQCGLLGTITGPPQC



duck/Korea/
DQLLEFSADLIIERREGTDVCYPGKFVNEEALRQILRESGGI



SH20-27/2008
EKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTD



2008/12/HA
NAAFPQMTKSYKNTRKDPALIWGIHHSGSTTEQTKLYGS



459253409
GSKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHWLML




NPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANC




EGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLMLA




TGMKNVPELPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQINPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFICVKNGNMR





266
AGL43637
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Taiwan/1/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013//HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



496297389
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGPSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIINNLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





267
AGL97639
IACMLVGAKGDKICLGHHAVANGTKVNTLTERGIEVVNA



A/mallard/Minnesota/
TETVETANIKKLCTQGKRPTDLGQCGLLGTLIGPPQCDQFL



AI09-3770/2009
EFDADLIIERREGTDVCYPGKFTNEESLRQILRGSGGIDKES



2009/09/12 HA
MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNSDNAA



505555371
FPQMTKSYRNPRNKPALIWGVHHSGSATEQTKLYGSGNK




LITVGSSKYQQSFTPSPGARPQVNGQSGRIDFHWLLLDPN




DTVTFTFNGAFIAPDRASFFRGESLGVQSDVPLDSGCEGDC




FHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSLLLATGMRN




VPENPKTRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQG




EGTAADYKSTQSAIDQITGKLNRLIDKTNQQFELIDNEFSEI




EQQIGNVINWTRDSMTELWSYNAELLVAMENQHTIDLAD




SEMNKLYERVRKQLRENAEEDGTGCFEIFHKCDDQCMESI




RNNTYDHTQYRTESLQNRIQIDPVKLS





268
AGO02477
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Xuzhou/1/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/04/25
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 512403688
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





269
AGR84942
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Suzhou/5/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/12
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304561
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGSKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASINNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





270
AGR84954
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/6/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/11
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304594
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNRNMRCTICI





271
AGR84978
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/4/2013
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2013/04/07 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



526304656
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





272
AGR84990
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Wuxi/3/2013
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013/04/07 HA
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



526304688
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





273
AGR85002
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Zhenjiang/1/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013 2013/04/07
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304708
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNKRCTICI





274
AGR85026
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Nanjing/2/
VEVVNATETVERTNIPRICSKGKMTVDLGQCGLLGTITGPP



2013 2013/04/05
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 526304762
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKSRNMRCTICI





275
AGU02230
LVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVN



A/Zhejiang/
ATETVERTNIPRICSKGKRTVDLGQCGLRGTITGPPQCDQF



DTID-ZJU05/2013
LEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKE



2013/04/ HA
AMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNA



532808765
AFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGN




KLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNP




NDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEG




DCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATG




MKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQN




AQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNE




FNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTID




LADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDC




MASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILW




FSFGASCFILLAIVMGLVFICVKNGNMRCT





276
AGU02233
FALIAIIPTNADKICLGHHAVSNGTKVNTLTERGGEVVNAT



A/Zhejiang/
ETVERTNFPRICSKGKRTVDLGQCGLRGTITGPPQCDQFLE



DTID-ZJU08/2013
FSADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEA



2013/04/HA
MGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNTDNAA



532808788
FPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNK




LVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN




DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD




CYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLLATGM




KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ




GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN




EVEKQIGNVINWIRDSITEVWSYNAELLVAMENQHTIDLA




DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIVMGLVFICVKNGNMRCT





277
AGW82588
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/tree
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



sparrow/Shanghai/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



01/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/05/09 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



546235348
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTIGI





278
AGW82600
ALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVEVVNATE



A/Shanghai/
TVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQCDQFLEF



CN01/2013
SADLIIERREGSDVCYPGKFVNEEALRQILRESGGIDKEAM



2013/04/11 HA
GFTYSGIRTNGATSACRRSRSSFYAEMKWLLSNTDNAAFP



546235368
QMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLYGSGNKL




VTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWLMLNPN




DTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDANCEGD




CYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQRSLLLATGM




KNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRHQNAQ




GEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELIDNEFN




EVEKQIGNVINWTRDSITEVWSYNAELLVAMENQHTIDLA




DSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDDDCMA




SIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVILWFSF




GASCFILLAIVMGLVFICVKNGNMRCTICI





279
AGW82612
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



JS01/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



546235388
NTDNAAFPQMTKSYKNTRKNPALIVWGIHHSGSTAEQTK




LYGSGNKLVTVGSSNYQQSFAPSPGARTQVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFTEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIAMGLVFICVKNGNMRCTICI





280
AHA11472
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



31676/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/12/08 HA
GSGGIDKESMGFTYSGIRINGETSACRRSGSSFYAEMKWL



557478625
LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITNKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCELLLAIAMGLVFICIKNGNMRCTICI





281
AHA11483
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



14135-2/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/08/07 HA
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



557478644
LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





282
AHA11500
TQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERGVE



A/Zhejiang/
VVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPPQC



DTID-ZJU10/2013
DQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRESGGI



2013/10/14 HA
DKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSNT



557478676
DNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY




GSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHWL




MLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVDA




NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMENQH




TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIVMGLVFICVKN





283
AHA57050
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



14659/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/08/12 HA
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



558484427
LSNSNNAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITSKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




NCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





284
AHA57072
MNTQILALIACMLIGAKGDKICLGHHAVANGTKVNTLTER



A/turkey/Minnesota/
GIEVVNATETVETANVKKICTQGKRPTDLGQCGLLGTLIG



18421/2009
PPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQILR



2009/09/09 HA
GSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKWL



558484465
LSNSNDAAFPQMTKSYRNPRDKPALIIWGVHHSGSATEQT




KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPEKPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTEVWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRKESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





285
AHD25003
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Guangdong/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



02/2013 2013/10/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 568260567
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL




SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNM





286
AHF20528
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Hong
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Kong/470129/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013 2013/11/30
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



HA 570933555
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





287
AHF20568
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



CN02/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/02 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



570933626
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIMSNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





288
AHH25185
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Guangdong/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



04/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/16 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



576106234
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





289
AHJ57411
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



PD-01/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/17 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



585478041
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVSSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCKGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





290
AHJ57418
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



PD-02/2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/01/17 HA
GIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLSN



585478256
TDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKLY




GSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFHWL




MLNPNDTVTFSFNGAFIAPDRASFLKGKSMGIQSGVQVDA




NCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFELID




NEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQH




TIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





291
AHK10800
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/01/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2014 2014/01/03
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



HA 587681014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





292
AHM24224
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Beijing/3/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2013 2013/04/16
QCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES



HA 594704802
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS




NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





293
AHN96472
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shanghai/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



PD-CN-
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



02/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/01/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



602701641
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





294
AHZ39686
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/DEWH72-
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



01/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013//HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632807036
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





295
AHZ39710
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



DEWH72-03/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013//HA
GGIDKEAMGFTYSGIRTDGATSACRRSGSSFYAEMKWLLS



632807076
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





296
AHZ39746
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Anhui/DEWH72-
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



06/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013//HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632807136
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGERPQVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





297
AHZ41929
MNTQILVEALVAIPINADKICLGHHAVSNGTKVNTLTERG



A/mallard/Sweden/
VEVVNATETVERTNVPRICSRGKRTVDLGQCGLLGTITGP



1621/2002
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2002/12/12 HA
GGIDKETMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



632810949
NTDNAAFPQMTKSYKNTRNDPALIIWGIHHSGSTTEQTKL




YGSGNKLITVGSSNYQQSFVPSPGARPQVNGQSGRIDFHW




LILNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQIDA




NCEGDCYHSGGTIISNLPFQNINSRAVGKCPRYVKQESLLL




ATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFRH




QNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELID




NEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVAMENQH




TIDLADSEMNKLYERVRRQLRENAEEDGTGCFEIFHKCDD




DCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKDVI




LWFSFGASCFILLAIAMGLVFMCVKNGNMRCTICI





298
AHZ42537
MNTQILAFIACMLVGAKGDKICLGHHAVANGTKVNTLTE



A/mallard/Minnesota/
RGIEVVNATETVETANIKKLCTQGKRPTDLGQCGLLGTLI



AI09-3770/2009
GPPQCDQFLEFDADLIIERREGTDVCYPGKFTNEESLRQIL



2009/09/12 HA
RGSGGIDKESMGFTYSGIRTNGATSACRRSGSSFYAEMKW



632811964
LLSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSATEQ




TKLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGVQSDVP




LDSGCEGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTS




LLLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQ




FELIDNEFSEIEQQIGNVINWTRDSMTELWSYNAELLVAM




ENQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFH




KCDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGY




KDIILWFSFGASCFLLLAIAMGLVFICIKNGNMRCTICI





299
AHZ42549
MNTQILAFIACMLVGVRGDKICLGHHAVANGTKVNTLTE



A/ruddy
KGIEVVNATETVESANIKKICTQGKRPTDLGQCGLLGTLIG



turnstone/Delaware/
PPQCDQFLEFDSDLIIERREGTDVCYPGKFTNEESLRQILRG



A100-1538/2000
SGGIDKESMGFTYSGIRTNGATSACRRLGSSSFYAEMKWL



2000/05/20 HA
LSNSDNAAFPQMTKSYRNPRNKPALIIWGVHHSGSANEQT



632811984
KLYGSGNKLITVGSSKYQQSFTPSPGARPQVNGQSGRIDF




HWLLLDPNDTVTFTFNGAFIAPDRASFFRGESLGIQSDVPL




DSSCGGDCFHSGGTIVSSLPFQNINPRTVGKCPRYVKQTSL




LLATGMRNVPENPKTRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIDKTNQQFE




LMDNEFNEIEQQIGNVINWTRDSMTEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVRKQLRENAEEDGTGCFEIFHK




CDDQCMESIRNNTYDHTQYRTESLQNRIQIDPVKLSSGYK




DIILWFSFGASCFLLLAIAMGLIFICIKNGNMRCTICI





300
AID70634
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shanghai/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Mix1/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/03 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



660304650
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRIIEKTNQQFE




LIDNEFNEVEKQISNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





301
AIN76383
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/Zhejiang/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



LS01/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/08 HA
GGIDKBAMGFTYSGIRTNGTTSACRRSGSSFYAEMKWLLS



684694637
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





302
AIU46619
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



Zbejiang/DTID-
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



ZJU06/2013
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2013/12/HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



699978931
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVEV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





303
AIU47013
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Suzhou/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



040201H/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/04/ HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



699979673
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDMILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





304
AJJ90490
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



742/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/10 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178094
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





305
AJJ90526
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



898/2013
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2013/12/09 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755178154
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





306
AJJ90538
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Shenzhen/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



918/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/09 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178174
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





307
AJJ90576
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1665/2013
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2013/12/12 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755178238
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





308
AJJ90588
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2110/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/13 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178258
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSIGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





309
AJJ90661
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2912/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/18 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178380
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





310
AJJ90673
MNTQILVFALTAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3049/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/18 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178400
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





311
AJJ90795
MNTQILVFALIAIIPTNADKICLGHHAVPNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3281/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/18 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755178604
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





312
AJJ90891
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



3520/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/19 HA
SNTDNAAFPQMTKSYKNTRKXPALIVWGIHHSVSTAEQT



755178764
KLYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDF




HWLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQ




VDANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





313
AJJ90951
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



3544/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755178864
SNTDNAAFPQMTKSYRNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





314
AJJ91035
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



3780/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755179004
SNTDNAAFPQMTKSYKNTRRSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDNRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





315
AJJ91155
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



4037/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755179204
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





316
AJJ92005
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



801/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/09 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180629
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





317
AJJ94254
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1374/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184382
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





318
AJJ94606
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



191/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184968
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





319
AJJ96552
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP



12206/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188219
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





320
AJJ96684
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKINTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13207/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188439
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





321
AJJ96732
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13223/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188519
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





322
AJK00354
MNTQILVFALVAIIPTNADKICLGHHAVSNGTKVNTLTER



A/duck/Zhejiang/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



LS02/2014
PQCDQFLEFSADLIVERREGSDVCYPGKFVNEEALRQILRE



2014/01/12 HA
SGGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



755194469
SNTDNAAFPQMTKSYKNTRKDPALIWGIHHSGSTTEQTK




LYGSGNKLITVGSSNYQQSFVPSPGARPLVNGQSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNINSRAVGKCPRYVKQES




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQ




QFELIDHEFTEVEKQIGNVINWTRDSMTEVWSYNAELLVA




MENQHTIDLADSEMNKLYERVKRQLRENAEEDGTGCFEIF




HKCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSS




GYKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





323
AJJ91264
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



4129/2013
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2013/12/19 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755179386
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLMEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





324
AJJ91314
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shaoxing/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2417/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179470
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPPVNGLSGRIDFHW




LMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQVD




ANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRSLL




LATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGFR




HQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFELI




DNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMENQ




HTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKCD




DDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYKD




VILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





325
AJJ91402
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Huzhou/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4045/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/24 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179618
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KEVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





326
AJJ91476
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Huzhou/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



4076/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2013/10/24 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755179743
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





327
AJJ91725
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shaoxing/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



5201/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/10/28 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755180161
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





328
AJJ91885
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP4/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/16 HA
GGIDKEAMGFTYSGIRANGVTSACRRSGSSFYAEMKWLL



755180429
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





329
AJJ91909
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP26/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/01/20 HA
GIDKEAMGFTYSGIRANGATSACKRSGSSFYAEMKWLLS



755180469
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDGCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSRGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





330
AJJ91945
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP38/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/22 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180529
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIGGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





331
AJJ91957
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP44/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/23 HA
GGIDKEAMGFTYSGIRANGTTSACRRSGSSFYAEMKWLLS



755180549
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISSLPFQNIDSRAVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





332
AJJ91969
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP48/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/23 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755180569
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





333
AJJ91993
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



4119/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180609
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLLGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFTLLAIVMGLVFICVKNGNMRCTICI





334
AJJ92031
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



4064/2013
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2013/12/19 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755180672
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVESSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





335
AJJ92967
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/silkie
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



chicken/Jiangxi/
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



9469/2014
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



2014/02/16 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755182232
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





336
AJJ93027
MNTQILVEALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



9558/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVKEEALRQILRES



2014/02/16 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755182332
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





337
AJJ93051
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



10573/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/18 HA
GGIDKBAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755182372
NTDDAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





338
AJJ93845
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



157/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/20 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755183695
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





339
AJJ93857
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



169/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACMRSGSSFYAEMKWLL



755183715
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





340
AJJ93869
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



173/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183735
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





341
AJJ93881
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



189/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183755
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPKYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





342
AJJ93907
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dong
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



guan/449/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755183799
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





343
AJJ93931
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



Dongguan/536/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755183839
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTIISKLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





344
AJJ93943
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



568/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755183859
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





345
AJJ93979
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTVTGP



chicken/Dongguan/
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



656/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/20 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755183919
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




GLIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





346
AJJ94134
MNTQILVLALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1051/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184182
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVXLSXGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





347
AJJ94158
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1075/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184222
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





348
AJJ94182
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1177/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACKRSGSSFYAEMKWLLS



755184262
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSIAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





349
AJJ94194
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTIDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



1264/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755184282
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQVTGKLNRLIEKTNQQ




FELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





350
AJJ94206
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



1268/2014
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



2014/02/21 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755184302
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISDLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





351
AJJ94344
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNSTETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



1451/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL



755184532
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRTVGKCPRYVKQRSL




LLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYGF




RHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQFE




LIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAMEN




QHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHKC




DDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGYK




DVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





352
AJJ94356
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1456/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755184552
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFBIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





353
AJJ94396
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1494/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755184618
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





354
AJJ94754
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dong
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



guan/748/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755185215
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSNAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





355
AJJ94838
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



835/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185356
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFGFGASCFILLAIVMGLVFICVKNGNMRCTICI





356
AJJ94862
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



843/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIEKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755185396
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





357
AJJ94886
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



851/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185436
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





358
AJJ94910
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



874/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/20 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185476
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSASTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





359
AJJ94959
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



967/2014
GGIDKEAMGFTYSGIRANGATSACXRSGSSFYAEMKWLL



2014/02/21 HA
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK



755185558
LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





360
AJJ95048
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



1009/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755185708
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPETPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDNDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





361
AJJ95171
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1314/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755185913
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFNFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





362
AJJ95227
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1382/2014
QCDQFLEFSADLIIERREGSDICYPGKFVNEEALRQILRESG



2014/02/21 HA
GIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755186006
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





363
AJJ95251
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dong
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



guan/1401/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186046
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





364
AJJ95346
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1548/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEBALRQILRES



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186206
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYKRVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHNKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





365
AJJ95382
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



1690/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/02/21 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186266
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV




DADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





366
AJJ95464
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shenzhen/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



138/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/19 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186404
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





367
AJJ95572
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Dongguan/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



1100/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/21 HA
GGIEKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLLS



755186584
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFBIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSGGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





368
AJJ95584
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



chicken/Dongguan/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



1519/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/02/21 HA
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL



755186604
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPERASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYRGEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFMLLAIVMGLVFICVKNGNMRCTICI





369
AJJ95596
MNTQILAFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP58/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/01/25 HA
GGIDKEAMGFTYSGIRANGATSACRRSGSSFYAEMKWLL



755186624
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





370
AJJ95620
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP75/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/15 HA
GGIDKEAMGFTYSGIRTNGSTSACRRSGSSFYAEMKWLLS



755186664
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAVVMGLVFICVKNGNMRCTICI





371
AJJ95632
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP62/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755186684
NTDNATFPQMTKSYKNTRKSPALIIWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVETQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





372
AJJ96720
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTTIPRICSKGKKTVDLGQCGLLGTITGPP



13220/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188499
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





373
AJJ96817
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Jiangxi/
GVEVVNATEIVERTNIPRICSKGKKTVDLGQCGLLGTITGP



9513/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/02/16 HA
GGIDKEAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755188661
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





374
AJJ96841
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/Shenzhen/SP139/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/04/02 HA
GGIDKEAMGFTYSGIRTNGATSTCRRSGSSFYAEMKWLLS



755188701
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRACFLRGKSMGIQSGVQ




VDADCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQR




SLLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVERQIGNVINWIRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





375
AJJ96889
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTXIPRICSKGKKTVDLGQCGLLGTITGPP



13496/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKXAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLL



755188781
SNTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSXGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





376
AJJ96901
MNTQILVEALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



13502/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755188801
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSXGTHISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





377
AJJ96925
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13513/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/11 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755188841
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHTVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDLH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





378
AJJ97267
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13252/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/03/30 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189411
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





379
AJJ97291
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13493/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189451
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





380
AJJ97331
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13512/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189517
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSIGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





381
AJJ97373
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



13521/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755189587
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPXRASFLRGKSXGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





382
AJJ97443
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTTIPRICSKGKRTVDLGQCGLLGTITGPP



13530/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/06 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189702
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSRGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





383
AJJ97582
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



14023/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/13 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755189933
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





384
AJJ97697
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



14517/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190125
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCDGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





385
AJJ97709
MNTQILVFALIAIIPANADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



14518/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYNGIRTNGATSACRRSGSSFYAEMKWLL



755190145
SNTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTK




LYGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGNCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFBIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





386
AJJ97745
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



14554/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/20 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190205
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELMDNEFNEVEKQIGNVINWTRDSITELWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





387
AJJ97757
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shantou/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



2537/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/04/16 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190225
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FKHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





388
AJJ97841
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/duck/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



15044/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/04/27 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190365
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENABEDGTGCFBIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVRLSSGY




KDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





389
AJJ97899
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Jiangxi/
VEVVNATETVERTNIPRICSKGKRTVDLGQCGLLGTITGPP



15524/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/05/05 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190462
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIAKTNQQF




ELIDNEFNEVEKQIGNVINWIRDSITEVWSYNAELLVAME




NQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFHK




CDDDCMASIRNNTYDHRKYREEAMQNRIQIDPVKLSSGY




KDVILWFSFGASCFILLAIVMGLVFMCVKNGNMRCTICI





390
AJJ97925
MNTQILVFALIAIIPTNADKICLGHHAVSNGTKVNTLTERG



A/silkie
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



chicken/Shantou/
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2050/2014
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



2014/03/25 HA
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL



755190506
YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSENGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





391
AJJ97973
MNTQILVFALISIIPTNADKICLGHHAVSNGTKVNTLTERG



A/chicken/Shantou/
VEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGPP



4325/2014
QCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRKS



2014/07/01 HA
GGIDKBAMGFTYSGIRTNGVTSACRRSGSSFYAEMKWLLS



755190586
NTDNAAFPQMTKSYKNTRKSPAIIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DADCEGDCYHSGGTHISNLPFQNIDSRAVGKCPRYVKQRS




LLLATGMKNVPEVPKGRGLFGAIAGFIENGWEGLIDGWY




GFRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQ




FELIDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI





392
AJJ97998
MNTQILVFALIAIVPTNADKICLGHHAVSNGTKVNTLTER



A/chicken/Shantou/
GVEVVNATETVERTNIPRICSKGKKTVDLGQCGLLGTITGP



4816/2014
PQCDQFLEFSADLIIERREGSDVCYPGKFVNEEALRQILRES



2014/07/22 HA
GGIDKEAMGFTYSGIRTNGATSACRRSGSSFYAEMKWLLS



755190628
NTDNAAFPQMTKSYKNTRKSPALIVWGIHHSVSTAEQTKL




YGSGNKLVTVGSSNYQQSFVPSPGARPQVNGLSGRIDFH




WLMLNPNDTVTFSFNGAFIAPDRASFLRGKSMGIQSGVQV




DANCEGDCYHSGGTIISNLPFQNIDSRAVGKCPRYVKQKS




LLLATGMKNVPEIPKGRGLFGAIAGFIENGWEGLIDGWYG




FRHQNAQGEGTAADYKSTQSAIDQITGKLNRLIEKTNQQF




ELVDNEFNEVEKQIGNVINWTRDSITEVWSYNAELLVAM




ENQHTIDLADSEMDKLYERVKRQLRENAEEDGTGCFEIFH




KCDDDCMASIRNNTYDHSKYREEAMQNRIQIDPVKLSSG




YKDVILWFSFGASCFILLAIVMGLVFICVKNGNMRCTICI
















TABLE 15







Examples of Wild type Hemagglutinin Antigens









SEQ




ID
Protein/



NO
Strain
Nucleic Acid Sequence





393
H1
AGCAAAAGCAGGGGAAAATAAAAACAACCAAAATGAAGGCAAACCTACTGGTCCTG




TTATGTGCACTTGCAGCTGCAGATGCAGACACAATATGTATAGGCTACCATGCGAA




CAATTCAACCGACACTGTTGACACAGTGCTCGAGAAGAATGTGACAGTGACACACT




CTGTTAACCTGCTCGAAGACAGCCACAACGGAAAACTATGTAGATTAAAAGGAATA




GCCCCACTACAATTGGGGAAATGTAACATCGCCGGATGGCTCTTGGGAAACCCAGA




ATGCGACCCACTGCTTCCAGTGAGATCATGGTCCTACATTGTAGAAACACCAAACT




CTGAGAATGGAATATGTTATCCAGGAGATTTCATCGACTATGAGGAGCTGAGGGAG




CAATTGAGCTCAGTGTCATCATTCGAAAGATTCGAAATATTTCCCAAAGAAAGCTC




ATGGCCCAACCACAACACAACCAAAGGAGTAACGGCAGCATGCTCCCATGCGGGGA




AAAGCAGTTTTTACAGAAATTTGCTATGGCTGACGGAGAAGGAGGGCTCATACCCA




AAGCTGAAAAATTCTTATGTGAACAAGAAAGGGAAAGAAGTCCTTGTACTGTGGGG




TATTCATCACCCGTCTAACAGTAAGGATCAACAGAATATCTATCAGAATGAAAATG




CTTATGTCTCTGTAGTGACTTCAAATTATAACAGGAGATTTACCCCGGAAATAGCA




GAAAGACCCAAAGTAAGAGATCAAGCTGGGAGGATGAACTATTACTGGACCTTGCT




AAAACCCGGAGACACAATAATATTTGAGGCAAATGGAAATCTAATAGCACCAAGGT




ATGCTTTCGCACTGAGTAGAGGCTTTGGGTCCGGCATCATCACCTCAAACGCATCA




ATGCATGAGTGTAACACGAAGTGTCAAACACCCCTGGGAGCTATAAACAGCAGTCT




CCCTTTCCAGAATATACACCCAGTCACAATAGGAGAGTGCCCAAAATACGTCAGGA




GTGCCAAATTGAGGATGGTTACAGGACTAAGGAACATTCCGTCCATTCAATCCAGA




GGTCTATTTGGAGCCATTGCCGGTTTTATTGAAGGGGGATGGACTGGAATGATAGA




TGGATGGTACGGTTATCATCATCAGAATGAACAGGGATCAGGCTATGCAGCGGATC




AAAAAAGCACACAAAATGCCATTAACGGGATTACAAACAAGGTGAACTCTGTTATC




GAGAAAATGAACATTCAATTCACAGCTGTGGGTAAAGAATTCAACAAATTAGAAAA




AAGGATGGAAAATTTAAATAAAAAAGTTGATGATGGATTTCTGGACATTTGGACAT




ATAATGCAGAATTGTTAGTTCTACTGGAAAATGAAAGGACTCTGGATTTCCATGAC




TCAAATGTGAAGAATCTGTATGAGAAAGTAAAAAGCCAATTAAAGAATAATGCCAA




AGAAATCGGAAATGGATGTTTTGAGTTCTACCACAAGTGTGACAATGAATGCATGG




AAAGTGTAAGAAATGGGACTTATGATTATCCCAAATATTCAGAAGAGTCAAAGTTG




AACAGGGAAAAGGTAGATGGAGTGAAATTGGAATCAATGGGGATCTATCAGATTCT




GGCGATCTACTCAACTGTCGCCAGTTCACTGGTGCTTTTGGTCTCCCTGGGGGCAA




TCAGTTTCTGGATGTGTTCTAATGGATCTTTGCAGTGCAGAATATGCATCTGAGAT




TAGAATTTCAGAAATATGAGGAAAAACACCCTTGTTTCTACT





394
H7
AGCGAAAGCAGGGGATACAAAATGAACACTCAAATCCTGGTATTCGCTCTGATTGC




GATCATTCCAACAAATGCAGACAAAATCTGCCTCGGACATCATGCCGTGTCAAACG




GAACCAAAGTAAACACATTAACTGAAAGAGGAGTGGAAGTCGTCAATGCAACTGAA




ACAGTGGAACGAACAAACATCCCCAGGATCTGCTCAAAAGGGAAAAGGACAGTTGA




CCTCGGTCAATGTGGACTCCTGGGGACAATCACTGGACCACCTCAATGTGACCAAT




TCCTAGAATTTTCAGCCGATTTAATTATTGAGAGGCGAGAAGGAAGTGATGTCTGT




TATCCTGGGAAATTCGTGAATGAAGAAGCTCTGAGGCAAATTCTCAGAGAATCAGG




CGGAATTGACAAGGAAGCAATGGGATTCACATACAGTGGAATAAGAACTAATGGAG




CAACCAGTGCATGTAGGAGATCAGGATCTTCATTCTATGCAGAAATGAAATGGCTC




CTGTCAAACACAGATGATGCTGCATTCCCGCAGATGACTAAGTCATATAAAAATAC




AAGAAAAAGCCCAGCTCTAATAGTATGGGGGATCCATCATTCCGTATCAACTGCAG




AGCAAACCAAGCTATATGGGAGTGGAAACAAACTGGTGACAGTTGGGAGTTCTAAT




TATCAACAATCTTTTGTACCGAGTCCAGGAGCGAGACCACAAGTTAATGGTCTATC




TGGAAGAATTGACTTTCATTGGCTAATGCTAAATCCCAATGATACAGTCACTTTCA




GTTTCAATGGGGCTTTCATAGCTCCAGACCGTGCAAGCTTCCTGAGAGGAAAATCT




ATGGGAATCCAGAGTGGAGTACAGGTTGATGCCAATTGTGAAGGGGACTGCTATCA




TAGTGGAGGGACAATAATAAGTAACTTGCCATTTCAGAACATAGATAGCAGGGCAG




TTGGAAAATGTCCGAGATATGTTAAGCAAAGGAGTCTGCTGCTAGCAACAGGGATG




AAGAATGTTCCTGAGATTCCAAAGGGAAGAGGCCTATTTGGTGCTATAGCGGGTTT




CATTGAAAATGGATGGGAAGGCCTAATTGATGGTTGGTATGGTTTCAGACACCAGA




ATGCACAGGGAGAGGGAACTGCTGCAGATTACAAAAGCACTCAATCGGCAATTGAT




CAAATAACAGGAAAATTAAACCGGCTTATAGAAAAAACCAACCAACAATTTGAGTT




GATAGACAATGAATTCAATGAGGTAGAGAAGCAAATCGGTAATGTGATAAATTGGA




CCAGAGATTCTATAACAGAAGTGTGGTCATACAATGCTGAACTCTTGGTAGCAATG




GAGAACCAGCATACAATTGATCTGGCTGATTCAGAAATGGACAAACTGTACGAACG




AGTGAAAAGACAGCTGAGAGAGAATGCTGAAGAAGATGGCACTGGTTGCTTTGAAA




TATTTCACAAGTGTGATGATGACTGTATGGCCAGTATTAGAAATAACACCTATGAT




CACAGCAAATACAGGGAAGAGGCAATGCAAAATAGAATACAGATTGACCCAGTCAA




ACTAAGCAGCGGCTACAAAGATGTGATACTTTGGTTTAGCTTCGGGGCATCATGTT




TCATACTTCTAGCCATTGTAATGGGCCTTGTCTTCATATGTGTAAAGAATGGAAAC




ATGCGGTGCACTATTTGTATATAAGTTTTGGAAAAAAACACCCTTGTTTCTAC





395
H10
ATGTACAAAATAGTAGTGATAATCGCGCTCCTTGGAGCTGTGAAAGGTCTTGATAA




AATCTGTCTAGGACATCATGCAGTGGCTAATGGGACCATCGTAAAGACTCTCACAA




ACGAACAGGAAGAGGTAACCAACGCTACTGAAACAGTGGAGAGTACAGGCATAAAC




AGATTATGTATGAAAGGAAGAAAACATAAAGACCTGGGCAACTGCCATCCAATAGG




GATGCTAATAGGGACTCCAGCTTGTGATCTGCACCTTACAGGGATGTGGGACACTC




TCATTGAACGAGAGAATGCTATTGCTTACTGCTACCCTGGAGCTACTGTAAATGTA




GAAGCACTAAGGCAGAAGATAATGGAGAGTGGAGGGATCAACAAGATAAGCACTGG




CTTCACTTATGGATCTTCCATAAACTCGGCCGGGACCACTAGAGCGTGCATGAGGA




ATGGAGGGAATAGCTTTTATGCAGAGCTTAAGTGGCTGGTATCAAAGAGCAAAGGA




CAAAACTTCCCTCAGACCACGAACACTTACAGAAATACAGACACGGCTGAACACCT




CATAATGTGGGGAATTCATCACCCTTCTAGCACTCAAGAGAAGAATGATCTATATG




GAACACAATCACTGTCCATATCAGTCGGGAGTTCCACTTACCGGAACAATTTTGTT




CCGGTTGTTGGAGCAAGACCTCAGGTCAATGGACAAAGTGGCAGAATTGATTTTCA




CTGGACACTAGTACAGCCAGGTGACAACATCACCTTCTCACACAATGGGGGCCTGA




TAGCACCGAGCCGAGTTAGCAAATTAATTGGGAGGGGATTGGGAATCCAATCAGAC




GCACCAATAGACAATAATTGTGAGTCCAAATGTTTTTGGAGAGGGGGTTCTATAAA




TACAAGGCTTCCCTTTCAAAATTTGTCACCAAGAACAGTGGGTCAGTGTCCTAAAT




ATGTGAACAGAAGAAGCTTGATGCTTGCAACAGGAATGAGAAACGTACCAGAACTA




ATACAAGGGAGAGGTCTATTTGGTGCAATAGCAGGGTTTTTAGAGAATGGGTGGGA




AGGAATGGTAGATGGCTGGTATGGTTTCAGACATCAAAATGCTCAGGGCACAGGCC




AGGCCGCTGATTACAAGAGTACTCAGGCAGCTATTGATCAAATCACTGGGAAACTG




AATAGACTTGTTGAAAAAACCAATACTGAGTTCGAGTCAATAGAATCTGAGTTCAG




TGAGATCGAACACCAAATCGGTAACGTCATCAATTGGACTAAGGATTCAATAACCG




ACATTTGGACTTATCAGGCTGAGCTGTTGGTGGCAATGGAGAACCAGCATACAATC




GACATGGCTGACTCAGAGATGTTGAATCTATATGAAAGAGTGAGGAAACAACTAAG




GCAGAATGCAGAAGAAGATGGGAAAGGATGTTTTGAGATATATCATGCTTGTGATG




ATTCATGCATGGAGAGCATAAGAAACAACACCTATGACCATTCACAGTACAGAGAG




GAAGCTCTTTTGAACAGATTGAATATCAACCCAGTGACACTCTCTTCTGGATATAA




AGACATCATTCTCTGGTTTAGCTTCGGGGCATCATGTTTTGTTCTTCTAGCCGTTG




TCATGGGTCTTTTCTTTTTCTGTCTGAAGAATGGAAACATGCGATGCACAATCTGT




ATTTAG
















TABLE 16







Codon Optimized Sequences Encoding H1 Hemagglutinin








Seq



ID



No.
Nucleotide sequence





396
ATGAAGGCAAACCTCTTAGTCCTTCTCTGCGCACTGGCCGCTGCCGACGCAGATACCATA



TGTATCGGTTATCACGCCAATAACTCTACCGATACAGTCGATACGGTGCTTGAGAAAAAC



GTCACCGTGACTCATAGCGTGAACCTGCTCGAGGACTCCCATAACGGTAAGCTATGCCGA



CTAAAGGGCATCGCCCCCCTGCAGCTGGGGAAATGCAACATCGCTGGCTGGTTGTTAGGT



AATCCCGAATGCGATCCACTGCTGCCCGTGAGATCCTGGTCTTACATCGTCGAAACCCCT



AACTCTGAAAATGGCATCTGCTATCCGGGAGACTTTATTGACTATGAGGAGCTCCGAGAA



CAGCTGAGCTCAGTATCCAGCTTTGAACGCTTCGAAATTTTTCCAAAGGAATCCAGCTGG



CCAAACCATAACACGAATGGCGTCACAGCCGCATGCAGCCACGAGGGAAAGAGCAGCTTT



TATAGGAACCTTCTGTGGTTGACGGAAAAAGAGGGAAGTTATCCCAAACTTAAAAACAGC



TATGTGAATAAAAAGGGCAAGGAGGTCTTGGTACTTTGGGGAATCCATCACCCTCCAAAC



AGTAAGGAACAACAAAATCTGTACCAGAATGAAAATGCATACGTGTCCGTGGTTACATCT



AATTACAACCGACGGTTTACTCCCGAGATCGCCGAGCGACCGAAAGTTCGCGACCAGGCC



GGGAGGATGAACTATTATTGGACGTTGCTGAAACCCGGTGACACAATTATCTTTGAGGCA



AATGGTAATCTTATCGCCCCGATGTACGCATTCGCACTGTCGCGCGGATTTGGCAGTGGG



ATTATAACCAGTAACGCATCTATGCATGAATGCAACACAAAGTGCCAGACTCCTTTAGGC



GCTATAAACTCTTCTTTGCCCTATCAGAATATACACCCAGTGACCATCGGCGAGTGTCCA



AAGTACGTACGCAGCGCCAAGCTCCGAATGGTTACAGGCCTCAGAAATAACCCCAGTATC



CAGAGCCGCGGCTTATTCGGGGCGATCGCTGGATTTATTGAGGGGGGCTGGACGGGAATG



ATAGATGGGTGGTACGGCTACCATCATCAGAATGAGCAGGGTAGCGGCTATGCGGCCGAC



CAGAAAAGCACCCAGAACGCTATCAACGGTATAACCAATAAAGTGAACACTGTGATCGAA



AAAATGAACATACAGTTCACTGCCGTGGGAAAGGAATTCAACAAACTGGAAAAAAGGATG



GAAAATCTTAACAAAAAAGTGGATGACGGGTTTTTGGACATTTGGACATACAATGCCGAA



CTGCTGGTTCTGCTGGAGAACGAAAGGACACTGGACTTTCACGATTCCAACGTCAAGAAT



CTCTATGAAAAAGTGAAGTCCCAATTGAAAAACAACGCCAAGGAGATCGGTAATGGGTGC



TTTGAGTTCTATCACAAGTGTGACAACGAGTGCATGGAGAGCGTTAGGAACGGCACATAC



GATTACCCAAAATATTCTGAGGAGTCTAAGTTGAACAGAGAGAAGGTCGATGGCGTTAAA



CTGGAAAGCATGGGAATTTACCAGATCCTTGCCATCTACTCCACCGTGGCCTCCTCCCTT



GTGCTGCTGGTGTCGCTGGGGGCCATCTCCTTTTGGATGTGCTCCAATGGTTCACTGCAA



TGTCGAATCTGCATC





397
ATGAAGGCTAACCTCCTAGTGCTGCTCTGTGCCTTGGCGGCTGCGGATGCTGACACCATT



TGCATTGGGTACCACGCCAATAATTCAACCGATACTGTCGACACCGTGTTGGAGAAGAAT



GTGACCGTGACTCATTCCGTGAACCTTCTTGAAGATTCGCACAACGGGAAGCTGTGTCGA



CTCAAAGGCATCGCGCCTCTACAGTTGGGCAAATGTAACATCGCTGGGTGGCTGCTCGGG



AACCCAGAATGTGATCCTTTGCTGCCAGTGAGATCGTGGTCATACATTGTGGAGACCCCC



AATTCAGAGAACGGGATATGCTACCCAGGTGACTTTATCGATTATGAGGAACTTCGGGAA



CAACTGTCTTCAGTGTCGTCATTTGAGCGTTTCGAGATCTTTCCCAAAGAGTCCTCGTGG



CCAAACCACAACACTAACGGCGTTACTGCCGCCTGCTCACATGAAGGAAAGAGCTCATTC



TACAGAAACCTGTTGTGGCTCACCGAGAAGGAGGGGAGTTATCCCAAGTTGAAAAACAGT



TATGTTAACAAGAAGGGCAAAGAAGTGTTAGTCCTGTGGGGAATCCACCACCCACCGAAT



TCTAAAGAGCAGCAGAATCTATATCAGAACGAGAACGCCTATGTGTCAGTTGTAACTTCA



AATTACAACCGCAGGTTTACTCCTGAAATCGCGGAGCGCCCGAAAGTGCGTGATCAGGCT



GGACGTATGAATTACTACTGGACTTTGCTAAAACCTGGCGACACCATCATTTTCGAAGCT



AACGGCAATCTCATTGCGCCGATGTACGCCTTTGCTCTCTCTAGGGGGTTCGGGTCTGGG



ATCATTACCAGCAATGCTTCCATGCACGAGTGTAATACAAAGTGCCAGACTCCCCTCGGC



GCGATTAATAGCTCGCTCCCCTACCAAAACATACACCCAGTGACAATTGGCGAGTGCCCT



AAATATGTGCGCTCTGCTAAGTTACGTATGGTGACGGGCCTAAGAAACAACCCCTCAATT



CAGAGCAGGGGGCTGTTCGGAGCTATTGCAGGTTTCATCGAAGGGGGCTGGACAGGGATG



ATCGACGGCTGGTATGGGTATCACCACCAGAACGAACAGGGATCCGGCTATGCTGCCGAT



CAGAAATCAACACAAAATGCAATCAATGGCATCACTAACAAAGTGAATACCGTAATTGAG



AAGATGAACATACAGTTTACCGCTGTCGGTAAAGAATTCAACAAGCTGGAGAAACGGATG



GAGAATCTGAACAAGAAAGTCGATGATGGCTTCTTGGATATCTGGACCTATAATGCTGAG



TTACTTGTGCTCTTGGAAAACGAGCGTACTCTCGACTTTCATGATTCAAATGTCAAGAAT



CTGTATGAAAAGGTAAAGTCCCAGCTAAAAAACAATGCCAAGGAGATCGGGAATGGCTGC



TTTGAATTCTACCACAAATGCGATAATGAGTGCATGGAGTCGGTGAGGAACGGAACCTAC



GATTACCCAAAATATAGCGAGGAATCAAAACTGAACAGAGAGAAGGTGGATGGTGTGAAG



CTGGAATCCATGGGTATCTACCAGATCCTCGCCATCTATTCAACTGTGGCTAGTTCCCTG



GTGCTGCTCGTGAGCCTTGGTGCAATCTCCTTCTGGATGTGTTCCAACGGGTCATTGCAG



TGTAGGATCTGCATA





398
ATGAAGGCTAACTTGCTGGTCTTGCTTTGCGCGCTGGCCGCTGCTGACGCCGACACCATC



TGTATTGGGTATCATGCTAACAACTCCACGGATACCGTGGATACAGTGTTGGAAAAAAAT



GTTACAGTTACTCATTCGGTGAACCTGCTGGAGGACTCTCACAATGGGAAGCTGTGCAGG



CTCAAAGGTATCGCTCCGCTCCAACTAGGCAAATGTAATATTGCCGGCTGGCTGTTAGGA



AACCCAGAGTGTGACCCTCTCTTACCCGTGAGATCTTGGTCCTACATCGTCGAGACCCCC



AACAGCGAAAACGGAATTTGTTATCCCGGAGACTTCATAGATTATGAGGAGCTGCGCGAA



CAGCTCTCTTCTGTTAGCTCTTTTGAGCGTTTTGAGATCTTTCCTAAAGAGAGTTCATGG



CCCAACCACAATACCAACGGAGTGACAGCCGCATGCTCCCATGAAGGGAAGTCTAGCTTC



TATAGAAATCTTCTGTGGCTGACTGAAAAAGAAGGATCTTACCCCAAGTTGAAGAATTCT



TATGTGAACAAAAAGGGCAAAGAGGTGTTGGTACTCTGGGGCATTCATCACCCACCTAAT



TCAAAGGAGCAGCAAAACCTTTATCAAAACGAGAATGCCTATGTTAGCGTCGTCACTTCT



AATTATAACCGGAGATTCACCCCGGAGATAGCGGAACGCCCCAAGGTTCGGGATCAGGCT



GGCCGCATGAATTACTACTGGACCCTCCTAAAACCTGGCGACACCATAATCTTCGAAGCA



AATGGCAACCTGATCGCACCTATGTACGCCTTTGCGCTGTCTAGGGGATTCGGCTCGGGC



ATTATTACCAGTAATGCCTCAATGCACGAGTGTAATACAAAATGCCAGACCCCTCTGGGA



GCCATTAATTCTAGTCTGCCTTATCAGAATATTCATCCTGTGACCATTGGCGAATGTCCG



AAATATGTTAGATCCGCAAAGCTGCGAATGGTTACCGGACTTCGCAACAACCCCTCTATA



CAAAGCCGCGGACTCTTTGGAGCAATCGCTGGCTTCATTGAGGGTGGCTGGACGGGCATG



ATCGATGGGTGGTACGGATACCATCATCAGAACGAGCAGGGAAGCGGATATGCCGCAGAC



CAAAAATCTACTCAGAACGCTATTAACGGAATTACCAACAAAGTCAACACAGTTATCGAG



AAAATGAATATTCAGTTCACCGCAGTTGGTAAGGAATTTAACAAACTGGAGAAACGAATG



GAGAACTTGAACAAGAAGGTCGACGATGGCTTCTTAGACATCTGGACATATAATGCCGAA



CTGTTGGTCCTCCTGGAGAACGAGAGAACCTTGGACTTTCACGACTCTAACGTGAAGAAT



CTTTACGAGAAGGTGAAGTCCCAACTGAAGAATAATGCAAAAGAGATCGGAAACGGCTGT



TTTGAGTTCTACCACAAGTGCGACAATGAGTGCATGGAGAGCGTGCGGAATGGGACATAT



GATTATCCCAAGTATAGTGAAGAAAGCAAGCTGAATCGAGAAAAGGTTGACGGAGTGAAG



CTGGAGAGCATGGGGATCTACCAGATCTTAGCAATTTATAGCACAGTGGCTTCTTCCCTT



GTGTTGCTGGTCTCGCTGGGAGCTATCAGCTTTTGGATGTGCAGCAACGGAAGTCTGCAG



TGCCGCATTTGCATT





399
ATGAAAGCCAACCTGTTGGTGCTGTTATGCGCGCTGGCAGCCGCAGATGCTGATACTATC



TGTATCGGATACCATGCCAATAACAGCACCGATACCGTGGATACTGTGTTAGAGAAGAAT



GTGACAGTGACGCATTCAGTAAACCTCCTCGAGGACAGTCATAATGGAAAACTGTGTAGG



CTCAAGGGTATAGCTCCGCTGCAGCTGGGCAAGTGTAACATCGCTGGGTGGCTGCTGGGC



AACCCTGAATGCGATCCCCTGTTGCCCGTTCGGAGTTGGTCTTACATCGTGGAGACCCCA



AACTCTGAGAACGGAATTTGTTACCCCGGTGACTTTATCGATTACGAGGAATTGCGGGAG



CAGCTTAGCTCAGTGTCTTCATTTGAACGGTTTGAAATCTTTCCCAAGGAAAGCAGCTGG



CCCAATCATAATACTAACGGCGTGACTGCCGCTTGTTCCCACGAAGGCAAGAGCTCCTTC



TACAGAAATCTGCTTTGGTTGACAGAGAAAGAGGGCAGCTATCCAAAGCTGAAGAACAGT



TATGTGAATAAGAAGGGCAAGGAGGTCCTGGTTCTTTGGGGGATCCATCATCCCCCTAAT



AGTAAGGAGCAGCAGAACTTATACCAGAATGAGAATGCCTACGTCAGCGTTGTCACCTCA



AACTATAACCGGCGATTTACACCCGAAATTGCCGAACGTCCCAAGGTCCGCGACCAAGCC



GGGCGTATGAACTACTATTGGACACTTCTGAAACCTGGGGACACAATAATTTTCGAAGCC



AACGGTAACTTAATCGCTCCCATGTACGCTTTCGCTCTCAGCAGGGGCTTCGGCAGCGGC



ATTATCACTTCCAATGCGTCCATGCATGAATGTAATACGAAGTGCCAGACCCCTCTCGGT



GCCATAAACTCTTCTCTCCCCTACCAGAACATTCACCCTGTCACCATAGGAGAATGCCCA



AAGTATGTCCGGTCGGCAAAGTTGAGGATGGTTACGGGCCTGCGTAACAACCCTTCTATA



CAGTCTAGGGGCCTGTTCGGAGCAATCGCCGGCTTCATCGAAGGAGGCTGGACTGGGATG



ATCGATGGCTGGTACGGCTATCATCACCAGAATGAGCAGGGCTCAGGTTATGCAGCCGAT



CAGAAGTCCACACAGAACGCTATTAACGGGATAACGAACAAGGTGAACACCGTCATTGAA



AAGATGAACATTCAGTTTACAGCCGTTGGAAAAGAGTTCAACAAACTGGAAAAGCGGATG



GAGAACCTGAACAAAAAGGTGGACGATGGATTTCTGGATATTTGGACATATAACGCCGAG



CTGCTGGTACTCCTTGAGAACGAGCGTACGCTTGACTTTCATGACAGTAACGTGAAGAAT



CTGTACGAGAAGGTCAAAAGCCAGCTGAAGAACAATGCCAAAGAAATTGGGAACGGGTGT



TTCGAATTCTACCACAAGTGTGACAATGAATGCATGGAGAGTGTTCGGAACGGAACCTAC



GACTATCCTAAATATTCTGAGGAGTCCAAGCTGAATCGGGAAAAGGTTGACGGGGTGAAA



CTGGAGAGTATGGGAATCTACCAGATCCTGGCTATTTACTCCACAGTCGCTTCCTCTCTC



GTCTTGTTGGTGTCCCTTGGTGCCATCTCATTTTGGATGTGTTCTAATGGTTCTCTTCAG



TGCCGAATCTGTATA





400
ATGAAAGCTAACCTTCTCGTATTGCTCTGCGCTTTGGCTGCAGCCGATGCCGATACGATT



TGCATCGGATACCACGCAAATAACAGCACTGACACTGTGGACACGGTACTGGAAAAGAAT



GTTACCGTGACACACTCCGTCAACCTGCTCGAGGACTCCCACAACGGAAAGTTGTGTAGG



CTTAAAGGTATCGCCCCTCTACAGTTAGGGAAGTGCAACATCGCAGGGTGGTTGTTAGGA



AACCCCGAATGTGACCCACTCCTGCCTGTGCGCTCTTGGAGCTATATTGTGGAAACCCCG



AATAGCGAAAACGGAATTTGTTACCCTGGCGACTTTATCGATTATGAAGAGCTCCGAGAG



CAACTGAGCAGCGTGTCCAGCTTTGAGCGATTTGAAATATTCCCCAAAGAGAGTTCCTGG



CCCAACCATAACACTAACGGAGTGACCGCTGCATGTTCGCACGAAGGCAAATCGAGTTTT



TACCGGAACCTGCTTTGGCTCACCGAGAAGGAAGGAAGTTATCCCAAACTCAAAAATTCA



TACGTGAATAAAAAGGGTAAGGAGGTGCTGGTGCTGTGGGGAATCCACCATCCTCCAAAC



AGCAAGGAACAACAGAATCTCTACCAGAATGAGAACGCCTATGTGAGCGTGGTAACCTCC



AACTACAATCGGCGGTTCACTCCTGAGATCGCCGAGCGCCCGAAGGTCCGGGATCAAGCA



GGTCGAATGAACTACTACTGGACCCTGCTGAAGCCAGGTGATACTATCATTTTCGAGGCT



AATGGAAACCTGATTGCGCCTATGTACGCTTTCGCCCTGTCTAGGGGGTTTGGGTCCGGT



ATCATCACGTCTAACGCTTCAATGCATGAATGCAACACGAAGTGTCAGACCCCGCTTGGC



GCCATAAACAGCTCCCTCCCCTACCAGAACATTCACCCCGTCACCATAGGCGAGTGTCCC



AAGTACGTGCGGTCAGCCAAGTTGCGGATGGTAACGGGCCTCCGGAATAATCCAAGTATA



CAATCCCGAGGACTTTTCGGGGCAATCGCGGGCTTCATTGAGGGGGGATGGACCGGCATG



ATTGATGGATGGTACGGTTACCACCACCAGAACGAGCAGGGCAGTGGATATGCCGCTGAC



CAGAAGAGCACTCAGAACGCAATTAATGGCATCACCAATAAGGTGAACACCGTCATTGAG



AAGATGAACATCCAGTTTACGGCAGTAGGCAAGGAGTTTAACAAGCTGGAGAAACGTATG



GAAAACCTGAATAAGAAAGTGGACGACGGGTTTTTGGATATTTGGACATATAACGCCGAA



CTCCTCGTGCTGCTCGAGAATGAAAGAACATTAGACTTTCACGATAGTAACGTGAAAAAC



CTGTATGAAAAGGTCAAATCCCAGCTAAAGAACAACGCCAAAGAGATCGGCAATGGCTGT



TTTGAGTTTTACCACAAGTGTGATAATGAATGCATGGAAAGTGTTCGGAACGGAACCTAC



GATTATCCAAAATACTCGGAGGAGTCCAAACTGAATAGAGAGAAGGTGGACGGCGTCAAA



CTAGAGAGTATGGGTATCTATCAGATACTTGCGATCTACTCAACCGTCGCCAGCTCCTTA



GTACTTCTCGTCAGCCTCGGTGCTATCTCCTTTTGGATGTGTAGTAACGGCAGTCTGCAG



TGTCGGATATGCATC





401
ATGAAGGCTAACCTGTTGGTGCTCCTATGTGCCCTGGCCGCTGCAGATGCTGACACAATC



TGCATTGGGTATCATGCAAACAACTCCACCGACACTGTTGACACAGTTTTGGAAAAGAAC



GTGACAGTCACTCACAGCGTAAACCTCCTGGAAGACTCACACAATGGGAAGTTATGTCGG



CTGAAGGGCATAGCCCCATTGCAACTGGGCAAGTGCAATATAGCGGGGTGGCTTCTCGGC



AACCCGGAATGCGACCCCCTGTTGCCCGTACGCAGCTGGAGTTACATTGTGGAGACGCCC



AATTCCGAGAATGGCATCTGTTACCCGGGCGATTTCATAGATTACGAAGAACTGCGGGAG



CAGCTCTCCTCCGTTTCCTCGTTCGAACGGTTCGAGATTTTCCCTAAAGAATCATCATGG



CCTAATCACAATACAAATGGCGTGACGGCCGCATGCTCACACGAGGGCAAGTCCAGCTTT



TACAGAAATCTCCTGTGGCTGACGGAGAAGGAAGGAAGCTACCCTAAGCTTAAGAATAGC



TATGTAAACAAAAAGGGGAAGGAGGTGCTGGTTCTCTGGGGGATTCATCATCCGCCAAAT



AGTAAGGAACAGCAGAACCTTTACCAGAATGAGAATGCATACGTCTCTGTGGTCACGTCT



AACTACAATCGGCGCTTCACACCCGAGATCGCTGAACGGCCCAAAGTCCGGGACCAAGCC



GGACGAATGAATTACTACTGGACCCTTTTGAAGCCCGGCGATACCATTATCTTCGAAGCG



AACGGGAACCTGATAGCTCCCATGTACGCCTTTGCTCTCAGTAGGGGATTCGGCTCCGGC



ATTATTACCTCTAATGCTTCTATGCACGAGTGCAACACAAAATGTCAGACTCCGCTCGGT



GCCATCAACAGTTCGTTGCCATACCAGAATATACACCCCGTCACTATCGGGGAATGTCCT



AAATACGTGAGGAGCGCCAAACTCAGGATGGTCACTGGACTCAGGAATAATCCAAGCATC



CAGTCGAGGGGCTTATTCGGAGCAATTGCTGGCTTCATCGAAGGCGGGTGGACTGGCATG



ATCGATGGATGGTATGGGTACCACCACCAGAACGAACAAGGTAGCGGATATGCCGCTGAC



CAGAAATCAACACAAAACGCCATCAACGGTATTACCAACAAGGTTAACACTGTTATTGAG



AAGATGAATATCCAATTTACCGCCGTAGGGAAGGAGTTTAATAAGTTGGAGAAACGTATG



GAGAATCTGAACAAGAAAGTTGACGACGGATTTCTGGACATCTGGACCTACAACGCCGAG



CTGTTAGTGCTGTTGGAAAATGAGAGAACCCTTGACTTCCATGATAGCAACGTGAAAAAC



CTATATGAAAAGGTCAAGTCCCAGCTGAAGAACAATGCAAAGGAAATAGGCAATGGCTGC



TTCGAGTTTTATCATAAATGCGACAACGAATGTATGGAAAGCGTCCGAAACGGCACTTAT



GACTATCCCAAATATAGCGAAGAGTCAAAGCTGAATCGGGAAAAGGTGGACGGGGTCAAG



CTCGAGTCAATGGGGATCTACCAGATTCTTGCAATCTATTCCACAGTGGCGTCTTCCCTC



GTGCTGCTGGTTAGTCTCGGCGCCATATCATTTTGGATGTGCAGCAATGGCTCCCTGCAG



TGTCGGATCTGTATC





402
ATGAAGGCGAACTTGCTGGTCCTGTTGTGCGCTTTAGCTGCTGCGGATGCCGATACAATC



TGTATCGGGTATCACGCAAACAACAGTACAGATACCGTGGATACAGTTCTCGAGAAGAAT



GTCACTGTTACGCACAGTGTAAACCTGCTGGAGGACAGTCACAATGGGAAGCTGTGCCGG



CTAAAGGGCATTGCGCCACTACAGCTCGGCAAGTGCAATATTGCGGGGTGGTTATTGGGT



AACCCCGAATGCGACCCACTATTGCCAGTGCGCTCTTGGTCGTACATCGTCGAAACCCCC



AATTCAGAAAATGGCATTTGCTACCCAGGGGATTTTATAGACTACGAAGAGTTACGAGAA



CAATTAAGTAGTGTTTCTTCCTTTGAGCGATTCGAGATTTTCCCCAAGGAGAGTTCTTGG



CCCAACCATAACACAAATGGAGTGACTGCCGCATGCTCACACGAGGGCAAATCATCCTTT



TATAGAAACCTGCTTTGGCTGACTGAAAAGGAGGGGAGTTACCCGAAGCTTAAAAACTCC



TATGTGAACAAGAAGGGCAAGGAAGTGCTGGTCCTGTGGGGGATCCACCACCCACCCAAC



TCCAAAGAGCAACAGAACCTCTACCAGAACGAGAATGCGTATGTGAGCGTGGTGACAAGT



AACTATAATCGAAGGTTCACTCCCGAGATAGCAGAGCGTCCAAAAGTGCGAGATCAAGCC



GGCCGAATGAACTACTATTGGACCTTACTGAAACCCGGCGATACCATCATATTCGAAGCT



AACGGCAATCTCATAGCTCCTATGTACGCTTTCGCTTTGAGTAGAGGTTTCGGATCTGGA



ATTATAACATCTAATGCATCAATGCACGAGTGCAATACTAAATGCCAGACCCCTCTTGGT



GCTATCAACTCTAGTTTACCCTATCAGAACATCCACCCTGTGACGATAGGAGAGTGTCCC



AAGTATGTGCGCTCCGCTAAGCTTAGAATGGTCACCGGGCTTCGGAACAACCCTTCAATC



CAAAGTCGAGGGCTTTTTGGCGCTATCGCTGGCTTCATCGAAGGCGGTTGGACAGGTATG



ATCGATGGTTGGTACGGCTACCATCATCAGAACGAGCAGGGGTCTGGTTATGCGGCCGAC



CAAAAATCTACTCAGAATGCCATCAACGGGATCACAAATAAGGTAAACACTGTGATTGAG



AAGATGAACATCCAGTTTACTGCAGTGGGAAAGGAGTTTAACAAACTGGAGAAACGTATG



GAAAACCTAAACAAAAAAGTGGACGACGGATTCTTAGACATTTGGACATACAACGCCGAG



CTGCTCGTGCTGCTTGAGAATGAGCGGACACTCGACTTCCACGACAGCAACGTGAAGAAC



CTATACGAAAAGGTCAAGAGCCAGCTCAAGAATAACGCGAAGGAGATTGGAAACGGCTGC



TTCGAGTTCTACCATAAGTGCGATAACGAATGTATGGAGTCTGTTCGGAATGGCACTTAC



GACTACCCAAAGTATAGCGAGGAATCTAAGCTCAACCGAGAGAAGGTGGATGGAGTGAAA



TTAGAGTCAATGGGAATTTATCAGATTCTGGCCATCTACTCAACAGTTGCGAGCTCGTTA



GTGCTGCTTGTCTCACTGGGCGCGATTAGTTTTTGGATGTGCAGTAATGGGTCCCTCCAG



TGTCGCATCTGCATT





403
ATGAAGGCCAACTTGCTGGTGTTACTATGTGCTCTCGCCGCCGCCGATGCCGATACTATT



TGCATTGGCTATCACGCCAACAATAGTACGGACACCGTGGACACTGTCCTGGAAAAAAAT



GTCACCGTCACCCATTCTGTGAATCTCCTAGAGGATTCTCATAACGGCAAGCTGTGCCGG



CTTAAAGGAATCGCTCCCTTGCAGCTTGGGAAGTGCAATATCGCCGGCTGGCTCCTTGGA



AACCCGGAGTGTGATCCATTGCTCCCTGTCAGAAGCTGGAGCTATATCGTTGAGACCCCG



AACAGTGAGAATGGCATCTGTTACCCCGGAGATTTCATTGATTACGAGGAGCTGCGCGAA



CAGCTCAGCTCAGTCTCTAGTTTCGAGCGATTTGAGATCTTCCCCAAGGAGTCTAGCTGG



CCAAATCATAACACCAACGGAGTGACAGCCGCCTGTAGCCATGAAGGGAAAAGCAGCTTC



TACCGAAATTTGCTGTGGCTAACTGAGAAAGAGGGGAGTTATCCTAAGCTCAAAAACAGC



TATGTGAACAAGAAGGGGAAAGAAGTCCTGGTGTTGTGGGGCATCCACCATCCCCCAAAT



AGCAAGGAACAGCAGAACCTTTACCAGAACGAGAATGCATACGTGAGCGTCGTAACATCC



AATTATAACAGACGGTTCACACCCGAGATAGCCGAACGGCCAAAAGTGAGGGACCAGGCC



GGAAGGATGAATTACTATTGGACTCTCTTAAAGCCAGGCGACACCATTATATTTGAGGCA



AACGGAAACTTGATTGCGCCAATGTACGCATTCGCACTGTCACGGGGATTCGGATCCGGG



ATTATCACGTCCAATGCATCGATGCATGAGTGCAACACCAAGTGTCAGACCCCACTGGGA



GCCATCAATTCCAGCTTGCCCTATCAGAACATTCACCCCGTGACTATAGGAGAGTGCCCT



AAATATGTCCGCAGCGCCAAACTGCGAATGGTTACCGGCCTGCGCAACAATCCTTCGATC



CAGTCACGGGGCCTGTTCGGGGCCATAGCTGGCTTCATTGAGGGGGGATGGACCGGTATG



ATTGATGGGTGGTACGGCTACCACCATCAGAACGAGCAGGGTTCAGGCTACGCGGCTGAC



CAGAAATCCACTCAGAACGCTATCAATGGCATCACAAACAAGGTCAATACTGTTATAGAA



AAAATGAATATCCAATTCACTGCTGTGGGTAAAGAGTTTAACAAGCTGGAGAAAAGAATG



GAAAATCTGAACAAAAAAGTGGATGACGGCTTCTTGGATATCTGGACATACAACGCTGAA



CTTCTGGTGCTGTTGGAAAACGAAAGGACTCTGGATTTCCACGATTCCAACGTGAAAAAT



CTCTACGAAAAAGTTAAGTCCCAACTGAAGAATAACGCGAAGGAGATCGGAAACGGATGC



TTTGAGTTCTATCATAAGTGTGATAATGAGTGTATGGAATCAGTTAGAAACGGTACGTAC



GATTACCCAAAATACTCCGAAGAGTCTAAGCTGAATCGCGAGAAAGTCGATGGGGTCAAA



CTCGAATCCATGGGAATTTACCAGATCTTAGCTATTTACAGTACAGTGGCCAGCTCTCTT



GTCTTACTGGTGTCACTTGGCGCGATTAGTTTCTGGATGTGCTCCAATGGCAGCCTCCAG



TGTCGGATTTGCATA





404
ATGAAGGCCAACCTGCTTGTACTGCTATGCGCCTTGGCTGCTGCAGACGCCGACACAATT



TGCATCGGCTATCATGCCAACAATTCTACAGATACAGTGGACACTGTGCTGGAGAAAAAC



GTTACTGTCACTCATAGCGTTAATCTCCTCGAGGACTCTCACAATGGAAAACTCTGTCGT



CTGAAAGGCATCGCGCCACTGCAGTTGGGTAAATGTAATATCGCCGGCTGGTTGTTGGGC



AACCCCGAATGTGACCCCCTCCTCCCAGTGAGGTCCTGGTCTTATATCGTAGAGACACCT



AATTCGGAGAATGGAATTTGTTACCCTGGCGACTTCATAGACTATGAGGAACTGAGGGAG



CAGCTTTCTTCTGTGAGTTCTTTTGAAAGATTTGAGATCTTCCCTAAAGAATCATCTTGG



CCCAACCATAATACCAACGGCGTTACAGCAGCCTGTTCCCACGAGGGCAAGTCGAGTTTC



TACAGGAATTTGTTATGGCTGACTGAGAAAGAGGGGTCTTATCCAAAGCTGAAAAACAGC



TATGTCAACAAGAAAGGCAAAGAGGTTTTGGTGCTGTGGGGAATCCATCACCCACCAAAC



TCGAAGGAACAGCAAAATCTTTACCAAAACGAAAATGCATACGTATCAGEGGTTACTAGC



AATTATAATCGGCGCTTTACGCCAGAGATTGCCGAAAGACCTAAGGTGAGAGACCAAGCA



GGAAGGATGAATTACTACTGGACACTACTGAAACCAGGCGATACTATCATTTTTGAGGCC



AACGGAAACCTGATCGCACCCATGTACGCCTTCGCACTGTCGCGGGGTTTTGGGTCTGGC



ATCATCACCTCAAATGCCAGCATGCATGAGTGCAATACTAAATGCCAAACACCTTTAGGT



GCCATTAATAGCTCACTCCCCTACCAGAACATCCATCCAGTAACTATCGGGGAGTGTCCC



AAGTACGTGCGATCTGCAAAACTGAGGATGGTCACTGGTTTGCGCAACAATCCCTCTATC



CAGTCAAGGGGCCTATTTGGCGCAATTGCGGGCTTTATCGAGGGAGGGTGGACGGGTATG



ATTGACGGATGGTACGGCTACCACCACCAGAATGAACAGGGTTCGGGGTACGCGGCAGAT



CAGAAGAGTACTCAGAACGCAATTAATGGTATAACTAATAAGGTCAACACCGTAATTGAA



AAAATGAATATCCAATTCACAGCTGTTGGGAAAGAATTTAACAAACTGGAGAAGAGGATG



GAGAATCTCAATAAGAAGGTTGATGACGGCTTTCTCGATATCTGGACTTACAATGCTGAG



CTGCTAGTTCTGCTCGAGAACGAACGGACACTCGATTTTCACGATTCCAACGTTAAAAAC



CTGTACGAAAAGGTCAAATCTCAGCTGAAGAATAATGCTAAGGAAATTGGTAATGGCTGT



TTCGAATTTTATCATAAATGTGATAATGAGTGCATGGAAAGTGTCCGTAACGGCACCTAC



GATTATCCAAAGTATAGCGAGGAAAGCAAGCTTAATCGTGAAAAAGTAGATGGCGTGAAG



CTGGAAAGTATGGGCATATATCAGATCCTGGCCATATACAGTACTGTTGCCTCCAGTCTA



GTTTTACTGGTATCCCTCGGAGCTATCTCATTCTGGATGTGTAGCAATGGCAGCCTTCAG



TGCCGTATCTGTATA





405
ATGAAAGCTAACCTGCTAGTTCTACTTTGTGCCCTTGCCGCTGCCGACGCTGACACCATC



TGCATAGGGTACCACGCTAACAACAGTACTGACACAGTGGATACCGTTCTTGAAAAGAAC



GTCACCGTAACTCACTCTGTGAATTTGCTCGAGGATTCACACAATGGGAAACTCTGCAGA



CTGAAAGGAATTGCTCCACTTCAGTTGGGCAAGTGTAACATCGCTGGCTGGCTGCTTGGG



AATCCGGAGTGCGACCCATTGCTGCCTGTGCGCAGTTGGAGCTACATTGTGGAGACCCCC



AACAGCGAGAATGGCATCTGTTATCCCGGAGATTTCATCGACTACGAGGAGCTCCGAGAA



CAATTATCCTCTGTGTCTAGTTTCGAACGGTTTGAGATCTTTCCCAAAGAATCAAGCTGG



CCCAACCACAACACAAACGGTGTGACAGCAGCATGCAGTCATGAGGGCAAGTCGTCCTTC



TATAGGAATCTGCTGTGGCTTACTGAGAAGGAGGGTAGCTACCCGAAACTCAAGAACTCC



TACGTCAATAAGAAGGGCAAAGAGGTGTTAGTCTTGTGGGGAATACACCACCCACCCAAC



TCTAAAGAGCAACAAAACCTGTACCAGAACGAAAACGCCTACGTCTCCGTAGTAACCTCA



AATTATAACAGACGCTTTACGCCCGAGATCGCAGAGCGCCCCAAGGTCAGGGACCAGGCA



GGGAGAATGAACTACTATTGGACTTTGTTGAAGCCCGGAGACACAATTATCTTCGAGGCG



AATGGCAATCTGATTGCCCCCATGTACGCTTTTGCACTGTCCCGCGGTTTTGGTTCCGGC



ATCATAACTTCCAACGCATCGATGCACGAATGTAACACCAAATGTCAGACACCATTGGGC



GCCATAAACTCCAGTCTCCCATATCAAAATATCCACCCAGTCACAATCGGGGAATGTCCT



AAATACGTGAGGTCAGCAAAGCTTAGGATGGTCACGGGACTGCGCAACAATCCCTCAATA



CAGTCCAGAGGGCTTTTCGGAGCCATAGCCGGCTTCATCGAAGGCGGCTGGACTGGGATG



ATCGATGGCTGGTATGGGTATCATCACCAGAATGAGCAGGGCTCCGGCTATGCTGCCGAT



CAGAAATCCACACAGAACGCTATCAATGGGATAACTAACAAAGTTAACACCGTGATTGAG



AAGATGAACATACAATTTACTGCAGTGGGAAAGGAGTTCAACAAACTGGAGAAGCGGATG



GAGAACTTAAATAAAAAGGTGGATGACGGCTTCCTGGACATCTGGACTTATAACGCTGAA



CTGTTGGTACTGCTTGAGAATGAGCGGACCCTCGACTTTCACGACTCAAACGTGAAGAAT



CTCTATGAGAAGGTAAAATCCCAGTTGAAAAACAACGCCAAGGAGATCGGGAATGGCTGC



TTTGAATTTTACCACAAGTGCGACAATGAGTGTATGGAAAGTGTGCGCAACGGAACATAT



GACTATCCTAAATATAGTGAAGAGTCCAAACTGAACCGTGAAAAGGTGGATGGGGTGAAA



CTCGAGTCCATGGGAATCTACCAAATCCTCGCCATTTATTCAACCGTGGCAAGCAGCCTC



GTGCTACTGGTCAGTCTCGGCGCGATTTCTTTCTGGATGTGCTCCAACGGGTCACTGCAG



TGTCGCATATGCATC





406
ATGAAGGCGAACCTCCTTGTGCTTCTCTGCGCTCTCGCAGCTGCTGATGCAGACACGATT



TGCATAGGGTATCATGCAAACAATAGTACAGACACTGTGGACACCGTGCTGGAGAAAAAC



GTGACTGTCACGCACTCAGTTAATCTTTTGGAGGACTCCCATAATGGAAAACTGTGCAGA



CTTAAGGGGATCGCACCCCTGCAGTTAGGCAAGTGTAATATAGCCGGGTGGCTTCTGGGG



AACCCAGAATGTGACCCACTGTTACCTGTGCGAAGCTGGTCTTACATAGTGGAGACGCCA



AATTCTGAGAACGGCATCTGTTACCCTGGGGACTTTATTGATTATGAGGAACTCCGGGAA



CAACTCTCGAGCGTTAGCAGCTTCGAAAGGTTTGAAATTTTTCCCAAGGAATCTTCATGG



CCTAACCACAACACTAACGGTGTGACGGCTGCTTGCTCACATGAGGGAAAGTCCAGTTTC



TATAGGAACCTGTTGTGGCTGACTGAGAAAGAAGGCAGCTACCCAAAGCTGAAGAACTCT



TACGTTAACAAAAAAGGCAAGGAAGTGTTAGTACTGTGGGGTATCCACCACCCACCAAAC



AGCAAGGAGCAGCAGAACTTGTACCAGAACGAAAATGCCTACGTCAGTGTTGTCACATCA



AACTACAATAGAAGATTTACGCCAGAAATTGCCGAAAGGCCAAAGGTGCGGGACCAAGCT



GGGCGGATGAACTATTATTGGACCCTTCTGAAGCCGGGAGACACGATCATATTCGAAGCA



AACGGGAATCTGATCGCTCCGATGTACGCCTTCGCACTCAGCCGGGGTTTTGGATCAGGG



ATCATCACATCTAACGCCTCTATGCATGAATGTAACACGAAGTGCCAGACTCCTCTAGGC



GCTATCAACTCTAGCTTACCCTACCAGAATATACATCCCGTCACCATCGGCGAGTGTCCT



AAGTATGTGCGCAGCGCCAAACTGCGGATGGTGACTGGCCTGAGAAATAATCCGTCCATC



CAGTCAAGAGGGCTGTTTGGAGCAATCGCCGGCTTCATTGAAGGGGGCTGGACAGGTATG



ATTGATGGTTGGTACGGATACCACCATCAGAATGAACAGGGGAGTGGCTACGCAGCAGAT



CAAAAGTCGACACAAAACGCGATAAACGGAATCACAAACAAGGTCAATACCGTGATTGAA



AAGATGAATATTCAGTTCACCGCCGTCGGCAAAGAATTTAACAAGCTTGAGAAACGTATG



GAAAATCTCAATAAGAAAGTTGACGACGGTTTCTTAGACATCTGGACCTATAACGCAGAA



CTGCTGGTGCTACTGGAAAACGAGAGAACCCTTGATTTCCATGATAGCAACGTGAAAAAC



CTTTACGAGAAAGTTAAGAGTCAGCTCAAAAACAATGCTAAAGAAATCGGAAACGGCTGC



TTCGAGTTTTATCATAAGTGCGACAATGAGTGTATGGAGAGTGTTCGAAACGGGACATAT



GATTACCCGAAGTATTCAGAGGAGAGCAAACTCAATCGCGAAAAAGTTGATGGTGTGAAG



CTGGAATCTATGGGCATCTACCAGATACTGGCCATCTACTCAACAGTGGCAAGTTCTCTG



GTATTGCTCGTTTCCCTGGGAGCTATCTCCTTCTGGATGTGTTCGAACGGCTCACTTCAG



TGTAGGATTTGCATA





407
ATGAAGGCCAACCTGTTGGTTCTCTTGTGTGCTCTGGCAGCCGCAGACGCTGACACTATT



TGTATCGGATACCACGCCAATAATAGTACTGACACCGTTGACACAGTACTTGAGAAGAAC



GTGACAGTAACCCACTCAGTGAACCTCCTTGAGGATAGCCACAATGGAAAATTATGTAGA



CTTAAGGGTATCGCTCCCCTCCAGCTGGGCAAATGTAATATTGCCGGCTGGCTACTGGGG



AATCCGGAATGTGATCCTCTCCTGCCAGTCCGATCATGGAGTTATATAGTAGAAACTCCA



AATAGCGAGAATGGAATTTGTTACCCCGGCGATTTTATTGACTACGAAGAGCTCCGAGAA



CAGCTCAGTTCAGTGTCTTCATTCGAACGGTTTGAAATCTTCCCAAAAGAATCCTCATGG



CCCAATCACAACACTAACGGGGTCACGGCAGCATGCAGCCACGAAGGGAAGTCGTCTTTC



TACCGAAATCTCCTGTGGCTGACCGAGAAAGAGGGTTCGTACCCCAAGCTCAAGAATTCT



TACGTTAACAAGAAGGGGAAGGAAGTACTTGTGCTGTGGGGTATACACCATCCACCTAAT



TCCAAAGAGCAGCAGAACCTGTATCAAAACGAAAATGCATACGTCAGCGTGGTTACAAGT



AACTACAACAGGCGCTTTACCCCAGAGATCGCCGAGAGGCCTAAGGTTCGGGATCAGGCC



GGGAGAATGAACTACTATTGGACTCTCCTCAAGCCCGGTGACACAATAATCTTCGAGGCC



AATGGAAATCTTATAGCACCGATGTATGCCTTCGCACTGTCACGCGGGTTTGGCTCAGGC



ATTATAACATCTAACGCTAGTATGCATGAGTGCAATACCAAGTGCCAGACCCCACTGGGT



GCAATCAACAGCTCCTTGCCTTACCAGAACATACACCCAGTCACTATTGGCGAGTGCCCG



AAATACGTACGCTCTGCCAAGCTGCGTATGGTCACCGGACTCCGCAATAACCCCAGTATC



CAAAGCCGAGGTTTGTTTGGCGCTATTGCTGGATTCATTGAAGGAGGCTGGACGGGAATG



ATTGACGGGTGGTACGGCTATCATCATCAGAATGAGCAAGGGTCAGGTTACGCCGCCGAC



CAGAAGAGTACACAGAATGCAATCAACGGAATAACCAATAAGGTCAACACCGTCATCGAA



AAGATGAATATCCAGTTCACGGCAGTGGGAAAGGAATTCAATAAGCTAGAAAAACGCATG



GAGAATCTCAACAAGAAGGTTGACGATGGGTTTCTGGATATCTGGACATACAACGCTGAG



CTGCTTGTGCTGCTGGAGAACGAGAGGACACTGGACTTCCACGACTCTAATGTCAAGAAT



CTTTATGAAAAAGTCAAATCCCAGCTCAAAAATAATGCAAAGGAGATCGGAAATGGCTGC



TTCGAATTCTACCACAAGTGTGACAACGAGTGCATGGAGTCTGTGCGGAACGGAACCTAC



GACTATCCAAAGTATTCTGAGGAATCAAAACTCAATCGAGAGAAAGTTGATGGGGTAAAA



CTGGAATCTATGGGGATTTACCAGATCCTGGCCATCTACTCCACAGTGGCTAGTTCCTTG



GTTCTGTTGGTGTCTCTAGGTGCGATCTCCTTCTGGATGTGTTCCAATGGGAGTCTTCAA



TGTCGAATCTGCATA





408
ATGAAGGCAAATTTGCTTGTTTTACTGTGTGCTTTGGCTGCGGCTGATGCCGACACCATA



TGCATCGGTTACCACGCTAATAACAGCACCGACACAGTGGATACGGTGCTGGAGAAAAAT



GTGACCGTAACTCACAGTGTGAACCTGCTTGAGGACAGCCACAACGGTAAGCTCTGCCGT



CTGAAAGGAATCGCCCCGCTGCAATTGGGAAAGTGCAACATTGCTGGCTGGCTCCTGGGT



AATCCTGAGTGTGACCCGCTGCTGCCCGTGCGAAGCTGGTCCTACATCGTGGAGACTCCA



AACTCAGAGAACGGGATCTGTTACCCTGGAGATTTTATAGACTATGAAGAGCTAAGGGAA



CAATTGTCGTCTGTCAGTTCCTTTGAACGGTTCGAGATTTTCCCAAAGGAGTCCAGTTGG



CCTAATCATAATACCAATGGTGTCACTGCTGCATGTAGTCACGAAGGCAAGTCCTCATTT



TATCGGAATTTGCTGTGGCTGACTGAGAAGGAGGGCAGCTATCCGAAGTTGAAGAATTCA



TACGTTAATAAAAAAGGTAAGGAAGTGCTTGTCCTTTGGGGCATTCATCATCCCCCTAAC



AGTAAGGAACAGCAGAATCTCTACCAGAACGAGAACGCATACGTGTCCGTGGTTACTAGT



AATTACAATAGGAGGTTCACACCAGAGATTGCGGAACGGCCTAAAGTCCGGGATCAGGCC



GGTAGAATGAACTATTATTGGACTTTGCTGAAACCCGGAGACACAATCATATTCGAAGCT



AATGGTAACCTGATTGCTCCTATGTACGCATTCGCTCTGTCCCGTGGCTTCGGCTCCGGG



ATTATCACCTCTAATGCTAGCATGCACGAGTGTAACACCAAATGCCAGACCCCACTCGGG



GCGATTAACAGCAGCCTCCCATACCAGAACATTCATCCCGTTACTATAGGCGAGTGCCCA



AAATATGTTCGGTCTGCAAAACTGCGGATGGTGACGGGGCTGCGAAATAACCCTTCAATA



CAGAGTAGGGGGCTGTTCGGAGCAATAGCTGGTTTTATTGAGGGCGGATGGACTGGCATG



ATCGATGGCTGGTATGGATACCATCACCAAAACGAGCAAGGATCTGGTTATGCAGCGGAC



CAGAAGTCAACTCAGAATGCCATTAACGGCATTACTAATAAAGTTAATACCGTTATTGAA



AAGATGAACATTCAGTTTACCGCCGTAGGGAAGGAGTTTAACAAGCTTGAAAAGCGCATG



GAGAACCTCAACAAGAAAGTGGATGATGGGTTCCTTGACATCTGGACATATAACGCCGAA



TTACTAGTGCTTTTGGAAAACGAAAGAACACTGGATTTCCATGACTCCAATGTGAAGAAT



TTATATGAAAAGGTCAAAAGTCAGCTCAAGAATAATGCAAAGGAAATCGGCAATGGTTGC



TTCGAATTTTACCATAAGTGTGACAACGAGTGTATGGAGAGTGTAAGGAATGGGACATAC



GATTACCCAAAGTATAGCGAGGAATCAAAGCTGAACAGAGAGAAAGTGGACGGCGTGAAA



TTGGAGTCCATGGGGATCTACCAGATTCTGGCGATCTATAGCACCGTCGCCAGCAGCTTG



GTCTTGCTGGTATCTCTCGGGGCCATTTCCTTTTGGATGTGTTCAAATGGGAGCCTCCAA



TGTAGAATCTGTATC





409
ATGAAAGCCAATCTACTGGTGTTGCTCTGTGCCCTGGCTGCTGCCGATGCTGACACGATA



TGTATCGGCTACCACGCAAACAACTCCACCGATACAGTTGATACCGTGCTCGAAAAGAAT



GTCACCGTAACACATAGCGTGAACCTTTTGGAGGATTCGCACAACGGTAAGCTGTGTCGT



TTAAAGGGCATCGCCCCTCTTCAGCTGGGAAAATGCAATATTGCGGGCTGGTTGCTCGGT



AACCCCGAGTGTGACCCTCTGCTCCCCGTGCGTAGTTGGTCATATATTGTGGAGACACCC



AATAGCGAGAATGGAATTTGTTACCCCGGGGACTTTATCGATTACGAAGAGCTGCGGGAA



CAACTGTCTAGTGTCAGCTCGTTCGAACGCTTTGAGATTTTCCCAAAAGAGAGCTCCTGG



CCCAACCATAACACTAACGGGGTGACTGCTGCCTGTTCCCATGAGGGGAAGTCTAGTTTT



TACCGAAATCTGCTGTGGCTAACGGAGAAAGAGGGCTCTTATCCAAAGCTAAAGAATAGT



TACGTAAACAAGAAAGGAAAAGAGGTGCTCGTTCTCTGGGGCATTCATCACCCACCAAAC



TCCAAGGAGCAGCAGAATCTGTATCAGAATGAAAACGCCTACGTATCCGTGGTGACAAGC



AACTACAACAGGCGATTCACGCCCGAGATCGCCGAGCGGCCTAAAGTGAGGGATCAGGCT



GGCAGGATGAACTACTATTGGACGCTGCTGAAGCCAGGGGATACTATTATTTTTGAGGCG



AACGGAAACTTAATTGCCCCCATGTACGCATTTGCGCTCTCCAGAGGATTCGGCTCTGGA



ATCATCACGTCAAACGCTAGCATGCACGAGTGTAATACAAAGTGTCAGACCCCACTGGGG



GCAATCAATAGCAGCTTACCTTACCAAAACATCCATCCAGTGACTATCGGTGAATGCCCG



AAGTACGTAAGGTCCGCAAAGCTGAGAATGGTGACGGGCCTCAGAAATAACCCTAGTATA



CAGAGTCGTGGCCTGTTTGGGGCCATTGCTGGATTTATCGAAGGAGGGTGGACCGGAATG



ATAGACGGCTGGTATGGCTACCACCACCAGAATGAGCAGGGATCTGGGTACGCTGCTGAT



CAGAAGAGCACGCAGAACGCCATTAACGGCATAACCAACAAGGTGAATACAGTCATCGAA



AAAATGAACATACAGTTTACAGCAGTTGGGAAAGAATTCAACAAACTGGAGAAGAGGATG



GAAAACTTGAACAAAAAAGTCGATGACGGGTTTCTCGACATCTGGACTTACAACGCCGAG



CTGCTTGTGTTACTGGAGAACGAAAGGACACTCGACTTTCACGACTCTAACGTGAAGAAT



CTTTATGAGAAAGTGAAAAGCCAACTGAAAAACAATGCCAAAGAAATTGGTAACGGCTGC



TTCGAGTTTTACCATAAGTGTGACAACGAGTGTATGGAATCAGTCCGCAACGGTACCTAC



GACTATCCAAAATACTCTGAAGAATCAAAGCTGAATAGGGAGAAGGTGGACGGCGTTAAA



TTGGAGAGCATGGGCATTTATCAAATCCTTGCCATTTATTCGACAGTGGCCTCCTCTTTA



GTGCTCTTAGTGTCCCTGGGCGCCATCAGTTTCTGGATGTGTAGTAACGGCTCACTCCAA



TGTCGAATTTGCATT





410
ATGAAAGCGAACCTCCTGGTTTTATTGTGCGCACTTGCCGCTGCTGATGCAGACACCATC



TGTATTGGGTATCACGCGAACAATTCGACCGACACGGTCGATACAGTGCTTGAGAAAAAT



GTGACTGTAACACATTCCGTGAATCTCCTCGAAGACAGCCATAACGGGAAGCTTTGCAGG



CTTAAGGGGATTGCACCGCTGCAGCTCGGGAAATGTAATATAGCCGGGTGGCTATTAGGG



AACCCGGAGTGCGACCCTTTGCTTCCAGTGAGGTCCTGGTCATATATTGTCGAGACCCCA



AATTCAGAAAACGGGATCTGTTACCCCGGCGACTTCATTGACTACGAAGAGCTGAGGGAA



CAATTAAGTTCTGTCTCCTCTTTTGAACGGTTTGAGATATTCCCAAAAGAGTCCTCCTGG



CCCAATCATAACACGAATGGCGTGACAGCTGCGTGTAGCCATGAAGGGAAGAGCAGTTTC



TACAGGAATCTTCTTTGGTTAACAGAAAAAGAAGGTAGTTATCCGAAACTGAAAAACAGC



TACGTAAATAAAAAAGGCAAGGAGGTCCTGGTGTTGTGGGGCATTCATCACCCTCCCAAT



AGCAAGGAACAGCAGAATCTCTATCAGAATGAAAACGCCTATGTCAGCGTTGTTACTAGC



AACTACAACCGGCGGTTTACCCCCGAAATTGCTGAGCGACCCAAAGTTCGCGATCAGGCC



GGTCGGATGAATTACTACTGGACCCTTCTGAAGCCTGGCGACACCATTATTTTTGAGGCC



AACGGCAACCTAATTGCCCCAATGTATGCATTCGCCCTGAGCCGAGGTTTTGGAAGTGGC



ATAATCACGTCCAATGCCTCTATGCACGAATGCAACACCAAGTGCCAGACACCCCTTGGC



GCTATCAACTCTTCTCTACCTTATCAGAACATCCATCCCGTTACTATTGGGGAGTGCCCC



AAATACGTCCGGTCTGCTAAACTTCGGATGGTGACAGGCCTCCGCAATAATCCTTCGATT



CAAAGTCGGGGCCTGTTTGGTGCAATCGCCGGGTTCATTGAGGGAGGGTGGACTGGCATG



ATCGACGGTTGGTATGGGTACCACCATCAGAACGAACAAGGCAGTGGGTACGCTGCCGAT



CAGAAAAGCACCCAGAATGCTATCAACGGCATTACGAACAAGGTGAACACTGTGATAGAG



AAGATGAACATCCAGTTCACTGCTGTCGGTAAAGAGTTTAACAAACTTGAAAAAAGAATG



GAGAACCTCAATAAAAAGGTGGACGATGGTTTCCTGGATATATGGACATATAACGCCGAA



CTACTTGTGCTCTTGGAAAATGAACGGACACTGGACTTCCACGACTCTAATGTGAAAAAT



TTATATGAGAAAGTGAAGTCACAGCTCAAGAATAACGCGAAGGAAATTGGCAACGGGTGT



TTCGAGTTCTATCATAAGTGCGACAATGAGTGCATGGAATCAGTTCGAAATGGAACCTAT



GACTATCCAAAGTACTCAGAAGAGAGTAAACTGAACCGGGAGAAAGTCGACGGAGTCAAG



CTCGAATCTATGGGTATTTATCAGATTCTGGCCATCTACAGCACAGTCGCTTCTTCTCTT



GTACTGCTGGTTTCTTTGGGCGCAATCTCTTTCTGGATGTGCTCAAACGGGAGCCTGCAG



TGCCGGATCTGCATC





411
ATGAAGGCTAATCTGTTAGTACTTTTATGTGCACTTGCCGCAGCTGACGCGGATACGATC



TGCATTGGGTACCATGCCAACAACAGTACCGACACCGTCGATACCGTTTTGGAAAAGAAT



GTGACCGTGACCCACAGCGTCAACCTTCTCGAGGATAGTCACAATGGGAAACTCTGTCGG



CTGAAAGGCATAGCTCCTCTGCAGCTCGGAAAATGTAACATCGCCGGCTGGTTATTGGGG



AACCCCGAATGCGATCCCCTCCTCCCAGTAAGGTCTTGGTCCTATATCGTGGAAACACCT



AACAGCGAGAATGGCATCTGCTACCCCGGGGACTTCATTGATTACGAAGAACTAAGAGAA



CAACTGTCGAGTGTGAGTAGTTTCGAAAGATTTGAAATATTCCCTAAGGAGTCAAGTTGG



CCCAATCACAACACGAACGGCGTTACGGCAGCGTGCTCCCATGAAGGGAAATCAAGCTTC



TATAGAAATCTGCTCTGGCTAACAGAAAAGGAGGGCTCATACCCAAAGTTGAAGAACTCC



TACGTCAATAAAAAAGGTAAGGAAGTATTGGTCCTGTGGGGGATCCATCACCCCCCAAAT



TCGAAAGAGCAACAGAACCTTTATCAGAATGAGAATGCTTACGTTAGCGTAGTTACGAGC



AACTATAATCGGCGATTCACACCCGAGATTGCTGAGAGACCTAAGGTGAGAGATCAGGCA



GGTCGGATGAACTACTACTGGACTCTTCTAAAGCCCGGCGATACTATAATCTTTGAGGCT



AACGGCAATCTGATTGCCCCTATGTATGCTTTCGCATTGTCCAGAGGTTTTGGGAGTGGG



ATCATCACGAGCAATGCCAGTATGCATGAGTGTAACACTAAATGTCAGACACCCTTAGGG



GCTATCAACAGTTCTCTTCCCTATCAGAATATCCACCCAGTAACCATCGGAGAATGCCCT



AAATACGTCAGATCTGCAAAACTCAGGATGGTGACTGGCCTCAGAAATAACCCCAGTATA



CAGAGCAGAGGTTTATTCGGGGCGATCGCTGGCTTTATAGAAGGAGGCTGGACGGGCATG



ATTGACGGCTGGTATGGCTATCATCATCAGAATGAACAGGGCAGCGGTTACGCAGCCGAC



CAGAAGAGCACACAAAACGCTATTAACGGAATCACCAACAAGGTGAATACAGTCATTGAA



AAAATGAATATTCAATTCACTGCAGTCGGAAAGGAATTCAACAAACTGGAAAAAAGGATG



GAGAATCTCAACAAAAAAGTCGACGACGGGTTCCTGGATATCTGGACATACAATGCCGAA



CTCCTCGTCCTGCTCGAGAATGAGCGGACCCTTGATTTCCACGATTCCAATGTCAAGAAC



CTTTACGAGAAGGTGAAATCCCAGTTAAAGAATAACGCCAAAGAGATTGGCAATGGGTGC



TTCGAATTTTATCACAAGTGCGACAACGAGTGTATGGAAAGCGTCAGAAATGGCACCTAC



GACTATCCTAAATATTCAGAAGAGTCTAAACTGAATAGGGAAAAAGTCGACGGCGTCAAG



CTTGAGTCTATGGGGATATATCAGATTCTTGCGATTTATTCAACTGTCGCATCCTCCCTC



GTTCTGCTCGTGTCCCTGGGCGCAATCTCATTCTGGATGTGCTCTAATGGTTCATTGCAG



TGTCGCATCTGTATC





412
ATGAAGGCAAACCTGCTGGTTCTTCTGTGTGCATTAGCCGCGGCCGACGCCGATACAATA



TGTATCGGATACCACGCAAATAACAGCACCGACACCGTTGACACAGTGCTTGAGAAAAAC



GTGACCGTGACACACAGTGTGAATCTGCTAGAGGACTCCCATAACGGGAAGCTGTGCCGG



TTGAAGGGAATCGCTCCGCTGCAGTTGGGCAAATGCAATATTGCTGGGTGGCTGTTAGGT



AACCCTGAATGCGATCCACTCCTCCCTGTACGTTCTTGGTCGTATATAGTGGAAACTCCC



AATAGCGAAAATGGTATTTGTTATCCTGGGGATTTCATAGATTACGAAGAGCTGCGCGAA



CAGCTCAGCTCTGTGAGCTCTTTCGAGCGCTTCGAAATATTCCCCAAGGAGTCCAGTTGG



CCCAACCACAATACCAACGGCGTTACCGCAGCCTGTAGCCACGAGGGCAAGTCCAGCTTT



TACCGCAACCTCTTGTGGTTGACCGAAAAGGAGGGAAGCTATCCGAAACTCAAGAACAGC



TACGTCAATAAAAAAGGCAAGGAGGTACTAGTGCTGTGGGGCATCCACCACCCTCCAAAT



AGTAAAGAGCAGCAGAATCTGTATCAGAACGAAAACGCGTATGTCTCAGTTGTGACAAGC



AATTACAACCGCAGGTTCACTCCGGAGATAGCTGAAAGACCCAAAGTACGGGATCAGGCT



GGGCGAATGAACTACTACTGGACACTACTCAAACCAGGTGACACCATTATTTTCGAAGCA



AATGGCAATTTGATCGCACCCATGTACGCATTTGCCTTGTCCCGGGGGTTCGGCTCCGGC



ATTATTACGTCTAACGCATCTATGCACGAGTGCAACACGAAATGCCAGACTCCCCTGGGG



GCCATAAACTCAAGCCTGCCATATCAGAACATCCACCCGGTCACCATCGGCGAGTGCCCC



AAATACGTCCGCTCAGCTAAACTCAGGATGGTCACGGGCCTCAGAAATAATCCTAGCATT



CAGTCTCGCGGTCTGTTTGGCGCCATCGCAGGCTTCATTGAAGGGGGCTGGACCGGAATG



ATCGATGGGTGGTACGGGTATCATCACCAGAACGAGCAAGGCAGTGGCTATGCTGCCGAT



CAGAAATCAACCCAGAATGCGATTAACGGAATAACTAACAAGGTGAACACCGTCATTGAG



AAGATGAATATTCAGTTCACGGCCGTCGGAAAGGAGTTTAACAAGCTCGAAAAGCGCATG



GAGAACCTGAACAAGAAGGTAGATGATGGCTTCCTGGACATTTGGACCTACAATGCTGAG



CTCCTCGTCTTGCTGGAGAATGAACGGACTCTCGACTTCCACGATTCCAACGTTAAGAAT



TTATATGAGAAAGTGAAGAGTCAACTTAAAAACAACGCGAAGGAAATCGGTAATGGCTGC



TTTGAGTTCTACCATAAGTGTGATAACGAGTGTATGGAAAGCGTGCGAAATGGGACTTAT



GACTACCCTAAGTATTCGGAAGAATCTAAACTGAATAGAGAGAAGGTGGATGGGGTGAAG



CTCGAATCTATGGGGATTTACCAGATCTTGGCTATCTATTCGACAGTGGCTTCCAGTCTT



GTCCTACTGGTGTCTCTTGGCGCCATTTCCTTCTGGATGTGCTCCAACGGATCTCTGCAG



TGCCGCATCTGTATA





413
ATGAAGGCAAATTTGTTAGTCTTGTTGTGCGCTCTGGCCGCTGCAGATGCAGACACCATC



TGTATCGGGTATCACGCAAATAATTCCACAGATACAGTGGACACCGTTCTCGAGAAAAAC



GTCACCGTGACCCATAGCGTGAACCTTCTCGAGGACTCTCACAACGGTAAATTATGCAGG



CTTAAGGGAATAGCTCCCCTGCAACTTGGTAAGTGCAATATAGCAGGATGGCTCCTGGGC



AACCCAGAATGTGACCCGCTACTGCCAGTGAGGAGCTGGTCTTACATCGTCGAAACGCCT



AACTCCGAAAACGGGATCTGTTATCCTGGCGATTTCATTGATTATGAAGAGTTACGGGAG



CAGTTATCAAGCGTGTCGAGCTTCGAAAGGTTTGAGATCTTCCCTAAGGAGTCAAGTTGG



CCGAACCACAACACGAATGGCGTCACAGCCGCATGTTCCCATGAAGGGAAGTCCTCTTTC



TATCGGAATCTTTTGTGGCTAACGGAGAAGGAGGGATCCTATCCTAAGCTTAAAAACTCC



TACGTAAACAAAAAGGGCAAGGAGGTCTTAGTACTGTGGGGCATACACCACCCACCTAAC



TCAAAGGAGCAGCAGAACCTTTATCAGAATGAAAATGCTTACGTCTCGGTGGTGACCAGC



AACTACAACAGACGCTTCACGCCGGAAATTGCCGAGAGACCAAAGGTAAGGGATCAAGCC



GGTCGAATGAATTACTATTGGACCTTATTGAAACCCGGGGACACCATCATATTTGAAGCT



AACGGCAATTTGATCGCTCCAATGTACGCGTTTGCCCTTTCCCGCGGGTTCGGTTCTGGG



ATCATAACCTCTAACGCTTCCATGCATGAATGTAACACAAAGTGCCAGACTCCATTAGGG



GCCATTAATAGCAGTTTACCTTATCAAAATATCCACCCAGTCACTATCGGAGAGTGCCCA



AAATACGTGAGGAGCGCGAAATTGAGGATGGTGACAGGCCTTCGGAACAATCCCTCTATC



CAGAGCAGAGGACTGTTTGGCGCAATTGCTGGGTTTATAGAGGGGGGATGGACCGGCATG



ATTGACGGATGGTACGGATACCATCATCAGAATGAGCAGGGAAGTGGATATGCTGCAGAC



CAAAAGTCAACTCAGAATGCTATTAATGGTATCACCAACAAGGTGAACACAGTCATAGAA



AAGATGAACATCCAGTTTACCGCCGTTGGGAAGGAATTTAACAAGCTGGAAAAAAGGATG



GAGAATCTCAATAAAAAGGTAGACGATGGGTTCCTTGATATTTGGACTTACAATGCTGAG



CTGTTAGTCCTACTAGAAAATGAGAGAACCCTTGACTTTCACGACTCCAACGTTAAAAAC



TTATACGAGAAAGTGAAATCCCAATTAAAGAATAACGCGAAAGAGATCGGCAACGGGTGT



TTCGAATTCTATCACAAATGCGACAACGAATGCATGGAGTCTGTGAGGAATGGGACTTAT



GATTATCCCAAGTATTCAGAGGAGTCTAAACTGAATCGAGAAAAAGTGGACGGAGTAAAG



CTGGAGTCCATGGGCATATATCAAATCCTCGCCATCTATTCCACAGTCGCCTCCTCCCTT



GTTTTGTTGGTTTCCCTTGGTGCGATCAGTTTTTGGATGTGCTCTAACGGGTCCCTACAG



TGCCGAATTTGTATT





414
ATGAAAGCTAATCTTCTCGTGCTACTGTGCGCCTTAGCAGCTGCCGACGCTGATACCATC



TGTATAGGCTATCATGCCAATAACTCCACAGACACCGTTGATACTGTGCTTGAGAAGAAT



GTGACGGTAACCCACAGCGTTAATCTCCTTGAGGACAGCCATAATGGCAAACTGTGTCGG



CTGAAGGGAATCGCTCCCCTACAATTGGGAAAATGCAACATTGCAGGATGGTTGTTAGGA



AACCCAGAATGCGACCCTCTACTGCCAGTGCGCAGCTGGAGTTACATTGTTGAAACACCT



AACAGCGAAAATGGTATTTGCTACCCTGGGGATTTCATAGATTACGAGGAGTTAAGAGAG



CAGCTGTCCAGTGTGTCTTCCTTCGAAAGGTTTGAAATCTTCCCAAAGGAGTCCTCATGG



CCCAACCACAACACGAATGGCGTCACAGCTGCCTGTTCACACGAGGGTAAGTCAAGTTTT



TATAGGAACTTGCTTTGGTTAACCGAAAAAGAGGGAAGCTACCCAAAGCTGAAAAATAGC



TACGTGAATAAAAAGGGCAAAGAGGTGCTGGTGCTATGGGGTATCCATCATCCGCCAAAC



AGCAAAGAGCAGCAAAACCTGTACCAGAACGAAAATGCCTACGTGTCTGTTGTGACGAGC



AACTACAACCGTAGATTTACCCCGGAAATCGCAGAGCGGCCGAAGGTGCGCGATCAGGCG



GGACGTATGAATTACTATTGGACATTGCTTAAGCCCGGAGACACAATTATTTTCGAAGCT



AACGGGAATCTCATTGCCCCAATGTATGCTTTCGCACTGAGCCGAGGCTTTGGGAGCGGC



ATCATCACAAGTAATGCTAGCATGCATGAGTGCAATACCAAGTGTCAAACGCCTCTGGGC



GCAATCAATTCCAGTTTACCATATCAGAACATTCATCCAGTCACCATCGGGGAGTGCCCT



AAATATGTAAGGTCTGCTAAACTGCGGATGGTCACTGGTCTCCGCAACAATCCATCTATC



CAGAGCCGGGGTTTGTTCGGAGCTATTGCTGGATTTATAGAGGGGGGCTGGACGGGGATG



ATTGATGGCTGGTACGGCTATCACCATCAGAACGAACAGGGCAGCGGCTACGCTGCAGAC



CAAAAAAGTACTCAGAACGCTATTAATGGCATTACCAACAAGGTTAACACTGTGATTGAG



AAGATGAACATCCAGTTCACTGCGGTAGGAAAGGAATTCAACAAACTTGAGAAGCGGATG



GAAAATCTCAACAAGAAGGTAGACGATGGGTTCCTAGATATATGGACCTATAATGCCGAG



CTCTTGGTCTTGTTAGAAAACGAGCGGACCTTAGACTTCCATGATAGCAACGTGAAAAAC



CTGTACGAGAAAGTGAAGAGCCAGTTAAAGAATAACGCTAAGGAAATCGGAAACGGGTGC



TTTGAGTTCTACCATAAGTGTGACAATGAGTGTATGGAATCTGTGCGTAACGGGACCTAC



GACTACCCCAAATATTCTGAGGAATCAAAACTAAATCGAGAGAAGGTAGACGGCGTGAAG



TTAGAATCTATGGGTATCTATCAAATCCTGGCTATATACTCAACCGTGGCCTCATCCCTA



GTTCTCCTGGTATCCCTCGGCGCCATCTCTTTCTGGATGTGCAGCAACGGCTCTCTCCAG



TGTCGCATTTGCATC





415
ATGAAGGCCAATTTGCTGGTGTTGTTGTGTGCTCTGGCAGCAGCCGATGCTGACACTATC



TGCATCGGCTACCATGCCAACAATAGTACCGATACTGTGGACACTGTGTTAGAGAAGAAC



GTGACAGTCACTCACTCAGTAAACTTGCTGGAGGATAGCCATAATGGCAAACTCTGTCGC



CTCAAGGGCATCGCCCCTCTGCAGCTGGGAAAATGCAACATTGCTGGATGGCTGCTGGGG



AACCCGGAATGCGACCCGCTGCTCCCCGTGAGATCCTGGAGTTATATAGTTGAAACTCCC



AACAGTGAGAACGGGATATGTTATCCTGGCGACTTCATTGACTACGAGGAGCTGCGCGAA



CAGCTCTCTAGCGTATCTTCGTTTGAACGTTTCGAAATATTTCCCAAGGAATCTTCTTGG



CCAAATCACAATACCAACGGAGTCACGGCGGCCTGCTCGCACGAGGGGAAGAGTTCCTTT



TATCGCAACCTACTGTGGCTCACCGAGAAGGAGGGTTCCTACCCCAAGCTGAAAAACAGC



TATGTGAACAAAAAAGGCAAAGAAGTCTTGGTACTGTGGGGCATTCATCACCCACCCAAC



AGCAAGGAACAGCAGAACCTGTATCAAAATGAAAATGCTTACGTCTCCGTTGTGACATCA



AACTACAACAGACGGTTCACCCCTGAAATTGCTGAGAGGCCTAAGGTCAGGGACCAGGCC



GGGCGGATGAATTACTACTGGACACTGCTGAAGCCGGGAGACACGATTATCTTCGAAGCA



AACGGCAATCTGATCGCCCCAATGTACGCGTTTGCTCTTTCTCGGGGATTTGGCTCTGGG



ATCATTACCTCTAATGCATCCATGCACGAATGCAACACCAAATGTCAGACCCCACTAGGC



GCTATTAATAGTTCCCTGCCCTATCAGAATATCCACCCGGTGACCATCGGCGAATGTCCT



AAATATGTGCGGAGTGCCAAGCTGAGGATGGTCACTGGCTTACGTAACAATCCCTCAATT



CAGAGCCGGGGCCTCTTTGGAGCAATCGCTGGATTCATCGAGGGGGGTTGGACCGGAATG



ATCGACGGCTGGTACGGATATCATCACCAGAATGAACAAGGGTCTGGCTACGCCGCCGAC



CAAAAATCTACCCAAAACGCTATTAATGGGATTACCAATAAGGTGAACACTGTAATAGAA



AAAATGAATATTCAGTTTACTGCCGTTGGAAAGGAATTCAATAAGCTGGAGAAACGTATG



GAGAATCTGAACAAGAAGGTAGATGACGGATTCCTGGACATCTGGACCTATAATGCAGAA



TTGCTCGTTCTGCTTGAAAATGAGCGCACACTGGACTTTCATGACTCTAACGTCAAAAAT



CTGTATGAAAAGGTCAAGTCCCAGCTGAAAAATAATGCGAAAGAGATTGGGAACGGATGT



TTCGAATTCTACCACAAGTGTGACAACGAATGCATGGAGTCCGTACGGAACGGCACGTAC



GACTACCCAAAATATTCTGAGGAAAGCAAGCTGAATAGAGAAAAGGTCGATGGGGTGAAA



CTGGAGAGTATGGGAATCTATCAGATTCTCGCCATCTACTCCACTGTCGCCAGCTCCTTG



GTACTTCTTGTTAGCTTGGGAGCCATATCATTCTGGATGTGCTCCAATGGATCCCTCCAA



TGCAGAATCTGCATC





416
ATGAAAGCTAACCTTTTGGTGCTGCTCTGTGCCCTGGCAGCTGCCGATGCCGATACCATC



TGTATCGGCTACCATGCTAATAATAGTACAGACACAGTGGACACCGTTCTGGAGAAAAAT



GTCACCGTGACACATAGCGTGAACTTGCTGGAGGATTCTCACAACGGGAAGCTGTGCCGT



CTGAAAGGGATTGCCCCTCTTCAGCTCGGTAAATGCAACATCGCCGGGTGGCTGCTAGGC



AATCCAGAGTGTGATCCCCTGCTGCCGGTGAGAAGCTGGAGCTACATCGTGGAGACACCC



AACTCCGAAAATGGCATTTGCTACCCCGGCGATTTCATCGACTACGAAGAACTGCGGGAG



CAGCTGTCGTCTGTGAGCTCCTTCGAGAGATTCGAGATCTTTCCAAAAGAAAGCAGTTGG



CCCAATCACAATACCAACGGCGTGACCGCTGCATGTAGTCACGAGGGCAAGAGCTCATTC



TATAGAAACCTGTTGTGGCTGACAGAGAAGGAGGGGAGCTATCCCAAACTGAAGAATTCC



TATGTGAATAAAAAGGGGAAGGAGGTTCTGGTATTATGGGGCATCCATCATCCTCCTAAC



AGCAAAGAGCAGCAAAACCTTTATCAGAACGAGAATGCCTATGTATCGGTTGTTACCAGC



AATTATAATCGGAGGTTTACCCCAGAGATAGCTGAGCGTCCAAAAGTGAGAGACCAAGCT



GGCCGGATGAATTACTATTGGACCCTCCTCAAACCGGGCGATACCATCATTTTCGAAGCC



AATGGCAACTTAATAGCGCCCATGTATGCTTTTGCCCTTTCGAGGGGATTTGGATCAGGT



ATCATCACAAGCAACGCATCAATGCACGAGTGTAACACTAAGTGTCAGACTCCACTCGGG



GCAATTAACAGCAGCCTACCTTACCAGAACATCCACCCCGTGACGATTGGAGAGTGTCCC



AAGTACGTAAGGTCAGCCAAGCTCAGGATGGTTACAGGGCTGCGAAATAACCCCTCTATT



CAGTCAAGGGGCTTGTTCGGCGCCATCGCCGGGTTTATCGAGGGCGGCTGGACCGGAATG



ATCGACGGATGGTATGGCTACCATCACCAGAACGAACAAGGGTCTGGCTATGCTGCGGAT



CAGAAGTCAACACAGAATGCTATAAATGGTATCACGAATAAGGTAAATACAGTCATTGAA



AAGATGAATATCCAGTTTACGGCCGTTGGGAAGGAGTTCAACAAGCTTGAAAAGAGAATG



GAAAATCTGAATAAAAAAGTGGACGACGGCTTTTTGGATATCTGGACATATAACGCGGAG



CTGCTAGTGCTCCTGGAAAACGAGCGGACTCTTGACTTTCACGATTCCAACGTCAAGAAC



CTCTATGAAAAGGTTAAATCACAATTGAAGAATAATGCTAAGGAGATTGGCAATGGGTGC



TTTGAGTTCTACCATAAGTGTGACAACGAATGTATGGAGTCAGTCCGGAACGGTACTTAC



GATTACCCCAAGTATTCGGAAGAGTCAAAGTTGAATAGAGAAAAAGTCGACGGCGTGAAA



CTCGAGTCTATGGGCATTTACCAGATCCTTGCGATTTATAGCACCGTCGCCAGTAGCTTG



GTACTCCTAGTATCTCTGGGTGCAATCTCCTTTTGGATGTGTTCTAACGGCAGCTTACAG



TGCAGGATCTGCATT





417
ATGAAAGCTAACTTGCTTGTGTTGTTGTGCGCTTTGGCCGCTGCCGACGCCGACACTATT



TGCATCGGGTATCACGCCAATAATTCCACAGATACCGTCGATACCGTGCTCGAGAAGAAC



GTGACCGTCACTCACTCAGTGAACCTTCTGGAGGACTCCCATAACGGGAAGCTCTGTAGG



TTGAAAGGAATCGCCCCACTGCAGCTTGGTAAATGCAATATAGCCGGTTGGCTGCTGGGA



AACCCTGAGTGCGACCCACTCCTCCCCGTACGGTCTTGGAGCTACATCGTGGAGACGCCA



AATTCCGAGAATGGAATCTGTTATCCCGGCGACTTTATCGATTATGAGGAGTTGCGCGAG



CAGCTGAGTTCAGTTTCATCCTTTGAACGGTTCGAGATTTTTCCAAAAGAGTCTAGCTGG



CCTAATCATAATACCAATGGGGTTACAGCCGCTTGCTCACATGAGGGGAAGTCCAGTTTC



TATAGGAACCTGCTTTGGCTGACCGAGAAAGAGGGCTCCTATCCAAAGCTCAAGAACAGC



TATGTAAATAAGAAAGGCAAGGAAGTGTTGGTCCTGTGGGGCATACACCACCCTCCCAAC



TCGAAGGAGCAGCAAAACCTATACCAGAACGAGAATGCCTACGTCAGCGTGGTCACTAGC



AATTACAATAGAAGGTTCACACCCGAAATTGCTGAGCGGCCGAAAGTGAGAGACCAGGCA



GGACGAATGAACTACTATTGGACCCTGCTGAAGCCCGGGGATACAATCATTTTCGAGGCG



AACGGGAACCTCATTGCCCCCATGTACGCTTTTGCCCTCAGCAGAGGCTTTGGGTCTGGT



ATAATCACCAGTAACGCTAGCATGCATGAATGTAATACCAAGTGCCAGACACCCTTAGGG



GCCATTAACTCATCTCTCCCATATCAGAACATACATCCTGTGACCATCGGTGAATGCCCG



AAATACGTAAGGAGCGCAAAATTAAGGATGGTGACCGGTCTTAGGAACAATCCATCCATT



CAGTCTCGAGGGCTTTTCGGCGCCATTGCTGGATTCATAGAAGGCGGATGGACAGGCATG



ATCGATGGATGGTACGGTTATCACCACCAGAATGAGCAGGGGTCGGGCTACGCTGCCGAT



CAGAAGTCTACCCAAAATGCCATCAATGGCATAACCAACAAGGTGAACACAGTTATCGAG



AAAATGAACATACAGTTTACTGCAGTGGGAAAGGAGTTCAACAAACTGGAGAAACGAATG



GAGAACTTGAATAAAAAAGTCGACGACGGCTTCCTTGATATTTGGACTTATAATGCCGAG



CTTTTAGTCCTGTTAGAGAATGAACGTACATTGGACTTCCACGATAGCAACGTAAAGAAC



CTCTATGAGAAAGTGAAAAGTCAGCTAAAAAATAATGCCAAAGAGATCGGGAATGGTTGT



TTCGAGTTTTATCACAAGTGTGATAATGAGTGCATGGAGTCTGTGAGAAACGGCACGTAC



GATTACCCTAAGTATTCTGAGGAGAGTAAGTTAAATCGCGAGAAAGTTGATGGTGTGAAG



CTTGAGTCAATGGGCATCTACCAGATCCTGGCCATCTACTCCACCGTGGCGTCTTCTCTG



GTGCTGCTTGTTAGCCTGGGTGCTATCTCCTTCTGGATGTGTTCTAACGGCTCCCTGCAG



TGTAGGATTCTGCATC





418
ATGAAAGCAAATCTGCTGGTGTTGCTGTGTGCCCTGGCTGCCGCAGACGCAGATACCATC



TGTATCGGCTATCACGCTAATAACAGTACAGACACTGTGGATACTGTTCTCGAGAAGAAC



GTCACTGTGACCCACTCAGTAAATTTACTCGAAGACAGTCACAACGGCAAGTTGTGTAGA



CTCAAAGGCATTGCCCCTCTCCAGCTGGGAAAGTGCAACATTGCTGGATGGCTCCTGGGG



AACCCCGAATGTGATCCGCTTTTGCCTGTGAGAAGCTGGTCCTACATAGTAGAAACCCCA



AACTCCGAAAATGGTATTTGCTATCCGGGCGATTTTATAGATTATGAAGAATTAAGGGAG



CAGTTGTCTTCCGTGTCCTCCTTCGAACGCTTCGAAATCTTCCCCAAAGAGAGTTCCTGG



CCAAACCATAATACTAACGGGGTGACAGCGGCTTGCTCTCACGAAGGAAAATCTTCCTTC



TACCGGAACCTGCTTTGGTTGACCGAGAAGGAGGGCAGTTACCCGAAATTGAAAAATAGT



TACGTTAATAAGAAAGGGAAGGAAGTCCTGGTGTTATGGGGTATTCATCACCCCCCAAAC



AGCAAGGAGCAGCAAAATTTGTACCAGAACGAGAATGCGTACGTGAGTGTGGTCACCAGT



AATTACAACCGGAGGTTTACCCCCGAGATCGCAGAACGCCCGAAAGTACGGGACCAGGCA



GGGAGGATGAATTACTATTGGACTCTTTTAAAGCCCGGGGATACCATCATCTTTGAGGCA



AACGGTAACCTCATAGCTCCCATGTACGCCTTCGCCCTGAGCCGCGGTTTCGGCAGTGGC



ATTATAACCTCTAACGCCAGCATGCACGAATGTAACACTAAATGTCAGACCCCTCTCGGC



GCCATTAATAGCAGTCTCCCTTACCAAAATATCCACCCCGTTACCATTGGCGAGTGTCCA



AAATACGTAAGGTCCGCAAAACTGCGCATGGTGACTGGACTGAGAAACAATCCCTCTATT



CAGTCGAGGGGACTATTCGGAGCCATCGCTGGGTTTATCGAAGGGGGATGGACTGGAATG



ATCGATGGTTGGTACGGGTACCACCACCAGAACGAGCAAGGCTCAGGGTATGCCGCAGAC



CAGAAGAGTACCCAGAACGCCATCAACGGTATCACTAATAAGGTGAATACCGTCATCGAG



AAGATGAATATCCAGTTTACCGCTGTGGGCAAAGAGTTTAATAAGCTGGAAAAGCGCATG



GAGAACCTGAATAAGAAGGTTGACGACGGCTTCCTCGATATTTGGACTTATAACGCCGAG



CTGCTCGTTCTCCTCGAAAATGAACGCACCCTTGACTTTCACGATTCAAACGTCAAGAAT



CTGTATGAGAAGGTGAAGAGCCAGCTGAAGAATAACGCGAAGGAAATCGGGAACGGTTGT



TTCGAATTTTACCACAAGTGCGATAATGAGTGCATGGAGAGCGTGCGAAATGGCACATAT



GACTATCCTAAGTACAGCGAGGAAAGTAAACTCAACAGAGAAAAGGTTGATGGCGTCAAG



CTCGAGTCAATGGGGATTTACCAGATTCTGGCCATCTATAGTACTGTGGCTTCCTCTCTG



GTTTTGCTCGTTTCACTGGGAGCCATTTCTTTCTGGATGTGTTCGAACGGATCCCTCCAA



TGCAGGATTTGTATT





419
ATGAAAGCAAATCTGCTCGTCCTCCTGTGCGCTCTTGCAGCCGCCGACGCCGACACCATA



TGCATTGGATATCATGCTAACAACTCAACAGACACCGTGGACACTGTCCTAGAAAAAAAC



GTGACCGTGACACACTCGGTCAATCTGTTAGAAGACAGCCATAACGGGAAGCTGTGCCGA



CTCAAGGGAATAGCCCCCCTGCAGCTGGGCAAGTGCAATATCGCCGGGTGGCTCCTCGGC



AACCCTGAGTGCGATCCCTTGCTTCCAGTTAGAAGTTGGTCCTATATCGTCGAAACTCCT



AACTCAGAGAATGGAATTTGCTATCCCGGAGATTTCATCGACTACGAAGAGCTCAGAGAG



CAACTTTCCAGTGTGTCAAGTTTCGAACGCTTTGAAATCTTCCCAAAGGAATCTTCATGG



CCCAACCACAATACGAATGGAGTGACCGCCGCCTGTAGTCACGAGGGAAAAAGTAGCTTC



TACCGCAATCTTTTGTGGCTGACCGAGAAGGAAGGAAGCTACCCAAAGCTGAAGAACTCC



TACGTGAACAAAAAAGGTAAGGAGGTCCTGGTGCTGTGGGGGATTCACCATCCCCCTAAC



AGTAAGGAGCAGCAAAATCTCTACCAGAACGAGAACGCTTACGTATCTGTTGTGACTTCT



AATTATAACAGGAGGTTCACGCCAGAAATTGCTGAGAGGCCAAAGGTCAGGGACCAGGCT



GGGCGCATGAACTACTACTGGACCCTGCTAAAGCCTGGTGACACTATCATCTTTGAGGCC



AATGGAAATTTAATTGCACCCATGTACGCATTTGCCCTATCGCGCGGGTTCGGGAGGGGG



ATAATTACCTCCAACGCATCGATGCATGAGTGCAACACAAAATGTCAAACACCTCTCGGG



GCCATTAACAGCTCCCTCCCCTATCAGAATATTCACCCGGTAACAATCGGTGAATGTCCT



AAGTACGTACGCTCCGCCAAGCTGAGGATGGTAACCGGTCTGCGGAATAATCCTAGCATC



CAGTCCCGGGGTCTTTTCGGCGCCATCGCAGGTTTTATAGAAGGGGGCTGGACTGGTATG



ATCGATGGATGGTACGGGTACCATCACCAAAATGAGCAAGGTTCGGGGTACGCAGCAGAC



CAGAAATCAACCCAAAATGCCATTAACGGAATTACAAATAAGGTTAACACCGTTATCGAA



AAGATGAATATCCAGTTTACAGCCGTAGGGAAAGAATTTAATAAGCTCGAGAAGCGGATG



GAAAACCTGAACAAGAAAGTGGATGACGGGTTCCTTGACATCTGGACTTATAATGCAGAG



CTATTAGTGCTGCTGGAGAACGAACGTACCCTGGATTTCCATGATTCAAACGTCAAAAAT



CTTTATGAGAAAGTTAAGTCCCAGCTCAAGAATAATGCGAAGGAAATCGGCAACGGGTGT



TTCGAATTCTATCACAAGTGCGATAACGAATGCATGGAGAGCGTTAGAAACGGCACCTAT



GACTACCCCAAGTACAGCGAAGAGTCTAAGCTGAACCGGGAAAAGGTCGACGGTGTGAAA



CTGGAATCCATGGGCATTTACCAGATCCTCGCTATTTACTCGACAGTCGCAAGTAGCCTG



GTGCTTTTGGTTTCTCTCGGCGCAATCTCATTCTGGATGTGCTCCAACGGATCCCTCCAG



TGTCGCATCTGTATC





420
ATGAAAGCTAACCTGCTGGTCCTTCTGTGCGCTCTCGCAGCAGCAGATGCGGACACCATC



TGCATAGGATACCATGCTAATAATTCCACAGACACTGTGGACACAGTGCTGGAAAAGAAT



GTAACGGTGACCCACAGCGTTAACTTGCTGGAGGATAGCCACAATGGTAAGCTTTGTCGT



TTGAAAGGGATCGCACCCCTGCAGTTGGGCAAATGTAATATCGCCGGGTGGCTCCTGGGC



AACCCGGAGTGCGACCCTTTGCTGCCCGTGCGGAGTTGGTCATACATTGTGGAAACTCCT



AACAGTGAGAATGGTATTTGCTATCCTGGGGACTTCATTGACTATGAAGAACTTCGCGAA



CAGTTATCTAGCGTGTCTAGCTTTGAACGCTTTGAGATCTTCCCAAAGGAGAGTAGTTGG



CCTAACCATAACACCAACGGGGTCACAGCGGCCTGTTCGCACGAAGGCAAGTCCAGCTTT



TATCGCAATCTGCTGTGGTTGACAGAGAAGGAGGGATCATACCCGAAGCTGAAAAATTCC



TACGTGAACAAGAAGGGCAAAGAAGTACTGGTGTTATGGGGCATTCACCACCCACCAAAT



AGCAAAGAGCAGCAGAACCTTTATCAGAACGAGAACGCCTACGTGAGCGTTGTTACGAGT



AATTACAACCGCCGATTTACTCCCGAGATTGCGGAAAGGCCGAAGGTGAGAGACCAGGCA



GGCCGCATGAACTATTACTGGACACTCCTGAAGCCTGGTGACACAATAATCTTCGAAGCT



AACGGCAACCTGATAGCCCCAATGTACGCCTTTGCCCTAAGTAGAGGTTTCGGCTCTGGA



ATTATTACGTCTAACGCCAGCATGCACGAGTGTAACACTAAATGCCAAACCCCACTAGGT



GCTATTAACTCGTCTCTGCCGTACCAGAATATCCACCCAGTAACGATTGGAGAGTGCCCT



AAATATGTGCGATCAGCAAAGCTTAGAATGGTGACTGGGTTACGCAACAATCCCTCTATT



CAGTCCCGCGGCCTGTTTGGGGCGATAGCCGGATTCATCGAAGGGGGCTGGACGGGCATG



ATTGACGGCTGGTATGGGTATCATCATCAGAACGAACAGGGATCAGGATACGCAGCTGAC



CAAAAATCCACGCAGAACGCCATCAACGGGATCACGAATAAAGTGAATACAGTGATCGAG



AAAATGAACATTCAGTTCACGGCAGTTGGAAAAGAGTTCAACAAACTTGAGAAGAGGATG



GAGAACCTGAATAAAAAGGTGGACGACGGATTCCTGGATATATGGACTTACAATGCCGAA



CTACTCGTCCTACTGGAAAATGAGCGAACGCTGGACTTCCATGATTCGAATGTCAAGAAT



CTGTATGAAAAGGTCAAGTCCCAGCTGAAAAATAATGCTAAAGAGATAGGCAACGGGTGT



TTCGAGTTTTACCATAAGTGCGATAATGAATGTATGGAGTCCGTGCGAAACGGTACTTAC



GACTACCCAAAATACTCAGAGGAGTCCAAACTCAACAGGGAGAAAGTGGACGGGGTTAAG



CTGGAAAGTATGGGTATTTATCAGATCCTGGCCATCTATTCTACAGTTGCATCTTCTCTA



GTGCTGCTGGTATCTCTGGGCGCAATATCTTTTTGGATGTGTTCAAATGGGAGCCTGCAG



TGCCGGATTTGTATC





421
ATGAAAGCAAATCTTCTGGTGTTACTGTGTGCTTTGGCAGCAGCCGATGCTGACACCATA



TGTATTGGCTATCACGCAAACAATTCAACCGACACAGTCGACACCGTCCTCGAAAAGAAC



GTTACCGTGACCCACTCAGTGAACCTCCTCGAGGACTCCCATAATGGCAAGCTGTGTAGG



TTAAAGGGGATCGCCCCACTGCAGTTGGGAAAGTGTAATATTGCTGGGTGGCTTCTGGGT



AACCCCGAATGCGATCCACTCCTCCCCGTTCGCAGCTGGAGTTACATTGTTGAAACCCCA



AACAGCGAGAACGGTATCTGTTACCCAGGAGATTTTATTGATTACGAGGAGTTACGAGAA



CAACTGTCCTCAGTGAGTTCTTTTGAAAGGTTTGAGATATTCCCTAAAGAGAGCAGCTGG



CCGAATCATAACACCAATGGGGTGACTGCAGCTTGCTCCCACGAGGGGAAGTCCTCCTTC



TATCGCAATCTGTTGTGGCTCACCGAAAAGGAGGGATCATATCCGAAGTTGAAAAATAGC



TACGTTAATAAGAAGGGAAAAGAGGTGCTGGTGCTGTGGGGAATCCATCATCCACCTAAT



TCCAAGGAGCAACAGAATCTATACCAAAACGAAAATGCTTACGTTTCTGTGGTGACCTCA



AATTATAACCGCCGCTTCACTCCAGAGATCGCTGAGCGACCAAAAGTGCGGGACCAAGCC



GGCAGAATGAATTACTATTGGACCTTGCTGAAACCCGGAGACACCATAATTTTTGAAGCC



AATGGGAACCTGATTGCCCCTATGTACGCCTTCGCCCTGTCTAGGGGTTTCGGCAGCGGG



ATCATAACATCTAACGCAAGCATGCACGAATGTAATACCAAGTGTCAGACCCCTCTGGGA



GCCATTAATTCCAGTCTCCCATACCAGAACATCCACCCCGTTACCATTGGGGAGTGTCCG



AAATACGTTAGAAGTGCCAAATTACGAATGGTGACAGGATTGCGGAACAACCCCAGCATC



CAGAGCAGAGGCCTATTTGGCGCCATCGCAGGATTCATCGAAGGCGGATGGACCGGAATG



ATCGACGGATGGTACGGGTATCACCACCAGAATGAACAGGGGTCGGGTTACGCCGCCGAC



CAGAAATCTACCCAGAATGCCATTAATGGGATAACAAACAAGGTCAACACCGTGATTGAG



AAGATGAATATACAGTTTACTGCCGTCGGCAAAGAGTTTAATAAACTGGAAAAGCGAATG



GAAAACCTGAACAAGAAAGTCGACGATGGGTTCCTGGATATCTGGACATACAACGCTGAG



TTGCTCGTGCTGCTCGAGAATGAGAGAACCTTGGACTTTCACGATTCAAACGTAAAAAAC



TTATACGAAAAAGTCAAGAGTCAGCTGAAAAATAATGCCAAGGAAATCGGGAACGGATGC



TTTGAGTTCTATCACAAGTGCGACAATGAGTGTATGGAATCCGTTAGGAACGGGACATAC



GATTACCCAAAATACTCCGAGGAGAGCAAGTTAAACAGAGAAAAAGTTGACGGAGTGAAA



CTAGAGTCCATGGGTATTTACCAGATCCTGGCCATTTATTCTACCGTCGCGTCATCACTG



GTACTCCTTGTCTCCCTTGGAGCGATATCCTTCTGGATGTGTTCCAACGGCTCCCTTCAG



TGCCGAATCTGCATT





422
ATGAAGGCTAATCTTCTGGTGTTACTGTGCGCCCTGGCTGCCGCCGACGCCGACACCATC



TGCATTGGTTATCACGCTAATAACTCGACGGATACAGTGGATACTGTACTGGAAAAGAAC



GTGACAGTCACCCACAGTGTTAACCTGCTCGAGGATAGTCACAATGGCAAGTTGTGCAGG



CTGAAGGGGATCGCTCCCCTGCAACTCGGCAAGTGTAATATCGCCGGCTGGCTTTTAGGC



AACCCCGAGTGCGACCCCCTACTGCCCGTTAGGTCCTGGAGCTACATCGTGGAAACTCCT



AACAGCGAGAACGGCATCTGCTATCCTGGGGACTTCATCGATTACGAAGAGCTCCGGGAA



CAGCTCTCTTCCGTGAGCTCCTTTGAGAGATTTGAGATCTTCCCTAAGGAATCGTCCTGG



CCTAACCACAATACAAATGGCGTGACAGCTGCCTGTTCACACGAAGGGAAAAGTTCCTTC



TATAGGAATCTGCTGTGGCTGACAGAGAAAGAGGGCTCTTATCCTAAATTAAAGAACTCC



TACGTGAACAAGAAGGGTAAAGAGGTCTTAGTGCTGTGGGGCATTCACCATCCCCCCAAT



TCCAAGGAGCAGCAAAATCTGTACCAGAACGAGAACGCTTATGTGTCCGTCGTTACTTCT



AACTATAATAGGCGTTTCACCCCGGAGATTGCTGAGAGGCCTAAGGTACGGGACCAGGCC



GGTAGAATGAATTACTACTGGACACTACTTAAGCCAGGTGACACAATCATCTTTGAGGCA



AACGGAAACCTAATCGCTCCAATGTATGCATTTGCCCTGAGCCGCGGATTCGGTAGCGGA



ATTATCACCAGCAATGCCTCTATGCACGAGTGCAATACTAAGTGTCAGACTCCTTTGGGA



GCGATCAACTCCAGCTTGCCATACCAAAACATTCACCCGGTGACTATTGGTGAATGCCCC



AAGTACGTGCGGTCTGCAAAACTGAGAATGGTTACCGGACTCCGGAATAACCCTAGTATA



CAGTCTAGGGGGCTCTTTGGAGCCATTGCAGGTTTCATCGAAGGCGGCTGGACCGGCATG



ATCGACGGATGGTATGGTTATCACCACCAAAACGAGCAGGGATCAGGATATGCTGCAGAT



CAAAAATCTACTCAAAATGCAATAAACGGTATCACCAATAAGGTGAACACCGTAATCGAA



AAAATGAACATCCAGTTTACAGCCGTGGGCAAGGAGTTTAATAAGCTGGAGAAACGCATG



GAGAACCTCAATAAGAAGGTTGACGATGGATTCCTGGACATCTGGACGTATAATGCCGAG



CTCCTGGTACTGCTCGAGAATGAACGAACCCTCGACTTCCATGATAGCAACGTGAAGAAC



TTATATGAGAAGGTGAAGTCACAACTGAAAAACAATGCTAAGGAAATAGGCAACGGATGT



TTTGAATTCTACCACAAGTGTGACAACGAATGTATGGAATCGGTGAGGAATGGGACATAT



GACTACCCCAAGTACTCGGAAGAAAGTAAGCTTAATAGGGAGAAGGTGGACGGCGTGAAA



CTCGAGAGCATGGGGATTTACCAAATCCTAGCAATCTATTCCACAGTTGCTTCTTCTCTG



GTGCTCCTTGTGTCACTTGGGGCGATTTCGTTCTGGATGTGCTCAAACGGGAGCCTCCAG



TGCCGGATCTGCATC





423
ATGAAGGCAAACCTGCTGGTCCTGCTCTGCGCACTGGCCGCGGCAGACGCCGACACAATC



TGCATAGGCTATCACGCAAATAACAGTACTGACACCGTCGATACAGTCCTGGAGAAAAAC



GTGACTGTGACCCACAGCGTAAATCTGCTGGAAGACAGCCACAATGGAAAATTGTGCAGA



TTGAAAGGAATAGCACCCCTGCAATTGGGGAAATGTAATATTGCCGGATGGCTGCTCGGC



AACCCCGAATGCGACCCGCTGCTGCCCGTCCGGTCTTGGAGTTATATCGTTGAGACACCG



AACTCCGAGAATGGTATCTGCTATCCGGGCGACTTCATCGACTATGAGGAACTCAGAGAG



CAGCTGTCATCTGTGTCTTCATTCGAGCGTTTCGAGATTTTCCCAAAGGAGTCATCGTGG



CCCAACCATAACACAAACGGAGTCACGGCAGCATGCTCTCACGAAGGGAAAAGCTCTTTC



TACCGCAACCTGCTCTGGTTGACTGAGAAAGAGGGGTCTTACCCCAAACTTAAGAACAGC



TACGTGAACAAGAAGGGCAAGGAGGTCTTGGTACTGTGGGGCATCCATCACCCACCTAAT



AGTAAAGAGCAACAAAACCTATACCAGAACGAGAACGCATACGTGTCAGTAGTCACCTCT



AATTACAACAGGCGGTTTACACCAGAGATAGCTGAGCGGCCAAAGGTCCGGGACCAGGCA



GGCAGGATGAACTACTATTGGACTTTGTTAAAGCCTGGAGACACCATCATCTTTGAGGCT



AACGGGAATCTGATTGCTCCCATGTATGCTTTTGCACTTTCCAGAGGCTTTGGATCCGGT



ATTATCACATCGAATGCGTCCATGCATGAGTGTAACACTAAGTGTCAAACACCACTCGGC



GCAATCAATTCTTCACTTCCTTATCAAAATATTCACCCCGTGACCATCGGCGAGTGCCCC



AAGTATGTCAGGAGCGCTAAGCTGCGGATGGTGACAGGGTTGAGGAATAATCCTTCAATT



CAGTCGAGGGGATTATTCGGTGCCATCGCGGGATTCATTGAGGGGGGGTGGACAGGAATG



ATAGACGGGTGGTATGGTTACCACCATCAGAACGAGCAGGGGTCAGGCTACGCCGCTGAC



CAAAAATCCACCCAAAATGCCATCAATGGAATCACAAATAAGGTAAATACAGTGATCGAA



AAAATGAACATTCAATTCACAGCTGTCGGAAAGGAGTTCAATAAGCTTGAGAAACGAATG



GAGAACTTAAATAAAAAAGTTGACGACGGTTTCCTGGACATTTGGACATACAACGCAGAA



CTGCTCGTTTTACTAGAGAACGAACGGACGCTGGACTTTCATGATTCTAACGTAAAGAAC



TTGTACGAGAAGGTGAAAAGCCAGCTTAAAAATAACGCCAAAGAAATCGGAAACGGCTGC



TTCGAATTCTACCACAAATGTGATAACGAGTGCATGGAGAGCGTGAGGAATGGGACATAT



GACTATCCCAAATATTCTGAAGAGTCAAAACTGAATCGGGAAAAGGTCGATGGTGTCAAA



CTGGAGTCTATGGGCATCTATCAGATACTGGCAATCTACTCCACCGTGGCCAGCAGTCTC



GTGCTGCTGGTGAGCCTGGGCGCAATAAGCTTCTGGATGTGCTCAAACGGAAGCCTGCAA



TGTAGGATTTGTATC





424
ATGAAGGCCAATCTCCTGGTGCTGTTGTGCGCACTGGCAGCGGCGGATGCAGATACAATA



TGTATCGGATATCACGCAAATAACAGCACAGATACAGTGGACACCGTGCTGGAGAAGAAT



GTGACTGTGACGCATAGTGTTAACCTCTTGGAAGATAGCCACAATGGCAAGCTGTGTCGC



TTGAAGGGAATCGCCCCCCTGCAGCTCGGGAAATGCAATATCGCGGGATGGCTTCTGGGT



AACCCTGAATGCGACCCGCTGCTGCCCGTGCGCTCATGGTCATACATTGTGGAGACACCT



AATTCAGAGAATGGGATTTGCTATCCTGGGGACTTTATCGATTACGAGGAACTGAGAGAG



CAGCTATCTTCAGTTAGTTCCTTCGAACGATTCGAGATCTTTCCAAAGGAGAGTAGCTGG



CCCAATCATAACACTAACGGAGTGACCGCCGCGTGCAGCCACGAGGGCAAATCCTCATTT



TACCGAAACCTGTTATGGCTCACAGAAAAGGAGGGGTCTTACCCGAAGCTGAAAAACTCT



TATGTGAACAAGAAGGGGAAAGAGGTGTTAGTTCTGTGGGGCATTCACCACCCTCCAAAT



TCCAAGGAACAACAAAACCTTTACCAAAACGAGAATGCATATGTCTCGGTCGTGACGTCG



AACTATAATAGAAGATTTACCCCCGAGATTGCTGAACGACCCAAGGTGAGAGATCAGGCG



GGAAGAATGAACTATTACTGGACCTTGCTCAAACCGGGAGATACAATCATATTCGAGGCT



AACGGAAACTTGATCGCCCCAATGTACGCCTTTGCCCTCTCCCGCGGTTTCGGGAGCGGT



ATCATCACCTCAAATGCTTCTATGCATGAATGCAATACCAAATGTCAAACACCTCTGGGC



GCAATCAACTCGAGCCTGCCTTATCAGAACATTCACCCTGTCACCATTGGTGAGTGCCCC



AAGTACGTAAGATCAGCTAAGCTGCGTATGGTGACCGGGCTGAGAAACAATCCCTCCATC



CAAAGTCGCGGTTTATTCGGCGCCATTGCCGGGTTCATAGAGGGTGGGTGGACAGGAATG



ATCGATGGCTGGTATGGATATCATCATCAGAACGAACAAGGATCAGGGTATGCAGCAGAC



CAGAAGTCTACTCAAAACGCAATTAATGGCATCACCAATAAGGTTAACACTGTCATAGAA



AAGATGAACATCCAGTTCACTGCGGTGGGCAAAGAGTTTAACAAGCTCGAGAAGCGGATG



GAGAACCTCAATAAGAAAGTCGATGACGGATTCCTGGATATATGGACATATAATGCCGAG



CTGCTGGTGCTGCTGGAAAACGAAAGAACCCTCGATTTCCACGACTCTAATGTGAAGAAT



CTGTACGAGAAGGTCAAGTCCCAGCTGAAAAATAACGCCAAGGAGATAGGGAACGGCTGC



TTTGAATTCTATCACAAGTGCGACAATGAGTGCATGGAGAGCGTTCGGAACGGGACTTAC



GATTATCCGAAGTATTCAGAGGAGAGCAAGCTTAATCGTGAAAAGGTCGACGGAGTGAAA



TTAGAAAGTATGGGAATCTATCAGATTCTTGCAATCTATAGCACCGTTGCCAGCTCTCTG



GTGTTACTGGTAAGCCTCGGGGCAATATCTTTTTGGATGTGTAGCAATGGGTCTCTCCAG



TGTCGAATTTGTATT





425
ATGAAGGCCAACCTGCTCGTGCTTCTGTGTGCGCTGGCCGCCGCCGACGCAGACACTATC



TGTATCGGCTATCACGCCAATAACAGCACGGATACCGTGGATACCGTATTGGAGAAAAAT



GTCACGGTAACACACTCTGTGAATCTGCTTGAAGACTCCCATAACGGAAAACTTTGTCGG



CTCAAGGGCATTGCCCCTCTGCAACTGGGCAAGTGCAACATCGCCGGGTGGCTGCTGGGC



AATCCGGAGTGCGACCCTCTCCTGCCAGTCAGGTCCTGGTCCTATATCGTAGAAACCCCC



AATAGTGAAAACGGCATATGCTACCCAGGTGATTTCATCGATTATGAAGAGCTCAGAGAG



CAACTGAGCTCCGTCAGCAGTTTTGAGCGGTTCGAGATTTTCCCAAAGGAATCATCATGG



CCGAATCACAACACCAATGGAGTGACCGCAGCGTGTTCTCATGAGGGGAAGAGCTCGTTC



TATCGGAACCTGCTTTGGTTGACGGAGAAGGAGGGGTCATACCCCAAACTTAAGAACTCA



TACGTGAATAAAAAGGGCAAGGAGGTCCTCGTGCTGTGGGGGATTCACCACCCCCCCAAT



TCCAAGGAGCAGCAGAATCTGTACCAAAACGAGAATGCTTATGTGAGTGTGGTGACGTCT



AATTATAATAGACGGTTTACACCTGAGATCGCAGAAAGACCCAAAGTGCGCGACCAGGCT



GGGAGGATGAATTACTATTGGACTCTGTTAAAGCCCGGCGATACCATCATTTTCGAGGCA



AATGGGAATCTTATCGCTCCAATGTACGCCTTCGCCCTGTCACGGGGGTTCGGGAGCGGG



ATTATCACATCAAATGCCAGCATGCATGAATGCAACACTAAGTGCCAGACCCCACTGGGC



GCCATCAATTCCAGCCECCCTTACCAGAACATACACCCTGTTACAATAGGAGAGTGCCCC



AAGTACGTCCGATCCGCTAAACTGCGGATGGTTACAGGCCTACGTAATAATCCTAGCATT



CAGTCACGGGGACTGTTTGGCGCAATAGCCGGGTTCATCGAGGGCGGGTGGACCGGAATG



ATTGATGGGTGGTACGGATACCACCATCAGAATGAGCAGGGATCTGGGTACGCCGCCGAC



CAGAAGAGCACACAGAATGCCATTAATGGCATAACCAACAAAGTGAACACCGTGATCGAG



AAGATGAACATTCAATTTACGGCTGTAGGTAAGGAATTCAACAAACTGGAGAAACGGATG



GAGAATTTGAACAAGAAGGTCGATGATGGGTTCCTCGATATTTGGACCTACAACGCTGAG



CTTTTGGTGCTGCTGGAGAACGAGAGGACACTTGATTTTCATGATTCGAATGTGAAAAAC



TTGTACGAAAAGGTCAAGTCACAGCTGAAGAACAACGCTAAAGAGATTGGAAATGGATGC



TTCGAGTTTTATCACAAATGCGACAATGAATGTATGGAGAGTGTGCGGAACGGAACATAC



GATTACCCCAAATATTCCGAGGAGTCTAAGCTTAACCGTGAGAAGGTCGATGGCGTTAAG



TTAGAGTCCATGGGAATCTACCAGATCCTGGCTATATATAGCACCGTCGCAAGCTCTCTA



GTCTTGCTCGTCTCACTGGGAGCAATCTCGTTTTGGATGTGCTCTAACGGGTCCCTACAG



TGTCGGATTTGCATC





426
ATGAAAGCTAATCTGCTGGTCCTGTTGTGTGCACTGGCGGCTGCAGATGCGGATACCATT



TGTATCGGTTATCACGCTAATAACTCTACTGACACAGTCGACACGGTGTTGGAAAAGAAC



GTCACAGTCACCCACAGCGTCAATCTGCTCGAAGATTCACACAACGGAAAGCTATGTAGG



TTAAAGGGTATTGCACCATTGCAACTGGGAAAGTGTAACATTGCTGGATGGCTGCTGGGG



AACCCCGAGTGTGATCCTTTGCTCCCTGTCAGATCCTGGTCCTACATTGTGGAAACCCCT



AACTCAGAGAACGGGATCTGCTATCCAGGAGATTTTATCGACTATGAAGAGCTGAGGGAA



CAACTATCCAGCGTCTCCAGCTTTGAGAGGTTCGAGATATTCCCTAAGGAGTCAAGCTGG



CCAAATCACAATACAAACGGTGTCACAGCCGCCTGCAGTCACGAAGGCAAGTCATCGTTC



TACCGAAATTTGTTGTGGTTGACGGAAAAAGAGGGATCATACCCAAAACTCAAGAATAGC



TATGTCAACAAGAAAGGCAAGGAAGTGCTTGTCCTCTGGGGCATACATCATCCTCCTAAC



TCTAAGGAGCAGCAAAACTTATACCAGAACGAGAACGCCTATGTGAGTGTGGTCACCAGC



AATTATAATCGCAGGTTCACGCCTGAGATTGCCGAGAGGCCAAAAGTCAGAGACCAGGCC



GGCAGGATGAATTACTATTGGACATTACTGAAACCAGGCGATACTATTATCTTCGAGGCT



AACGGAAATCTGATAGCACCAATGTACGCCTTTGCCTTGTCCCGTGGGTTCGGCTCTGGG



ATCATAACATCCAACGCAAGCATGCATGAGTGCAACACAAAGTGCCAGACACCGCTTGGA



GCCATTAATTCTTCTCTGCCATATCAGAACATTCATCCTGTAACAATCGGGGAATGCCCA



AAGTACGTTAGAAGTGCCAAGCTGCGCATGGTGACCGGCCTGAGGAATAATCCCTCTATT



CAGTCCAGAGGACTGTTCGGAGCCATCGCTGGGTTTATTGAGGGCGGCTGGACCGGAATG



ATAGATGGCTGGTACGGGTACCACCACCAGAATGAACAGGGCTCTGGCTATGCCGCGGAC



CAGAAATCTACCCAAAATGCCATCAATGGAATCACCAATAAAGTTAACACGGTGATTGAG



AAAATGAACATTCAATTTACCGCGGTAGGAAAGGAGTTTAATAAGCTTGAGAAGCGTATG



GAGAATTTGAACAAGAAGGTGGATGACGGTTTCCTCGATATTTGGACCTATAATGCCGAA



CTACTAGTTTTATTGGAGAACGAACGCACACTGGATTTCCACGACTCTAATGTTAAAAAT



CTGTACGAGAAAGTGAAGTCACAGCTAAAGAATAATGCCAAGGAAATAGGAAATGGATGC



TTTGAATTTTACCACAAATGTGACAACGAATGCATGGAATCTGTGCGGAATGGAACTTAC



GATTACCCTAAGTACTCTGAGGAGAGTAAACTGAACAGAGAGAAGGTAGACGGCGTAAAG



CTCGAATCAATGGGAATCTACCAAATTCTGGCCATCTACTCTACCGTCGCCTCCTCTCTG



GTTTTATTGGTCTCTCTTGGAGCCATTAGTTTCTGGATGTGCAGTAACGGCTCCCTGCAG



TGCAGGATTTGTATC





427
ATGAAGGCCAACCTCCTCGTGCTGCTCTGCGCCTTGGCAGCCGCAGACGCCGATACCATC



TGTATAGGGTACCACGCCAACAATTCAACAGATACCGTCGATACCGTACTGGAGAAAAAC



GTCACCGTCACGCACAGCGTTAACCTGTTGGAAGATAGTCATAATGGAAAGCTCTGTCGC



CTAAAAGGAATCGCGCCTCTGCAGCTGGGAAAGTGCAACATAGCCGGGTGGCTCCTCGGG



AACCCGGAGTGTGACCCTCTTTTGCCGGTGCGCTCATGGTCATATATTGTTGAGACCCCT



AACAGCGAAAACGGAATATGTTACCCAGGGGACTTCATCGATTATGAGGAATTACGAGAA



CAACTAAGTTCCGTCTCTTCCTTCGAGCGCTTTGAAATCTTTCCTAAAGAGAGTTCCTGG



CCCAACCACAACACTAATGGCGTGACAGCTGCTTGCAGTCATGAGGGCAAAAGTTCATTC



TATAGAAATCTTCTCTGGCTAACTGAGAAAGAAGGATCCTACCCTAAACTCAAAAATTCC



TATGTTAACAAGAAGGGCAAAGAGGTGCTCGTGCTGTGGGGGATCCACCACCCACCAAAT



TCAAAAGAGCAACAAAACCTCTACCAGAATGAAAATGCCTACGTGAGCGTTGTGACTTCA



AATTACAATAGACGGTTTACCCCAGAGATCGCAGAACGCCCTAAGGTACGTGATCAGGCT



GGGCGAATGAACTACTACTGGACACTCCTCAAACCAGGCGACACTATAATCTTCGAGGCT



AACGGCAACCTGATTGCTCCAATGTACGCGTTCGCTCTTTCACGCGGATTCGGCTCCGGC



ATCATTACTAGTAATGCATCTATGCATGAATGCAATACTAAGTGCCAGACCCCACTCGGA



GCCATAAACAGTTCTCTGCCATATCAGAACATACACCCTGTGACTATAGGAGAATGCCCA



AAATATGTTCGGTCCGCTAAGCTGCGCATGGTGACCGGACTCCGGAACAACCCATCCATA



CAATCACGGGGGCTGTTTGGCGCCATTGCCGGCTTCATCGAGGGTGGATGGACTGGTATG



ATCGATGGTTGGTATGGATACCATCATCAGAATGAACAGGGCTCCGGCTATGCCGCCGAT



CAGAAGTCCACCCAGAACGCCATTAACGGAATTACCAACAAGGTTAATACTGTGATCGAG



AAGATGAATATTCAGTTCACAGCAGTCGGGAAGGAATTCAACAAACTGGAGAAACGTATG



GAAAATCTCAACAAGAAGGTGGACGATGGGTTTTTAGACATTTGGACTTATAATGCCGAA



CTGCTGGTGCTGCTGGAAAACGAGAGAACGTTGGACTTTCACGACAGCAACGTGAAAAAC



CTGTATGAAAAAGTGAAGTCCCAGCTCAAAAACAATGCAAAGGAAATCGGCAACGGTTGC



TTTGAGTTCTACCATAAGTGCGACAACGAATGTATGGAATCTGTGCGCAATGGAACCTAC



GACTATCCTAAGTATAGCGAAGAATCTAAATTAAATAGGGAAAAGGTTGATGGAGTGAAA



CTGGAGTCTATGGGGATCTACCAGATCCTTGCTATCTACTCAACCGTCGCTAGCTCCCTC



GTACTGCTGGTCAGTTTAGGAGCGATATCTTTCTGGATGTGTTCTAATGGGTCACTGCAG



TGTAGAATTTGCATC





428
ATGAAGGCCAATCTGCTGGTGCTTCTCTGCGCCTTAGCCGCCGCCGATGCAGATACCATT



TGTATTGGATATCACGCTAACAACAGTACAGATACTGTGGACACTGTCCTGGAAAAGAAC



GTCACCGTCACGCATAGCGTAAACCTGCTCGAGGACTCACACAACGGGAAGCTCTGTCGT



CTGAAGGGCATCGCCCCCCTGCAGCTCGGCAAATGCAACATTGCGGGATGGCTTCTTGGA



AACCCCGAGTGTGATCCCTTATTACCAGTGCGCTCTTGGTCCTATATAGTAGAAACCCCA



AACAGCGAGAACGGGATTTGTTACCCCGGCGATTTCATAGACTACGAGGAGTTGCGCGAA



CAGCTGTCTAGCGTCTCCTCATTCGAACGTTTCGAGATTTTCCCAAAGGAATCCTCGTGG



CCCAATCATAATACCAATGGAGTCACTGCCGCCTGCAGCCACGAGGGAAAGTCATCTTTC



TATCGGAATCTGCTCTGGCTGACCGAAAAGGAGGGATCTTATCCTAAACTGAAAAATTCT



TACGTCAATAAGAAAGGCAAGGAAGTCTTAGTATTATGGGGAATTCATCACCCTCCCAAC



AGTAAGGAGCAGCAGAACCTGTACCAGAACGAGAACGCCTATGTTTCTGTCGTGACATCT



AACTATAACAGACGTTTCACCCCAGAAATTGCTGAAAGGCCAAAGGTCCGTGATCAGGCC



GGCAGGATGAATTACTACTGGACTCTTCTGAAGCCTGGTGACACAATCATTTTCGAAGCC



AACGGCAACCTGATTGCTCCCATGTACGCGTTCGCTCTGAGTCGCGGCTTTGGATCGGGT



ATTATTACGTCCAATGCCTCTATGCATGAATGCAATACTAAATGTCAGACCCCTCTAGGC



GCCATCAATTCTAGCCTCCCGTACCAGAACATTCATCCTGTGACTATTGGTGAATGCCCA



AAGTACGTGAGGTCCGCCAAGCTTCGCATGGTGACCGGCCTGCGTAACAACCCCTCCATC



CAATCCAGAGGTCTCTTTGGGGCAATCGCCGGTTTTATTGAGGGTGGTTGGACCGGAATG



ATCGATGGTTGGTACGGGTACCACCATCAGAATGAGCAGGGCAGTGGATATGCCGCTGAC



CAAAAATCTACACAAAACGCGATCAATGGAATCACCAATAAAGTGAACACAGTCATAGAA



AAAATGAACATCCAGTTTACTGCGGTCGGGAAGGAATTTAATAAGCTCGAGAAAAGAATG



GAAAATCTAAACAAAAAGGTCGATGACGGTTTCCTCGATATCTGGACATACAATGCCGAA



TTACTGGTCCTGCTCGAGAATGAGCGGACATTAGACTTCCACGACAGCAATGTAAAGAAC



CTTTACGAGAAGGTGAAGTCCCAGCTGAAGAACAATGCTAAAGAGATTGGGAATGGCTGT



TTTGAATTTTACCATAAATGCGACAACGAGTGTATGGAAAGCGTGCGGAACGGGACTTAC



GATTACCCAAAATATAGTGAGGAGAGCAAATTAAACCGTGAGAAGGTCGACGGGGTGAAG



TTGGAATCCATGGGCATTTACCAAATCCTCGCAATTTACTCCACCGTGGCTTCTTCATTG



GTTCTCCTGGTGTCCCTTGGGGCCATATCATTTTGGATGTGCTCTAATGGGAGTCTCCAG



TGCCGTATATGCATT





429
ATGAAGGCTAACCTACTGGTTCTGCTGTGTGCGCTTGCCGCCGCAGATGCCGACACCATC



TGCATCGGGTATCACGCAAATAACTCCACCGACACAGTAGACACAGTATTGGAAAAAAAC



GTGACCGTCACCCACTCTGTGAACCTGCTCGAAGATAGCCATAATGGCAAATTGTGTAGA



CTCAAAGGTATCGCTCCCTTGCAGCTAGGAAAGTGCAACATTGCAGGATGGCTCCTCGGC



AACCCTGAGTGTGACCCCCTCCTGCCCGTCCGATCCTGGTCCTACATCGTGGAGACTCCA



AACTCGGAGAACGGAATATGTTATCCTGGGGATTTCATTGACTATGAGGAGCTTAGGGAG



CAACTATCCAGCGTATCTAGTTTCGAACGGTTCGAGATCTTTCCAAAAGAGTCCAGTTGG



CCTAACCATAACACGAACGGTGTGACCGCTGCTTGTAGCCATGAGGGGAAATCATCTTTC



TATCGCAACTTGCTTTGGCTCACAGAGAAGGAGGGCTCCTACCCTAAGTTGAAAAACAGC



TATGTCAATAAAAAAGGCAAAGAGGETCTCGTGTTATGGGGTATTCACCACCCTCCTAAC



TCTAAAGAGCAACAAAATCTGTATCAGAACGAGAATGCGTATGTGTCAGTCGTTACATCA



AATTACAATAGGCGGTTTACACCAGAGATCGCTGAAAGACCTAAAGTTCGGGACCAGGCC



GGCCGCATGAATTACTACTGGACTCTGCTGAAGCCAGGGGATACGATTATCTTTGAAGCT



AATGGTAACCTGATTGCTCCCATGTACGCCTTTGCCTTATCAAGAGGATTTGGATCCGGC



ATAATCACATCCAATGCTAGCATGCACGAGTGCAACACCAAATGCCAGACTCCTTTGGGA



GCCATCAACTCTAGTCTGCCATATCAGAATATCCATCCTGTGACCATCGGGGAGTGCCCG



AAGTATGTGCGATCAGCCAAGCTGCGGATGGTCACCGGATTAAGAAATAACCCCTCCATT



CAGTCTCGAGGACTGTTCGGTGCTATCGCTGGTTTTATTGAAGGTGGTTGGACAGGCATG



ATCGATGGCTGGTACGGTTATCACCACCAGAACGAACAGGGGTCTGGGTACGCTGCCGAT



CAGAAGAGTACCCAGAACGCGATCAATGGCATTACCAACAAAGTGAACACAGTAATAGAA



AAGATGAACATTCAGTTCACCGCTGTTGGTAAAGAGTTCAACAAGCTGGAAAAACGGATG



GAGAATCTCAACAAAAAGGTTGATGATGGGTTCCTGGATATCTGGACCTACAACGCGGAA



CTGCTGGTACTGCTGGAAAATGAACGGACACTTGACTTTCACGACTCTAACGTGAAGAAT



CTGTACGAAAAGGTAAAATCACAGCTAAAGAACAATGCAAAGGAGATTGGGAATGGATGC



TTCGAGTTCTACCATAAGTGCGACAACGAGTGTATGGAGTCTGTGCGGAATGGCACTTAC



GATTACCCTAAGTACTCCGAGGAATCTAAACTGAATCGAGAGAAAGTGGATGGTGTAAAG



CTCGAGAGTATGGGCATTTATCAGATTCTGGCTATCTACTCGACTGTAGCCTCCTCACTG



GTGTTACTGGTGAGCCTCGGTGCAATCTCATTCTGGATGTGTAGTAACGGCTCCTTACAG



TGTCGCATTTGTATC





430
ATGAAGGCCAACTTGTTAGTCCTGCTGTGCGCTTTAGCGGCTGCCGACGCCGATACAATC



TGTATTGGCTATCACGCTAACAATAGCACTGACACAGTCGATACAGTTCTGGAGAAGAAT



GTTACAGTCACGCATAGCGTGAACTTACTGGAAGACTCTCACAATGGCAAGTTGTGTCGG



CTGAAGGGGATCGCTCCATTGCAACTCGGAAAATGCAATATAGCGGGCTGGCTGCTCGGA



AATCCAGAATGTGATCCCCTTCTGCCTGTCCGCTCCTGGTCCTACATCGTGGAGACTCCT



AATTCTGAGAACGGAATATGCTACCCTGGCGACTTCATCGACTACGAAGAACTCCGGGAA



CAGCTCTCTAGCGTGAGTTCCTTTGAGAGATTCGAAATTTTTCCAAAAGAGTCCAGCTGG



CCTAATCATAATACAAACGGCGTGACTGCTGCATGCAGCCACGAAGGGAAATCGTCTTTT



TATAGAAATCTGCTGTGGCTGACGGAGAAAGAAGGATCATACCCAAAGCTAAAGAACTCA



TATGTTAACAAGAAAGGGAAGGAGGTGCTGGTGCTGTGGGGGATACATCACCCACCCAAT



TCTAAAGAGCAGCAGAACTTGTATCAGAACGAAAATGCCTACGTGAGCGTCGTGACTTCC



AACTATAACCGAAGATTCACTCCCGAAATTGCCGAACGCCCCAAGGTCCGGGATCAGGCG



GGACGCATGAATTACTATTGGACCCTGCTGAAACCTGGAGACACTATTATCTTCGAGGCC



AACGGCAACTTGATCGCTCCCATGTATGCCTTTGCCCTGAGTCGAGGTTTTGGAAGGGGG



ATTATCACTTCCAATGCATCAATGCATGAATGCAATACAAAGTGTCAGACACCCCTTGGC



GCAATTAACTCATCTCTGCCCTACCAGAACATTCATCCAGTCACTATCGGGGAGTGCCCT



AAATATGTTAGATCTGCCAAGCTGCGGATGGTGACAGGGCTTAGAAATAACCCCAGCATT



CAGAGCCGCGGCTTGTTTGGAGCCATTGCTGGGTTTATTGAGGGAGGGTGGACCGGAATG



ATAGACGGTTGGTACGGGTACCATCATCAGAATGAGCAGGGCAGTGGGTACGCCGCTGAC



CAAAAGAGCACCCAGAACGCTATCAACGGAATTACCAATAAGGTCAATACAGTGATAGAA



AAGATGAACATTCAGTTTACTGCTGTGGGGAAGGAGTTCAATAAACTGGAAAAACGGATG



GAGAACCTCAACAAGAAAGTGGACGACGGATTTCTGGACATTTGGACCTATAACGCCGAG



TTACTGGTACTGCTTGAAAACGAAAGGACCTTAGACTTTCATGATTCTAATGTTAAAAAT



CTGTATGAAAAGGTCAAGAGCCAACTTAAGAACAACGCCAAAGAAATCGGAAACGGTTGC



TTCGAGTTTTATCATAAGTGTGACAATGAGTGCATGGAGTCTGTTCGAAATGGTACATAC



GACTATCCCAAGTATAGTGAAGAGAGCAAACTTAATCGGGAGAAGGTGGATGGCGTGAAA



CTGGAAAGCATGGGAATCTACCAGATCTTAGCCATATACAGTACAGTCGCTTCATCTCTC



GTGCTTCTCGTCAGCCTCGGAGCAATCAGCTTTTGGATGTGTAGCAACGGCAGCCTCCAA



TGCCGAATCTGCATC





431
ATGAAGGCAAACCTCCTTGTCCTCCTGTGTGCACTGGCAGCCGCCGACGCCGACACTATT



TGTATCGGGTACCATGCAAATAACTCCACCGATACCGTGGACACAGTCCTGGAAAAAAAC



GTGACAGTGACGCATTCAGTGAATCTCCTTGAAGATAGCCACAATGGAAAGTTGTGCCGG



CTGAAAGGAATCGCACCTTTACAGCTGGGAAAGTGTAACATTGCAGGGTGGCTGTTGGGG



AACCCTGAGTGTGACCCCCTCTTACCCGTCCGGTCTTGGAGTTACATAGTGGAAACACCA



AATAGTGAGAACGGCATCTGCTACCCAGGAGATTTCATCGATTATGAAGAGCTGCGTGAA



CAACTCTCTAGTGTTAGTTCTTTCGAAAGGTTCGAGATCTTTCCTAAAGAATCGTCATGG



CCCAATCACAATACAAACGGGGTCACAGCTGCTTGCTCACACGAAGGAAAGAGCAGTTTC



TATAGAAATCTGCTGTGGCTGACCGAGAAGGAGGGTTCTTACCCTAAACTTAAAAATTCT



TATGTTAACAAGAAGGGCAAAGAAGTGCTTGTCCTGTGGGGCATCCACCATCCCCCTAAC



TCTAAAGAGCAGCAGAACTTGTACCAGAATGAGAACGCCTATGTGTCAGTGGTTACCTCA



AATTATAACCGGAGATTTACGCCTGAGATCGCCGAGCGGCCCAAAGTGCGGGATCAAGCC



GGACGTATGAACTACTATTGGACACTCCTTAAGCCAGGCGATACCATTATCTTTGAGGCA



AATGGCAACCTGATCGCACCCATGTACGCGTTCGCCTTGTCTCGAGGATTCGGCAGCGGC



ATCATCACGTCCAACGCCAGTATGCATGAGTGTAATACAAAATGCCAAACTCCCCTCGGG



GCAATTAACTCGTCTCTGCCATACCAGAACATACATCCAGTGACTATTGGTGAATGTCCC



AAGTACGTCCGGTCTGCCAAGCTGCGGATGGTGACTGGCTTGCGCAATAACCCTAGCATT



CAGTCCAGAGGGCTGTTCGGCGCAATCGCCGGGTTCATCGAGGGGGGCTGGACTGGCATG



ATCGATGGCTGGTATGGATATCACCATCAGAATGAACAGGGGAGCGGTTATGCGGCCGAT



CAGAAATCGACCCAGAACGCAATCAATGGAATTACCAACAAGGTTAACACAGTCATAGAG



AAAATGAACATCCAGTTCACGGCCGTTGGGAAGGAGTTTAATAAGTTGGAAAAGCGAATG



GAAAACCTGAATAAAAAAGTCGACGACGGCTTCCTGGATATCTGGACCTATAACGCCGAG



CTACTCGTTCTGTTGGAGAACGAGAGGACACTCGACTTCCATGACAGCAATGTGAAAAAC



CTGTACGAAAAGGTGAAAAGTCAGCTCAAGAACAATGCAAAAGAGATCGGCAACGGATGT



TTCGAGTTTTACCACAAGTGCGATAATGAGTGTATGGAAAGCGTGCGCAATGGCACTTAT



GACTACCCCAAGTATTCTGAGGAGTCCAAATTGAATCGAGAAAAGGTGGATGGCGTCAAG



CTAGAATCGATGGGGATATACCAGATATTGGCCATCTACTCCACCGTGGCCTCCTCCCTC



GTCCTTCTTGTTTCGCTGGGCGCCATCTCTTTTTGGATGTGCTCAAACGGCTCGCTTCAG



TGTCGCATTTGCATC





432
ATGAAGGCAAACCTGTTAGTTCTCCTCTGCGCTTTGGCTGCGGCCGACGCCGACACAATC



TGTATCGGTTATCATGCGAACAACTCAACTGACACAGTGGATACTGTGCTGGAAAAAAAT



GTGACAGTCACCCACTCTGTGAATCTGCTAGAGGACTCACACAACGGAAAGCTGTGCAGG



CTCAAGGGCATTGCGCCACTGCAATTAGGAAAGTGTAACATCGCTGGATGGCTACTGGGA



AACCCCGAGTGTGACCCCCTGCTTCCTGTGCGTAGTTGGAGTTATATCGTCGAAACTCCA



AACAGCGAAAACGGCATTTGTTATCCCGGCGATTTCATCGATTATGAGGAATTGCGGGAG



CAACTATCTAGCGTGTCTAGTTTTGAGAGATTCGAGATCTTCCCTAAAGAGTCTTCCTGG



CCCAATCATAACACAAATGGTGTCACCGCAGCCTGCAGTCACGAGGGGAAGAGTAGCTTT



TATCGCAACCTGCTGTGGCTGACCGAAAAGGAAGGCTCCTATCCTAAACTTAAGAACAGC



TACGTGAACAAAAAGGGTAAGGAGGTCCTTGTTCTCTGGGGAATCCACCACCCCCCTAAT



AGCAAAGAGCAGCAAAACCTTTATCAGAATGAGAACGCTTATGTTTCTGTGGTGACCTCA



AACTATAATAGACGTTTCACACCTGAAATCGCCGAAAGGCCCAAGGTTCGAGATCAAGCC



GGTCGTATGAATTACTATTGGACGCTGCTAAAGCCAGGCGACACCATAATTTTCGAAGCG



AACGGTAACTTGATCGCCCCTATGTATGCATTCGCCCTGTCACGTGGCTTTGGCTCTGGT



ATTATCACCAGCAATGCCTCTATGCACGAGTGTAATACTAAATGTCAGACCCCACTCGGC



GCTATCAACTCATCCTTGCCCTACCAGAACATACATCCAGTGACAATTGGAGAATGCCCG



AAATACGTGCGTAGTGCCAAGCTGAGAATGGTGACTGGTCTCCGGAATAACCCCTCTATA



CAGTCCAGGGGCCTGTTTGGGGCTATTGCCGGTTTTATTGAGGGAGGTTGGACTGGCATG



ATCGATGGATGGTACGGCTATCACCACCAGAACGAGCAAGGCTCTGGCTATGCCGCAGAC



CAGAAATCAACACAAAACGCTATCAATGGAATAACTAACAAGGTCAACACAGTGATTGAA



AAAATGAACATCCAGTTTACGGCTGTGGGCAAGGAGTTCAACAAGCTGGAAAAGAGGATG



GAAAATCTCAACAAAAAAGTCGACGACGGCTTCTTGGACATCTGGACTTACAATGCAGAG



TTGCTTGTTCTGCTGGAAAACGAACGTACGCTGGACTTCCACGACAGTAATGTCAAGAAT



TTGTATGAAAAAGTGAAATCACAGCTGAAAAATAATGCGAAGGAGATAGGCAATGGCTGT



TTTGAGTTCTATCATAAGTGCGATAATGAGTGCATGGAGTCAGTGCGAAACGGGACCTAC



GACTACCCCAAATATAGTGAAGAGAGCAAGCTGAATAGAGAGAAAGTCGATGGCGTTAAA



CTTGAGAGCATGGGTATCTATCAAATCCTGGCTATTTACAGTACAGTGGCCTCCTCTCTA



GTGCTGCTCGTATCTCTCGGAGCGATATCCTTCTGGATGTGTTCCAATGGCTCTCTACAG



TGCCGGATATGCATA





433
ATGAAAGCTAATCTGCTTGTACTGCTGTGCGCACTGGCAGCCGCAGACGCTGACACTATC



TGTATCGGGTACCACGCCAACAATTCGACCGATACTGTGGACACAGTGTTGGAGAAGAAC



GTCACCGTAACGCACAGCGTGAACCTTTTAGAAGATAGTCATAATGGAAAGCTGTGTAGG



CTCAAGGGAATCGCTCCACTTCAGTTGGGAAAATGCAATATCGCTGGCTGGCTACTGGGC



AACCCTGAATGCGACCCCCTGCTGCCTGTGCGATCCTGGTCCTATATTGTAGAGACCCCC



AACTCAGAGAATGGCATTTGCTACCCAGGCGATTTTATTGACTACGAGGAGCTGAGAGAG



CAGTTGTCCTCCGTCTCCAGCTTTGAAAGGTTTGAGATTTTCCCAAAAGAGTCCAGCTGG



CCAAATCACAATACAAATGGTGTGACCGCCGCTTGTTCTCACGAAGGCAAAAGCTCCTTC



TATAGAAATCTTCTGTGGCTAACAGAAAAAGAAGGATCATACCCAAAGTTGAAAAACAGC



TACGTTAATAAGAAAGGCAAAGAGGTGCTGGTCCTGTGGGGTATCCACCACCCACCCAAT



TCTAAAGAACAACAAAATTTGTACCAAAATGAAAACGCCTACGTTTCTGTCGTCACTAGC



AATTATAACCGGAGGTTCACACCCGAGATCGCAGAAAGACCTAAGGTGAGAGACCAAGCC



GGCAGAATGAATTATTACTGGACTCTCCTCAAACCCGGGGACACCATCATCTTCGAAGCT



AACGGCAATCTGATTGCTCCTATGTACGCTTTTGCTCTGTCCCGGGGGTTTGGCAGCGGT



ATTATCACATCAAACGCCAGTATGCACGAGTGTAATACGAAATGCCAGACTCCTCTGGGG



GCTATCAATTCCAGTCTGCCCTATCAGAATATTCATCCTGTCACGATCGGTGAGTGCCCT



AAGTATGTGCGAAGCGCCAAACTGCGGATGGTAACGGGCCTGAGGAATAACCCCTCTATT



CAGTCTCGCGGGCTGTTTGGCGCAATCGCCGGCTTTATCGAGGGCGGTTGGACTGGCATG



ATCGACGGATGGTACGGGTACCATCACCAGAACGAACAGGGGTCCGGCTACGCCGCCGAC



CAGAAATCAACCCAGAACGCGATTAACGGGATCACCAACAAGGTGAATACTGTGATTGAG



AAGATGAATATTCAGTTTACAGCAGTGGGCAAGGAGTTTAACAAACTTGAGAAACGCATG



GAGAATCTCAACAAAAAGGTTGACGATGGATTCCTTGATATTTGGACATATAATGCCGAG



CTGCTGGTCCTTCTGGAAAATGAACGCACACTGGATTTTCACGACTCGAACGTGAAGAAT



CTGTACGAGAAGGTAAAGTCCCAATTAAAAAACAATGCTAAGGAGATAGGCAACGGCTGC



TTCGAGTTTTACCACAAGTGCGATAACGAGTGCATGGAGTCTGTGAGAAACGGTACGTAC



GATTACCCCAAATATTCCGAAGAGAGCAAGCTCAACCGCGAGAAAGTAGACGGCGTTAAA



CTGGAGAGCATGGGCATCTACCAGATCCTCGCCATTTACTCCACTGTGGCCTCGTCACTA



GTTCTCTTGGTGTCCCTGGGAGCCATCTCATTTTGGATGTGCTCCAACGGCTCACTACAG



TGCCGGATTTGTATC





434
ATGAAGGCCAACCTCCTGGTGTTACTTTGTGCCCTAGCAGCCGCAGACGCCGACACTATC



TGCATCGGATACCATGCTAATAACAGCACCGATACAGTAGATACCGTTTTGGAAAAGAAT



GTCACTGTCACCCACAGCGTTAATCTGTTGGAGGATAGCCACAACGGTAAACTGTGCAGG



CTGAAGGGAATTGCCCCCCTTCAACTGGGCAAGTGCAACATTGCAGGCTGGCTCCTCGGT



AACCCTGAGTGCGATCCTTTACTCCCTGTTAGAAGCTGGAGCTACATCGTGGAGACCCCC



AATAGTGAGAACGGAATCTGCTACCCTGGAGATTTCATCGACTATGAAGAACTTCGGGAA



CAGCTCAGTTCAGTGTCGAGCTTCGAGAGATTCGAGATCTTTCCAAAGGAGTCCAGCTGG



CCTAATCACAACACAAATGGCGTTACAGCAGCATGCTCACACGAAGGCAAGAGCAGCTTC



TACCGCAACCTGCTGTGGCTTACCGAGAAGGAGGGATCCTATCCCAAGCTCAAGAATTCT



TATGTGAATAAAAAGGGTAAGGAAGTGCTGGTCCTGTGGGGTATCCATCATCCGCCAAAT



TCTAAGGAACAGCAGAATCTGTATCAGAATGAAAATGCCTACGTGAGTGTTGTGACTTCG



AATTACAACAGGCGGTTTACCCCGGAGATTGCTGAGCGGCCCAAAGTCCGGGATCAGGCT



GGCCGCATGAATTATTATTGGACTCTGCTCAAGCCTGGCGACACCATCATTTTTGAGGCC



AATGGCAACCTTATCGCTCCCATGTACGCCTTCGCCCTCAGTAGGGGATTCGGGTCTGGT



ATCATCACTTCAAACGCCAGCATGCACGAGTGCAATACCAAGTGCCAGACACCACTCGGT



GCCATTAATAGCTCTCTTCCATATCAGAATATACATCCAGTCACGATCGGGGAATGCCCC



AAATATGTAAGAAGTGCCAAACTGCGCATGGTGACAGGCCTGCGGAACAACCCAAGCATC



CAAAGCAGAGGGCTGTTTGGCGCCATCGCGGGCTTCATTGAAGGTGGTTGGACTGGCATG



ATTGATGGCTGGTACGGATATCATCATCAGAACGAGCAGGGATCAGGGTACGCGGCCGAT



CAGAAGAGTACCCAGAATGCCATTAACGGCATCACGAATAAAGTAAATACTGTCATCGAA



AAGATGAACATCCAATTTACTGCTGTCGGGAAGGAGTTCAACAAACTGGAAAAAAGGATG



GAGAACCTGAATAAGAAAGTTGACGACGGCTTTTTAGATATTTGGACGTATAACGCAGAA



CTGCTCGTGCTCCTGGAGAACGAGAGGACCCTGGACTTTCACGACTCCAATGTGAAGAAC



CTTTATGAGAAAGTCAAATCTCAGCTCAAAAACAACGCTAAAGAAATTGGGAATGGTTGT



TTTGAGTTTTATCACAAATGCGACAACGAATGCATGGAGAGCGTCAGGAACGGGACATAC



GACTATCCAAAGTACTCAGAAGAGTCAAAACTCAACAGAGAGAAGGTTGACGGAGTCAAA



CTTGAGTCTATGGGCATATACCAGATCTTGGCGATCTATTCCACGGTGGCCTCAAGCCTT



GTTCTGTTGGTCTCATTGGGTGCCATCAGCTTTTGGATGTGTAGTAACGGCAGTCTGCAG



TGTAGAATTTGCATC





435
ATGAAAGCAAACCTGCTCGTGCTCCTGTGCGCTCTGGCAGCCGCAGATGCCGACACTATT



TGCATCGGTTACCATGCCAACAACAGCACTGATACGGTGGATACCGTACTAGAGAAGAAT



GTCACCGTAACCCACTCAGTGAACCTGCTCGAAGACTCTCACAACGGTAAGCTGTGTAGA



TTAAAGGGAATTGCCCCCTTGCAGTTAGGAAAGTGTAACATAGCAGGTTGGCTCCTTGGC



AATCCTGAGTGTGACCCCCTACTGCCAGTCCGCAGCTGGAGCTATATCGTTGAGACTCCC



AACTCTGAAAATGGAATCTGTTATCCAGGTGACTTCATCGATTATGAAGAATTACGCGAG



CAGTTGTCCAGTGTTAGCTCTTTCGAGAGATTTGAAATATTCCCAAAGGAGTCGTCCTGG



CCCAATCACAACACCAATGGAGTGACCGCTGCTTGCTCCCACGAAGGGAAGAGCTCTTTC



TATCGGAATCTGTTGTGGCTGACAGAAAAGGAGGGCAGCTATCCTAAACTAAAGAACAGC



TACGTGAACAAGAAGGGAAAGGAGGTGCTCGTGCTGTGGGGCATTCATCATCCTCCAAAT



TCCAAGGAGCAGCAGAACTTATATCAGAATGAGAATGCTTATGTCTCAGTGGTGACGTCA



AATTACAACAGGCGCTTCACACCCGAGATCGCTGAGCGGCCCAAGGTCCGCGACCAGGCT



GGTAGAATGAATTACTATTGGACCCTCCTGAAGCCCGGAGATACTATTATCTTCGAAGCA



AATGGAAATTTGATCGCACCCATGTATGCTTTCGCTCTGTCCAGGGGATTCGGTAGTGGC



ATTATCACCAGCAATGCAAGTATGCATGAGTGCAACACAAAATGTCAGACGCCGTTAGGG



GCTATTAACAGCAGCCTCCCTTATCAGAACATTCATCCGGTTACCATCGGGGAGTGCCCT



AAGTACGTGAGAAGTGCCAAACTGAGGATGGTGACAGGCCTGCGCAATAATCCCAGTATC



CAGAGCCGAGGTCTCTTTGGTGCCATTGCGGGCTTTATTGAAGGGGGCTGGACCGGCATG



ATCGACGGTTGGTACGGATACCACCACCAGAACGAACAGGGCAGTGGCTACGCCGCCGAC



CAGAAGAGTACTCAGAACGCAATCAATGGAATTACGAACAAAGTTAATACCGTAATCGAA



AAAATGAATATCCAGTTTACCGCCGTAGGCAAGGAGTTTAACAAGCTCGAAAAACGCATG



GAAAACCTGAATAAGAAAGTGGATGATGGATTCCTTGACATCTGGACCTACAACGCGGAA



CTTCTTGTCCTGCTCGAAAATGAGAGAACGCTCGACTTTCACGACAGCAATGTCAAGAAT



CTGTACGAAAAGGTAAAGTCACAGCTGAAGAACAACGCTAAGGAGATAGGCAACGGCTGC



TTCGAGTTTTACCATAAATGCGACAATGAATGCATGGAATCCGTGAGAAACGGCACTTAC



GATTACCCCAAATACAGCGAAGAATCAAAGCTAAACAGGGAGAAGGTGGACGGGGTGAAA



CTAGAAAGCATGGGCATCTATCAGATCCTCGCCATTTACTCCACAGTCGCATCTTCTTTA



GTGCTCCTTGTGTCACTGGGCGCTATCTCGTTTTGGATGTGCTCAAACGGATCTCTGCAG



TGTCGGATCTGTATT





436
ATGAAAGCAAATCTGCTAGTGCTGCTGTGCGCCCTGGCCGCCGCAGATGCAGATACTATC



TGCATTGGTTACCATGCCAACAACTCTACCGATACCGTGGATACTGTCCTCGAGAAGAAT



GTGACTGTGACTCATTCCGTGAACTTACTCGAAGACAGCCACAACGGAAAGCTGTGCCGA



TTGAAGGGCATCGCGCCACTCCAGCTGGGGAAATGCAACATCGCCGGCTGGCTTTTGGGA



AACCCCGAGTGCGATCCGCTATTGCCCGTAAGATCATGGTCCTACATCGTGGAAACACCA



AATTCAGAAAATGGCATCTGCTACCCCGGAGATTTTATCGATTACGAGGAACTGAGGGAG



CAACTGAGCAGCGTTAGTTCTTTTGAGCGATTCGAAATTTTCCCAAAGGAGTCCTCATGG



CCCAATCACAATACCAATGGCGTTACAGCCGCTTGTAGCCATGAAGGTAAGAGTTCATTT



TATCGAAATCTTCTCTGGCTGACGGAGAAGGAGGGTAGTTACCCTAAATTGAAAAATTCA



TACGTGAACAAGAAAGGAAAGGAGGTGCTGGTCCTCTGGGGGATTCACCATCCCCCCAAT



AGCAAAGAGCAACAGAATCTGTACCAGAACGAAAACGCTTATGTCTCCGTGGTCACCTCA



AATTACAATAGACGGTTTACCCCGGAGATAGCCGAGAGGCCCAAAGTCCGCGATCAGGCC



GGCCGCATGAACTACTACTGGACCCTCCTCAAGCCAGGGGATACCATCATATTCGAGGCG



AATGGGAACTTGATTGCCCCGATGTACGCATTTGCTTTGTCCAGAGGCTTTGGCTCCGGG



ATCATCACATCTAATGCCTCCATGCATGAATGCAACACAAAATGCCAGACACCCCTGGGC



GCTATTAACTCCTCTCTACCTTACCAGAACATCCACCCGGTTACTATTGGCGAGTGTCCT



AAATATGTCCGCAGCGCCAAACTGAGGATGGTGACAGGGCTGAGGAATAACCCCAGCATT



CAGTCCAGAGGCTTGTTCGGCGCTATAGCGGGGTTCATAGAAGGAGGCTGGACCGGAATG



ATCGATGGCTGGTACGGCTACCACCATCAGAACGAGCAGGGCTCCGGGTACGCCGCTGAC



CAGAAGAGTACGCAGAACGCCATTAATGGAATCACCAACAAGGTGAATACCGTAATCGAG



AAAATGAATATTCAGTTCACAGCTGTGGGGAAGGAATTCAATAAGCTGGAAAAACGCATG



GAGAACCTGAATAAAAAAGTGGATGATGGCTTCTTGGATATCTGGACCTATAATGCGGAA



CTCCTGGTCCTTTTGGAAAATGAGCGCACACTTGACTTTCATGACTCAAACGTTAAAAAC



CTGTACGAAAAAGTCAAGTCACAGCTAAAGAATAATGCAAAGGAGATTGGCAACGGGTGC



TTCGAATTTTATCATAAATGCGACAACGAATGCATGGAAAGCGTAAGGAATGGTACATAC



GATTATCCTAAGTACAGTGAGGAGTCAAAGTTGAATCGCGAAAAAGTTGACGGTGTCAAA



CTGGAATCCATGGGGATTTATCAGATTCTTGCAATTTACTCAACGGTGGCTAGTTCTCTG



GTGCTGCTGGTCTCCCTGGGCGCAATTAGTTTCTGGATGTGTAGCAACGGCTCTCTCCAG



TGCCGGATCTGTATT





437
ATGAAAGCAAATCTTCTGGTCCTGCTGTGTGCACTAGCCGCCGCCGACGCAGACACAATT



TGCATCGGATATCACGCCAACAACTCTACGGATACAGTGGACACAGTGCTGGAGAAGAAC



GTAACTGTTACACACAGCGTGAACCTGCTAGAAGATTCTCACAATGGCAAACTGTGCAGA



CTGAAAGGAATTGCACCCTTGCAGTTGGGAAAATGTAATATCGCGGGTTGGCTCCTCGGT



AATCCCGAATGCGACCCCCTACTTCCCGTCCGTTCTTGGTCTTACATAGTGGAGACACCC



AACTCGGAGAATGGGATTTGCTATCCTGGGGATTTTATTGACTACGAGGAGCTCAGGGAA



CAGTTGAGTTCTGTGTCATCATTCGAGAGGTTTGAAATCTTTCCCAAAGAGTCTTCTTGG



CCTAATCACAACACTAACGGTGTGACCGCTGCTTGTTCTCACGAAGGCAAATCATCCTTC



TACAGAAATCTGCTCTGGCTGACGGAGAAGGAAGGATCATACCCAAAGCTAAAGAATTCA



TATGTGAATAAAAAGGGGAAGGAGGTCCTCGTTCTGTGGGGTATTCACCATCCCCCTAAT



TCTAAAGAACAGCAGAACCTTTATCAGAATGAAAATGCATACGTGTCAGTGGTGACAAGC



AACTATAACAGGCGCTTTACCCCGGAAATCGCCGAACGCCCGAAGGTGAGGGACCAGGCC



GGGAGGATGAACTACTACTGGACCTTGCTGAAGCCGGGCGACACAATCATTTTTGAAGCT



AACGGGAATCTAATTGCTCCCATGTACGCCTTTGCTCTGTCTCGCGGCTTTGGCAGGGGG



ATTATCACTAGCAACGCGTCCATGCACGAGTGTAATACTAAATGCCAGACGCCACTGGGC



GCAATCAATAGCAGCCTTCCATACCAGAACATACATCCCGTCACCATAGGAGAATGTCCA



AAGTACGTCCGGTCTGCAAAACTAAGGATGGTGACCGGGCTTAGAAACAACCCAAGTATT



CAGAGCCGGGGGCTCTTTGGTGCCATCGCAGGCTTTATCGAGGGAGGGTGGACAGGCATG



ATAGACGGATGGTATGGATACCATCACCAGAATGAGCAGGGCAGCGGATACGCTGCCGAC



CAAAAAAGCACCCAAAACGCTATCAATGGCATTACTAATAAGGTGAACACTGTGATTGAG



AAGATGAACATTCAGTTCACCGCAGTCGGGAAGGAATTTAACAAGCTGGAGAAAAGGATG



GAGAACTTAAACAAGAAGGTTGATGACGGGTTTCTCGACATATGGACGTATAACGCGGAG



TTGCTGGTATTACTGGAGAATGAACGGACTCTTGACTTCCACGATTCAAATGTGAAGAAT



CTCTATGAAAAAGTCAAATCGCAGCTCAAAAATAATGCCAAGGAGATCGGCAACGGCTGT



TTCGAGTTTTATCACAAATGCGACAACGAATGTATGGAATCAGTGCGAAATGGCACATAT



GACTATCCGAAATACTCCGAGGAAAGTAAGCTGAATAGAGAAAAGGTGGACGGAGTAAAG



CTCGAGTCCATGGGGATCTACCAGATTTTGGCTATCTATTCCACAGTTGCTTCATCTCTG



GTGCTGCTGGTTTCCTTAGGCGCCATATCGTTCTGGATGTGCTCCAACGGGTCCCTGCAG



TGTCGAATCTGCATC





438
ATGAAGGCGAATCTACTTGTCCTGCTGTGCGCGCTTGCGGCTGCTGACGCCGACACGATC



TGCATAGGCTACCATGCAAATAACTCCACTGACACCGTCGACACCGTTCTTGAGAAGAAT



GTGACGGTTACTCACTCCGTGAACCTCTTAGAGGATAGTCACAATGGCAAGTTGTGCAGA



TTAAAAGGCATAGCTCCTCTTCAGCTGGGGAAATGTAATATCGCCGGGTGGCTCCTCGGG



AACCCTGAATGCGATCCTCTGCTACCTGTGAGGAGTTGGAGCTACATAGTCGAAACTCCT



AACTCGGAGAATGGAATTTGTTACCCTGGAGACTTCATTGATTACGAAGAGCTGCGGGAA



CAATTGTCCTCTGTGTCATCATTTGAGCGGTTTGAGATTTTCCCCAAAGAAAGTAGTTGG



CCAAATCATAACACTAACGGGGTCACCGCCGCATGTTCCCATGAAGGAAAGAGCTCTTTT



TATCGAAACCTCCTCTGGCTTACTGAGAAGGAAGGATCCTATCCCAAGCTCAAGAACTCC



TACGTGAATAAAAAGGGCAAAGAAGTTCTGGTGCTGTGGGGTATTCACCATCCCCCCAAC



TCAAAAGAGCAACAGAACCTCTACCAGAATGAGAATGCGTACGTGTCAGTGGTTACTAGC



AACTACAATAGGCGGTTTACACCGGAGATCGCCGAGCGTCCTAAAGTGAGAGACCAGGCT



GGAAGAATGAACTATTATTGGACGCTGCTCAAACCCGGTGACACTATCATTTTCGAGGCT



AATGGGAACTTGATTGCCCCTATGTATGCTTTCGCCTTATCACGCGGATTTGGCTCCGGG



ATCATTACCTCAAATGCCTCAATGCACGAGTGTAACACCAAGTGTCAGACACCCCTGGGC



GCGATTAACAGCAGTCTGCCGTACCAAAATATCCACCCCGTGACGATTGGGGAGTGCCCT



AAGTACGTGCGGAGTGCCAAACTGCGTATGGTGACAGGGCTGCGCAACAATCCTTCCATT



CAGTCGAGAGGCCTGTTTGGCGCCATCGCCGGGTTCATCGAAGGGGGGTGGACCGGAATG



ATTGATGGATGGTATGGGTACCATCATCAGAATGAGCAGGGGTCTGGATATGCAGCAGAC



CAGAAATCGACTCAAAATGCAATAAATGGCATAACGAATAAAGTTAATACAGTGATAGAG



AAGATGAATATCCAGTTTACTGCCGTGGGCAAGGAGTTCAATAAACTCGAGAAGCGCATG



GAGAACCTTAACAAAAAGGTGGACGATGGATTCCTGGATATCTGGACTTATAATGCCGAG



CTGCTGGTACTTCTCGAAAATGAGCGTACACTAGACTTCCATGACTCAAATGTAAAAAAT



TTATATGAGAAGGTGAAATCCCAGCTCAAGAACAATGCAAAGGAGATCGGCAATGGGTGT



TTCGAATTTTATCACAAGTGTGACAACGAGTGCATGGAATCAGTGAGAAACGGAACATAC



GACTACCCTAAATATAGTGAAGAGTCTAAGCTGAATCGTGAGAAAGTGGACGGGGTGAAA



CTCGAGTCTATGGGCATTTACCAGATTCTGGCTATTTATAGTACAGTGGCTTCAAGCTTA



GTCCTTCTAGTGAGCTTGGGTGCCATTTCATTTTGGATGTGTAGTAATGGGTCATTGCAG



TGTAGGATTTGTATC





439
ATGAAAGCAAACCTGCTGGTCTTATTGTGCGCCTTGGCAGCTGCCGATGCCGACACCATC



TGCATCGGGTACCACGCCAATAATAGTACTGACACCGTCGATACCGTGCTCGAAAAGAAC



GTAACTGTGACTCACAGTGTGAACCTGCTGGAGGATAGCCATAACGGCAAACTCTGCCGA



CTGAAAGGAATCGCTCCCTTGCAACTGGGCAAGTGCAACATAGCAGGGTGGTTACTGGGG



AACCCCGAGTGCGACCCGCTGCTCCCTGTAAGATCTTGGAGCTATATCGTGGAAACACCT



AACTCAGAAAATGGGATATGTTACCCAGGTGACTTTATCGATTACGAAGAATTGAGGGAA



CAGCTGAGCAGCGTTAGTAGCTTTGAACGATTTGAGATCTTCCCAAAGGAGTCCTCTTGG



CCTAATCACAACACAAATGGGGTGACCGCCGCTTGCTCTCATGAGGGTAAAAGTAGCTTT



TACCGGAACTTACTATGGCTGACCGAGAAAGAAGGAAGCTACCCCAAACTGAAAAATTCG



TACGTGAATAAAAAGGGGAAAGAGGTGTTAGTGCTCTGGGGGATACATCACCCTCCAAAT



TCCAAGGAGCAGCAGAATCTGTACCAAAACGAGAACGCCTACGTTTCCGTGGTGACTAGC



AATTATAACAGGCGGTTTACACCTGAAATCGCCGAACGGCCTAAAGTTCGAGATCAGGCC



GGGCGGATGAACTACTATTGGACTTTGCTCAAGCCTGGCGACACAATCATTTTTGAAGCC



AACGGGAACCTGATCGCACCGATGTATGCTTTTGCACTGAGTCGGGGGTTTGGCTCTGGC



ATTATCACCTCTAATGCGTCCATGCACGAATGTAATACCAAGTGTCAGACACCCCTGGGG



GCTATAAACTCCTCCCTCCCCTATCAGAACATCCACCCTGTGACCATCGGAGAATGTCCT



AAATATGTCCGCTCCGCCAAACTGCGGATGGTTACTGGCCTCAGAAATAATCCAAGCATT



CAGAGTCGAGGCCTCTTCGGCGCGATCGCCGGCTTCATTGAGGGTGGCTGGACCGGCATG



ATCGATGGGTGGTACGGGTATCATCATCAGAATGAACAGGGATCCGGCTACGCAGCAGAT



CAAAAAAGCACACAGAACGCGATTAATGGCATTACTAACAAGGTGAACACGGTGATCGAG



AAGATGAATATACAATTCACTGCTGTCGGGAAAGAGTTCAATAAGCTCGAAAAGAGGATG



GAGAATTTGAACAAGAAAGTGGATGATGGCTTCCTGGACATTTGGACCTACAATGCTGAA



CTCCTGGTCCTTCTGGAAAACGAAAGAACCCTAGATTTCCATGACTCTAACGTGAAGAAC



CTTTACGAAAAGGTGAAGAGCCAGTTGAAAAACAACGCAAAGGAAATTGGAAATGGGTGC



TTCGAGTTTTATCATAAGTGCGACAACGAGTGCATGGAAAGTGTCCGTAATGGCACTTAC



GATTACCCCAAATATTCTGAAGAATCCAAGCTGAACAGGGAGAAAGTCGATGGGGTTAAA



TTAGAATCCATGGGCATCTATCAGATACTGGCCATTTATTCCACTGTGGCGAGCTCCTTA



GTGCTCTTGGTCTCTTTAGGTGCCATCTCCTTTTGGATGTGCAGTAACGGGTCCCTCCAA



TGCAGGATTTGTATC





440
ATGAAGGCCAACCTCCTCGTTCTGCTGTGTGCGCTGGCAGCGGCAGATGCCGATACCATT



TGTATCGGTTACCATGCCAACAATTCCACCGACACCGTCGACACTGTTCTTGAAAAGAAT



GTAACTGTCACCCATTCTGTCAACTTGCTTGAAGATAGTCACAACGGCAAACTGTGTCGG



CTTAAAGGCATAGCCCCGCTGCAACTGGGCAAATGTAACATCGCCGGATGGCTGCTGGGA



AATCCAGAATGCGACCCCCTGTTGCCTGTGCGGTCTTGGAGTTACATAGTAGAAACCCCC



AATTCCGAAAATGGGATTTGTTATCCTGGCGACTTCATCGATTATGAGGAGTTGAGAGAG



CAATTGAGTAGCGTTTCTTCATTTGAGCGCTTCGAAATATTCCCGAAAGAGAGTTCATGG



CCTAACCACAACACAAATGGAGTGACAGCTGCCTGTTCCCACGAAGGAAAAAGCTCCTTT



TACCGTAACCTGCTATGGCTGACTGAAAAGGAGGGGTCCTACCCCAAACTTAAGAACTCT



TATGTCAACAAGAAGGGGAAAGAGGTACTGGTTCTGTGGGGAATTCATCATCCCCCGAAT



TCAAAAGAGCAGCAAAATCTGTACCAAAATGAAAACGCGTACGTCTCCGTTGTGACATCT



AACTACAATAGGCGGTTCACGCCCGAGATCGCTGAACGGCCGAAAGTCCGGGACCAAGCT



GGCAGAATGAACTATTACTGGACACTGCTCAAACCCGGCGACACCATTATTTTCGAGGCA



AATGGGAACCTGATTGCACCAATGTACGCCTTCGCTCTGTCCAGGGGCTTTGGTAGCGGA



ATTATCACCTCGAATGCTTCAATGCATGAGTGCAACACCAAGTGCCAGACACCTTTGGGC



GCCATCAATAGTAGCCTTCCTTACCAGAACATTCACCCTGTCACCATTGGTGAATGTCCT



AAGTACGTGCGAAGCGCCAAACTGCGGATGGTTACTGGCCTGCGAAATAATCCCTCCATC



CAGTCTCGCGGTCTGTTCGGAGCCATTGCAGGGTTCATCGAGGGAGGCTGGACCGGGATG



ATTGACGGCTGGTATGGGTACCACCATCAGAACGAGCAAGGATCCGGGTATGCCGCCGAC



CAGAAGAGCACCCAGAACGCTATCAATGGGATTACAAATAAAGTCAACACCGTCATCGAG



AAGATGAACATCCAATTCACTGCGGTTGGCAAGGAGTTCAACAAACTCGAGAAAAGAATG



GAAAACTTGAATAAGAAGGTAGACGACGGGTTTCTGGATATCTGGACTTATAACGCCGAA



TTATTGGTGCTGCTGGAGAATGAACGGACTTTAGATTTCCACGACTCCAATGTGAAGAAT



CTATACGAGAAAGTGAAGTCTCAGTTGAAGAACAACGCCAAGGAGATAGGAAATGGCTGT



TTCGAGTTTTATCACAAGTGCGATAATGAGTGCATGGAAAGCGTGCGCAACGGGACATAT



GATTACCCGAAGTACTCCGAGGAAAGCAAACTAAATCGCGAAAAGGTAGATGGCGTGAAG



CTGGAATCGATGGGAATCTACCAGATCCTAGCTATTTACTCTACTGTTGCCAGCTCTCTG



GTGCTTCTGGTATCTCTGGGGGCCATTAGTTTCTGGATGTGCAGTAACGGCTCATTACAG



TGTAGGATATGCATT





441
ATGAAAGCAAACTTGCTGGTTCTGTTGTGCGCTCTCGCGGCCGCTGACGCGGACACTATC



TGCATCGGGTACCACGCGAATAATTCGACTGACACAGTTGACACTGTGCTCGAAAAGAAT



GTGACCGTCACGCACTCCGTCAATCTCCTGGAGGACTCACACAATGGCAAACTTTGTCGT



TTGAAGGGCATCGCACCCCTCCAACTCGGGAAATGCAACATTGCAGGTTGGCTTTTAGGT



AATCCTGAGTGTGATCCCCTGCTGCCTGTGCGCAGCTGGAGCTATATTGTCGAGACACCC



AACTCCGAAAATGGAATCTGTTACCCAGGAGACTTCATTGACTATGAAGAATTAAGAGAG



CAATTAAGCTCCGTGAGCTCCTTTGAGAGGTTTGAGATCTTCCCGAAGGAAAGCTCCTGG



CCTAACCATAACACCAATGGAGTGACTGCCGCCTGCAGCCACGAAGGAAAGTCTTCCTTC



TATAGAAACCTACTGTGGTTGACAGAGAAGGAAGGCTCCTATCCTAAATTGAAGAACTCA



TATGTCAACAAGAAGGGGAAAGAGGTCCTCGTGCTGTGGGGAATCCATCATCCTCCTAAC



TCTAAGGAGCAACAAAATTTATACCAGAACGAAAATGCATACGTTTCTGTGGTTACATCA



AACTATAATAGGCGCTTCACACCTGAGATTGCTGAACGTCCCAAAGTGAGGGATCAAGCG



GGGCGTATGAACTACTACTGGACACTGTTAAAACCGGGGGATACCATCATCTTTGAGGCG



AACGGCAATCTTATTGCACCTATGTATGCTTTTGCCCTCTCGCGCGGTTTCGGCAGTGGA



ATAATAACATCAAATGCCAGTATGCACGAGTGCAATACGAAGTGCCAGACTCCCTTAGGC



GCTATAAATAGTTCCTTACCTTACCAGAATATTCACCCAGTGACCATCGGCGAATGCCCA



AAGTACGTCAGGTCTGCGAAACTGAGAATGGTCACAGGGTTGAGAAATAATCCATCTATC



CAGTCACGAGGCCTGTTTGGCGCGATCGCGGGCTTTATTGAAGGAGGGTGGACGGGTATG



ATTGACGGATGGTACGGTTACCATCATCAAAATGAACAAGGTTCAGGGTATGCCGCGGAC



CAGAAGAGCACCCAGAATGCAATCAATGGCATTACCAACAAGGTGAACACGGTGATCGAG



AAGATGAATATTCAGTTTACCGCTGTGGGCAAGGAGTTTAATAAGCTCGAGAAACGCATG



GAAAATCTGAACAAAAAAGTAGACGATGGATTCCTCGACATATGGACGTACAATGCCGAG



CTTCTCGTCCTCTTAGAGAACGAGCGGACCCTGGATTTCCACGATTCAAACGTCAAAAAC



CTGTATGAGAAAGTCAAGAGCCAGCTTAAGAATAACGCCAAGGAAATCGGGAACGGCTGC



TTCGAGTTCTATCATAAATGCGACAATGAGTGTATGGAATCTGTACGCAATGGAACATAC



GACTACCCTAAGTACTCCGAAGAAAGCAAACTGAATAGGGAGAAGGTAGACGGAGTGAAA



TTGGAGAGCATGGGCATATACCAGATCCTGGCCATTTACTCAACCGTCGCCTCATCCTTG



GTGTTGCTGGTGTCCTTGGGTGCTATTTCTTTTTGGATGTGCAGCAATGGCAGTCTCCAG



TGCAGGATTTGTATC





442
ATGAAGGCTAACCTGCTGGTGCTCCTCTGCGCTCTGGCAGCTGCAGACGCTGATACCATT



TGCATTGGCTACCATGCCAATAACAGCACCGATACAGTCGATACAGTTCTGGAGAAGAAC



GTGACAGTGACTCACAGCGTTAATCTGTTGGAGGACAGCCATAATGGGAAGCTGTGTCGC



CTGAAGGGAATTGCTCCATTACAGCTGGGGAAATGTAACATCGCTGGATGGCTGTTGGGA



AACCCAGAGTGTGATCCCCTACTTCCTGTACGGAGTTGGAGTTATATCGTGGAGACACCC



AATAGTGAGAACGGTATCTGTTATCCTGGAGATTTTATAGACTATGAAGAGTTAAGGGAG



CAGCTGAGCTCCGTCAGTTCATTCGAACGCTTCGAAATTTTCCCTAAGGAGTCTTCCTGG



CCCAACCACAATACCAACGGGGTCACCGCTGCTTGTAGTCATGAAGGAAAATCTAGCTTC



TACCGAAACCTGCTCTGGCTAACTGAGAAAGAAGGATCATACCCGAAGCTGAAGAATAGC



TACGTGAACAAGAAGGGGAAGGAAGTGCTGGTTCTGTGGGGCATTCACCACCCCCCTAAC



AGTAAGGAACAGCAGAACCTCTATCAGAATGAGAACGCATACGTGAGTGTCGTTACAAGC



AACTACAATCGCCGGTTTACTCCAGAGATCGCGGAAAGACCCAAAGTCAGGGACCAGGCT



GGTAGGATGAATTACTATTGGACCCTTCTCAAACCTGGGGACACTATCATATTCGAGGCC



AATGGCAACCTGATTGCCCCTATGTACGCCTTTGCTCTGAGCCGCGGATTCGGCTCCGGC



ATAATCACGTCTAATGCTTCCATGCACGAGTGTAACACAAAATGTCAGACGCCCTTGGGC



GCTATCAATTCTAGTCTGCCTTATCAGAACATACATCCAGTCACTATCGGAGAGTGCCCA



AAGTACGTTCGCTCTGCAAAGCTCCGGATGGTTACAGGTCTAAGAAATAATCCTAGTATT



CAGAGCAGGGGCCTGTTTGGAGCCATAGCTGGATTTATAGAGGGCGGATGGACTGGGATG



ATAGATGGGTGGTATGGCTACCATCACCAGAATGAACAGGGGAGCGGATACGCTGCCGAC



CAAAAATCTACTCAGAACGCAATTAATGGTATCACAAACAAAGTGAACACAGTGATCGAA



AAGATGAACATTCAGTTCACTGCTGTGGGGAAAGAGTTCAACAAGCTGGAGAAACGAATG



GAAAATCTGAATAAAAAGGTGGACGACGGATTCCTTGACATTTGGACTTACAACGCCGAA



TTACTTGTCCTCTTGGAAAACGAACGGACCCTGGATTTTCATGACTCCAATGTTAAGAAC



CTGTATGAGAAGGTGAAGAGCCAGCTGAAAAATAACGCAAAGGAAATCGGGAACGGATGT



TTTGAGTTTTACCACAAGTGCGATAATGAATGTATGGAGAGTGTTCGGAATGGGACATAC



GACTACCCTAAGTATTCTGAGGAGTCTAAGCTCAACCGGGAGAAGGTGGATGGTGTTAAG



TTAGAGAGTATGGGAATTTACCAGATTCTGGCCATATACTCTACAGTAGCATCTTCTCTG



GTGTTATTGGTCAGTCTCGGTGCTATTTCTTTTTGGATGTGCTCAAACGGCTCACTGCAG



TGCCGCATCTGTATC





443
ATGAAAGCAAACCTGCTGGTCCTCTTGTGCGCGCTGGCAGCCGCCGATGCTGACACCATA



TGTATTGGCTATCACGCTAACAATTCTACGGACACTGTGGATACGGTGCTGGAGAAAAAC



GTAACCGTCACACACAGCGTGAATCTGCTGGAGGATTCGCATAATGGTAAACTTTGCAGA



CTGAAGGGGATAGCCCCGCTCCAGTTGGGTAAGTGTAATATCGCCGGATGGTTGCTTGGG



AACCCCGAGTGTGATCCTCTGTTGCCGGTGCGCAGTTGGTCGTACATCGTGGAAACCCCG



AATAGTGAGAATGGCATTTGTTATCCAGGGGACTTCATCGATTACGAAGAGCTCAGGGAG



CAGCTCAGCTCTGTAAGTAGCTTCGAACGGTTCGAGATCTTCCCCAAAGAAAGCTCCTGG



CCCAATCACAACACTAACGGGGTGACAGCGGCCTGCAGCCACGAGGGCAAAAGTTCTTTC



TATCGCAACCTACTGTGGCTCACCGAGAAGGAGGGAAGTTACCCTAAGCTGAAGAACAGC



TATGTCAACAAGAAAGGCAAGGAGGTCCTTGTGTTATGGGGCATTCACCACCCTCCCAAT



AGCAAAGAGCAGCAAAACCTTTATCAAAATGAGAACGCCTACGTGAGCGTGGTGACCTCT



AACTACAACAGAAGGTTTACACCAGAGATCGCCGAAAGGCCTAAAGTTAGGGACCAGGCC



GGACGGATGAATTACTATTGGACGTTATTAAAGCCTGGGGATACCATTATCTTTGAGGCC



AATGGCAACTTGATCGCCCCTATGTACGCCTTTGCTCTCTCGCGCGGATTTGGTTCCGGA



ATCATTACCAGCAATGCTTCAATGCATGAGTGCAATACAAAGTGTCAGACCCCACTGGGC



GCTATTAACTCGTCTTTACCGTATCAAAATATACATCCCGTGACTATTGGTGAGTGCCCT



AAATATGTTCGCTCTGCTAAGCTCAGGATGGTTACTGGACTGCGGAACAATCCGTCGATT



CAGTCCAGGGGACTCTTCGGCGCAATTGCGGGTTTCATCGAGGGTGGCTGGACGGGCATG



ATCGACGGCTGGTACGGTTACCACCATCAGAACGAACAGGGATCCGGCTACGCAGCCGAT



CAAAAGTCTACGCAGAACGCTATTAATGGAATCACCAACAAGGTGAATACAGTTATCGAA



AAGATGAATATACAGTTTACTGCCGTGGGGAAAGAATTCAACAAACTGGAGAAGAGAATG



GAGAATCTTAACAAGAAGGTCGACGATGGCTTCCTTGATATCTGGACGTACAATGCCGAG



CTGCTGGTCCTCCTCGAGAATGAACGAACTCTGGACTTCCACGACTCCAATGTAAAGAAT



CTCTATGAAAAGGTGAAATCCCAGCTGAAAAATAACGCCAAGGAGATAGGAAATGGCTGC



TTCGAATTTTACCACAAATGTGACAATGAATGCATGGAGTCCGTGAGAAATGGAACCTAC



GACTATCCCAAATATTCAGAAGAGTCAAAGCTAAATCGCGAAAAAGTTGACGGAGTCAAG



CTCGAGTCTATGGGCATATATCAGATTCTGGCCATCTACTCCACCGTGGCCTCTTCCCTT



GTCCTTCTAGTGTCCTTGGGTGCAATTTCTTTTTGGATGTGCAGCAACGGGTCCCTGCAA



TGCAGGATTTGTATA





444
ATGAAGGCCAACCTTCTCGTCTTACTATGTGCACTTGCCGCAGCAGATGCCGATACTATC



TGCATCGGCTATCATGCCAATAACAGCACAGACACCGTGGATACGGTGCTGGAGAAGAAC



GTTACAGTGACCCACTCCGTTAATCTGCTTGAAGATAGTCATAACGGCAAGCTGTGTCGC



TTGAAAGGGATCGCCCCTCTCCAGCTGGGTAAGTGCAACATTGCTGGGTGGCTCCTTGGC



AACCCTGAGTGTGACCCACTACTTCCTGTGAGAAGTTGGAGCTATATCGTAGAGACACCA



AATTCTGAAAACGGAATCTGTTATCCCGGAGACTTCATCGACTACGAGGAACTGCGCGAA



CAACTGTCTTCCGTCTCTTCCTTTGAGAGATTTGAGATCTTTCCCAAAGAAAGTAGTTGG



CCAAACCATAATACTAACGGCGTGACAGCAGCCTGTAGTCACGAAGGCAAGTCCAGTTTT



TACCGCAACCTGCTCTGGCTGACAGAAAAGGAGGGGAGTTATCCAAAGCTGAAAAACTCT



TACGTCAACAAGAAAGGGAAAGAGGTCCTGGTTCTTTGGGGCATTCATCATCCCCCAAAT



TCAAAGGAACAGCAGAATCTTTACCAGAACGAAAATGCTTACGTGAGTGTGGTCACCAGT



AACTACAACAGGAGGTTCACACCAGAGATAGCAGAACGGCCAAAAGTAAGAGATCAGGCT



GGTAGGATGAACTATTACTGGACACTGCTCAAGCCGGGTGACACCATAATCTTTGAGGCT



AATGGCAACCTTATTGCTCCCATGTACGCTTTCGCTCTTAGCAGAGGGTTTGGCAGCGGC



ATTATCACATCAAATGCAAGCATGCACGAGTGCAACACCAAGTGTCAAACACCCCTCGGC



GCAATAAATAGCAGCTTGCCATATCAGAATATACACCCCGTGACAATCGGCGAGTGTCCT



AAATACGTACGCTCTGCAAAACTCCGCATGGTGACCGGCCTCCGTAACAACCCCAGCATC



CAGAGTCGGGGGCTCTTTGGCGCCATCGCCGGGTTTATTGAAGGGGGGTGGACAGGGATG



ATTGATGGTTGGTATGGATATCACCACCAGAACGAACAAGGATCAGGTTACGCGGGGGAC



CAGAAGAGCACCCAAAACGCTATAAACGGCATAACCAACAAGGTAAACACCGTTATTGAA



AAGATGAATATTCAGTTTACCGCAGTCGGTAAAGAGTTTAATAAGCTCGAGAAGAGGATG



GAAAATCTGAACAAGAAGGTTGATGATGGGTTTTTAGATATTTGGACCTACAATGCGGAG



CTGCTCGTCCTGTTAGAAAATGAGAGGACACTGGACTTCCACGATAGTAATGTGAAGAAC



CTCTATGAGAAGGTGAAAAGTCAGCTCAAGAATAACGCTAAAGAGATTGGGAATGGTTGT



TTTGAATTTTATCACAAATGCGACAATGAATGTATGGAGAGTGTAAGGAACGGTACGTAC



GACTACCCAAAATATTCAGAAGAGTCTAAACTCAATAGAGAGAAGGTTGACGGAGTGAAA



CTGGAGTCCATGGGCATTTACCAGATCCTGGCAATCTACTCTACTGTTGCTAGCTCGTTG



GTGTTGCTCGTCAGTCTGGGAGCTATCTCCTTCTGGATGTGTAGTAATGGGAGCCTGCAG



TGCCGGATCTGTATT





445
ATGAAGGCTAATCTACTGGTTCTTCTGTGCGCGCTCGCCGCAGCAGATGCTGATACTATC



TGCATCGGGTATCATGCTAATAACAGCACCGACACCGTCGATACGGTACTAGAGAAAAAC



GTTACTGTGACTCACTCCGTGAACCTGCTGGAAGACTCACATAACGGCAAACTGTGTCGC



CTGAAGGGGATTGCCCCCCTGCAGCTGGGGAAGTGTAATATAGCGGGATGGCTGTTGGGG



AATCCTGAGTGTGATCCACTTCTCCCCGTGAGATCCTGGAGTTACATTGTGGAGACTCCA



AATTCGGAGAACGGGATCTGCTATCCAGGAGACTTCATCGACTACGAAGAATTGCGAGAG



CAACTGTCTAGCGTGTCCTCCTTTGAAAGATTCGAGATTTTTCCAAAGGAGTCCAGTTGG



CCTAACCATAACACTAACGGCGTGACTGCCGCTTGTTCTCACGAGGGCAAGTCTTCTTTT



TATAGAAACCTTCTCTGGCTCACCGAAAAAGAAGGTTCCTATCCCAAACTCAAAAACTCC



TACGTGAATAAGAAAGGCAAAGAAGTCCTGGTGTTGTGGGGTATACACCATCCGCCTAAC



TCCAAGGAACAGCAGAATCTCTACCAGAACGAGAATGCATACGTGTCAGTTGTCACCTCC



AACTACAACCGGCGGTTCACCCCTGAGATCGCCGAAAGGCCAAAAGTGCGTGACCAGGCC



GGACGCATGAACTACTACTGGACTCTCTTGAAGCCAGGAGACACCATTATCTTCGAAGCC



AATGGCAACCTGATTGCCCCCATGTACGCTTTCGCACTCAGCAGAGGTTTCGGGTCCGGC



ATAATTACTAGCAACGCCAGCATGCACGAATGCAACACTAAATGTCAGACCCCACTCGGA



GCCATCAACTCCAGTCTGCCCTACCAGAATATTCACCCTGTCACCATCGGCGAATGCCCC



AAGTACGTGAGGAGTGCTAAACTTCGAATGGTGACCGGCCTGCGGAACAATCCGAGCATT



CAGTCCCGGGGATTGTTTGGAGCCATCGCTGGATTTATAGAGGGGGGCTGGACCGGCATG



ATCGACGGCTGGTATGGCTATCATCATCAAAATGAACAGGGCAGCGGCTATGCAGCTGAC



CAAAAGTCAACCCAGAACGCTATTAACGGAATCACAAACAAGGTGAATACCGTGATAGAA



AAGATGAATATTCAGTTCACGGCTGTGGGAAAGGAATTCAACAAGTTAGAGAAGAGGATG



GAAAATCTGAATAAGAAGGTGGACGACGGGTTCTTGGATATCTGGACATACAACGCTGAG



CTCTTGGTGCTGCTCGAAAATGAACGGACTCTTGACTTTCACGACTCAAACGTAAAAAAT



CTCTATGAAAAGGTGAAATCTCAGTTGAAGAATAACGCAAAGGAGATTGGCAATGGGTGC



TTCGAATTCTATCACAAGTGTGATAACGAGTGTATGGAGTCAGTCCGGAATGGGACTTAC



GACTATCCCAAGTATAGTGAAGAATCTAAGCTCAATCGCGAAAAGGTGGACGGGGTGAAG



TTGGAATCAATGGGTATTTATCAGATCCTCGCAATTTACTCTACCGTGGCCTCCTCATTG



GTTTTGCTGGTGTCCCTTGGAGCTATAAGCTTCTGGATGTGCAGTAATGGGTCACTACAG



TGCCGTATTTGCATT





446
ATGAAGGCCAACTTGCTGGTGCTTCTTTGCGCCCTCGCAGCAGCTGACGCCGATACCATC



TGTATAGGCTATCACGCAAACAATAGCACCGATACTGTGGATACCGTGCTTGAGAAGAAC



GTTACAGTGACACATTCAGTGAACCTACTCGAGGACTCCCACAATGGAAAGCTGTGTAGG



CTGAAAGGCATTGCACCACTGCAGCTCGGGAAATGTAATATAGCAGGGTGGCTCCTCGGC



AATCCCGAGTGCGATCCCCTGCTGCCCGTCAGGTCATGGAGCTACATTGTAGAAACCCCG



AACTCTGAGAATGGCATTTGTTATCCCGGAGATTTCATCGACTACGAAGAACTGCGAGAG



CAACTCTCATCCGTGTCTTCATTTGAAAGGTTCGAGATCTTCCCCAAGGAGTCTAGCTGG



CCTAATCACAACACAAACGGCGTGACTGCCGCCTGTTCACACGAGGGTAAGAGTTCATTT



TACAGGAACCTCCTGTGGCTGACTGAGAAGGAAGGCAGCTATCCAAAGTTGAAGAATTCG



TACGTGAACAAGAAGGGGAAAGAAGTTCTGGTACTCTGGGGGATCCACCACCCGCCTAAT



TCCAAAGAACAGCAGAATCTATACCAGAACGAAAATGCTTACGTCAGCGTTGTGACATCC



AATTACAACAGAAGATTTACCCCAGAGATAGCCGAGCGACCCAAGGTGAGGGACCAGGCG



GGACGAATGAATTATTACTGGACCCTGTTGAAGCCAGGAGACACCATCATTTTTGAAGCC



AACGGAAATCTTATCGCGCCGATGTACGCGTTCGCACTGTCACGAGGATTTGGCTCGGGG



ATTATTACCTCAAATGCTAGCATGCACGAATGCAACACTAAGTGTCAGACTCCGCTGGGA



GCTATCAATTCATCTCTCCCATATCAGAATATTCATCCCGTGACCATAGGCGAGTGCCCC



AAATACGTCCGGTCGGCAAAATTGCGGATGGTTACTGGTCTGAGAAATAATCCATCCATA



CAGTCTCGCGGTTTATTTGGGGCGATTGCAGGCTTTATTGAGGGGGGATGGACGGGCATG



ATCGATGGTTGGTACGGATATCACCACCAAAACGAGCAAGGGAGTGGTTATGCCGCCGAT



CAGAAGTCGACACAAAACGCAATAAATGGTATAACAAATAAAGTTAACACCGTAATCGAG



AAGATGAACATCCAGTTTACAGCCGTGGGGAAGGAATTCAACAAGCTGGAAAAGCGCATG



GAGAACCTGAACAAAAAGGTGGATGACGGCTTCCTGGACATTTGGACCTACAACGCAGAG



TTGTTAGTGCTGCTGGAGAATGAGCGAACACTGGATTTTCATGACTCCAATGTGAAGAAT



CTCTACGAGAAGGTGAAGTCACAGCTCAAGAACAATGCTAAAGAGATTGGGAACGGGTGC



TTCGAATTTTACCATAAATGCGACAACGAGTGTATGGAGTCCGTCCGTAATGGCACTTAT



GACTACCCTAAATACTCTGAAGAGTCCAAACTCAATCGGGAGAAAGTGGACGGTGTGAAG



CTGGAGTCAATGGGGATATACCAGATCTTAGCAATTTACAGCACCGTCGCCTCCTCATTG



GTGCTTCTGGTCTCTCTCGGAGCAATTAGTTTTTGGATGTGTTCCAATGGGTCTCTCCAG



TGCCGGATATGCATT





447
ATGAAAGCCAACCTTCTAGTGTTACTTTGCGCTCTCGCCGCTGCCGATGCCGATACAATC



TGTATCGGTTATCACGCGAATAATTCCACCGACACTGTCGATACAGTGTTGGAAAAGAAT



GTCACAGTCACACATTCCGTCAATTTGTTGGAGGACAGCCATAACGGAAAGTTGTGTAGA



TTGAAAGGGATTGCCCCACTGCAGCTGGGTAAGTGTAATATTGCTGGTTGGCTACTGGGC



AACCCAGAATGTGACCCCCTTCTACCCGTCAGGAGTTGGAGCTACATTGTGGAGACCCCT



AACAGCGAGAATGGCATTTGCTACCCAGGCGACTTTATCGATTACGAAGAACTGCGGGAA



CAGTTGAGCTCTGTTAGTAGCTTCGAGAGATTCGAGATATTCCCAAAGGAGTCAAGCTGG



CCCAATCACAACACCAATGGGGTTACAGCAGCTTGTAGCCATGAAGGCAAAAGCAGCTTC



TATCGAAATCTACTCTGGCTCACCGAAAAGGAAGGATCCTACCCGAAACTCAAAAACAGC



TACGTCAACAAGAAGGGAAAAGAGGTGCTGGTGCTGTGGGGAATCCATCATCCTCCCAAC



AGCAAAGAGCAACAGAATTTGTATCAAAACGAAAACGCTTACGTGAGCGTGGTAACCTCA



AACTATAACAGACGGTTTACACCAGAAATCGCAGAGAGGCCAAAAGTGGGGGACCAAGCC



GGTAGAATGAACTATTACTGGACCCTCTTGAAACCTGGAGACACCATAATATTCGAGGCC



AACGGAAATCTGATCGCCCCAATGTATGCCTTCGCTCTCTCTAGGGGCTTCGGCAGCGGG



ATAATTACCTCCAACGCCAGCATGCATGAGTGCAATACCAAGTGTCAAACTCCCCTGGGC



GCAATTAACAGCTCCCTGCCTTACCAAAACATTCACCCAGTCACCATCGGAGAGTGCCCC



AAATACGTTAGATCTGCAAAGCTGCGGATGGTGACAGGTCTACGCAACAACCCCTCAATC



CAGTCACGGGGGCTTTTCGGTGCCATTGCCGGGTTTATTGAAGGTGGCTGGACCGGCATG



ATAGATGGGTGGTATGGCTACCACCATCAGAATGAACAGGGAAGTGGGTATGCAGGGGAC



CAGAAAAGCACGCAGAACGCAATAAACGGGATCACGAATAAAGTGAACACCGTCATTGAA



AAGATGAACATCCAGTTTACCGCGGTTGGAAAAGAATTTAACAAGCTCGAAAAAAGAATG



GAAAATCTGAACAAGAAGGTCGACGACGGATTCCTTGATATTTGGACTTACAATGCTGAG



CTTCTTGTACTGTTAGAAAACGAGCGAACCTTGGATTTCCACGATTCAAACGTCAAAAAC



TTGTACGAGAAAGTGAAGAGCCAACTCAAGAACAACGCCAAGGAAATTGGGAATGGTTGC



TTTGAATTTTACCATAAGTGCGACAATGAATGCATGGAGTCGGTACGAAACGGGACTTAT



GATTATCCAAAGTATAGCGAAGAGAGTAAACTCAACCGGGAGAAAGTCGATGGGGTGAAA



CTGGAGTCAATGGGAATTTATCAAATTCTGGCTATCTATTCTACAGTGGCCTCTTCTCTC



GTCTTGCTAGTGAGCCTCGGAGCAATCTCTTTTTGGATGTGCAGCAATGGCTCCCTGCAA



TGCCGCATCTGCATA





448
ATGAAGGCTAACCTCCTGGTGTTGTTGTGTGCCCTGGCTGCAGCTGACGCCGATACTATT



TGCATAGGCTATCATGCTAATAATAGTACAGATACGGTTGACACCGTTCTCGAAAAGAAC



GTGACGGTGACACATAGCGTTAATCTGCTAGAAGACTCCCACAATGGGAAGCTGTGCCGG



CTGAAGGGGATCGCACCACTCCAGCTAGGTAAGTGCAATATCGCCGGGTGGCTGTTAGGA



AATCCGGAGTGCGACCCTCTTCTCCCCGTGAGGTCTTGGTCCTACATCGTGGAAACTCCA



AACAGTGAAAACGGAATCTGCTATCCTGGCGATTTTATAGACTATGAAGAGCTGCGTGAG



CAACTGAGCAGCGTATCCAGCTTCGAAAGATTCGAGATTTTCCCTAAGGAATCGTCATGG



CCGAATCACAACACTAATGGCGTCACTGCTGCATGCAGCCATGAGGGCAAAAGCAGCTTC



TATAGAAATCTCCTGTGGCTTACCGAGAAAGAGGGTAGCTATCCTAAGCTCAAGAATAGC



TATGTCAATAAGAAAGGCAAGGAGGTGCTGGTGTTGTGGGGAATCCATCACCCACCTAAC



TCCAAAGAGCAGCAGAACCTGTATCAAAACGAGAACGCCTACGTGTCTGTAGTGACGAGC



AACTACAACAGGCGTTTCACACCTGAGATCGCGGAGCGCCCCAAGGTTCGCGACCAAGCG



GGGCGCATGAATTACTATTGGACTCTTTTAAAGCCGGGAGATACGATCATCTTTGAGGCT



AACGGCAACTTAATCGCCCCTATGTACGCCTTTGCGTTGTCGCGGGGATTCGGATCCGGT



ATAATAACAAGCAACGCAAGTATGCACGAATGTAATACTAAATGTCAAACCCCTTTAGGG



GCCATTAACAGCAGCCTTCCGTACCAGAACATTCATCCCGTCACCATCGGCGAATGCCCA



AAATATGTGCGGTCCGCGAAACTCAGAATGGTAACAGGCCTGCGGAATAATCCTAGTATA



CAGTCCAGAGGACTTTTTGGGGCGATAGCTGGATTCATTGAAGGCGGATGGACTGGGATG



ATTGACGGATGGTACGGCTACCACCATCAGAACGAACAGGGCAGTGGGTACGCTGCTGAT



CAAAAATCCACACAAAATGCCATTAATGGAATTACAAACAAAGTTAATACAGTCATCGAG



AAAATGAATATTCAGTTCACAGCTGTGGGCAAAGAGTTTAACAAACTGGAGAAACGAATG



GAGAACCTGAACAAAAAGGTTGATGATGGCTTTCTGGACATCTGGACATATAATGCTGAG



CTGTTGGTCCTACTGGAGAATGAGAGGACCTTGGACTTCCACGACTCCAATGTTAAGAAC



CTATATGAGAAGGTTAAGTCGCAATTGAAAAACAATGCAAAGGAAATCGGGAACGGGTGC



TTTGAATTCTATCATAAATGTGATAATGAGTGCATGGAAAGCGTGCGTAATGGGACTTAC



GATTATCCTAAGTATAGTGAGGAATCTAAGTTGAACAGAGAGAAAGTGGATGGAGTCAAG



TTAGAAAGTATGGGTATCTACCAAATTCTTGCTATATATAGCACAGTGGCTTCCAGCCTC



GTCTTGCTTGTCTCTCTCGGGGCTATCAGCTTTTGGATGTGCTCAAACGGCAGCCTCCAG



TGTCGGATATGTATC





449
ATGAAGGCTAACCTGCTGGTGCTGTTGTGTGCACTCGCAGCCGCGGACGCCGACACTATC



TGCATAGGCTATCACGCTAATAACTCAACGGATACGGTGGATACCGTTCTGGAGAAGAAT



GTAACCGTCACACACAGCGTCAATCTGCTCGAGGATAGCCACAACGGCAAACTATGCCGC



CTGAAGGGGATAGCTCCCCTCCAGCTGGGAAAGTGTAACATTGCCGGATGGCTCCTGGGA



AATCCAGAGTGCGATCCCCTGTTACCTGTCAGATCATGGTCTTACATCGTGGAGACCCCT



AACTCCGAGAATGGGATCTGCTACCCCGGAGACTTTATTGACTACGAGGAGCTGAGAGAG



CAATTGTCTTCAGTGAGTTCTTTTGAGAGGTTTGAAATCTTCCCGAAGGAGAGTTCATGG



CCAAATCACAATACGAATGGAGTTACCGCAGCTTGCTCTCATGAGGGCAAGAGCAGTTTC



TACAGGAACCTACTGTGGCTGACCGAGAAGGAAGGTAGCTACCCGAAGCTGAAGAATTCA



TACGTCAATAAAAAGGGCAAGGAAGTGTTAGTGCTCTGGGGCATCCATCACCCCCCCAAC



TCCAAAGAGCAGCAGAACCTTTATCAGAATGAAAACGCTTATGTTTCAGTGGTGACCTCT



AATTATAACCGACGTTTTACTCCAGAGATCGCTGAAAGACCCAAGGTCCGTGACCAAGCA



GGGCGGATGAACTATTACTGGACCCTGCTAAAGCCTGGCGATACTATAATTTTCGAAGCT



AACGGCAACCTTATTGCTCCCATGTATGCATTCGCCCTGAGTCGTGGATTTGGCAGCGGT



ATTATCACCTCTAATGCATCGATGCATGAATGTAATACAAAATGCCAGACTCCATTGGGC



GCTATTAACTCAAGCCTTCCTTATCAAAATATCCACCCTGTAACTATCGGGGAGTGTCCC



AAATATGTGCGCTCAGCCAAGCTCCGCATGGTAACTGGACTCCGCAACAATCCATCAATA



CAGAGCAGAGGACTGTTCGGGGCGATAGCCGGGTTCATCGAAGGAGGCTGGACCGGCATG



ATCGACGGGTGGTACGGTTACCATCACCAAAACGAGCAGGGCAGCGGCTACGCTGCCGAT



CAAAAGTCCACACAAAATGCCATAAACGGAATAACCAATAAGGTCAACACTGTGATCGAA



AAGATGAATATTCAGTTCACTGCTGTCGGTAAAGAATTCAATAAGCTGGAAAAGCGCATG



GAGAACCTTAACAAAAAGGTGGACGACGGCTTTTTAGACATCTGGACCTACAATGCCGAA



CTGCTAGTGCTACTTGAAAACGAAAGGACCTTGGATTTTCACGACAGTAATGTTAAAAAT



CTCTACGAGAAAGTAAAGTCTCAGTTGAAGAACAATGCTAAGGAGATCGGCAATGGATGC



TTTGAGTTCTATCACAAGTGCGATAACGAATGCATGGAAAGTGTGCGCAACGGAACCTAT



GACTACCCCAAGTATTCCGAAGAGAGCAAGCTTAACAGAGAGAAGGTCGACGGAGTGAAG



CTGGAAAGTATGGGGATCTACCAAATACTGGCAATATACAGCACAGTTGCAAGCAGTCTC



GTGTTACTCGTCTCCCTTGGAGCAATCTCTTTCTGGATGTGTTCTAACGGCAGCCTGCAG



TGCAGAATTTGTATC





450
ATGAAGGCAAACTTGCTCGTGCTGTTGTGCGCATTAGCCGCCGCCGATGCCGACACAATC



TGCATCGGCTATCACGCTAACAACTCCACTGACACTGTGGATACCGTACTTGAAAAAAAT



GTGACCGTCACACACTCGGTTAATCTCTTAGAGGACTCGCACAATGGCAAACTGTGTCGT



CTGAAAGGGATCGCTCCACTTCAACTCGGGAAGTGTAATATTGCCGGGTGGCTGCTGGGC



AACCCCGAGTGCGACCCTCTTCTGCCTGTACGGTCGTGGTCTTATATAGTGGAAACACCC



AATAGTGAGAACGGCATATGCTATCCCGGAGACTTCATTGATTATGAAGAACTTAGGGAA



CAGCTAAGCTCCGTGTCAAGCTTTGAAAGGTTTGAAATATTCCCCAAGGAGAGCTCCTGG



CCTAATCACAATACCAACGGTGTGACCGCCGCCTGTTCGCACGAGGGCAAGAGCTCATTT



TACAGGAATCTACTGTGGCTCACCGAGAAGGAAGGTTCGTACCCTAAGCTCAAGAATAGC



TACGTGAATAAAAAGGGCAAAGAGGTACTGGTGCTGTGGGGGATTCACCACCCCCCTAAT



TCGAAGGAGCAGCAAAACTTGTACCAGAATGAGAATGCCTACGTCTCTGTTGTCACTAGT



AATTACAACCGTAGATTCACGCCTGAAATTGCTGAGCGACCAAAAGTTCGAGATCAGGCT



GGCAGGATGAATTATTATTGGACCCTCCTGAAGCCCGGAGATACCATTATCTTCGAGGCT



AATGGTAACCTGATCGCTCCTATGTACGCCTTCGCTTTGAGTCGAGGCTTCGGCAGCGGG



ATAATTACGTCTAACGCTTCTATGCACGAGTGCAATACAAAGTGTCAGACTCCCCTTGGG



GCAATCAATTCAAGCCTTCCCTATCAGAATATCCACCCTGTTACTATAGGGGAGTGTCCG



AAATACGETAGGTCGGCAAAGCTGAGGATGGTCACTGGCCTGCGAAATAACCCGTCCATT



CAGTCCAGGGGGCTTTTCGGTGCTATCGCTGGATTTATTGAAGGTGGTTGGACTGGCATG



ATCGACGGATGGTACGGGTATCACCACCAGAACGAACAGGGATCTGGGTACGCTGCCGAT



CAAAAATCGACCCAGAACGCCATAAACGGCATTACAAATAAGGTGAATACCGTCATCGAA



AAAATGAATATTCAATTCACCGCCGTAGGCAAAGAGTTTAATAAACTTGAGAAAAGGATG



GAGAACCTCAATAAAAAAGTCGACGATGGGTTTCTGGATATCTGGACCTATAACGCTGAG



CTTCTTGTGCTGCTCGAAAATGAACGCACACTGGATTTCCACGATTCCAACGTGAAAAAT



TTGTACGAAAAGGTGAAGTCACAACTGAAGAATAACGCAAAGGAAATCGGGAATGGCTGT



TTTGAATTCTATCACAAGTGTGACAACGAATGCATGGAGAGTGTCCGAAACGGAACCTAC



GATTATCCAAAGTACTCGGAAGAATCTAAGCTGAATCGGGAGAAGGTGGACGGGGTCAAG



CTGGAGTCAATGGGTATTTATCAGATCCTAGCGATTTACTCAACCGTGGCATCGAGCCTG



GTCCTACTTGTTAGTCTTGGGGCAATAAGCTTCTGGATGTGCAGCAACGGCAGCTTGCAG



TGCAGAATATGTATA





451
ATGAAGGCTAACCTGCTCGTTCTCTTATGTGCACTGGCCGCCGCAGACGCGGATACTATT



TGTATAGGCTACCACGCGAATAACTCTACTGATACGGTGGACACAGTTCTCGAGAAAAAC



GTGACAGTGACTCACTCCGTGAATCTGCTGGAGGATTCACACAACGGCAAACTGTGTCGA



CTGAAAGGAATCGCACCGTTGCAACTTGGTAAGTGCAATATTGCCGGATGGCTCCTGGGA



AACCCCGAATGCGATCCTTTGCTTCCCGTGCGGAGTTGGTCCTACATCGTGGAGACCCCT



AACTCTGAGAACGGAATCTGTTATCCCGGGGATTTCATTGATTATGAAGAGCTCAGAGAA



CAATTGAGTTCTGTTTCTAGCTTTGAGAGATTCGAGATTTTCCCTAAGGAGTCGTCCTGG



CCAAATCACAACACTAACGGAGTAACCGCCGCCTGTTCTCACGAGGGCAAGTCAAGCTTT



TACAGGAATCTCCTGTGGTTAACAGAAAAGGAAGGGAGTTACCCAAAACTAAAAAACTCG



TACGTGAACAAGAAAGGCAAGGAGGTCCTGGTGCTGTGGGGAATTCATCACCCCCCGAAT



TCCAAGGAACAACAGAATCTGTATCAAAACGAAAACGCTTATGTGTCCGTCGTGACATCG



AACTACAATAGAAGATTTACCCCCGAGATTGCAGAGCGCCCTAAAGTCAGGGATCAGGCT



GGGAGAATGAACTATTATTGGACACTGCTAAAGCCCGGCGATACAATTATCTTTGAGGCC



AATGGCAATCTGATTGCTCCCATGTATGCATTTGCCCTGAGCAGAGGGTTTGGCAGTGGA



ATCATTACCAGCAATGCTAGCATGCATGAATGTAATACAAAGTGTCAGACACCATTAGGA



GCCATAAACAGTTCACTCCCTTATCAGAACATCCATCCCGTGACAATCGGAGAGTGTCCT



AAATACGTCAGAAGTGCAAAATTGAGAATGGTTACCGGCTTGAGGAATAATCCATCTATT



CAATCCCGCGGGCTCTTTGGAGCCATCGCTGGCTTTATTGAAGGAGGATGGACCGGAATG



ATTGATGGATGGTATGGTTACCACCATCAGAATGAGCAGGGCTCCGGCTACGCCGCCGAC



CAGAAGTCTACCCAAAACGCCATAAACGGAATCACCAATAAGGTGAACACTGTCATTGAA



AAGATGAATATACAATTCACTGCCGTCGGGAAGGAGTTTAACAAACTCGAAAAGCGGATG



GAGAATTTGAATAAAAAGGTCGACGACGGCTTCCTGGATATCTGGACATACAATGCCGAG



CTCCTGGTCCTGTTGGAGAATGAACGCACACTCGATTTTCACGACAGCAATGTGAAGAAT



CTTTACGAAAAGGTTAAAAGTCAGTTGAAAAACAACGCTAAAGAAATAGGTAATGGGTGT



TTCGAGTTTTACCACAAGTGCGACAATGAGTGCATGGAATCTGTCAGAAATGGGACCTAC



GACTACCCTAAGTACTCCGAAGAGTCTAAGCTGAATAGGGAGAAGGTGGATGGGGTGAAG



CTGGAATCCATGGGCATCTACCAGATCCTCGCTATCTACAGCACAGTGGCCTCTAGCTTG



GTGCTTTTGGTGTCACTTGGGGGGATTTCGTTCTGGATGTGCTCCAACGGAAGCCTGCAA



TGCCGAATCTGTATC





452
ATGAAGGCTAACCTTCTTGTGCTTCTCTGTGCACTTGCTGCCGCAGATGCTGATACAATA



TGCATCGGTTACCACGCTAATAATTCTACCGATACGGTTGACACGGTTCTTGAAAAGAAC



GTCACAGTGACTCACAGCGTCAACCTCCTGGAGGACTCTCATAACGGAAAATTGTGCCGC



CTCAAAGGCATTGCCCCATTGCAATTAGGCAAGTGTAATATTGCAGGTTGGCTCCTGGGT



AACCCGGAATGCGACCCTCTGTTGCCTGTCAGGTCTTGGAGTTATATAGTCGAAACCCCA



AATTCCGAAAATGGAATATGTTACCCTGGCGACTTTATCGACTACGAAGAACTGAGGGAG



CAGCTTAGTTCCGTCAGTTCTTTCGAACGTTTCGAAATCTTCCCCAAGGAATCTAGTTGG



CCCAACCATAACACCAACGGTGTGACGGCGGCATGCAGTCACGAGGGCAAGTCCAGCTTC



TATAGAAACTTGCTGTGGTTAACCGAGAAAGAGGGAAGTTACCCTAAGCTGAAGAACAGC



TACGTAAACAAAAAAGGCAAAGAAGTCCTGGTTCTCTGGGGCATTCACCACCCACCCAAT



TCCAAGGAACAGCAAAATCTCTATCAAAATGAAAATGCTTATGTCTCTGTTGTGACCTCG



AACTATAATCGGCGTTTTACCCCTGAGATCGCCGAGAGGCCTAAGGTCAGGGACCAAGCT



GGCCGAATGAATTATTACTGGACCCTACTGAAGCCTGGCGATACCATAATCTTCGAGGCT



AATGGAAATCTGATTGCGCCAATGTATGCTTTTGCACTGAGCCGCGGGTTTGGGAGCGGA



ATTATCACCTCTAACGCATCTATGCACGAGTGTAACACAAAGTGTCAGACCCCGCTGGGG



GCTATTAACTCCAGTTTGCCATACCAAAATATTCATCCGGTCACAATCGGTGAATGCCCC



AAGTATGTTAGAAGCGCTAAGTTAAGAATGGTGACCGGGCTGCGTAACAACCCTAGTATC



CAGTCACGCGGCCTCTTTGGGGCTATTGCCGGGTTCATCGAGGGAGGTTGGACTGGGATG



ATCGACGGATGGTATGGGTACCACCATCAAAACGAGCAGGGATCAGGCTACGCCGCAGAC



CAGAAGAGCACTCAGAACGCCATCAACGGGATCACTAATAAAGTTAATACCGTGATTGAA



AAAATGAACATACAATTTACTGCAGTGGGCAAGGAGTTCAACAAACTAGAGAAACGCATG



GAGAACTTGAACAAAAAAGTTGACGACGGATTTCTGGACATCTGGACATATAATGCAGAG



CTGCTGGTCCTGCTAGAGAACGAACGGACCCTAGACTTCCATGACTCAAACGTCAAGAAT



CTGTACGAGAAGGTGAAATCTCAGCTCAAAAATAATGCCAAAGAGATCGGCAATGGATGC



TTTGAATTCTATCACAAGTGTGACAATGAGTGCATGGAGAGCGTGCGAAATGGAACTTAC



GACTACCCAAAGTACAGCGAGGAGAGTAAGCTTAACAGGGAGAAGGTGGACGGCGTGAAG



CTCGAAAGCATGGGGATATACCAGATCCTCGCCATATACTCTACTGTGGCGTCGTCTCTC



GTGCTTTTGGTATCACTCGGCGCTATCAGCTTCTGGATGTGTTCCAATGGCAGCTTGCAG



TGCCGGATATGCATT





453
ATGAAAGCCAATCTCTTAGTGCTACTGTGCGCCCTTGCCGCCGCAGACGCAGATACGATT



TGCATTGGGTATCACGCAAACAATTCCACCGACACAGTGGATACCGTGCTCGAAAAGAAC



GTAACTGTGACTCACTCTGTGAATTTACTCGAGGACAGTCACAACGGGAAGCTCTGCAGA



CTTAAGGGGATCGCACCCTTGCAACTCGGAAAGTGTAACATTGCCGGGTGGCTTCTCGGC



AACCCCGAGTGTGACCCTCTTCTTCCAGTTCGGAGCTGGAGTTATATAGTGGAAACGCCA



AATTCCGAGAACGGCATATGTTACCCAGGAGACTTTATCGATTATGAAGAACTCCGCGAA



CAGCTCAGCAGCGTGAGTTCTTTCGAACGTTTCGAGATCTTCCCAAAAGAGTCCAGTTGG



CCAAATCATAACACCAATGGCGTAACAGCAGCGTGCAGCCACGAGGGAAAATCTAGCTTT



TACAGGAACCTACTTTGGCTCACAGAAAAGGAGGGATCCTATCCTAAACTGAAGAATTCA



TACGTCAATAAAAAAGGTAAAGAGGTGTTGGTGCTGTGGGGGATTCATCACCCACCAAAC



TCCAAAGAACAGCAGAACCTGTACCAAAACGAGAACGCCTACGTCTCCGTGGTGACGAGC



AACTATAACCGACGCTTTACCCCCGAAATCGCGGAGCGTCCAAAGGTGCGGGACCAGGCA



GGGCGTATGAACTATTATTGGACACTTCTAAAACCCGGTGACACCATTATCTTTGAAGCG



AACGGCAACTTGATTGCGCCAATGTATGCTTTCGCTCTGAGTCGGGGATTTGGATCGGGG



ATTATTACCTCCAACGCGTCTATGCATGAATGTAACACCAAATGTCAAACCCCTCTTGGG



GCCATCAACAGCTCCCTGCCATATCAGAACATTCACCCAGTCACCATCGGAGAATGCCCC



AAGTATGTCCGCAGTGCTAAGCTCCGCATGGTAACCGGCCTGAGAAACAATCCCAGTATT



CAGTCTAGGGGCCTCTTCGGCGCTATTGCAGGATTCATTGAGGGCGGATGGACAGGCATG



ATCGATGGCTGGTACGGTTATCATCACCAGAACGAGCAAGGATCCGGCTACGCTGCGGAC



CAGAAGAGCACCCAGAACGCTATTAACGGCATTACGAATAAGGTGAACACTGTCATCGAG



AAGATGAACATTCAGTTTACCGCGGTTGGGAAGGAGTTCAACAAACTTGAAAAACGAATG



GAGAATCTAAACAAAAAAGTCGACGATGGATTCCTGGATATCTGGACCTACAACGCTGAG



CTGCTGGTGCTGCTGGAAAATGAGCGGACATTGGACTTCCACGATTCCAACGTGAAGAAT



CTTTACGAGAAAGTTAAATCACAGTTGAAGAATAATGCCAAAGAGATTGGGAACGGCTGT



TTTGAATTCTACCACAAATGCGATAACGAATGTATGGAATCTGTACGGAATGGTACGTAT



GACTATCCAAAATACTCCGAAGAGTCCAAGCTGAACCGAGAAAAAGTGGACGGGGTCAAA



CTGGAAAGCATGGGGATATACCAGATCCTGGCCATATATAGCACTGTGGCTTCTTCTTTG



GTTCTCCTTGTGTCACTCGGGGCCATAAGCTTCTGGATGTGTTCAAACGGAAGCTTGCAG



TGCAGAATTTGCATC





454
ATGAAGGCCAACTTACTGGTGTTGCTATGCGCTCTGGCCGCCGCTGACGCCGATACCATC



TGTATTGGATACCACGCCAACAACAGCACCGACACTGTGGACACAGTGCTTGAGAAGAAT



GTCACCGTCACACATAGTGTAAACTTGCTCGAAGATAGTCACAACGGGAAGCTGTGCCGC



CTTAAAGGTATTGCACCACTGCAGTTAGGCAAGTGCAATATTGCCGGGTGGCTGCTTGGG



AACCCCGAGTGTGATCCTCTATTGCCAGTTCGGTCGTGGAGCTATATCGTGGAGACACCG



AACAGCGAAAACGGCATCTGTTATCCTGGAGATTTTATCGACTATGAGGAACTCAGGGAA



CAGCTCTCGTCTGTGTCTAGCTTCGAACGCTTTGAAATTTTCCCAAAAGAGAGTTCCTGG



CCAAATCATAACACTAACGGTGTGACTGCCGCTTGCTCCCATGAAGGCAAATCAAGCTTT



TATAGGAATCTGTTGTGGTTGACTGAAAAAGAAGGCTCCTACCCGAAACTCAAGAACAGC



TATGTGAACAAGAAAGGTAAGGAAGTGCTGGTGCTGTGGGGCATCCATCATCCTCCTAAC



TCAAAGGAGCAGCAAAATCTTTACCAGAATGAAAACGCATACGTGTCCGTTGTAACCTCT



AATTATAACCGCCGGTTCACCCCAGAAATCGCCGAGCGTCCAAAGGTTAGAGATCAAGCA



GGGCGCATGAATTATTACTGGACACTGCTCAAGCCCGGCGATACCATCATCTTTGAGGCT



AACGGCAACCTCATTGCTCCGATGTATGCGTTCGCTCTGAGTCGCGGCTTTGGCTCAGGC



ATTATTACTTCCAATGCCTCTATGCACGAGTGCAACACTAAATGCCAGACGCCCCTGGGT



GCAATCAACTCTAGCCTCCCATATCAGAACATACATCCCGTGACCATCGGCGAATGCCCT



AAATACGTCCGGTCCGCAAAGCTGCGAATGGTGACGGGCCTGAGAAATAACCCCTCAATA



CAGTCGCGAGGGCTGTTCGGCGCCATTGCCGGGTTTATTGAGGGGGGATGGACTGGGATG



ATAGATGGTTGGTATGGGTATCATCATCAGAACGAGCAAGGGTCTGGGTATGCCGCTGAC



CAAAAAAGCACCCAGAACGCCATAAACGGGATTACCAATAAGGTTAACACAGTTATTGAG



AAGATGAATATTCAGTTTACCGCTGTCGGGAAAGAATTCAATAAATTGGAAAAAAGGATG



GAGAACCTGAACAAAAAGGTGGACGATGGGTTTCTCGATATCTGGACATATAACGCTGAG



CTTCTCGTACTGCTGGAAAATGAAAGGACGCTCGATTTCCATGATTCCAATGTCAAGAAT



CTCTACGAGAAGGTCAAGTCTCAGCTGAAGAACAATGCCAAAGAGATCGGGAATGGATGT



TTTGAGTTCTATCACAAGTGCGATAACGAATGCATGGAGTCCGTCAGGAACGGCACCTAT



GATTACCCTAAGTACAGTGAAGAAAGCAAACTTAATAGGGAAAAGGTGGATGGTGTGAAG



CTGGAGTCAATGGGCATTTACCAGATTCTGGCCATTTACAGTACAGTAGCCTCTAGTCTG



GTGCTGCTTGTCAGCCTTGGCGCCATCTCCTTTTGGATGTGTAGCAACGGATCACTGCAG



TGCAGGATCTGCATT





455
ATGAAAGCAAACTTGCTTGTGCTGTTATGCGCTCTGGCAGCTGCGGACGCCGATACTATC



TGCATCGGTTACCACGCTAACAATTCAACAGATACCGTTGATACTGTGCTGGAGAAGAAC



GTGACCGTCACCCACAGTGTGAACCTCTTGGAAGACAGCCACAACGGAAAACTGTGCCGC



CTGAAGGGCATCGCGCCGTTACAGCTGGGAAAGTGCAATATCGCCGGATGGCTTTTGGGT



AATCCAGAATGTGATCCATTGCTCCCCGTGAGAAGCTGGAGCTATATTGTTGAAACCCCT



AACTCAGAGAATGGGATCTGCTACCCCGGGGACTTCATTGACTACGAGGAACTGCGCGAG



CAGTTGTCATCCGTCAGTTCATTCGAGCGGTTTGAAATATTTCCCAAGGAGTCAAGTTGG



CCAAACCACAACACGAACGGAGTAACAGCGGCTTGTAGCCATGAAGGTAAAAGCTCTTTT



TACAGGAATCTGCTGTGGTTGACTGAGAAGGAGGGCTCCTACCCCAAACTGAAAAACAGC



TACGTGAACAAAAAGGGCAAGGAGGTCCTGGTGCTCTGGGGAATTCACCATCCGCCCAAT



TCCAAAGAGCAGCAGAATTTATACCAAAATGAGAACGCCTACGTTTCTGTCGTCACGTCA



AATTATAACCGACGCTTTACACCTGAAATAGCTGAGAGACCCAAGGTGAGAGATCAGGCT



GGGAGGATGAATTACTATTGGACTCTGCTAAAACCTGGAGACACTATAATCTTCGAAGCC



AACGGGAACCTGATTGCCCCTATGTACGCATTTGCTTTATCCCGAGGGTTTGGAAGCGGG



ATCATTACTTCAAATGCTTCTATGCACGAGTGCAATACCAAATGCCAGACACCTTTAGGC



GCTATCAATTCATCTCTGCCTTATCAGAACATTCACCCAGTGACAATAGGAGAGTGTCCT



AAGTATGTCCGCTCCGCGAAGCTTCGTATGGTCACAGGCCTCAGGAATAACCCAAGTATC



CAGTCGAGAGGCCTTTTTGGTGCCATCGCTGGCTTTATCGAAGGAGGGTGGACCGGCATG



ATTGATGGGTGGTATGGATACCATCATCAGAACGAGCAAGGCTCAGGTTACGCCGCGGAC



CAGAAGTCCACGCAAAATGCCATTAACGGCATCACGAACAAAGTCAACACCGTTATCGAG



AAGATGAATATACAGTTCACAGCCGTAGGCAAAGAATTTAATAAACTCGAAAAGCGGATG



GAGAATTTAAACAAAAAAGTCGATGATGGATTTCTCGATATCTGGACTTATAACGCCGAA



CTTCTAGTGCTGCTTGAGAACGAGAGAACGCTTGATTTTCACGACAGTAACGTTAAAAAC



CTGTACGAAAAGGTAAAGTCCCAACTGAAAAACAATGCCAAAGAAATTGGAAACGGTTGC



TTTGAATTTTACCACAAGTGCGATAATGAGTGCATGGAAAGTGTAAGAAATGGCACGTAT



GACTATCCCAAATACTCCGAAGAAAGCAAGCTCAATCGTGAGAAGGTGGATGGTGTGAAG



CTGGAATCGATGGGGATTTATCAGATCCTAGCTATCTATTCAACAGTCGCCTCTAGTCTT



GTTCTTCTTGTATCTCTTGGAGCCATCTCATTTTGGATGTGTTCAAACGGATCCCTGCAG



TGTCGGATCTGTATC





456
ATGAAGGCTAACCTGCTGGTTCTACTCTGCGCACTCGCAGCTGCGGACGCCGACACAATT



TGTATTGGATATCACGCTAACAATAGCACCGATACCGTAGACACCGTACTGGAAAAGAAT



GTGACGGTCACACACTCAGTAAATCTCCTGGAAGACAGCCATAATGGCAAGCTGTGTAGA



TTAAAAGGGATTGCTCCTCTCCAGTTGGGCAAATGTAACATCGCCGGTTGGCTGCTGGGG



AACCCCGAGTGCGACCCATTGCTGCCCGTAAGGAGCTGGTCCTATATAGTTGAGACACCC



AATTCTGAGAATGGCATCTGCTACCCCGGAGATTTTATCGATTATGAGGAGTTGCGTGAG



CAGCTCTCTAGCGTGAGCTCGTTTGAAAGATTTGAAATTTTTCCGAAAGAATCTAGTTGG



CCCAACCACAATACGAACGGAGTGACTGCCGCCTGCTCCCACGAGGGAAAATCCTCATTT



TACAGGAACTTACTCTGGCTTACTGAGAAGGAAGGTAGCTACCCAAAGCTCAAGAACAGC



TACGTCAACAAGAAGGGCAAGGAAGTCCTGGTCCTGTGGGGAATCCATCATCCGCCAAAC



TCCAAGGAGCAACAGAATCTATATCAGAATGAGAATGCCTACGTTTCAGTGGTTACGTCT



AATTATAACCGCAGGTTTACCCCCGAGATCGCTGAGCGCCCCAAAGTTAGAGACCAGGCA



GGGCGCATGAACTACTATTGGACCCTCCTGAAACCTGGCGACACAATTATCTTCGAGGCA



AACGGTAATCTCATCGCGCCTATGTACGCTTTTGCCCTTAGCCGGGGTTTTGGATCAGGC



ATCATAACTTCTAACGCCTCTATGCACGAATGTAACACCAAGTGTCAGACCCCCCTAGGA



GCTATCAACAGCTCGCTTCCTTACCAGAACATTCATCCCGTGACCATAGGTGAGTGTCCA



AAATACGTCAGGAGTGCAAAACTAAGGATGGTTACCGGACTCCGGAATAACCCTTCGATT



CAGTCGCGCGGGCTCTTTGGAGCAATCGCCGGGTTCATCGAAGGCGGGTGGACCGGGATG



ATTGACGGTTGGTACGGCTACCATCACCAAAACGAACAAGGCTCAGGTTATGCAGCTGAC



CAGAAGTCCACTCAGAATGCCATAAATGGCATTACCAACAAAGTTAATACAGTCATTGAG



AAGATGAATATACAGTTCACCGCGGTGGGCAAAGAGTTCAACAAACTGGAGAAACGTATG



GAAAACTTGAACAAAAAAGTGGACGATGGGTTCTTGGACATCTGGACGTATAATGCCGAG



TTATTAGTGCTGCTGGAAAATGAAAGAACGTTAGACTTCCACGACTCTAATGTTAAAAAT



TTGTACGAAAAGGTCAAATCCCAACTGAAAAATAACGCCAAGGAAATAGGCAATGGCTGT



TTTGAATTCTATCATAAGTGCGATAACGAGTGTATGGAGAGTGTTCGCAATGGTACATAC



GACTACCCTAAATACTCCGAGGAAAGTAAGCTGAACAGGGAAAAGGTCGATGGAGTCAAG



CTGGAATCCATGGGGATTTATCAGATCCTGGCCATTTATAGCACTGTAGCCTCCTCCCTG



GTGCTGCTGGTATCACTCGGCGCAATAAGCTTCTGGATGTGTTCTAACGGGAGCCTGCAA



TGCAGAATATGCATT





457
ATGAAAGCAAACCTCCTCGTGTTGCTCTGTGCCCTGGCTGCAGCCGACGCCGACACCATA



TGTATCGGGTACCACGCCAATAACTCCACTGATACCGTCGATACCGTCCTTGAGAAAAAT



GTGACAGTCACACACAGCGTTAATTTATTGGAGGACAGCCACAACGGCAAGCTCTGTAGG



CTGAAAGGGATCGCCCCCTTACAGCTGGGGAAATGTAATATCGCTGGATGGCTGCTGGGA



AACCCCGAGTGCGACCCCTTGCTGCCTGTGAGGTCTTGGAGCTACATTGTTGAGACCCCT



AACAGCGAGAACGGCATTTGTTACCCTGGCGACTTCATTGACTACGAGGAGCTGAGGGAA



CAATTGTCATCTGTCAGCTCATTTGAGCGATTCGAGATCTTTCCCAAGGAATCGTCATGG



CCAAATCACAACACAAACGGGGTGACCGCGGCTTGCTCACATGAAGGAAAGAGCTCCTTT



TACCGAAATCTTCTGTGGCTGACGGAGAAGGAAGGATCATACCCAAAATTGAAAAACTCC



TATGTGAACAAGAAAGGTAAAGAGGTCCTTGTTTTATGGGGCATTCACCACCCACCTAAC



TCAAAAGAACAGCAAAACCTGTACCAGAACGAGAATGCATACGTTTCAGTAGTCACCTCT



AACTATAATAGGAGATTCACCCCCGAAATCGCCGAGAGGCCAAAGGTACGGGATCAGGCT



GGCAGGATGAATTACTATTGGACCCTACTTAAACCTGGAGACACGATCATCTTCGAGGCA



AATGGAAACCTCATCGCCCCTATGTATGCCTTTGCCCTTAGCCGAGGGTTTGGATCAGGG



ATAATAACCTCTAACGCCAGTATGCACGAATGCAATACGAAGTGTCAAACCCCTCTGGGA



GCAATAAATTCTTCCCTTCCTTATCAGAACATTCACCCCGTCACAATTGGAGAGTGCCCC



AAATACGTCAGGTCCGCCAAACTGAGAATGGTTACCGGCTTGCGGAATAATCCGAGCATT



CAGAGCCGCGGATTATTTGGTGCTATTGCTGGCTTTATCGAAGGAGGGTGGACCGGAATG



ATCGACGGGTGGTACGGCTACCATCATCAGAACGAGCAGGGTAGCGGTTACGCTGCCGAT



CAGAAATCCACTCAGAATGCCATCAATGGCATTACTAACAAAGTAAATACTGTGATTGAA



AAGATGAACATCCAGTTTACCGCAGTAGGAAAAGAGTTCAACAAATTGGAGAAAAGGATG



GAAAACCTCAACAAAAAAGTCGACGATGGATTCCTTGATATTTGGACATACAACGCTGAG



CTGCTAGTGCTGCTGGAGAACGAGCGAACACTCGATTTCCATGATAGCAACGTCAAAAAC



CTGTACGAGAAGGTCAAAAGCCAGCTGAAAAATAACGCTAAGGAGATTGGGAATGGCTGT



TTCGAATTCTACCACAAATGTGATAATGAATGCATGGAGAGTGTGCGGAATGGGACATAC



GACTACCCAAAATATTCTGAAGAGAGTAAACTTAATCGAGAGAAAGTGGATGGTGTTAAA



CTTGAGTCTATGGGCATTTACCAGATCCTGGCAATTTACAGTACCGTCGCTTCTTCTTTG



GTCCTACTAGTGAGCCTCGGAGCAATCAGCTTCTGGATGTGTAGTAACGGGAGCCTTCAG



TGTCGAATTTGCATC





458
ATGAAAGCTAATCTGCTCGTACTGCTCTGCGCTCTGGCTGCCGCTGATGCCGACACCATC



TGTATTGGATATCACGCAAACAATTCTACTGATACCGTGGACACCGTGCTCGAGAAAAAC



GTGACCGTGACGCATTCCGTTAATCTGCTGGAAGATTCACACAACGGAAAGCTGTGTAGA



CTGAAGGGAATCGCCCCACTGCAATTGGGTAAATGTAACATTGCAGGATGGCTTCTGGGT



AATCCTGAATGCGATCCACTGCTCCCTGTTAGATCATGGTCATATATCGTCGAAACACCG



AATTCTGAAAATGGTATTTGCTACCCTGGCGATTTCATCGACTACGAAGAGCTGAGAGAG



CAGCTATCTAGCGTGAGTAGCTTCGAACGCTTCGAAATTTTTCCCAAAGAGAGCTCTTGG



CCGAACCACAATACCAATGGCGTGACCGCCGCATGCAGCCATGAGGGCAAATCTTCTTTC



TACAGAAATCTACTTTGGCTGACCGAAAAAGAGGGAAGTTACCCAAAGCTGAAAAATTCC



TATGTCAACAAAAAAGGGAAGGAGGTACTTGTGTTATGGGGAATTCACCACCCCCCTAAC



TCCAAGGAGCAGCAGAACCTGTATCAGAATGAGAACGCGTATGTTTCAGTGGTCACCAGC



AACTATAATCGTCGGTTCACCCCTGAGATCGCCGAACGGCCCAAGGTGAGAGATCAGGCT



GGAAGAATGAATTACTATTGGACCTTGCTGAAGCCTGGGGATACCATCATCTTTGAAGCT



AATGGAAACCTGATCGCGCCTATGTACGCATTCGCCCTATCCCGTGGCTTCGGTTCCGGC



ATTATCACCTCAAATGCCTCAATGCACGAGTGCAACACTAAATGTCAGACCCCGCTGGGT



GCCATCAACTCCAGCCTTCCCTACCAAAACATACATCCAGTGACGATTGGCGAGTGCCCA



AAGTACGTCCGCTCTGCCAAGCTACGCATGGTCACGGGCCTGCGAAATAACCCCTCTATA



CAATCCCGTGGGCTGTTTGGCGCGATTGCCGGGTTCATCGAGGGAGGATGGACAGGTATG



ATCGATGGCTGGTACGGATACCATCATCAGAACGAACAGGGCTCCGGCTACGCTGCGGAC



CAGAAGTCTACGCAAAACGCAATTAATGGAATCACAAACAAGGTGAACACTGTGATCGAG



AAAATGAATATTCAGTTTACCGCCGTCGGTAAAGAATTCAATAAGCTCGAGAAGAGAATG



GAGAACTTGAACAAAAAAGTGGATGATGGGTTTCTCGATATTTGGACATATAACGCGGAA



CTCCTGGTGCTGCTCGAGAATGAGCGCACCCTGGATTTTCACGACTCTAACGTCAAGAAT



TTATACGAGAAAGTAAAATCCCAGCTGAAGAACAATGCTAAAGAAATTGGCAACGGATGT



TTCGAGTTTTATCATAAATGCGATAATGAGTGCATGGAGAGCGTGCGCAATGGAACATAC



GACTACCCTAAATACAGCGAGGAATCTAAGCTGAATAGAGAGAAGGTAGACGGAGTCAAG



CTGGAATCTATGGGAATATATCAAATTTTAGCTATTTACTCCACAGTTGCTTCATCCCTG



GTCTTACTGGTTTCCCTCGGCGCGATCTCGTTTTGGATGTGCAGTAATGGCTCCCTTCAG



TGTCGAATCTGCATC





459
ATGAAAGCTAATCTGTTGGTGCTGCTCTGCGCTTTGGCCGCTGCCGATGCAGATACCATC



TGTATCGGCTATCACGCGAACAATTCCACAGATACAGTGGACACCGTCCTGGAGAAAAAT



GTGACCGTGACCCACTCTGTCAACCTGCTCGAAGACAGCCATAACGGCAAACTGTGTAGA



CTGAAGGGCATTGCACCTTTACAGCTGGGCAAGTGCAATATAGCTGGATGGCTCCTCGGC



AATCCCGAATGCGACCCTCTACTGCCCGTGAGAAGCTGGTCATATATCGTTGAAACCCCG



AATTCCGAGAATGGAATCTGCTATCCCGGAGATTTCATCGACTATGAAGAGCTCAGGGAA



CAGCTGTCCTCTGTATCCTCCTTTGAACGTTTTGAGATTTTCCCAAAGGAGTCATCTTGG



CCTAACCACAACACGAACGGGGTAACCGCAGCCTGCAGTCACGAAGGTAAGAGCAGCTTT



TACAGGAATCTGCTGTGGCTAACCGAGAAAGAGGGCAGTTATCCTAAACTGAAAAATTCA



TATGTGAACAAGAAAGGAAAGGAAGTGCTGGTGCTTTGGGGAATCCACCATCCGCCCAAC



AGCAAGGAGCAGCAGAACCTATACCAGAACGAAAACGCTTATGTGTCAGTGGTGACTAGC



AACTACAACCGACGTTTTACCCCCGAGATTGCCGAGCGACCCAAGGTGAGAGACCAGGCC



GGTCGCATGAACTACTACTGGACACTCCTTAAGCCAGGCGATACAATCATATTTGAAGCT



AACGGGAACCTCATTGCTCCTATGTACGCTTTCGCGCTGTCTAGGGGTTTCGGCTCCGGA



ATAATTACAAGCAATGCTTCCATGCACGAGTGCAATACCAAGTGTCAGACTCCCCTGGGG



GCCATTAACAGCAGTCTGCCATACCAAAATATTCATCCAGTAACAATCGGCGAGTGTCCA



AAGTACGTGCGATCTGCCAAGTTACGAATGGTGACCGGCCTGCGCAATAACCCCTCAATT



CAGTCTAGGGGCTTATTCGGGGCTATCGCCGGCTTCATTGAGGGAGGATGGACAGGAATG



ATCGATGGATGGTACGGCTACCATCACCAGAATGAGCAAGGCAGCGGTTACGCTGCCGAC



CAGAAATCGACACAGAATGCTATCAATGGAATCACTAACAAAGTCAACACGGTGATTGAA



AAGATGAATATCCAATTCACTGCAGTGGGCAAGGAATTCAACAAATTAGAGAAGCGGATG



GAGAACCTGAATAAAAAAGTTGATGACGGTTTCCTGGATATCTGGACATACAATGCAGAA



CTTCTCGTCCTGCTCGAGAACGAGCGAACTCTCGATTTTCACGATTCTAATGTCAAAAAT



CTGTATGAAAAGGTGAAGTCCCAGCTGAAGAACAACGCAAAGGAAATCGGGAATGGATGC



TTCGAGTTTTACCATAAATGTGATAACGAGTGCATGGAAAGCGTCCGAAATGGCACTTAT



GACTATCCAAAATACTCAGAGGAGAGTAAACTTAACCGCGAGAAGGTTGATGGCGTTAAA



CTGGAATCCATGGGCATTTACCAGATCTTGGCTATCTATAGCACGGTGGCTTCTTCGCTG



GTGCTCTTGGTCAGTCTCGGTGCCATCTCATTCTGGATGTGTTCGAACGGATCTCTTCAA



TGCCGAATCTGTATA





460
ATGAAAGCCAACCTTCTAGTTTTACTATGTGCTCTCGCTGCTGCTGACGCCGACACTATT



TGTATTGGATATCACGCAAATAATTCCACAGATACTGTCGACACCGTTTTGGAAAAGAAC



GTGACTGTCACTCACTCAGTCAACCTGCTCGAAGATTCTCACAATGGCAAATTATGCCGC



CTCAAGGGAATCGCTCCGCTCCAATTGGGAAAATGTAACATCGCAGGATGGCTCCTCGGC



AATCCTGAATGCGACCCTCTCCTGCCCGTCCGCTCTTGGTCATACATAGTGGAAACTCCC



AACAGTGAAAATGGAATATGTTACCCCGGTGACTTCATCGACTATGAGGAATTGCGCGAG



CAACTGTCCTCAGTTTCCTCGTTCGAAAGATTTGAGATCTTCCCCAAGGAGTCCTCCTGG



CCCAATCACAATACGAATGGCGTTACGGCAGCCTGCTCTCATGAGGGGAAATCCTCATTC



TACCGCAACCTGCTCTGGCTGACAGAGAAGGAGGGGTCCTACCCTAAGCTCAAAAATTCC



TATGTGAATAAAAAGGGCAAAGAAGTACTGGTCCTGTGGGGCATTCACCATCCCCCAAAT



AGTAAAGAACAACAGAACCTCTACCAGAATGAGAACGCTTACGTGAGTGTGGTCACTAGC



AACTACAACAGGAGATTCACACCCGAGATAGCGGAACGACCCAAGGTCCGCGATCAGGCT



GGTCGCATGAATTACTACTGGACCTTGCTGAAGCCCGGAGATACGATTATTTTTGAGGCC



AATGGCAATCTTATCGCCCCAATGTACGCCTTTGCACTCAGCCGTGGGTTCGGAAGTGGA



ATCATAACTTCAAATGCCTCCATGCATGAGTGCAATACAAAATGTCAGACCCCTCTCGGA



GCCATCAACTCATCACTGCCATACCAGAATATTCACCCTGTTACAATTGGAGAGTGTCCA



AAATACGTCAGAAGTGCAAAACTGCGCATGGTTACCGGACTACGTAACAACCCGTCCATC



CAGTCAAGAGGGCTGTTTGGAGCCATCGCAGGATTTATAGAGGGAGGCTGGACCGGGATG



ATTGATGGCTGGTACGGCTACCATCACCAAAATGAGCAGGGAAGTGGGTATGCTGCCGAC



CAGAAATCCACCCAAAACGCGATCAATGGTATCACCAACAAAGTCAATACCGTGATCGAA



AAAATGAACATACAGTTTACAGCAGTGGGAAAGGAATTCAATAAACTTGAGAAACGCATG



GAGAATCTGAATAAAAAGGTCGACGATGGCTTCCTAGATATTTGGACCTACAATGCAGAA



TTACTGGTATTGTTGGAGAATGAGCGGACCCTCGACTTCCATGATTCGAACGTTAAAAAC



CTCTACGAGAAGGTAAAGTCGCAACTGAAAAACAACGCTAAGGAGATCGGGAACGGCTGC



TTCGAATTTTATCACAAATGCGACAACGAATGCATGGAATCAGTGCGAAATGGCACCTAT



GATTATCCAAAGTATTCGGAGGAGTCAAAGCTGAATAGAGAGAAGGTGGATGGTGTGAAG



TTGGAGAGTATGGGGATTTACCAGATCTTAGCAATCTATTCCACGGTTGCTAGTTCCCTC



GTGTTACTTGTGAGCCTGGGTGCGATCAGTTTCTGGATGTGCAGTAACGGTTCACTGCAA



TGCAGAATCTGCATC





461
ATGAAAGCTAATCTCCTGGTTTTGTTGTGTGCACTGGCCGCTGCCGACGCCGACACAATC



TGCATAGGATACCATGCTAACAACAGTACAGATACAGTTGACACCGTGCTGGAAAAGAAT



GTTACTGTAACCCATAGCGTTAACTTGCTAGAGGACTCTCATAATGGAAAGCTCTGTAGG



CTTAAAGGGATCGCCCCCTTACAATTGGGCAAGTGCAATATCGCCGGATGGCTGCTCGGG



AACCCTGAGTGTGATCCATTGCTGCCAGTTCGTTCCTGGTCTTACATAGTTGAAACGCCA



AACTCCGAGAACGGGATCTGTTACCCAGGTGACTTCATTGATTACGAAGAACTGAGAGAA



CAGCTAAGTTCTGTGTCTAGCTTCGAGAGATTCGAGATCTTTCCCAAAGAGTCAAGTTGG



CCTAACCACAATACCAACGGGGTTACCGCGGCTTGCTCCCACGAAGGTAAAAGCTCATTC



TACCGGAACCTTTTGTGGCTCACTGAGAAAGAGGGTAGCTACCCAAAGCTCAAGAACTCC



TACGTGAATAAGAAGGGGAAGGAGGTGCTCGTTTTATGGGGTATCCACCACCCCCCTAAT



AGTAAGGAACAGCAAAATCTCTATCAGAACGAAAACGCATATGTCTCGGTGGTGACCTCA



AACTATAATCGGAGATTCACTCCAGAGATCGCCGAGAGACCCAAAGTCCGGGACCAGGCA



GGAAGGATGAACTATTATTGGACTTTACTGAAGCCCGGGGATACTATTATTTTTGAAGCC



AATGGCAATCTTATTGCCCCCATGTACGCTTTCGCCCTGAGTCGCGGCTTCGGGAGTGGC



ATTATTACTTCCAATGCCTCGATGCATGAGTGCAATACGAAGTGTCAGACCCCATTAGGA



GCTATCAATAGCAGCCTGCCATATCAGAACATCCACCCGGTGACTATTGGAGAGTGTCCA



AAGTACGETAGGTCCGCCAAGTTACGGATGGTAACAGGCCTCCGCAATAATCCTTCTATC



CAAAGTCGGGGGCTGTTTGGAGCAATCGCCGGCTTCATCGAGGGAGGTTGGACTGGGATG



ATTGACGGATGGTATGGGTACCATCATCAGAATGAGCAAGGCAGTGGCTACGCAGCCGAC



CAGAAGTCAACCCAAAACGCCATCAATGGAATCACGAATAAAGTGAACACAGTGATCGAG



AAGATGAACATTCAGTTCACTGCAGTGGGGAAGGAATTTAACAAGTTGGAGAAGAGAATG



GAGAACCTGAACAAGAAGGTAGACGATGGATTCCTAGACATATGGACATATAATGCCGAG



CTGTTGGTCCTCCTCGAAAACGAAAGAACACTGGACTTTCATGACAGTAACGTGAAGAAT



TTGTATGAGAAAGTTAAGTCTCAACTGAAAAACAACGCCAAAGAAATAGGGAACGGTTGT



TTCGAGTTCTATCATAAGTGCGATAACGAGTGCATGGAGTCTGTGCGGAATGGCACGTAC



GATTATCCAAAATACTCCGAGGAGTCCAAACTTAACAGAGAGAAAGTGGATGGCGTGAAA



CTTGAAAGCATGGGCATTTACCAAATCCTCGCCATTTACAGCACAGTCGCTTCTAGTCTA



GTACTGCTTGTATCACTCGGCGCCATATCATTCTGGATGTGTAGTAATGGCAGCCTGCAG



TGCCGAATTTGCATT





462
ATGAAAGCCAACCTGCTCGTACTCCTGTGTGCCCTGGCTGCCGCTGACGCCGATACTATT



TGCATAGGGTATCACGCCAATAATTCAACTGACACCGTCGATACCGTTCTTGAGAAGAAC



GTGACCGTCACACATTCAGTTAACCTTCTTGAGGACTCTCATAATGGTAAATTGTGTCGC



CTCAAGGGTATCGCACCGCTACAACTAGGCAAGTTGTAATATAGCAGGGGGTTGTTGGGA



AACCCTGAGTGTGACCCGCTGCTGCCCGTTCGCAGTTGGTCTTACATCGTCGAGACACCA



AACTCTGAGAACGGGATTTGCTATCCAGGGGATTTTATCGACTATGAAGAGCTTCGCGAG



CAGTTGAGCAGTGTTTCCTCTTTTGAGCGTTTTGAAATTTTCCCGAAAGAGAGTAGCTGG



CCTAACCATAACACAAACGGGGTCACCGCAGCTTGCTCTCATGAGGGGAAGTCAAGCTTC



TATCGGAATCTGCTGTGGCTGACGGAAAAAGAAGGCTCGTACCCAAAGCTAAAAAATTCA



TACGTGAACAAGAAGGGGAAAGAGGTCCTGGTCCTGTGGGGGATCCACCATCCACCTAAT



AGTAAAGAGCAGCAAAATTTGTACCAAAACGAGAATGCGTACGTGAGCGTAGTGACATCA



AACTACAACCGCCGCTTCACTCCTGAGATTGCTGAACGGCCCAAGGTGCGTGATCAGGCC



GGCAGGATGAACTATTATTGGACTTTGCTAAAACCTGGGGATACTATAATTTTTGAGGCG



AATGGCAATCTAATCGCACCGATGTATGCCTTCGCCTTGAGCCGGGGCTTCGGCAGTGGG



ATTATTACCAGTAACGCCTCCATGCACGAATGTAACACAAAGTGTCAGACTCCATTAGGG



GCAATCAACTCGTCACTTCCGTATCAAAATATTCACCCTGTGACCATCGGCGAGTGTCCA



AAATACGTTAGAAGTGCCAAGCTGAGAATGGTGACGGGTCTCCGGAACAATCCCTCAATC



CAATCAAGGGGGTTATTTGGCGCTATTGCTGGTTTCATTGAGGGGGGATGGACCGGAATG



ATCGACGGCTGGTACGGATATCATCATCAGAACGAACAGGGGTCCGGCTATGCTGCCGAC



CAGAAGTCCACTCAGAACGCGATCAATGGGATCACCAACAAGGTCAACACCGTCATCGAA



AAGATGAATATTCAGTTTACAGCCGTCGGAAAGGAATTCAATAAGTTGGAGAAACGCATG



GAAAACTTAAACAAGAAAGTGGACGACGGATTCTTAGACATATGGACTTATAACGCAGAG



CTGCTTGTACTCCTGGAGAATGAGCGAACCTTGGATTTTCATGATTCAAACGTTAAGAAC



TTATATGAGAAGGTGAAGTCTCAACTCAAAAACAATGCCAAAGAAATCGGGAATGGGTGC



TTCGAATTCTATCATAAATGTGATAACGAGTGTATGGAGAGCGTGCGGAATGGAACTTAT



GACTACCCCAAATACAGCGAAGAAAGCAAGTTGAACAGAGAGAAGGTGGATGGCGTGAAG



CTGGAAAGCATGGGGATTTACCAGATTCTTGCAATCTATTCTACTGTTGCATCCAGTCTA



GTTCTGCTCGTCTCTCTGGGGGCAATCAGCTTTTGGATGTGCTCTAATGGTTCCCTGCAG



TGCCGTATCTGCATA





463
ATGAAAGCAAACCTTCTGGTACTGCTCTGCGCCTTAGCCGCCGCTGATGCGGACACGATT



TGTATTGGCTATCACGCCAATAATTCAACAGATACTGTCGACACAGTCTTGGAGAAAAAT



GTGACTGTAACCCATTCTGTCAATCTGCTCGAGGATTCACACAATGGAAAACTGTGTCGG



CTTAAAGGAATCGCTCCTCTGCAGTTGGGCAAGTGTAATATAGCTGGCTGGCTGTTAGGA



AACCCAGAATGCGATCCTCTCTTACCTGTGCGATCCTGGTCTTACATCGTTGAGACACCG



AACAGCGAGAATGGTATATGCTACCCGGGTGACTTTATCGATTATGAAGAATTGAGAGAA



CAGCTGTCAAGCGTCAGCTCTTTCGAACGATTCGAGATCTTTCCCAAAGAGTCAAGCTGG



CCTAACCACAATACAAATGGAGTGACAGCTGCGTGTTCCCATGAAGGCAAGAGTTCTTTC



TACCGAAACCTGCTTTGGCTGACCGAGAAGGAGGGATCATACCCTAAGTTAAAAAATTCA



TACGTCAACAAGAAGGGAAAAGAGGTACTAGTTCTTTGGGGTATTCACCACCCACCCAAC



TCCAAAGAGCAGCAGAATCTGTATCAAAATGAAAACGCGTACGTCTCCGTGGTGACCTCG



AACTACAATCGACGATTCACTCCCGAAATCGCTGAGAGGCCCAAAGTCCGGGATCAGGCC



GGACGCATGAATTATTACTGGACTCTACTAAAGCCAGGTGATACAATTATCTTCGAAGCC



AATGGCAATCTTATCGCTCCCATGTACGCATTCGCTCTGAGCCGTGGTTTTGGGTCTGGA



ATCATCACCTCCAACGCTTCTATGCATGAATGTAATACAAAATGCCAGACTCCGTTAGGG



GCAATCAACAGTTCACTGCCATACCAAAACATCCACCCCGTGACTATTGGGGAGTGCCCA



AAGTATGTCCGGAGCGCCAAACTCCGGATGGTCACCGGCCTACGCAATAACCCCAGTATC



CAGTCTAGGGGATTGTTCGGTGCTATCGCAGGTTTTATTGAGGGCGGCTGGACAGGAATG



ATCGACGGATGGTATGGGTATCATCACCAGAATGAACAAGGCTCCGGGTATGCGGCTGAC



CAAAAATCCACGCAGAACGCAATCAACGGAATCACCAATAAAGTGAATACTGTGATAGAA



AAGATGAACATTCAGTTCACGGCTGTAGGCAAGGAGTTCAATAAGCTGGAGAAGAGAATG



GAGAACCTAAATAAGAAGGTCGATGACGGCTTCCTTGACATCTGGACTTACAATGCAGAA



CTGCTGGTACTGCTTGAGAACGAACGCACCCTGGATTTCCACGACTCTAATGTGAAGAAC



CTATACGAAAAAGTGAAGTCCCAGCTGAAAAACAATGCTAAAGAGATAGGCAACGGCTGC



TTCGAATTCTATCATAAATGCGACAACGAGTGCATGGAGTCAGTCCGAAATGGTACGTAC



GATTACCCAAAATATTCTGAAGAGTCCAAGCTAAATAGAGAAAAGGTGGACGGCGTAAAA



CTCGAGTCCATGGGCATCTACCAGATTCTGGCCATCTACAGTACGGTGGCTTCATCGCTT



GTACTCCTGGTGAGCCTAGGGGCCATCTCTTTTTGGATGTGTTCTAACGGTTCCCTGCAG



TGCCGCATTTGTATT





464
ATGAAAGCTAACCTGCTGGTACTCTTATGCGCTCTGGCCGCTGCAGACGCCGATACCATC



TGTATCGGGTATCATGCCAACAATAGCACCGACACCGTGGATACAGTCCTAGAAAAGAAT



GTGACCGTCACTCACTCAGTGAACCTATTAGAAGATTCCCACAACGGCAAGTTGTGTCGC



CTCAAAGGCATCGCCCCACTGCAACTTGGGAAATGCAACATAGCCGGGTGGCTGCTGGGC



AACCCAGAGTGCGATCCCCTGTTGCCAGTGCGCAGTTGGTCATATATCGTGGAGACTCCA



AATTCAGAAAATGGGATTTGCTATCCAGGGGACTTCATCGACTACGAAGAACTGCGCGAA



CAGCTGTCCAGCGTGAGTTCCTTCGAACGATTTGAAATTTTCCCAAAGGAGAGCAGCTGG



CCTAACCACAACACGAACGGAGTGACTGCCGCTTGCAGCCACGAGGGAAAGAGCTCTTTC



TACCGCAACCTTCTGTGGTTGACAGAGAAGGAAGGGAGCTACCCCAAACTGAAGAACTCC



TACGTTAATAAGAAAGGTAAGGAAGTGCTAGTGCTCTGGGGTATCCATCATCCACCAAAT



AGCAAAGAGCAACAGAATCTGTATCAGAACGAGAACGCTTACGTGTCAGTTGTCACTTCC



AACTATAACCGCCGGTTCACTCCAGAGATCGCTGAGCGCCCCAAGGTGCGCGATCAGGCT



GGCCGCATGAACTATTACTGGACCTTGCTGAAGCCAGGGGACACAATTATCTTTGAGGCC



AATGGAAATCTCATCGCACCGATGTACGCCTTTGCCCTTTCCCGGGGCTTCGGGTCTGGC



ATCATTACCTCGAATGCTTCGATGCACGAGTGCAACACCAAGTGCCAAACTCCCTTGGGA



GCTATTAATTCTTCACTCCCATACCAGAATATTCACCCAGTTACAATCGGCGAGTGTCCA



AAGTACGTGCGTTCCGCAAAACTGCGGATGGTTACAGGTCTGCGAAACAATCCAAGTATA



CAGAGTAGAGGACTTTTTGGAGCTATTGCCGGATTCATAGAAGGGGGCTGGACCGGAATG



ATTGACGGTTGGTACGGCTACCACCATCAAAACGAACAGGGGTCCGGATACGCCGCAGAC



CAAAAAAGTACCCAAAATGCTATTAATGGCATAACCAATAAAGTCAACACGGTCATTGAA



AAGATGAACATCCAGTTCACTGCTGTGGGAAAGGAGTTCAATAAGCTGGAGAAACGAATG



GAGAACCTCAACAAAAAAGTAGATGACGGCTTTTTGGACATCTGGACCTACAATGCAGAG



CTTCTGGTGCTATTAGAGAACGAACGTACATTAGACTTTCACGACTCCAACGTCAAAAAC



CTGTATGAGAAGGTGAAATCCCAGCTTAAGAATAACGCAAAGGAAATCGGGAACGGCTGC



TTTGAATTCTATCACAAGTGTGACAATGAGTGTATGGAGAGCGTGCGCAATGGGACCTAC



GACTATCCTAAGTACTCAGAAGAGTCTAAACTGAACCGTGAAAAGGTCGACGGCGTTAAG



CTGGAGTCTATGGGGATCTATCAGATCCTTGCAATTTATTCCACCGTGGCGTCTTCCTTG



GTTTTGCTAGTGAGTTTAGGTGCTATCAGTTTCTGGATGTGCTCCAATGGCTCCCTGCAA



TGTAGGATCTGCATT





465
ATGAAGGCCAACCTCCTGGTCTTGCTGTGCGCCCTGGCTGCTGCCGATGCAGATACCATT



TGCATCGGCTATCACGCCAACAATTCTACAGATACCGTGGATACAGTACTCGAAAAAAAT



GTTACTGTGACGCACTCAGTCAACCTGTTGGAAGACTCGCACAATGGCAAACTGTGCAGG



CTGAAAGGCATTGCCCCCCTACAGCTGGGGAAGTGCAACATTGCAGGCTGGCTGTTGGGA



AACCCTGAATGTGATCCATTGCTCCCAGTGCGGTCCTGGTCTTACATCGTGGAGACACCA



AACAGCGAGAATGGGATGTGTTACCCTGGCGATTTTATAGACTACGAGGAGCTCAGGGAG



CAGCTCAGCTCTGTGTCGTCTTTCGAGCGCTTTGAGATTTTTCCTAAGGAGTCCTCCTGG



CCAAACCACAACACGAATGGAGTGACAGCCGCCTGTAGCCACGAGGGCAAGTCCTCATTC



TATAGAAACTTGCTTTGGCTAACTGAAAAGGAGGGCAGCTACCCTAAACTGAAAAATAGC



TATGTGAACAAAAAAGGCAAAGAAGTGCTCGTCCTGTGGGGGATCCATCATCCTCCTAAC



TCAAAGGAGCAGCAGAACCTGTATCAGAATGAAAACGCTTACGTGTCTGTCGTGACTTCA



AATTATAACCGGAGGTTCACTCCCGAAATTGCCGAGAGACCAAAGGTCAGGGACCAGGCA



GGCCGCATGAATTACTATTGGACACTTCTGAAACCAGGCGACACAATTATTTTCGAGGCA



AACGGGAACCTTATAGCCCCAATGTACGCCTTCGCACTATCAAGAGGCTTCGGTTCCGGC



ATCATTACAAGCAACGCGAGCATGCATGAATGCAACACCAAGTGCCAAACCCCACTGGGT



GCAATTAATAGTTCCCTGCCATATCAGAATATCCACCCGGTGACAATTGGAGAGTGCCCT



AAGTACGTGAGGAGCGCTAAGTTAAGAATGGTGACGGGACTGAGAAACAACCCTTCCATT



CAGTCCCGAGGACTTTTTGGAGCAATCGCCGGCTTTATTGAGGGGGGCTGGACGGGGATG



ATTGATGGCTGGTATGGGTATCACCACCAGAATGAACAGGGAAGTGGGTACGCTGCTGAT



CAGAAGTCAACTCAGAATGCCATCAACGGGATAACAAATAAGGTAAATACTGTGATTGAA



AAAATGAATATCCAGTTCACTGCCGTTGGGAAGGAGTTTAACAAGCTTGAGAAAAGGATG



GAAAACCTGAATAAGAAGGTAGATGACGGATTCCTCGATATATGGACCTACAACGCTGAG



CTGCTGGTTTTGCTAGAGAACGAAAGAACTTTGGATTTTCATGATTCTAACGTGAAGAAC



TTGTACGAAAAAGTGAAAAGTCAGCTTAAAAACAACGCAAAGGAGATTGGGAATGGCTGC



TTTGAGTTTTATCACAAGTGCGACAATGAATGTATGGAGAGCGTGAGGAACGGCACGTAT



GACTACCCCAAGTACAGTGAGGAATCCAAGCTGAACCGAGAAAAGGTCGACGGCGTGAAG



CTGGAGTCTATGGGAATCTATCAGATTCTCGCAATTTACTCAACTGTCGCATCATCCCTA



GTGCTCCTGGTGAGCCTGGGAGCCATTTCTTTCTGGATGTGTAGCAATGGTAGTTTACAA



TGCAGAATCTGTATT





466
ATGAAGGCAAATCTGCTGGTCTTACTGTGCGCTCTGGCCGCTGCTGATGCTGATACAATC



TGTATTGGCTACCACGCCAATAACTCCACTGATACAGTGGATACTGTGCTGGAAAAAAAT



GTTACAGTCACACATTCAGTGAACCTCCTAGAAGACAGCCATAACGGAAAACTCTGCCGG



CTGAAAGGTATCGCACCTTTGCAGCTAGGAAAGTGCAATATTGCGGGCTGGCTGCTTGGT



AATCCCGAGTGCGACCCACTCTTACCAGTGAGAAGTTGGAGCTATATCGTAGAGACCCCC



AACTCTGAGAATGGAATCTGTTATCCAGGCGACTTTATTGATTACGAGGAACTGCGCGAG



CAACTCTCTTCTGTGTCTTCATTCGAGAGGTTTGAAATCTTCCCTAAGGAGTCGTCTTGG



CCTAATCACAATACCAACGGGGTGACCGCCGCTTGCAGCCACGAGGGGAAGAGTTCTTTT



TACCGAAATCTTCTGTGGCTAACAGAAAAGGAAGGATCATACCCAAAATTAAAGAATAGC



TATGTAAACAAGAAGGGTAAGGAGGTTCTTGTCTTATGGGGCATACATCATCCCCCCAAC



TCTAAGGAACAACAGAATCTATATCAGAACGAGAATGCTTACGTGAGTGTGGTGACCAGT



AATTATAATAGAAGATTCACTCCTGAGATTGCCGAAAGGCCTAAAGTGCGCGACCAAGCG



GGACGGATGAACTACTACTGGACCTTGCTCAAGCCGGGTGACACAATTATTTTTGAAGCA



AATGGTAATCTCATTGCACCAATGTATGCGTTTGCCCTGAGTCGTGGATTTGGCAGCGGA



ATAATAACTTCAAACGCCAGCATGCACGAATGCAATACTAAATGTCAGACCCCACTGGGG



GCAATCAACTCCTCACTGCCATATCAGAACATCCACCCCGTGACCATTGGTGAGTGCCCT



AAGTATGTTAGATCAGCGAAGCTTCGGATGGTAACAGGACTTAGAAATAATCCGAGCATT



CAAAGCCGCGGGCTGTTTGGAGCCATTGCAGGGTTTATCGAAGGGGGTTGGACCGGCATG



ATTGATGGCTGGTATGGATACCACCATCAGAACGAACAAGGCAGCGGGTATGCAGCTGAC



CAAAAGTCTACCCAGAACGCCATCAATGGAATCACGAACAAGGTTAATACAGTGATTGAG



AAGATGAATATTCAGTTTACAGCCGTTGGCAAGGAGTTCAACAAGCTGGAGAAGCGAATG



GAGAACTTAAATAAAAAGGTCGACGACGGCTTCCTGGACATTTGGACATACAACGCTGAA



CTGTTGGTGCTTCTCGAGAATGAACGAACTTTAGATTTTCACGATAGCAACGTTAAAAAC



TTATATGAGAAAGTGAAGTCTCAGCTCAAGAATAATGCCAAGGAGATAGGTAATGGTTGC



TTCGAATTCTATCACAAGTGTGACAACGAATGCATGGAGAGTGTTAGAAACGGTACATAC



GATTATCCCAAGTATAGTGAGGAGTCCAAACTCAATAGGGAAAAGGTGGACGGGGTGAAG



CTCGAGAGCATGGGCATTTATCAGATCCTTGCAATATACTCAACCGTAGCATCTTCTCTC



GTTCTTCTGGTGTCCCTGGGCGCTATTTCTTTTTGGATGTGCAGTAATGGCAGCCTTCAA



TGTAGAATTTGCATC





467
ATGAAGGCCAATCTCCTGGTGCTTCTATGTGCACTGGCCGCGGCCGATGCCGACACCATT



TGCATTGGCTATCACGCCAATAATTCCACTGACACAGTTGATACCGTGCTCGAAAAAAAC



GTAACCGTGACCCATTCCGTTAACCTGCTTGAGGATTCTCACAACGGGAAACTCTGCAGA



CTGAAGGGCATCGCCCCCCTGCAGCTGGGAAAATGCAATATTGCCGGCTGGCTCTTAGGT



AACCCAGAATGTGATCCATTACTGCCGGTCAGAAGCTGGAGCTACATCGTGGAAACCCCC



AACTCTGAGAATGGAATCTGTTATCCCGGAGATTTTATTGATTACGAGGAGCTCCGCGAA



CAGCTATCCTCTGTATCTTCTTTTGAGAGATTCGAGATTTTCCCCAAGGAGAGCAGCTGG



CCAAACCACAACACTAATGGTGTCACCGCCGCCTGCTCCCATGAAGGAAAGTCCAGCTTT



TATCGGAACTTACTGTGGCTGACAGAGAAGGAGGGCTCTTACCCCAAGCTGAAGAACAGC



TATGTCAATAAAAAGGGCAAGGAAGTCCTAGTGTTGTGGGGGATCCACCATCCACCTAAC



AGCAAAGAGCAGCAGAACCTCTACCAGAATGAGAATGCGTACGTTTCTGTGGTGACTTCA



AACTATAACCGCCGATTCACACCCGAGATCGCAGAGAGACCTAAAGTCAGGGACCAAGCG



GGGAGAATGAACTACTACTGGACCCTCTTGAAGCCCGGCGATACCATTATTTTTGAGGCT



AACGGCAACCTGATCGCCCCCATGTATGCATTCGCTCTGAGCCGTGGCTTCGGATCTGGT



ATTATAACCTCAAACGCAAGCATGCATGAATGTAACACCAAATGCCAGACCCCCCTGGGG



GCCATCAACAGCAGTCTGCCATACCAGAACATCCACCCTGTCACCATTGGTGAATGCCCC



AAGTATGTCCGATCAGCGAAACTGCGGATGGTCACGGGGCTGCGAAACAATCCTTCAATC



CAGAGCCGAGGACTTTTTGGAGCTATCGCCGGATTCATTGAAGGCGGCTGGACAGGGATG



ATCGACGGTTGGTACGGGTATCACCACCAGAACGAGCAAGGCAGTGGCTACGCAGCTGAC



CAGAAATCCACCCAAAACGCCATTAACGGGATCACTAACAAAGTGAACACGGTCATCGAG



AAGATGAATATTCAATTCACTGCCGTTGGCAAAGAGTTTAATAAGTTGGAAAAGCGCATG



GAGAATCTAAACAAAAAGGTTGACGATGGTTTCTTGGATATCTGGACATATAATGCCGAG



CTGTTAGTCCTGTTAGAAAACGAGAGAACCCTTGATTTTCATGATAGCAACGTCAAAAAC



TTATACGAGAAGGTGAAAAGCCAGCTTAAAAATAATGCCAAAGAGATAGGAAATGGCTGT



TTTGAGTTCTATCATAAGTGCGATAACGAGTGCATGGAGTCCGTTCGGAATGGTACCTAC



GATTACCCGAAGTACTCTGAGGAGAGCAAGTTGAATCGGGAGAAAGTTGATGGCGTCAAG



CTCGAATCCATGGGTATCTACCAGATATTAGCTATTTACTCCACAGTCGCATCTAGCCTG



GTCCTGCTGGTTTCGCTGGGCGCCATATCTTTTTGGATGTGTTCTAATGGCAGCTTACAA



TGCAGGATTTGTATC





468
ATGAAAGCCAACCTCCTCGTGTTGCTGTGCGCTTTGGCCGCTGCCGACGCCGACACCATC



TGTATAGGCTATCATGCGAATAATAGCACCGACACAGTAGATACCGTTCTGGAGAAGAAC



GTGACCGTGACTCACAGCGTGAATCTGTTGGAGGACTCCCATAATGGGAAGCTGTGTAGA



TTGAAAGGTATTGCACCGCTACAACTCGGGAAGTGCAATATCGCCGGGTGGCTGCTTGGT



AACCCCGAGTGTGACCCACTGCTGCCAGTTCGTTCTTGGAGTTACATCGTGGAGACTCCT



AATAGCGAGAATGGTATCTGCTACCCTGGGGACTTCATCGATTATGAGGAGCTCAGAGAG



CAGTTGAGTTCCGTGTCATCATTTGAGCGGTTTGAGATTTTTCCAAAGGAAAGTTCGTGG



CCGAACCATAACACTAACGGAGTCACCGCCGCCTGTAGTCACGAGGGCAAATCTTCTTTT



TACCGGAATTTGCTGTGGCTTACAGAAAAAGAGGGCTCCTATCCGAAGCTGAAGAACTCT



TATGTGAATAAAAAAGGAAAGGAAGTCCTAGTGCTGTGGGGAATCCATCATCCTCCAAAT



AGTAAGGAGCAGCAGAACCTATATCAGAACGAGAACGCATACGTGTCCGTGGTCACGTCA



AACTACAACCGGAGGTTCACTCCCGAGATCGCCGAAAGGCCTAAGGTTCGGGATCAGGCT



GGGCGCATGAACTACTACTGGACTTTACTGAAACCAGGAGACACCATTATCTTCGAGGCT



AACGGCAATCTCATAGCTCCGATGTACGCCTTTGCCTTGAGTCGCGGATTCGGAAGTGGT



ATCATTACTAGCAATGCCTCAATGCATGAGTGTAACACAAAATGCCAGACCCCCTTGGGA



GCAATTAACTCATCTCTACCATATCAGAACATCCACCCTGTCACTATAGGGGAGTGTCCC



AAGTATGTCAGATCCGCCAAGTTGCGGATGGTAACCGGGCTGCGGAATAACCCCTCCATC



CAGTCCCGTGGCCTTTTTGGCGCCATTGCGGGATTTATTGAGGGAGGCTGGACGGGCATG



ATTGATGGCTGGTATGGTTATCACCACCAGAATGAACAGGGGTCTGGTTATGCTGCCGAC



CAGAAGAGTACCCAAAACGCCATCAATGGAATTACAAACAAGGTGAATACAGTGATCGAA



AAAATGAACATCCAGTTTACTGCAGTTGGTAAAGAATTCAACAAACTAGAAAAGCGGATG



GAGAACCTCAACAAGAAGGTCGATGACGGCTTTCTGGACATCTGGACATACAACGCCGAA



CTTCTAGTGCTTCTGGAGAATGAGCGCACACTGGATTTTCACGACTCAAATGTTAAGAAC



CTCTACGAAAAGGTGAAGTCCCAGCTCAAAAACAACGCCAAGGAGATTGGCAATGGCTGT



TTTGAATTTTACCACAAATGCGACAATGAATGTATGGAGTCCGTCCGGAATGGCACCTAT



GACTATCCAAAGTATTCTGAGGAATCCAAGCTGAATCGGGAAAAAGTGGATGGTGTGAAA



CTTGAGTCAATGGGAATTTATCAGATCCTGGCCATTTACAGTACGGTGGCCTCCTCACTG



GTGCTACTGGTAAGTCTGGGAGCAATTTCATTCTGGATGTGCTCCAATGGTTCACTGCAG



TGCAGAATCTGCATA





469
ATGAAGGCTAACCTGCTGGTACTTCTGTGTGCGCTCGCGGCAGCTGATGCCGACACGATC



TGTATTGGATATCATGCGAACAATAGCACAGACACCGTGGATACAGTTCTGGAAAAGAAC



GTGACTGTCACGCACTCCGTCAACTTACTAGAGGACTCTCACAACGGGAAGCTCTGCAGA



CTGAAGGGAATTGCACCCTTGCAGCTGGGTAAGTGTAACATCGCTGGATGGCTACTTGGT



AACCCCGAGTGTGACCCTCTCCTGCCCGTGCGGTCCTGGAGCTACATAGTTGAGACACCA



AACTCTGAGAACGGGATCTGCTATCCTGGGGACTTCATTGACTACGAGGAGCTGCGGGAG



CAGCTCTCCTCCGTCTCGTCTTTCGAAAGGTTCGAGATTTTCCCAAAAGAATCAAGTTGG



CCCAACCACAACACAAATGGTGTTACCGCCGCCTGTAGCCATGAAGGGAAATCAAGCTTC



TACCGTAATCTGCTTTGGCTTACCGAAAAAGAAGGAAGCTACCCTAAGTTAAAAAACTCT



TATGTCAACAAAAAAGGGAAAGAAGTTTTGGTGCTGTGGGGCATCCACCACCCTCCTAAT



TCGAAAGAACAGCAGAACTTGTATCAGAACGAAAATGCCTACGTGTCCGTGGTGACCAGT



AACTACAACCGACGGTTCACCCCGGAGATAGCAGAGAGGCCAAAAGTCAGAGATCAGGCT



GGCAGAATGAACTATTACTGGACCCTCCTAAAACCCGGAGACACTATTATATTTGAGGCA



AATGGTAATCTGATCGCTCCAATGTATGCTTTCGCCCTCTCCCGCGGATTCGGGTCAGGG



ATAATCACCTCTAACGCTTCTATGCACGAATGTAACACCAAGTGCCAAACTCCCCTTGGA



GCCATCAACAGTTCTCTACCATACCAGAATATCCATCCAGTGACGATCGGCGAATGCCCT



AAATACGTCAGAAGTGCTAAGCTAAGAATGGTTACTGGGCTGAGAAATAATCCGTCCATT



CAGAGCAGGGGGCTGTTTGGAGCGATCGCTGGATTTATTGAAGGAGGTTGGACCGGGATG



ATCGATGGCTGGTACGGTTATCACCATCAAAATGAGCAGGGAAGCGGATACGCCGCAGAC



CAGAAAAGCACACAGAACGCTATTAACGGAATCACTAATAAGGTGAATACTGTCATCGAG



AAAATGAACATTCAGTTCACAGCAGTGGGCAAAGAGTTTAACAAGCTTGAAAAGAGGATG



GAGAATCTCAACAAGAAGGTGGATGACGGCTTCCTCGACATCTGGACTTATAACGCCGAG



CTCCTCGTCCTGCTCGAAAATGAAAGGACTTTGGACTTCCACGATTCAAACGTGAAGAAT



TTGTACGAAAAGGTGAAGTCCCAGCTGAAAAACAACGCTAAGGAGATAGGGAATGGCTGT



TTCGAATTCTACCACAAGTGCGACAATGAGTGCATGGAGAGTGTTAGAAATGGGACGTAT



GACTATCCTAAGTATTCGGAGGAATCAAAGTTGAATCGAGAGAAGGTGGACGGTGTGAAG



TTAGAGTCGATGGGCATCTACCAGATTCTGGCTATCTATTCCACCGTGGCTAGCAGCTTG



GTCCTCCTCGTATCATTGGGCGCAATTAGCTTCTGGATGTGCTCCAACGGTTCCCTTCAG



TGCAGAATCTGTATC





470
ATGAAAGCAAATCTGCTGGTGCTGTTGTGCGCGCTGGCGGCTGCTGACGCAGACACCATT



TGCATCGGCTACCACGCCAACAACAGTACTGATACTGTGGACACAGTTTTAGAAAAGAAT



GTGACCGTAACACATAGCGTAAACTTGCTGGAAGACAGTCACAATGGAAAACTCTGCCGG



CTGAAGGGAATCGCCCCTCTACAGCTCGGCAAATGCAATATCGCCGGGTGGCTATTGGGG



AATCCAGAGTGCGACCCACTTCTGCCTGTGCGCAGTTGGTCATATATCGTGGAAACACCA



AACTCCGAAAACGGCATTTGCTATCCTGGAGACTTTATTGACTACGAAGAGCTAAGAGAG



CAGCTGAGCTCCGTGTCCAGTTTTGAGCGATTTGAGATCTTCCCAAAGGAGAGCTCTTGG



CCAAATCACAATACCAACGGAGTGACCGCGGCTTGTTCTCACGAGGGTAAATCCTCCTTT



TATAGGAACCTGCTGTGGCTGACCGAGAAAGAGGGATCTTACCCAAAACTTAAGAACAGC



TATGTTAACAAGAAGGGAAAAGAAGTGCTTGTGCTGTGGGGTATTCACCACCCTCCTAAT



TCCAAGGAGCAGCAGAATCTGTATCAGAATGAGAATGCCTACGTCAGCGTGGTCACCTCA



AATTATAACAGACGGTTCACCCCAGAGATTGCGGAGCGTCCCAAGGTAAGGGACCAAGCC



GGACGCATGAACTATTATTGGACTCTGCTGAAACCTGGTGATACTATCATCTTTGAGGCC



AATGGCAATCTTATCGCCCCTATGTATGCATTTGCCCTATCTCGCGGATTTGGGAGCGGC



ATCATCACAAGTAATGCCAGCATGCACGAATGTAATACCAAATGCCAGACACCTCTGGGC



GCTATCAACAGCAGCCTGCCTTATCAGAATATACACCCTGTCACCATCGGGGAATGCCCT



AAATATGTTCGCAGTGCCAAACTTCGTATGGTGACTGGGCTGCGCAACAACCCATCAATT



CAGAGCAGGGGCCTGTTCGGAGCGATTGCCGGGTTTATCGAGGGAGGGTGGACGGGCATG



ATAGATGGCTGGTACGGATACCACCATCAAAATGAACAGGGCAGTGGCTACGCAGCGGAC



CAGAAATCCACCCAGAATGCTATAAACGGTATCACAAATAAGGTGAATACAGTCATCGAA



AAGATGAATATTCAGTTCACTGCGGTCGGTAAGGAGTTCAACAAACTGGAGAAGAGGATG



GAAAATCTTAACAAAAAAGTGGACGACGGCTTCCTGGATATATGGACGTATAATGCAGAA



CTGTTAGTGTTACTCGAGAATGAGAGGACTCTCGACTTCCATGATTCCAACGTGAAGAAT



CTCTATGAGAAGGTGAAATCCCAACTGAAGAACAACGCCAAAGAGATAGGGAATGGATGC



TTCGAATTCTACCATAAGTGTGATAACGAGTGTATGGAGTCTGTGCGGAATGGCACTTAC



GACTATCCGAAATACAGTGAGGAGTCAAAGTTGAACCGGGAGAAGGTCGATGGCGTCAAG



CTGGAGAGTATGGGAATCTATCAGATCCTCGCAATTTACTCAACCGTGGCTAGCTCCCTG



GTACTCCTGGTCTCACTTGGAGCCATCTCCTTCTGGATGTGCAGCAACGGCAGCCTTCAG



TGCAGAATCTGCATT





471
ATGAAGGCCAATCTTTTAGTGCTGTTGTGTGCACTGGCGGCAGCTGATGCTGACACCATC



TGCATCGGATACCACGCCAATAACAGCACTGACACAGTTGACACTGTTCTGGAAAAAAAC



GTGACGGTGACCCACTCCGTCAATCTTCTGGAGGACTCCCACAACGGGAAGCTGTGTAGG



TTGAAGGGTATCGCCCCGTTGCAGCTGGGCAAATGCAACATCGCGGGTTGGCTGCTTGGC



AATCCTGAGTGCGATCCACTGCTACCCGTACGGTCTTGGTCATATATCGTTGAGACCCCA



AATAGCGAGAATGGCATCTGTTATCCTGGCGATTTCATCGACTACGAAGAGCTGCGAGAA



CAACTGAGTTCGGTGTCTAGTTTCGAGAGGTTTGAGATCTTCCCAAAAGAAAGTTCCTGG



CCTAACCACAATACCAACGGGGTAACGGCCGCTTGTAGCCACGAGGGCAAATCAAGCTTT



TACAGAAATCTGCTGTGGCTCACAGAAAAAGAAGGGAGCTATCCTAAATTAAAGAATTCA



TACGTGAACAAAAAAGGAAAGGAAGTACTCGTCCTGTGGGGAATTCACCACCCTCCAAAT



TCTAAAGAACAACAGAACTTGTACCAGAATGAAAACGCCTATGTATCCGTGGTTACCTCA



AACTACAATCGGCGGTTCACCCCCGAAATAGCTGAGAGACCGAAGGTTCGGGACCAAGCG



GGAAGAATGAACTATTACTGGACTCTCCTTAAGCCCGGTGATACTATCATCTTTGAAGCC



AACGGAAACCTTATCGCCCCAATGTATGCCTTCGCGTTATCCCGCGGGTTTGGAAGCGGT



ATTATTACTTCAAACGCGAGCATGCACGAATGTAATACTAAATGTCAGACACCCCTTGGC



GCCATCAATAGCAGTCTGCCATACCAAAATATTCACCCCGTGACAATTGGCGAGTGTCCA



AAATATGTTAGAAGCGCCAAACTCAGAATGGTTACTGGCTTGCGGAATAACCCGTCCATT



CAGTCCAGAGGGTTATTTGGGGCAATCGCCGGCTTTATAGAAGGGGGCTGGACTGGAATG



ATCGACGGTTGGTACGGATATCATCACCAGAATGAACAGGGATCAGGATATGCCGCGGAC



CAAAAGTCTACCCAGAACGCCATCAACGGCATCACTAATAAGGTCAACACTGTGATTGAG



AAGATGAATATTCAGTTCACCGCAGTCGGCAAGGAATTCAACAAACTCGAGAAACGCATG



GAAAACCTTAACAAAAAGGTGGACGATGGGTTTCTGGACATTTGGACCTACAATGCCGAG



CTGCTAGTGCTGCTGGAAAACGAGCGGACTCTTGATTTCCATGACTCTAATGTAAAAAAC



CTTTACGAAAAAGTTAAATCACAACTTAAAAATAATGCCAAAGAAATAGGGAACGGATGT



TTCGAGTTCTACCACAAATGTGATAACGAATGCATGGAGAGTGTTCGCAACGGAACATAT



GACTATCCTAAGTACAGCGAAGAGTCAAAACTAAATCGGGAGAAAGTCGACGGCGTGAAA



CTCGAATCCATGGGGATTTACCAGATCCTCGCAATCTATTCTACCGTGGCTAGCTCGCTG



GTGCTGCTTGTTAGTCTGGGAGCTATCTCCTTTTGGATGTGTAGCAATGGAAGCCTGCAG



TGTAGAATTTGCATA





472
ATGAAGGCCAACCTGCTGGTCCTGCTGTGTGCACTCGCCGCCGCCGATGCCGACACTATT



TGTATTGGCTACCACGCTAACAACTCCACAGATACAGTCGATACTGTGCTGGAAAAGAAT



GTTACCGTCACCCATAGCGTGAACTTGCTCGAGGATTCTCATAATGGGAAACTCTGTCGG



TTAAAGGGGATTGCACCTCTCCAACTGGGCAAGTGTAACATCGCGGGTTGGCTGCTTGGA



AACCCTGAGTGCGATCCTCTACTTCCGGTCAGGTCGTGGAGTTACATTGTCGAGACCCCT



AACTCAGAAAACGGTATCTGTTATCCGGGTGATTTTATCGATTACGAAGAGCTCAGAGAA



CAGCTGTCCAGCGTGTCTTCATTCGAGCGATTCGAAATTTTCCCGAAGGAATCATCTTGG



CCAAATCATAATACTAACGGGGTGACGGCCGCATGTTCACATGAGGGCAAATCCAGCTTC



TACCGAAACCTTTTGTGGTTGACGGAGAAGGAGGGCTCTTATCCCAAGCTGAAAAACAGC



TATGTGAACAAGAAGGGGAAGGAGGTGCTCGTTCTGTGGGGGATCCATCACCCTCCTAAC



AGCAAAGAGCAGCAAAACCTGTATCAGAATGAAAACGCCTATGTGTCCGTGGTGACGAGC



AACTACAACCGGCGCTTTACCCCCGAAATTGCTGAACGGCCGAAGGTGAGGGATCAAGCC



GGCCGGATGAATTATTACTGGACGCTGCTGAAACCTGGTGATACCATCATCTTTGAAGCT



AACGGAAACTTGATCGCTCCAATGTATGCATTCGCCCTGTCACGGGGATTCGGCAGCGGT



ATAATCACCAGTAATGCCTCAATGCACGAATGCAATACCAAGTGCCAAACGCCCCTTGGT



GCCATCAACTCATCTCTGCCCTATCAGAATATCCATCCTGTAACCATCGGAGAGTGTCCC



AAGTATGTCAGATCAGCAAAACTGCGGATGGTCACAGGTCTCCGAAATAATCCCTCAATC



CAGTCTCGCGGCCTGTTCGGCGCTATCGCCGGCTTTATTGAGGGGGGTTGGACCGGGATG



ATCGACGGCTGGTATGGATACCATCATCAGAACGAGCAGGGGAGCGGCTACGCGGCTGAC



CAGAAGTCAACCCAGAATGCTATCAATGGTATCACTAATAAGGTGAATACGGTGATTGAA



AAAATGAACATACAGTTCACCGCAGTGGGTAAAGAGTTCAATAAGCTGGAGAAGCGGATG



GAGAATCTGAACAAAAAGGTCGATGATGGCTTCTTGGACATCTGGACCTATAACGCCGAG



CTTCTTGTGCTGCTCGAGAACGAGAGAACACTGGACTTCCATGACTCTAACGTGAAGAAC



CTCTACGAGAAGGTGAAATCTCAGTTGAAGAACAACGCTAAGGAGATCGGCAATGGCTGC



TTCGAATTCTACCACAAGTGCGATAACGAATGCATGGAATCTGTTCGAAATGGAACTTAC



GATTACCCTAAATACAGCGAGGAAAGTAAGTTAAACAGAGAGAAAGTAGACGGGGTTAAG



CTCGAAAGCATGGGGATCTATCAGATCCTAGCCATCTACTCGACTGTCGCGTCAAGTTTG



GTGCTGCTGGTGTCTCTTGGAGCCATATCGTTTTGGATGTGCTCTAACGGCTCCCTGCAG



TGCAGAATCTGCATA





473
ATGAAGGCCAACTTGCTAGTGCTGCTGTGCGCGCTTGCAGCTGCGGATGCGGATACGATA



TGCATAGGATATCACGCCAATAATTCGACGGATACCGTGGACACAGTGCTGGAAAAGAAT



GTAACGGTCACACACAGCGTGAACCTGCTTGAAGATTCACACAACGGCAAACTGTGCAGG



CTCAAAGGAATCGCACCATTACAGCTGGGGAAATGCAACATTGCGGGGTGGCTGCTAGGA



AACCCAGAGTGCGATCCCCTGCTGCCCGTGCGGTCTTGGTCCTACATTGTAGAGACTCCG



AACTCGGAGAACGGTATTTGCTACCCTGGAGATTTCATTGACTATGAAGAACTCAGGGAG



CAACTGTCCTCAGTTTCGAGCTTTGAAAGGTTCGAGATCTTTCCTAAGGAGTCCAGCTGG



CCTAACCACAATACAAACGGGGTGACCGCGGCCTGTTCACATGAGGGTAAATCTTCATTC



TACCGCAACCTCCTGTGGTTAACCGAAAAAGAAGGAAGCTATCCTAAGCTGAAGAATTCT



TACGTGAATAAAAAGGGTAAGGAAGTTCTGGTGCTGTGGGGCATCCACCACCCACCTAAT



AGTAAGGAACAGCAGAACCTATACCAGAACGAAAATGCGTACGTGAGCGTGGTAACTTCA



AACTATAATCGGAGGTTCACACCCGAAATCGCGGAGCGGCCCAAGGTGCGGGACCAGGCT



GGGCGCATGAATTATTACTGGACACTGTTGAAACCTGGAGACACTATAATCTTCGAGGCG



AACGGAAACTTAATCGCTCCCATGTACGCATTCGCCCTGTCCCGTGGCTTTGGCAGCGGT



ATCATCACATCCAACGCCTCTATGCACGAATGCAATACGAAGTGCCAAACCCCTCTCGGA



GCCATTAATAGCTCCCTCCCATATCAGAACATTCACCCAGTGACCATAGGAGAGTGTCCT



AAGTACGTTCGGAGCGCAAAACTCCGCATGGTGACGGGGTTGCGAAACAACCCTTCCATC



CAGTCGAGGGGCCTTTTCGGGGCGATCGCTGGCTTCATCGAGGGAGGGTGGACCGGGATG



ATTGACGGCTGGTACGGGTATCACCACCAGAACGAGCAGGGTAGCGGCTACGCCGCAGAC



CAGAAATCTACGCAGAATGCCATTAATGGGATTACAAACAAGGTTAATACCGTGATCGAG



AAAATGAACATTCAGTTCACAGCCGTCGGCAAAGAATTTAACAAATTAGAGAAGCGGATG



GAGAATCTGAATAAAAAAGTGGACGATGGATTCCTGGATATCTGGACGTATAATGCCGAG



TTGCTCGTCCTTCTGGAAAACGAGAGAACCCTGGACTTTCACGATTCAAATGTAAAGAAC



CTTTACGAAAAGGTGAAGTCTCAACTGAAAAACAACGCCAAGGAGATAGGGAATGGCTGC



TTTGAATTCTACCATAAATGCGACAATGAATGTATGGAGTCTGTTAGGAATGGTACTTAC



GACTACCCGAAGTATTCCGAAGAGAGCAAGCTGAATAGGGAGAAGGTGGATGGAGTGAAA



CTGGAATCTATGGGGATTTATCAGATCCTAGCTATTTATTCTACAGTAGCCAGCTCCCTC



GTCCTTCTGGTCTCCCTGGGCGCAATTTCATTTTGGATGTGCAGCAACGGGTCCTTACAA



TGCCGCATCTGTATT





474
ATGAAGGCTAACCTGCTTGTGTTATTGTGCGCCCTGGCGGCAGCAGACGCAGATACCATA



TGTATCGGGTATCACGCTAATAATAGCACTGACACCGTTGACACCGTCCTGGAAAAAAAC



GTGACCGTGACTCATTCAGTTAATCTTTTGGAGGACAGCCATAATGGCAAGCTTTGTAGA



CTCAAGGGCATCGCACCTTTACAGTTGGGTAAGTGCAACATCGCAGGATGGCTCCTTGGC



AACCCTGAATGTGACCCGCTGCTCCCAGTCCGGAGTTGGTCATATATCGTAGAAACTCCC



AATAGCGAAAACGGCATTTGCTACCCAGGCGACTTTATAGATTACGAAGAGCTCCGGGAG



CAGCTATCAAGTGTCTCGTCGTTTGAGCGTTTTGAGATTTTTCCGAAAGAATCCAGTTGG



CCAAATCACAACACAAACGGTGTAACAGCGGCTTGTTCACACGAGGGTAAAAGTTCTTTC



TACAGAAATTTATTGTGGCTTACAGAGAAAGAAGGCTCTTACCCAAAGCTGAAGAATTCT



TATGTGAACAAGAAGGGTAAGGAGGTGTTAGTACTGTGGGGAATACATCACCCTCCTAAT



AGCAAGGAGCAGCAGAACTTGTATCAGAACGAAAACGCATATGTGTCTGTGGTGACATCC



AATTATAATAGGCGTTTTACTCCCGAAATTGCAGAGCGACCTAAAGTGCGTGACCAGGCA



GGTAGAATGAATTACTACTGGACCCTGTTGAAGCCCGGTGACACCATCATTTTCGAAGCA



AATGGTAACCTGATCGCACCAATGTACGCATTTGCACTGTCCCGCGGATTTGGCTCCGGA



ATCATTACCAGTAATGCCTCTATGCATGAATGTAACACCAAATGCCAGACCCCCCTGGGC



GCCATTAACTCCAGCCTGCCTTATCAGAATATACATCCTGTGACAATAGGTGAGTGCCCC



AAGTACGTGAGATCTGCAAAACTAAGAATGGTCACCGGACTCAGGAACAATCCCTCCATC



CAGAGTAGGGGTCTGTTCGGAGCCATAGCAGGGTTCATTGAAGGTGGATGGACAGGGATG



ATCGATGGATGGTACGGCTACCACCACCAGAATGAGCAGGGCTCTGGCTACGCCGCTGAC



CAGAAATCTACACAGAACGCCATTAATGGCATCACTAACAAAGTGAATACCGTCATTGAG



AAGATGAATATTCAGTTCACTGCCGTTGGCAAGGAATTTAACAAACTGGAGAAGCGGATG



GAGAATCTAAATAAGAAAGTAGACGACGGGTTTCTCGATATTTGGACATATAACGCTGAG



CTTCTAGTCCTACTCGAGAACGAGAGGACCCTCGACTTCCATGATAGCAACGTGAAGAAC



CTATACGAGAAGGTCAAGTCTCAACTGAAGAACAACGCTAAGGAGATCGGAAATGGATGT



TTCGAGTTTTATCACAAGTGTGATAACGAGTGTATGGAGTCTGTAAGGAACGGTACCTAT



GACTACCCAAAATACAGCGAGGAATCAAAGCTCAATCGTGAGAAAGTCGATGGAGTTAAG



CTGGAATCTATGGGGATTTATCAGATCTTAGCTATCTATTCAACCGTTGCTTCCAGCTTA



GTCCTCCTCGTGTCACTGGGGGCTATAAGTTTTTGGATGTGCAGTAATGGCAGTTTGCAG



TGTAGGATCTGCATC





475
ATGAAGGCTAATTTATTGGTGCTGTTGTGTGCACTGGCTGCCGCAGACGCCGACACCATC



TGCATTGGATATCATGCCAACAATTCAACTGATACGGTCGATACGGTGCTTGAGAAAAAT



GTGACAGTTACACACTCTGTGAACCTTCTGGAAGACTCTCATAACGGCAAACTTTGTCGG



TTGAAGGGTATCGCCCCACTGCAGCTTGGTAAGTGCAACATCGCCGGTTGGCTCCTCGGA



AATCCAGAGTGTGATCCACTGTTACCTGTGCGTAGTTGGAGTTACATCGTGGAGACTCCT



AATAGTGAAAACGGCATATGCTATCCAGGCGATTTCATCGATTATGAAGAACTGCGTGAG



CAGCTGTCCAGCGTGTCCTCATTCGAGCGCTTTGAGATCTTCCCGAAAGAGTCCAGTTGG



CCAAACCACAATACCAATGGGGTCACTGCCGCCTGTAGTCATGAGGGTAAAAGCTCCTTC



TATCGGAATCTTCTCTGGCTGACCGAAAAAGAAGGGTCCTACCCCAAACTTAAGAATTCG



TACGTCAACAAGAAGGGCAAAGAAGTACTTGTGCTGTGGGGTATCCACCACCCTCCCAAC



TCTAAGGAGCAGCAGAATCTGTACCAGAATGAGAACGCTTACGTCAGCGTGGTGACCTCA



AATTATAACCGAAGGTTCACTCCCGAGATAGCCGAGCGGCCTAAGGTCAGAGACCAAGCG



GGTAGAATGAATTACTACTGGACACTACTAAAGCCCGGCGACACCATCATCTTTGAGGCA



AATGGAAATCTGATCGCCCCCATGTATGCATTTGCACTGAGCCGGGGGTTCGGATCTGGA



ATCATAACTTCAAACGCCAGTATGCATGAATGCAATACAAAGTGTCAGACTCCCTTGGGT



GCCATCAATTCCAGCCTGCCTTATCAGAATATCCACCCTGTGACAATTGGAGAGTGCCCA



AAATACGTTCGTTCAGCTAAACTGAGAATGGTCACCGGCCTCCGGAACAATCCTAGTATA



CAGTCACGCGGCCTTTTCGGCGCCATTGCCGGATTTATTGAAGGAGGCTGGACAGGCATG



ATAGACGGATGGTACGGATATCACCACCAGAACGAACAAGGGTCTGGCTATGCCGCAGAC



CAGAAATCCACCCAGAACGCTATCAATGGTATCACGAATAAAGTCAATACCGTCATCGAG



AAGATGAATATCCAGTTTACAGCTGTGGGAAAAGAGTTCAATAAGCTTGAAAAGAGGATG



GAGAACCTGAATAAAAAAGTTGATGACGGATTTCTCGACATCTGGACGTATAACGCTGAA



CTGCTTGTGCTGCTCGAAAACGAGAGGACATTGGATTTTCACGACTCCAATGTTAAGAAT



CTGTACGAGAAGGTGAAATCTCAGCTCAAGAATAATGCTAAGGAAATAGGCAACGGATGT



TTCGAATTTTATCATAAGTGCGACAATGAATGCATGGAATCAGTGCGCAACGGGACCTAT



GACTACCCCAAGTACAGCGAGGAGTCCAAGCTGAATAGAGAAAAGGTGGACGGCGTCAAA



CTGGAAAGTATGGGCATTTACCAAATTCTCGCCATCTACTCTACCGTTGCCAGCAGTCTC



GTGCTGTTAGTATCACTCGGTGCCATCTCTTTTTGGATGTGTAGTAATGGAAGCCTGCAG



TGCCGGATCTGTATC





476
ATGAAGGCCAACCTGCTCGTGTTGCTGTGTGCACTAGCTGCCGCCGACGCAGACACCATC



TGTATCGGCTACCATGCCAACAACAGCACCGACACAGTGGATACGGTGCTCGAGAAGAAC



GTGACTGTCACCCATAGTGTGAATCTCCTAGAGGATTCTCATAATGGGAAGCTATGCCGA



CTCAAGGGGATTGCACCTCTGCAACTGGGTAAGTGCAATATCGCCGGTTGGCTTCTTGGG



AACCCCGAATGTGATCCCCTGCTCCCCGTGCGATCTTGGTCATATATCGTTGAAACACCC



AATAGCGAAAATGGCATATGCTACCCTGGAGATTTCATTGACTATGAGGAACTCCGAGAA



CAGCTGTCAAGCGTGTCTAGTTTCGAACGGTTTGAAATATTCCCTAAGGAGAGTTCCTGG



CCCAACCATAACACAAACGGAGTGACCGCAGCCTGCTCTCATGAGGGGAAGTCCTCATTT



TATCGCAATCTCCTGTGGCTCACTGAAAAGGAGGGAAGTTACCCAAAATTGAAAAACTCA



TACGTGAATAAGAAAGGCAAGGAGGTCCTCGTGCTGTGGGGGATTCATCACCCCCCTAAC



TCAAAAGAACAGCAGAACCTGTATCAGAACGAAAACGCCTACGTGAGTGTGGTGACCTCT



AACTATAACCGGAGGTTCACGCCAGAGATTGCTGAAAGACCTAAAGTCAGGGACCAAGCC



GGCAGAATGAATTACTATTGGACCCTGTTGAAGCCCGGCGATACCATTATATTCGAGGCA



AACGGCAACCTGATTGCCCCCATGTACGCGTTCGCCCTGAGTCGAGGCTTCGGCAGTGGG



ATTATTACCTCTAACGCCTCGATGCATGAGTGCAACACAAAATGTCAAACTCCACTTGGG



GCCATCAACTCGTCTCTTCCTTACCAAAATATCCACCCGGTTACAATTGGGGAATGTCCC



AAATACGTGCGGTCCGCAAAGCTTCGCATGGTCACGGGCCTGAGGAACAACCCCTCTATTC



CAGTCTCGCGGTCTATTTGGCGCTATTGCTGGCTTTATCGAGGGGGGGTGGACAGGGATG



ATTGATGGCTGGTACGGGTACCATCACCAAAATGAACAGGGGTCCGGCTATGCTGCTGAC



CAAAAATCTACTCAAAACGCCATTAATGGAATCACAAATAAAGTGAATACGGTCATAGAA



AAGATGAACATTCAATTTACAGCCGTGGGTAAGGAGTTCAACAAACTGGAGAAGCGAATG



GAGAACTTAAACAAAAAGGTAGATGATGGTTTCCTCGATATCTGGACATATAATGCTGAG



TTGTTGGTGCTCTTGGAGAATGAGCGGACCTTAGATTTCCACGACAGCAATGTTAAAAAC



CTCTATGAAAAGGTGAAAAGTCAACTGAAGAACAATGCGAAAGAGATCGGTAACGGGTGC



TTCGAGTTCTACCACAAATGCGACAACGAGTGTATGGAGAGTGTAAGGAATGGTACATAT



GATTATCCTAAATACTCTGAAGAGTCGAAGCTGAACAGAGAGAAAGTCGACGGCGTAAAG



CTGGAGAGTATGGGTATCTACCAAATCTTGGCCATTCTATCTACCGTGGCGTCATCACTA



GTTCTTCTGGTGTCCTTGGGGGCCATATCATTCTGGATGTGTTCAAACGGGTCCCTCCAG



TGCCGCATCTGCATC





477
ATGAAGGCAAACCTGTTGGTATTGTTGTGTGCCCTGGCAGCTGCGGATGCAGACACTATT



TGCATCGGCTATCATGCAAATAATTCCACGGACACAGTTGACACCGTTCTGGAGAAAAAT



GTGACGGTCACTCATTCTGTGAACCTGCTGGAAGACTCTCATAACGGAAAGCTGTGCCGG



TTGAAGGGAATTGCACCACTACAACTGGGAAAATGCAACATCGCCGGCTGGTTGCTAGGT



AACCCTGAGTGCGATCCACTCCTTCCAGTGAGATCCTGGTCCTACATCGTCGAGACCCCA



AACTCAGAGAACGGGATCTGTTATCCAGGAGATTTCATTGACTATGAAGAGTTACGTGAA



CAGCTCTCTTCCGTGTCGTCATTCGAACGGTTTGAAATCTTCCCCAAAGAGTCATCCTGG



CCAAATCATAACACTAACGGCGTGACTGCAGCTTGTTCCCACGAAGGGAAATCATCTTTC



TACAGAAATCTGCTGTGGCTCACCGAAAAAGAGGGGAGTTATCCCAAGCTGAAAAACTCC



TACGTTAATAAAAAGGGAAAAGAAGTGCTTGTCTTATGGGGTATCCATCACCCCCCAAAT



TCTAAAGAACAGCAGAACCTGTACCAGAACGAGAACGCGTATGTGTCAGTGGTGACCTCT



AACTATAATCGCAGATTTACACCAGAGATCGCAGAGCGCCCTAAAGTACGGGACCAGGCC



GGTCGGATGAACTACTATTGGACCCTACTGAAACCAGGCGATACCATCATCTTCGAGGCT



AATGGGAACTTAATTGCCCCCATGTACGCTTTCGCACTTAGCCGTGGCTTTGGCAGGGGG



ATTATCACGTCTAATGCTTCCATGCACGAGTGTAATACGAAGTGTCAGACACCTCTTGGT



GCCATTAACTCAAGTCTTCCCTATCAGAACATCCACCCGGTGACCATCGGCGAGTGTCCC



AAGTACGTTCGAAGCGCCAAACTGCGGATGGTCACAGGTCTAAGGAATAACCCCTCCATC



CAGAGCCGCGGCTTGTTTGGTGCGATTGCCGGGTTTATCGAGGGAGGGTGGACTGGCATG



ATAGACGGATGGTACGGATACCACCACCAAAATGAACAAGGCTCCGGATACGCCGCCGAC



CAAAAATCCACGCAGAACGCCATAAACGGAATTACAAACAAGGTAAACACAGTCATAGAA



AAAATGAATATTCAGTTTACAGCCGTCGGGAAAGAATTTAACAAGCTGGAAAAGAGAATG



GAAAACCTGAATAAGAAGGTCGACGATGGTTTTCTCGATATATGGACTTACAATGCTGAA



CTTCTGGTCCTTCTGGAAAACGAACGAACCTTGGATTTCCATGACTCTAATGTGAAGAAC



TTGTACGAAAAGGTGAAATCACAGTTAAAGAACAACGCCAAAGAAATAGGAAACGGGTGC



TTCGAATTTTACCATAAATGTGATAACGAGTGTATGGAGAGCGTTCGTAATGGTACGTAC



GACTATCCTAAATATAGTGAAGAGAGCAAACTCAACCGTGAAAAAGTAGACGGCGTGAAA



CTGGAATCCATGGGGATCTACCAAATCCTGGCCATCTACTCGACGGTGGCAAGTTCTCTC



GTGCTTCTTGTAAGCCTGGGTGCTATCTCTTTTTGGATGTGTAGTAACGGATCCCTGCAG



TGTCGAATTTGCATT





478
ATGAAAGCAAATCTTTTAGTTCTTCTGTGTGCGTTGGCTGCAGCCGACGCAGACACTATC



TGCATTGGCTACCATGCTAATAATAGCACTGACACTGTAGATACAGTGTTGGAAAAGAAC



GTTACAGTGACTCACTCTGTCAATCTGCTGGAGGATTCCCATAACGGCAAATTGTGCCGT



CTAAAGGGCATTGCGCCACTCCAGCTGGGAAAGTGCAATATCGCAGGCTGGCTCCTGGGC



AACCCAGAATGCGACCCGCTGCTGCCTGTTCGCTCATGGTCATACATCGTCGAAACCCCT



AACAGTGAGAACGGGATTTGCTATCCCGGGGATTTCATCGATTACGAAGAATTACGCGAG



CAACTGAGTTCCGTGTCGTCTTTTGAGAGGTTTGAGATCTTCCCGAAGGAATCTTCATGG



CCCAACCATAACACCAATGGTGTGACTGCTGCCTGTTCACACGAGGGCAAAAGCTCTTTC



TACCGAAATCTACTGTGGCTCACAGAGAAAGAGGGATCGTACCCCAAGCTGAAAAATTCC



TATGTGAACAAGAAAGGCAAAGAGGTGCTGGTGCTTTGGGGAATTCATCACCCACCCAAT



TCTAAGGAGCAGCAGAATCTGTATCAGAACGAAAATGCCTATGTTTCCGTGGTAACATCT



AATTATAATAGGCGATTCACACCTGAGATTGCAGAGCGGCCGAAAGTCCGAGACCAGGCA



GGCCGCATGAACTATTACTGGACGCTTCTCAAACCAGGCGACACCATCATCTTCGAGGCC



AATGGGAACTTGATCGCACCAATGTACGCGTTTGCCTTGAGTCGGGGCTTTGGGAGCGGT



ATTATCACCTCGAACGCCTCTATGCATGAATGTAATACGAAGTGTCAGACCCCTCTGGGG



GCAATAAATAGCTCACTGCCCTATCAGAACATCCACCCCGTGACCATCGGTGAGTGTCCC



AAATACGTCAGGTCAGCTAAACTCCGTATGGTGACCGGCCTAAGGAATAATCCGTCCATT



CAGTCCAGAGGTCTGTTCGGTGCAATCGCCGGGTTCATTGAGGGAGGATGGACGGGTATG



ATCGACGGCTGGTATGGCTATCACCACCAGAACGAACAGGGTAGTGGCTACGCCGCTGAT



CAAAAGTCCACTCAAAATGCTATCAACGGAATCACGAACAAAGTGAACACAGTGATAGAG



AAGATGAACATTCAGTTCACCGCTGTGGGTAAAGAGTTTAATAAGCTGGAGAAAAGGATG



GAAAATCTCAATAAGAAAGTTGACGATGGATTCCTTGACATTTGGACTTACAATGCCGAG



CTGCTGGTGCTTCTGGAGAATGAGAGGACCTTAGACTTTCACGACAGCAACGTTAAAAAT



CTCTATGAGAAAGTGAAATCACAGCTGAAGAATAATGCAAAAGAGATTGGGAATGGGTGC



TTCGAGTTTTATCACAAATGCGATAACGAATGTATGGAGTCCGTGAGAAATGGAACGTAC



GACTATCCTAAGTATAGCGAGGAAAGCAAACTCAACAGGGAAAAGGTGGACGGTGTTAAA



CTCGAATCCATGGGGATTTATCAGATATTAGCGATCTATTCGACCGTGGCATCATCTCTC



GTTCTTCTTGTGTCTTTGGGCGCCATCAGCTTTTGGATGTGTTCAAATGGCTCTCTGCAG



TGTCGCATCTGTATT





479
ATGAAAGCCAATCTACTGGTCCTCCTCTGCGCCTTGGCTGCCGCAGATGCTGACACGATC



TGTATTGGCTACCATGCGAACAATAGCACGGATACAGTGGACACCGTTCTGGAGAAAAAT



GTCACCGTGACACATAGCGTAAACCTGCTCGAAGATTCCCACAACGGTAAGCTCTGTAGA



CTCAAAGGTATTGCTCCCCTGCAGTTGGGCAAATGTAATATAGCCGGCTGGCTTCTCGGC



AATCCCGAATGCGATCCCCTGTTGCCCGTGCGGTCTTGGTCTTATATCGTCGAAACCCCA



AATTCAGAAAACGGAATTTGTTATCCTGGCGACTTCATCGATTACGAAGAGTTGAGGGAG



CAGCTTTCAAGCGTTAGCAGTTTCGAGAGATTTGAGATATTTCCAAAGGAAAGTTCCTGG



CCCAATCATAACACCAACGGCGTGACCGCCGCTTGCTCTCACGAAGGCAAAAGTAGTTTC



TATCGAAATCTGCTCTGGCTGACGGAGAAGGAAGGAAGTTACCCCAAGCTGAAAAACTCC



TACGTCAACAAGAAGGGCAAAGAAGTGCTCGTACTGTGGGGCATCCATCACCCTCCCAAT



TCCAAAGAGCAGCAGAACCTGTATCAGAATGAGAACGCTTATGTATCCGTTGTGACTTCA



AACTATAATCGCCGGTTCACTCCTGAGATCGCAGAGCGGCCCAAAGTGAGAGACCAGGCC



GGGAGGATGAATTATTATTGGACACTCCTCAAGCCAGGCGACACAATTATTTTTGAGGCT



AACGGGAACTTGATCGCTCCCATGTATGCGTTCGCCTTGTCAAGAGGATTCGGATCCGGG



ATTATCACCTCTAATGCTTCGATGCACGAATGTAACACAAAGTGTCAAACTCCACTGGGA



GCCATAAATTCGTCCTTGCCATATCAGAATATTCACCCTGTTACAATTGGCGAGTGTCCC



AAGTATGTCCGCTCTGCCAAGTTACGGATGGTGACCGGGTTGCGCAACAACCCAAGTATA



CAGTCACGCGGACTGTTCGGAGCTATCGCGGGATTCATTGAGGGAGGCTGGACAGGGATG



ATCGATGGGTGGTACGGGTATCATCACCAGAACGAACAGGGATCGGGATATGCCGCGGAC



CAAAAGTCAACACAAAACGCCATCAACGGTATTACCAATAAGGTCAACACAGTGATCGAA



AAGATGAATATCCAGTTCACTGCTGTGGGCAAGGAGTTTAATAAACTGGAGAAGCGCATG



GAGAACCTGAACAAGAAGGTTGACGACGGGTTCCTGGACATATGGACGTACAATGCCGAG



CTGCTTGTCCTCCTGGAGAATGAGAGAACCCTGGATTTTCACGATTCTAATGTGAAGAAT



CTGTATGAAAAAGTGAAGTCCCAACTCAAAAACAACGCAAAAGAGATCGGCAACGGATGC



TTTGAATTCTATCATAAGTGCGATAATGAATGTATGGAAAGTGTGAGGAATGGGACTTAC



GATTACCCGAAATATTCCGAAGAGAGCAAACTGAATCGCGAGAAAGTTGACGGTGTAAAG



CTGGAGTCTATGGGAATTTACCAAATTCTGGCCATTTATTCTACCGTGGCATCAAGCCTG



GTTCTGCTGGTGTCCCTTGGCGCCATTTCATTCTGGATGTGTTCCAATGGCAGCCTCCAG



TGCCGGATATGTATC





480
ATGAAGGCTAACCTTTTGGTCCTTTTGTGCGCGCTTGCCGCGGCGGATGCAGACACCATT



TGCATAGGATACCACGCCAATAATAGCACAGACACAGTGGATACAGTCCTTGAGAAAAAT



GTCACTGTAACTCATAGTGTTAACTTGCTAGAAGACTCTCATAATGGTAAATTATGTCGG



CTTAAGGGAATCGCGCCACTCCAATTGGGCAAATGCAACATTGCTGGCTGGTTGTTAGGT



AATCCCGAGTGCGATCCCCTGCTCCCTGTCCGGTCTTGGTCTTACATCGTTGAAACACCC



AACAGTGAGAATGGCATCTGTTACCCCGGAGACTTCATCGACTACGAAGAGCTGCGAGAG



CAGCTTTCTTCCGTCTCCTCCTTTGAACGATTCGAAATCTTCCCCAAAGAGAGCTCATGG



CCGAACCATAACACTAATGGAGTTACAGCCGCCTGCTCCCATGAGGGGAAAAGCAGTTTT



TATAGGAACCTGCTGTGGCTGACAGAAAAGGAGGGCAGCTACCCCAAGCTGAAGAATTCT



TACGTGAACAAGAAGGGCAAAGAAGTATTGGTGCTGTGGGGCATTCATCATCCTCCGAAC



TCCAAGGAGCAGCAGAACCTTTACCAGAACGAGAACGCCTACGTATCAGTTGTTACTAGC



AACTATAACAGACGATTCACTCCTGAAATCGCCGAGCGGCCTAAGGTTCGGGATCAGGCT



GGGAGAATGAACTATTACTGGACCCTGTTGAAGCCTGGAGACACTATTATCTTTGAGGCA



AATGGAAACCTGATCGCACCTATGTATGCTTTCGCACTCAGCCGGGGCTTTGGCTCCGGG



ATCATCACTAGTAATGCTAGCATGCATGAGTGTAACACGAAATGTCAGACCCCACTGGGT



GCTATAAACAGTTCCCTGCCTTATCAGAACATCCACCCTGTGACTATTGGAGAGTGTCCC



AAGTACGTCAGGAGCGCAAAGCTCCGGATGGTCACAGGGCTGAGGAATAACCCAAGCATT



CAGAGCCGGGGTCTATTTGGGGCCATCGCCGGATTCATCGAGGGAGGCTGGACTGGCATG



ATCGATGGCTGGTATGGCTATCATCACCAAAATGAACAGGGATCCGGCTACGCCGCAGAC



CAGAAATCTACACAGAATGCAATCAACGGAATCACAAATAAAGTGAATACCGTCATCGAG



AAGATGAACATACAATTTACCGCTGTGGGTAAAGAGTTTAATAAACTAGAGAAACGGATG



GAAAATCTTAATAAAAAGGTGGACGACGGGTTCCTCGATATTTGGACATATAATGCCGAG



CTATTGGTGCTCCTGGAAAATGAAAGAACGCTTGATTTTCACGACTCTAACGTGAAAAAT



CTGTACGAAAAGGTTAAGAGTCAGCTAAAGAACAATGCCAAAGAAATCGGAAATGGTTGC



TTCGAGTTCTACCACAAATGTGATAATGAATGCATGGAATCAGTCCGAAACGGTACCTAC



GATTATCCTAAATATTCTGAAGAATCAAAGCTAAACCGAGAGAAGGTCGATGGCGTCAAG



CTTGAGAGCATGGGTATCTACCAGATACTGGCCATCTATAGTACTGTGGCATCTTCCCTG



GTGCTTCTCGTGTCCCTGGGGGCGATCTCCTTTTGGATGTGTTCAAACGGATCCCTGCAG



TGTCGGATATGCATC





481
ATGAAGGCCAACCTGCTGGTTCTGCTTTGCGCTCTCGCCGCCGCCGATGCTGATACTATT



TGCATAGGTTATCATGCTAACAACTCCACTGATACTGTTGATACAGTTCTCGAAAAAAAC



GTAACGGTCACTCACTCTGTAAACCTATTGGAAGACAGCCACAATGGGAAGTTGTGTAGG



CTTAAAGGCATCGCTCCACTGCAGCTGGGCAAATGTAACATCGCAGGCTGGCTCCTGGGC



AACCCGGAGTGTGATCCTTTACTGCCCGTCCGCTCCTGGTCTTACATTGTTGAGACACCC



AACAGTGAAAACGGTATCTGTTATCCCGGCGATTTTATTGACTACGAGGAGTTGCGGGAA



CAACTGTCTTCTGTGAGCAGTTTCGAGCGCTTCGAGATTTTTCCTAAGGAGTCTTCTTGG



CCCAACCATAACACAAACGGGGTGACCGCTGCCTGCTCACACGAGGGCAAGAGTAGCTTC



TATAGAAATCTTCTCTGGCTTACTGAAAAAGAGGGATCTTATCCAAAGTTGAAAAACAGT



TATGTGAACAAGAAGGGAAAAGAAGTGCTGGTCCTTTGGGGGATCCATCACCCACCCAAC



TCCAAGGAGCAGCAGAACCTGTACCAAAACGAGAACGCATATGTTAGCGTCGTGACCAGC



AACTACAATCGCAGGTTCACTCCCGAGATCGCCGAGAGGCCTAAAGTTCGCGACCAGGCT



GGACGGATGAACTACTATTGGACACTATTAAAGCCAGGCGATACCATAATATTTGAAGCA



AATGGGAACTTAATTGCACCGATGTACGCCTTCGCACTGTCCCGGGGGTTCGGAAGCGGG



ATTATTACCTCTAACGCCTCCATGCATGAGTGCAACACCAAGTGTCAAACACCCCTGGGA



GCTATTAACTCTAGCTTGCCCTATCAGAACATCCACCCAGTCACTATCGGCGAGTGTCCT



AAGTACGTTAGATCAGCCAAGCTGCGCATGGTTACGGGGCTTCGGAACAACCCCTCAATC



CAATCTCGGGGGCTTTTCGGTGCAATCGCCGGCTTTATAGAAGGCGGTTGGACCGGAATG



ATTGATGGCTGGTATGGCTACCACCACCAAAACGAACAGGGAAGCGGGTATGCTGCAGAC



CAGAAGAGCACACAGAATGCTATCAATGGGATCACCAACAAAGTAAACACGGTGATTGAG



AAAATGAATATTCAGTTCACAGCGGTGGGCAAGGAGTTCAACAAACTGGAGAAGCGTATG



GAAAATCTGAATAAAAAAGTTGACGACGGTTTCCTAGACATCTGGACATATAACGCCGAG



TTGTTGGTGCTCCTCGAAAACGAGCGCACACTCGACTTCCACGATTCTAACGTTAAGAAT



CTTTACGAAAAAGTTAAATCGCAGCTGAAAAACAACGCGAAGGAGATCGGTAACGGCTGT



TTCGAGTTTTATCATAAGTGTGATAATGAATGCATGGAATCCGTGCGGAACGGTACCTAC



GATTATCCTAAATATTCAGAGGAGAGTAAACTCAATCGCGAGAAGGTCGATGGAGTCAAG



CTTGAGAGTATGGGAATTTATCAGATTCTGGCAATCTATAGCACCGTCGCATCCAGTCTC



GTCCTCCTTGTTTCACTGGGAGCTATTTCATTCTGGATGTGCTCTAACGGGTCGCTGCAG



TGCAGAATCTGCATT





482
ATGAAGGCAAATCTTCTGGTACTTCTCTGCGCCCTCGCTGCAGCCGACGCAGATACCATT



TGTATCGGCTACCACGCGAATAACTCAACGGATACCGTGGACACCGTGTTGGAGAAGAAC



GTTACCGTCACACATAGTGTGAATCTGCTTGAAGATTCACATAACGGAAAACTTTGTAGG



CTCAAAGGCATCGCGCCACTGCAGCTGGGGAAATGCAATATTGCAGGTTGGTTACTGGGT



AACCCAGAATGCGATCCTCTGTTACCTGTGCGTAGTTGGAGCTATATCGTTGAGACCCCA



AATTCGGAGAATGGGATCTGCTATCCAGGGGACTTCATTGACTATGAAGAGCTGCGAGAA



CAGCTCAGCAGCGTATCTAGCTTCGAGAGATTTGAAATTTTCCCGAAGGAATCCAGCTGG



CCAAACCACAATACCAATGGCGTTACGGCCGCCTGTAGCCACGAAGGTAAGTCTAGCTTC



TACAGAAACCTGCTGTGGCTGACAGAAAAGGAGGGGTCTTACCCGAAGTTGAAGAATAGC



TACGTCAATAAGAAAGGAAAAGAGGTCCTTGTCCTCTGGGGCATCCACCACCCTCCAAAC



TCGAAGGAACAGCAGAACCTTTATCAGAACGAGAACGCTTATGTCTCCGTGGTGACATCC



AATTATAACAGGCGTTTCACACCAGAGATAGCCGAAAGGCCCAAGGTCCGCGACCAAGCT



GGTAGGATGAATTACTATTGGACACTCCTCAAACCAGGAGACACAATTATTTTTGAAGCA



AATGGGAACCTGATTGCCCCCATGTATGCCTTTGCGCTAAGCCGCGGTTTCGGAAGCGGC



ATTATCACGAGTAATGCATCAATGCACGAGTGTAACACCAAATGTCAAACCCCCTTGGGC



GCAATTAACTCTTCCCTCCCTTACCAGAACATCCACCCCGTCACCATCGGTGAGTGCCCT



AAATACGTACGGTCTGCTAAGTTGCGGATGGTCACCGGCCTGCGAAATAACCCTAGCATT



CAGTCCAGAGGGTTATTTGGCGCGATCGCAGGATTCATCGAGGGAGGGTGGACCGGCATG



ATAGACGGGTGGTATGGATACCATCATCAGAACGAGCAAGGCAGCGGCTACGCTGCTGAC



CAAAAGAGCACGCAGAACGCGATCAATGGAATCACGAATAAGGTTAACACGGTCATCGAA



AAGATGAACATACAGTTCACAGCTGTGGGCAAGGAGTTCAACAAGCTTGAAAAAAGAATG



GAGAACTTGAACAAAAAAGTAGACGACGGCTTTCTCGATATTTGGACTTACAACGCCGAA



TTGCTAGTCTTGTTGGAGAATGAACGCACCTTGGACTTCCACGACTCCAACGTCAAGAAT



TTATACGAAAAGGTCAAAAGCCAGCTTAAGAATAACGCCAAGGAGATCGGCAATGGCTGT



TTCGAATTTTACCATAAATGCGATAATGAATGTATGGAAAGTGTTAGGAACGGCACATAC



GACTACCCTAAATACTCCGAAGAGAGCAAACTCAATCGGGAGAAGGTTGATGGAGTGAAG



TTAGAGAGCATGGGAATTTACCAAATACTCGCCATCTATAGCACCGTTGCCTCAAGCCTG



GTCCTCCTAGTGTCCCTGGGCGCCATTAGTTTCTGGATGTGTTCCAATGGGTCTTTGCAA



TGTCGCATCTGTATA





483
ATGAAAGCTAACCTGCTGGTCCTCCTATGTGCTCTCGCTGCCGCAGATGCCGATACCATA



TGCATTGGATATCACGCGAACAACAGCACCGATACGGTGGATACAGTGCTGGAAAAAAAC



GTGACTGTGACACATTCTGTCAATCTCCTGGAAGACTCCCACAATGGCAAGCTGTGTCGT



TTGAAGGGGATCGCCCCCCTGCAGCTCGGAAAGTGCAACATAGCAGGGTGGCTGCTCGGG



AATCCAGAGTGCGATCCGCTGCTCCCGGTACGGAGCTGGTCTTACATTGTTGAGACACCT



AACAGCGAGAATGGCATTTGTTATCCTGGAGACTTCATCGACTACGAGGAACTCCGGGAA



CAGCTTAGCTCCGTAAGCAGCTTCGAAAGATTTGAGATTTTCCCTAAGGAGTCATCCTGG



CCCAACCATAATACAAACGGAGTGACCGCTGCCTGTTCTCATGAAGGGAAAAGTTCCTTT



TACAGAAATCTCCTGTGGCTGACTGAGAAAGAAGGAAGCTATCCTAAGCTGAAGAATTCT



TACGTTAATAAGAAAGGAAAAGAAGTGCTGGTCCTCTGGGGGATACATCACCCCCCAAAT



AGCAAGGAGCAACAGAATTTATATCAGAATGAGAACGCATACGTCTCGGTTGTGACTTCG



AACTACAACAGGCGGTTTACACCCGAGATCGCAGAGCGCCCCAAGGTTAGAGACCAGGCT



GGGAGGATGAATTACTATTGGACGCTTCTCAAGCCAGGGGATACCATTATTTTTGAGGCT



AATGGCAATCTGATTGCCCCTATGTACGCCTTCGCTCTGTCAAGGGGATTTGGAAGCGGC



ATCATCACCTCCAACGCTTCCATGCATGAGTGCAACACCAAGTGTCAGACACCCTTAGGC



GCAATCAACAGCAGTCTGCCCTATCAAAACATTCATCCCGTGACAATCGGCGAGTGTCCG



AAATACGTTCGATCCGCGAAGTTAAGGATGGTTACGGGCCTACGTAATAACCCTTCAATC



CAGTCTCGTGGCCTCTTCGGTGCTATCGCTGGTTTCATCGAAGGAGGCTGGACAGGAATG



ATCGACGGATGGTATGGATATCACCATCAGAATGAGCAGGGCAGTGGGTATGCCGCAGAC



CAGAAATCCACCCAGAATGCCATAAATGGAATCACCAACAAGGTGAACACAGTTATCGAA



AAGATGAACATCCAGTTCACCGCCGTGGGAAAGGAGTTTAACAAACTTGAGAAGAGAATG



GAGAATCTTAATAAAAAGGTAGATGATGGGTTCCTTGATATCTGGACATATAACGCCGAG



CTTCTAGTGCTCCTGGAGAACGAGAGGACTCTGGACTTTCACGACTCCAACGTCAAAAAC



CTATACGAAAAGGTCAAGAGTCAACTGAAAAATAACGCAAAAGAGATAGGTAACGGATGT



TTTGAGTTCTACCACAAATGCGATAACGAGTGCATGGAATCCGTGAGGAATGGTACCTAT



GACTATCCAAAATATTCTGAGGAGTCCAAGCTCAACCGAGAAAAGGTGGACGGCGTAAAG



CTCGAAAGCATGGGGATTTATCAGATACTTGCAATTTATTCCACTGTGGCTTCTTCCCTG



GTGCTTTTGGTCAGCTTAGGGGCTATCAGCTTCTGGATGTGTTCCAACGGCTCCCTTCAG



TGTAGAATTTGCATC





484
ATGAAGGCAAACTTGTTGGTGCTACTCTGCGCATTAGCAGCTGCTGACGCAGATACAATT



TGTATCGGGTACCACGCCAATAACTCTACAGATACAGTAGATACCGTCCTTGAAAAAAAT



GTCACCGTGACCCATAGTGTAAACCTCCTAGAAGATAGCCATAACGGCAAACTGTGTCGG



CTTAAGGGCATCGCGCCTCTACAGCTGGGCAAGTGTAACATTGCTGGCTGGCTCCTTGGC



AATCCTGAGTGCGACCCCTTGCTGCCAGTGAGGTCCTGGAGCTACATCGTGGAAACTCCC



AATTCTGAGAATGGAATATGTTATCCGGGGGATTTCATCGACTACGAAGAGCTGCGCGAA



CAACTCTCATCAGTCAGCTCCTTTGAAAGATTCGAAATCTTCCCCAAGGAATCTAGCTGG



CCAAACCATAACACTAATGGAGTAACAGCTGCATGTTCCCACGAGGGCAAGAGCTCTTTT



TACAGGAACCTCCTATGGCTGACGGAGAAAGAAGGGTCCTACCCCAAGCTGAAAAATAGC



TACGTTAACAAGAAAGGAAAAGAGGTGTTGGTTCTGTGGGGAATTCATCATCCTCCCAAC



AGTAAGGAGCAGCAGAATCTCTATCAAAATGAAAACGCTTACGTCAGTGTGGTGACGTCT



AATTACAACAGGAGATTTACACCAGAGATTGCCGAGCGGCCGAAAGTGAGAGATCAGGCA



GGCAGGATGAATTATTACTGGACACTTCTGAAACCTGGAGACACAATCATTTTCGAAGCT



AATGGAAACCTCATCGCACCGATGTACGCATTCGCCTTGTCCCGGGGATTCGGCTCCGGC



ATCATCACCTCCAACGCTTCAATGCATGAATGTAATACTAAATGCCAGACGCCGCTTGGC



GCTATTAACTCATCCTTGCCTTATCAGAATATTCATCCCGTTACCATTGGAGAGTGTCCC



AAATACGTGCGTTCAGCCAAACTGCGGATGGTCACTGGCCTGCGAAATAACCCTTCAATT



CAATCTCGCGGACTGTTCGGAGCTATCGCCGGCTTCATAGAAGGGGGCTGGACCGGCATG



ATTGACGGATGGTACGGTTACCATCACCAAAACGAGCAGGGTTCCGGCTATGCCGCCGAC



CAGAAATCAACCCAGAACGCCATAAATGGTATTACCAACAAGGTTAATACGGTCATCGAG



AAAATGAACATCCAGTTCACAGCAGTGGGAAAAGAATTTAATAAGCTCGAGAAAAGAATG



GAAAACCTGAACAAAAAAGTGGACGATGGTTTCCTCGACATATGGACCTATAATGCTGAG



CTACTCGTCCTTCTGGAAAATGAGCGAACGCTTGACTTCCACGATTCGAATGTGAAAAAC



CTATACGAAAAAGTGAAGTCCCAGCTCAAGAACAATGCGAAGGAGATCGGGAACGGCTGC



TTTGAGTTTTACCACAAATGTGATAACGAATGCATGGAGTCTGTGCGAAATGGGACATAC



GACTATCCTAAGTATTCAGAAGAGTCAAAACTCAACCGGGAAAAGGTTGACGGAGTTAAG



CTTGAGTCAATGGGAATTTACCAAATCCTGGCAATCTACTCTACTGTTGCCTCTTCACTC



GTCCTCTTAGTTTCACTAGGGGCTATCAGTTTCTGGATGTGTTCTAATGGTAGCCTGCAG



TGTCGAATTTGTATA





485
ATGAAAGCTAATCTCTTAGTTCTGCTCTGCGCCTTAGCGGCTGCAGATGCCGACACCATA



TGCATTGGCTACCACGCTAATAACTCCACCGATACAGTGGACACCGTGCTGGAAAAGAAC



GTCACTGTGACCCACTCAGTGAACCTGTTGGAGGATTCACACAACGGCAAGTTATGCAGA



CTCAAGGGAATTGCACCACTGCAGCTGGGTAAGTGTAATATCGCTGGCTGGCTTCTCGGA



AATCCCGAGTGCGACCCTCTGTTACCTGTCAGGAGCTGGAGTTATATCGTGGAAACTCCT



AATAGTGAAAATGGAATATGCTATCCCGGCGACTTCATCGACTACGAGGAGCTAAGGGAA



CAGCTGTCAAGCGTCTCCTCCTTCGAAAGATTCGAGATCTTCCCGAAGGAGAGTTCGTGG



CCAAACCATAACACTAACGGGGTCACCGCGGCCTGTTCTCACGAGGGGAAGTCATCCTTC



TACCGAAACCTTCTGTGGCTGACGGAGAAAGAAGGCAGCTATCCCAAACTGAAGAATAGT



TACGTGAATAAGAAGGGAAAGGAGGTACTGGTCCTCTGGGGCATCCATCATCCCCCCAAC



AGTAAGGAGCAGCAGAATCTTTACCAGAACGAGAACGCTTATGTGAGCGTCGTAACCTCA



AACTACAACCGCAGGTTCACTCCTGAAATTGCCGAACGGCCGAAAGTGAGGGACCAAGCC



GGCCGCATGAACTACTATTGGACGCTTCTCAAGCCCGGTGATACTATTATTTTCGAGGCA



AACGGCAACTTAATCGCTCCTATGTACGCATTTGCACTGAGTCGGGGTTTTGGTTCGGGC



ATCATCACCTCAAATGCTTCCATGCACGAATGCAATACAAAATGCCAGACCCCACTTGGA



GCCATCAACTCCTCACTGCCTTATCAGAATATCCACCCAGTCACTATCGGGGAATGCCCG



AAATATGTCAGAAGCGCTAAGCTTCGGATGGTGACCGGTCTGCGCAATAATCCGTCTATA



CAATCCAGGGGACTGTTTGGCGCGATAGCCGGATTTATTGAGGGGGGATGGACTGGCATG



ATCGATGGGTGGTACGGGTACCATCACCAGAATGAACAGGGTTCCGGCTACGCCGCAGAT



CAAAAGTCCACCCAGAACGCTATTAACGGAATCACCAACAAGGTCAATACTGTCATTGAG



AAAATGAATATCCAGTTCACTGCCGTGGGCAAGGAGTTCAATAAGCTAGAGAAGCGTATG



GAAAACCTTAACAAGAAGGTGGACGATGGATTTTTGGATATTTGGACCTATAATGCTGAG



TTGTTGGTCCTCCTGGAGAATGAAAGAACTCTGGACTTCCATGATAGCAATGTGAAAAAC



CTCTACGAAAAAGTCAAATCACAGCTTAAGAACAACGCCAAAGAAATTGGGAATGGATGC



TTTGAGTTTTACCATAAATGCGACAACGAGTGTATGGAGTCTGTCAGAAACGGCACATAC



GATTACCCCAAGTATTCCGAAGAATCAAAACTGAATCGGGAAAAGGTTGATGGAGTGAAA



TTAGAAAGCATGGGAATCTATCAAATTCTTGCAATTTATAGCACCGTTGCTAGCTCACTG



GTCCTGCTCGTTAGTTTGGGCGCCATTAGCTTCTGGATGTGTAGCAATGGGTCTCTCCAA



TGCAGAATTTGCATT





486
ATGAAAGCGAATCTGCTGGTCCTGCTGTGCGCCCTGGCGGCTGCTGACGCGGATACTATT



TGCATCGGCTATCACGCTAATAACTCGACAGACACCGTGGATACAGTCTTGGAGAAAAAT



GTGACTGTAACCCACTCGGTTAACCTTCTCGAGGACTCGCATAACGGGAAACTGTGTAGG



CTGAAGGGAATCGCACCACTCCAGCTGGGCAAGTGCAATATAGCTGGCTGGCTGCTCGGG



AATCCTGAGTGCGACCCTCTCCTGCCCGTCCGGTCCTGGAGCTATATAGTGGAAACACCT



AACAGCGAGAATGGTATCTGCTATCCGGGGGATTTTATCGACTATGAGGAACTACGAGAA



CAGCTCTCCTCCGTTAGCAGCTTCGAGCGATTTGAAATCTTTCCTAAGGAGAGCAGTTGG



CCTAACCACAACACTAATGGGGTGACAGCCGCCTGTAGCCATGAGGGAAAGTCTTCTTTT



TATAGAAACTTGCTGTGGTTGACTGAGAAAGAGGGGAGCTACCCGAAACTAAAGAACTCC



TACGTGAACAAGAAAGGCAAAGAGGTTTTGGTTCTGTGGGGCATCCACCATCCTCCCAAT



AGCAAGGAACAGCAGAATCTCTATCAGAACGAAAACGCCTACGTGTCAGTGGTGACCAGT



AATTATAATCGACGCTTTACCCCCGAAATTGCAGAGCGGCCGAAAGTCCGCGACCAGGCC



GGACGCATGAATTACTATTGGACCCTGCTAAAGCCCGGGGACACTATCATATTTGAAGCC



AACGGGAACCTGATTGCACCCATGTATGCGTTTGCTCTGTCACGCGGGTTTGGTAGCGGG



ATTATCACTTCCAACGCTTCAATGCATGAATGTAACACTAAGTGTCAGACCCCACTGGGC



GCCATTAACAGCTCGCTGCCATACCAGAATATACACCCAGTTACTATTGGTGAATGTCCT



AAGTATGTACGGTCCGCCAAGCTGCGGATGGTTACTGGCCTCAGGAACAATCCTTCAATT



CAGTCTAGGGGGCTGTTCGGAGCCATAGCTGGCTTTATTGAGGGAGGCTGGACAGGCATG



ATTGACGGCTGGTACGGCTACCACCATCAGAACGAGCAAGGCTCCGGCTACGCCGCGGAC



CAGAAGTCAACTCAAAATGCGATAAACGGAATCACCAACAAGGTGAACACCGTCATAGAA



AAAATGAATATACAATTCACAGCCGTGGGAAAGGAGTTCAATAAGCTCGAGAAGCGTATG



GAGAATCTCAATAAAAAAGTGGATGATGGGTTCCTCGATATCTGGACCTATAACGCTGAA



CTCTTAGTCCTCCTCGAAAACGAGCGAACGCTCGACTTCCATGATTCTAATGTAAAAAAT



CTTTACGAAAAGGTTAAGTCACAGCTGAAGAACAACGCCAAGGAGATAGGAAACGGCTGT



TTCGAGTTTTATCATAAGTGTGACAACGAGTGTATGGAATCTGTCCGCAATGGCACTTAT



GATTACCCCAAGTACTCCGAGGAAAGTAAACTTAATAGAGAAAAAGTTGATGGCGTTAAG



CTGGAGTCAATGGGGATTTATCAGATCCTAGCTATATATTCTACTGTGGCTTCTAGTCTC



GTTTTGCTGGTGAGCCTGGGAGCCATAAGCTTTTGGATGTGTAGCAATGGGTCCCTCCAG



TGTCGAATCTGTATC





487
ATGAAAGCCAACTTGCTGGTGTTGCTCTGCGCCCTTGCCGCCGCCGACGCAGATACCATT



TGTATTGGCTACCATGCCAATAATTCTACGGACACTGTGGATACCGTCTTGGAGAAAAAT



GTAACTGTAACTCACTCCGTTAATCTTCTCGAAGATTCACACAATGGCAAGCTGTGCCGC



CTTAAAGGCATTGCCCCCTTGCAGCTGGGCAAGTGTAATATTGCTGGATGGCTCCTCGGC



AATCCTGAGTGTGACCCCCTCCTGCCCGTTAGGTCGTGGAGCTACATTGTGGAGACCCCA



AATTCGGAAAATGGGATATGTTACCCAGGCGACTTTATCGACTATGAGGAACTACGTGAG



CAGCTGAGTTCTGTTTCCAGTTTTGAAAGATTTGAGATCTTTCCAAAGGAGAGCTCTTGG



CCGAACCATAACACCAATGGGGTCACCGCCGCTTGCAGTCATGAAGGAAAATCAAGCTTC



TACCGAAACTTGCTGTGGCTCACGGAAAAGGAGGGCTCCTACCCCAAGTTGAAGAACTCC



TATGTGAACAAAAAGGGCAAAGAGGTTCTCGTGCTCTGGGGAATTCACCACCCTCCCAAC



AGCAAGGAGCAGCAGAACTTGTATCAGAACGAAAATGCTTACGTTAGCGTGGTGACTTCC



AATTATAATCGACGCTTTACACCGGAGATTGCTGAACGCCCGAAAGTTCGGGATCAAGCC



GGCCGGATGAACTATTATTGGACCCTCCTGAAACCCGGTGATACTATTATTTTTGAGGCA



AACGGAAACCTGATTGCTCCCATGTACGCCTTCGCCCTGTCCCGGGGGTTTGGCAGCGGA



ATTATAACTAGCAACGCTAGCATGCACGAGTGTAATACTAAGTGTCAGACCCCTCTGGGG



GCAATAAACTCCAGCTTACCTTATCAGAACATCCACCCTGTTACCATAGGCGAGTGCCCG



AAGTACGTTAGGTCAGCTAAGCTAAGAATGGTCACTGGTTTGAGGAATAACCCCAGCATT



CAGAGTAGGGGGCTGTTTGGGGCAATTGCAGGTTTTATCGAGGGCGGTTGGACTGGTATG



ATCGACGGCTGGTATGGATATCATCATCAGAATGAGCAGGGGTCTGGGTATGCTGCGGAC



CAGAAGTCCACGCAAAATGCCATAAACGGAATCACGAATAAGGTTAATACCGTCATCGAA



AAAATGAACATTCAGTTTACTGCGGTGGGTAAGGAATTCAATAAACTCGAAAAGAGAATG



GAGAACTTAAATAAGAAAGTCGACGACGGATTTTTGGATATCTGGACCTATAACGCCGAA



CTCCTCGTTCTGTTGGAGAACGAGCGCACCCTCGACTTCCACGATAGTAACGTGAAAAAT



CTGTATGAGAAGGTGAAGTCCCAGCTCAAGAACAATGCCAAGGAAATCGGAAACGGATGT



TTTGAGTTCTACCACAAGTGCGACAATGAATGCATGGAGAGTGTGCGCAATGGGACGTAC



GACTACCCTAAATATAGTGAAGAGTCTAAGCTCAACCGGGAGAAGGTGGACGGAGTGAAG



CTGGAGAGTATGGGAATTTACCAGATACTGGCTATCTACAGTACAGTTGCCAGCTCCCTC



GTTCTTCTGGTGTCTCTGGGGGCCATCTCTTTCTGGATGTGTTCCAATGGCAGCCTCCAA



TGCCGGATCTGCATT





488
ATGAAAGCAAATCTTCTGGTGTTACTATGCGCATTAGCTGCCGCTGACGCCGACACCATT



TGCATTGGCTATCACGCCAATAATAGCACTGACACTGTCGACACAGTTCTTGAAAAGAAC



GTGACTGTTACCCACTCCGTGAATCTACTCGAGGATTCTCATAACGGAAAGCTCTGTCGC



CTTAAGGGTATTGCCCCTCTCCAGCTTGGAAAATGCAACATTGCTGGCTGGCTGCTTGGA



AACCCTGAATGTGACCCACTCCTGCCCGTCCGGAGCTGGAGTTACATAGTGGAGACTCCA



AATAGCGAGAACGGTATATGTTACCCAGGTGATTTCATTGACTATGAGGAGTTGAGAGAG



CAGTTGAGCTCCGTTTCGTCTTTTGAAAGGTTCGAGATCTTCCCAAAAGAGTCAAGCTGG



CCTAACCATAACACCAATGGTGTTACGGCCGCATGTAGCCATGAGGGCAAGTCGTCCTTT



TATCGAAATCTCCTATGGCTCACAGAGAAGGAAGGATCTTACCCAAAGCTCAAGAACTCG



TACGTAAACAAGAAGGGGAAGGAAGTCCTTGTTCTGTGGGGTATACATCACCCACCAAAT



TCCAAGGAACAGCAGAATTTATATCAGAACGAAAACGCATATGTTTCTGTCGTTACATCC



AACTATAACCGGAGATTCACCCCAGAGATCGCCGAAAGACCGAAGGTGGGGGACCAGGCA



GGGCGAATGAACTATTACTGGACATTGCTCAAGCCCGGAGACACCATAATTTTCGAGGCT



AATGGCAACCTCATTGCCCCGATGTACGCATTCGCTCTTTCTCGGGGATTTGGCAGTGGG



ATTATCACCTCGAACGCCTCCATGCATGAATGTAATACTAAATGTCAAACACCACTGGGA



GCCATTAACAGTAGCCTGCCCTATCAAAATATCCACCCGGTCACTATTGGGGAGTGCCCA



AAGTATGTGCGGTCTGCAAAGTTGAGAATGGTTACCGGGCTGCGCAACAATCCAAGTATT



CAGAGTAGGGGGCTATTTGGTGCAATAGCAGGCTTTATCGAAGGGGGCTGGACTGGAATG



ATAGATGGCTGGTATGGATATCACCACCAGAACGAGCAGGGTAGCGGCTACGCCGCCGAT



CAGAAGAGCACTCAGAATGCTATCAACGGAATCACAAATAAAGTTAATACCGTAATAGAA



AAGATGAATATCCAGTTCACAGCTGTGGGTAAAGAGTTCAACAAGCTGGAAAAACGGATG



GAAAACCTGAATAAAAAGGTGGATGATGGTTTCCTCGATATATGGACTTATAACGCTGAG



CTTCTGGTTCTGCTGGAAAATGAACGCACACTGGACTTCCACGATAGTAATGTAAAAAAT



CTGTATGAAAAGGTTAAATCACAACTGAAAAATAATGCTAAGGAAATTGGGAACGGGTGT



TTCGAATTCTATCACAAGTGCGATAATGAGTGTATGGAGTCAGTTCGGAACGGGACCTAC



GATTATCCTAAGTATTCAGAAGAGTCTAAACTGAACCGCGAAAAAGTGGATGGAGTCAAA



CTGGAGTCGATGGGCATCTATCAGATCCTCGCCATTTATAGCACCGTGGCATCGTCCCTG



GTGCTTTTGGTTAGCCTGGGCGCCATTAGTTTCTGGATGTGTAGTAACGGGTCTCTGCAG



TGTAGGATTTGTATT





489
ATGAAGGCAAATCTGCTCGTGTTACTCTGCGCTTTGGCCGCCGCTGACGCCGACACTATT



TGCATCGGTTACCACGCCAACAACAGCACCGATACAGTGGACACGGTATTGGAAAAAAAC



GTAACTGTGACACATTCAGTAAACCTGCTCGAGGACAGCCACAACGGTAAGCTGTGCCGG



TTGAAAGGTATCGCACCACTGCAGCTTGGAAAATGTAATATCGCCGGGTGGCTGCTGGGC



AATCCTGAGTGTGATCCTCTGCTCCCTGTACGGAGTTGGTCGTATATTGTGGAAACCCCT



AACAGCGAAAACGGGATTTGTTATCCTGGCGACTTTATCGACTATGAGGAGCTCCGGGAG



CAGCTGTCCAGCGTAAGTTCATTCGAGAGGTTCGAGATTTTCCCCAAAGAGAGTTCCTGG



CCTAACCACAACACAAACGGTGTGACAGCTGCCTGCAGCCACGAGGGGAAGTCCTCATTC



TATAGGAATTTGCTCTGGCTGACCGAAAAGGAAGGTTCGTACCCGAAGCTTAAAAATTCT



TACGTTAACAAAAAGGGGAAGGAGGTACTCGTTCTGTGGGGGATCCATCATCCCCCAAAT



TCTAAGGAACAGCAGAACCTATACCAGAATGAAAACGCATATGTCAGCGTGGTCACATCT



AACTACAACAGACGCTTCACACCCGAAATCGCTGAGCGCCCCAAGGTACGAGATCAGGCT



GGCAGGATGAACTACTATTGGACTTTACTGAAGCCGGGCGATACAATAATTTTCGAGGCT



AACGGAAATCTGATCGCCCCAATGTATGCCTTTGCTCTTTCCCGCGGCTTTGGTTCAGGG



ATTATTACTTCTAACGCTTCGATGCACGAGTGTAATACCAAATGCCAGACCCCGCTGGGC



GCCATTAATAGCTCATTGCCTTATCAGAATATCCATCCCGTTACCATTGGCGAATGTCCC



AAGTATGTGAGGAGCGCAAAACTTCGGATGGTAACAGGTCTAAGGAATAACCCTAGCATT



CAGTCACGGGGGCTGTTTGGGGCAATAGCAGGCTTTATTGAGGGCGGATGGACAGGCATG



ATCGATGGCTGGTATGGTTACCACCATCAGAACGAGCAGGGCTCTGGATATGCAGCCGAC



CAGAAGAGTACACAAAATGCAATCAATGGCATTACTAACAAAGTGAACACGGTCATTGAA



AAAATGAATATCCAGTTCACAGCCGTGGGAAAGGAGTTTAACAAGCTGGAAAAACGGATG



GAAAATCTAAATAAGAAAGTCGACGACGGTTTTTTGGATATCTGGACCTACAACGCTGAA



CTACTGGTTCTTCTGGAGAACGAAAGAACCCTGGACTTTCACGACTCTAATGTGAAGAAT



CTGTACGAAAAAGTGAAGTCTCAGTTGAAGAACAACGCTAAAGAGATTGGGAATGGCTGT



TTCGAATTCTACCACAAATGCGATAATGAGTGCATGGAGTCTGTCAGGAATGGTACTTAC



GACTATCCCAAGTATTCTGAGGAGAGTAAGCTCAACAGGGAAAAAGTCGACGGAGTCAAA



CTGGAGTCGATGGGCATATACCAGATTCTAGCCATCTACTCCACCGTGGCCAGTAGTTTA



GTCTTGCTCGTAAGCCTTGGCGCTATCTCCTTCTGGATGTGCTCCAATGGATCCCTGCAG



TGTAGAATCTGTATC





490
ATGAAGGCGAATCTACTGGTTTTATTGTGCGCCCTCGCTGCTGCCGACGCCGATACCATC



TGCATCGGATACCATGCCAATAACTCCACAGATACCGTGGACACTGTGCTGGAAAAGAAT



GTTACAGTGACACATTCAGTGAACCTGCTGGAAGATAGTCATAATGGCAAACTGTGTAGA



CTAAAGGGCATCGCCCCCCTGCAACTTGGTAAGTGTAACATCGCTGGTTGGCTTCTGGGG



AACCCCGAATGCGATCCACTGCTGCCTGTCCGCAGTTGGTCCTATATTGTCGAAACCCCC



AACTCTGAAAACGGGATTTGTTATCCAGGAGACTTCATTGACTATGAAGAATTGCGGGAA



CAGCTTTCAAGTGTGAGCTCTTTCGAACGGTTTGAAATCTTTCCGAAGGAGTCCTCGTGG



CCAAATCATAACACTAATGGCGTGACAGCGGCATGTAGTCACGAAGGAAAATCTTCCTTT



TATAGAAACCTCCTGTGGCTGACAGAGAAGGAAGGCAGTTATCCCAAACTGAAGAACAGT



TACGTCAATAAAAAGGGGAAAGAAGTACTGGTACTTTGGGGAATCCACCATCCCCCCAAC



AGCAAGGAGCAGCAGAATCTTTATCAAAATGAGAACGCCTACGTCAGCGTGGTGACCTCG



AATTACAACAGGCGGTTCACACCAGAAATCGCGGAAAGGCCGAAGGTGGGGGATCAGGCC



GGCAGGATGAACTACTATTGGACTCTCCTAAAACCAGGCGACACTATTATATTTGAAGCC



AACGGCAACCTTATCGCTCCAATGTACGCCTTCGCTTTGAGCCGTGGGTTTGGCTCCGGA



ATTATAACATCAAATGCAAGTATGCACGAGTGCAACACAAAGTGCCAGACACCACTCGGA



GCAATCAACAGCTCCTTGCCATACCAAAACATTCATCCTGTTACCATCGGCGAATGCCCG



AAGTATGTGAGGAGCGCAAAACTGAGGATGGTGACGGGCTTGCGGAACAACCCTTCTATC



CAGTCCCGGGGCCTGTTTGGAGCGATCGCAGGATTCATTGAAGGGGGATGGACGGGGATG



ATCGATGGATGGTACGGATATCATCACCAAAATGAACAAGGGTCAGGTTATGCTGCTGAT



CAAAAGTCAACACAGAATGCAATCAACGGCATAACCAATAAAGTTAACACAGTGATTGAA



AAAATGAATATTCAGTTTACCGCCGTGGGAAAAGAGTTCAATAAACTGGAGAAGAGGATG



GAGAATTTGAACAAGAAGGTAGATGACGGCTTTCTCGACATTTGGACTTATAATGCAGAG



CTATTAGTGCTCCTCGAGAATGAGAGAACTCTTGACTTTCACGACAGTAACGTAAAAAAC



CTCTATGAAAAGGTCAAATCACAGCTTAAGAATAATGCAAAAGAGATCGGAAACGGATGC



TTCGAATTTTACCACAAATGCGACAACGAATGTATGGAATCCGTGAGGAACGGTACCTAC



GATTACCCCAAGTACAGCGAGGAAAGCAAGCTGAATCGAGAAAAAGTTGACGGTGTGAAG



CTGGAGTCCATGGGCATCTACCAGATTCTTGCTATCTATTCTACAGTAGCTTCCTCCCTT



GTACTTCTGGTGTCCCTGGGTGCCATTTCATTCTGGATGTGCAGCAACGGTTCCTTGCAG



TGTCGGATCTGCATA





491
ATGAAAGCTAATCTTCTCGTGTTGCTGTGCGCCTTAGCGGCCGCAGACGCGGACACAATC



TGTATTGGGTACCATGCCAATAATTCCACTGACACCGTAGACACTGTACTGGAAAAGAAT



GTGACGGTAACCCACTCCGTTAATCTGCTGGAGGACTCTCACAACGGCAAACTCTGTCGG



CTGAAAGGTATTGCACCACTTCAGCTGGGGAAGTGTAACATTGCCGGATGGCTACTAGGC



AACCCTGAATGTGACCCCCTGCTGCCAGTGCGAAGCTGGAGTTACATTGTGGAAACTCCC



AATAGTGAAAACGGTATCTGCTACCCTGGCGATTTCATTGATTATGAAGAGCTGAGGGAA



CAGCTTTCTAGTGTGTCGTCCTTCGAGAGGTTTGAGATCTTCCCCAAGGAGAGCTCATGG



CCAAACCACAATACAAACGGGGTCACTGCGGCATGTAGCCATGAGGGCAAGTCATCCTTC



TATCGAAACCTCCTGTGGCTGACCGAAAAGGAAGGTAGCTACCCCAAACTTAAAAACAGT



TATGTGAACAAAAAGGGCAAGGAAGTCTTAGTGCTTTGGGGCATCCACCACCCCCCAAAT



AGCAAAGAGCAACAGAATTTGTACCAGAACGAAAATGCTTATGTGTCTGTAGTAACCTCT



AACTATAACAGGCGTTTCACTCCCGAGATTGCCGAGCGACCGAAAGTTAGAGACCAGGCC



GGACGCATGAATTACTACTGGACCCTGTTGAAACCTGGAGATACGATAATCTTTGAGGCC



AACGGAAACCTGATAGCTCCTATGTATGCGTTCGCACTCAGTCGCGGGTTCGGGTCCGGG



ATAATCACCAGTAACGCGTCCATGCACGAGTGTAATACGAAGTGCCAGACCCCACTAGGA



GCGATTAACTCGTCTCTGCCATATCAGAATATCCATCCTGTGACAATCGGAGAGTGTCCT



AAATACGTCCGCTCAGCCAAACTGCGAATGGTGACGGGCCTTCGCAACAATCCCAGTATC



CAGTCTCGGGGACTCTTTGGAGCCATCGCCGGTTTTATCGAAGGCGGATGGACTGGGATG



ATCGATGGCTGGTACGGCTACCACCACCAAAATGAGCAAGGCTCCGGGTACGCTGCCGAC



CAGAAGTCAACTCAGAATGCAATTAACGGGATCACCAACAAGGTTAACACCGTAATCGAA



AAGATGAACATCCAGTTCACGGCCGTGGGGAAGGAGTTTAATAAACTTGAGAAACGGATG



GAGAACCTCAACAAAAAGGTGGACGACGGCTTTCTGGACATCTGGACCTATAATGCTGAG



CTTTTGGTGCTGCTGGAAAACGAGCGCACACTGGATTTCCACGATAGTAATGTGAAGAAC



CTGTACGAAAAGGTTAAGTCCCAACTCAAAAATAACGCGAAAGAAATCGGCAATGGGTGC



TTTGAATTTTATCACAAGTGTGACAACGAATGCATGGAATCTGTGCGGAATGGGACCTAC



GATTACCCAAAATATAGCGAAGAATCCAAGCTGAACAGAGAGAAGGTGGACGGCGTGAAA



CTCGAAAGTATGGGTATCTACCAAATCCTAGCCATCTACTCTACCGTTGCCAGTAGTCTA



GTGTTGCTGGTGTCGTTAGGTGCCATCTCTTTTTGGATGTGTAGCAATGGCTCTCTGCAA



TGTCGGATCTGTATC





492
ATGAAGGCCAACCTGCTTGTGCTGCTTTGCGCACTAGCCGCTGCAGACGCCGACACAATT



TGTATTGGATACCATGCTAATAACTCGACCGACACAGTTGACACAGTCCTTGAGAAGAAC



GTGACAGTTACTCACTCCGTGAACCTGCTCGAGGACTCGCATAATGGCAAACTCTGCCGT



CTGAAGGGTATCGCCCCCCTCCAACTGGGGAAATGCAATATAGCCGGCTGGCTGCTGGGA



AATCCAGAGTGCGATCCACTGTTGCCTGTGCGCAGTTGGAGTTATATCGTGGAGACACCC



AACTCAGAGAACGGTATCTGCTACCCTGGGGACTTCATAGATTATGAAGAGCTGCGCGAG



CAGCTATCTTCCGTTAGCTCTTTCGAACGCTTTGAAATCTTTCCTAAAGAAAGCAGCTGG



CCAAATCATAACACAAACGGAGTGACAGCTGCCTGCAGTCACGAGGGTAAAAGTTCTTTT



TATAGAAATCTCCTGTGGTTGACGGAGAAAGAGGGCAGCTATCCAAAGCTCAAGAATAGC



TACGTCAATAAAAAAGGTAAGGAGGTGCTAGTCTTATGGGGAATCCATCACCCACCCAAT



TCCAAGGAACAGCAGAACCTCTATCAGAACGAGAACGCCTATGTGTCCGTAGTGACTAGC



AACTATAATCGTAGATTCACACCTGAGATTGCAGAGAGACCCAAGGTTAGAGACCAAGCC



GGCCGCATGAATTATTACTGGACACTGCTTAAACCCGGGGATACTATCATCTTCGAAGCG



AATGGAAACCTGATCGCTCCAATGTATGCTTTTGCTCTGTCCAGGGGTTTTGGCTCGGGG



ATTATCACAAGCAACGCATCTATGCACGAGTGTAATACCAAGTGTCAGACCCCCCTTGGC



GCTATCAACTCTAGTCTACCGTACCAGAACATCCACCCTGTTACCATTGGTGAATGCCCG



AAATACGTGCGGAGTGCCAAGCTGAGAATGGTGACCGGCCTGAGGAACAATCCTTCCATC



CAGTCCCGGGGACTTTTCGGAGCTATCGCTGGCTTCATTGAAGGTGGGTGGACCGGCATG



ATCGACGGGTGGTATGGATATCACCATCAGAACGAGCAAGGAAGCGGGTATGCTGCAGAC



CAGAAGTCCACACAGAACGCAATAAACGGCATCACTAACAAAGTGAACACCGTGATTGAA



AAAATGAATATACAGTTTACCGCCGTAGGGAAGGAATTTAATAAACTGGAAAAGCGCATG



GAAAATTTGAACAAAAAAGTCGACGATGGTTTTTTAGACATTTGGACCTATAATGCGGAA



CTGCTAGTACTGCTCGAGAACGAACGGACCCTCGACTTTCACGATTCAAACGTCAAAAAT



CTATACGAGAAGGTGAAGTCGCAGCTGAAGAATAATGCCAAAGAAATCGGCAACGGATGT



TTCGAATTCTACCACAAATGCGACAATGAATGTATGGAATCTGTTAGAAACGGCACGTAT



GATTACCCCAAGTACAGCGAAGAATCTAAACTCAACCGGGAGAAAGTCGACGGAGTTAAG



CTTGAGTCCATGGGAATCTATCAGATCTTGGCGATCTATTCCACCGTGGCAAGTTCCCTC



GTATTGCTGGTGTCCCTTGGAGCAATTTCATTCTGGATGTGCAGTAACGGCAGCCTTCAA



TGCCGCATCTGTATA





493
ATGAAGGCAAACCTTCTTGTCCTGCTGTGCGCACTCGCCGCAGCCGACGCCGACACAATC



TGCATTGGGTATCACGCTAATAATTCAACTGACACTGTGGATACCGTACTGGAAAAGAAT



GTTACTGTGACTCATAGTGTAAATCTGCTCGAGGACAGTCACAATGGAAAACTTTGCCGG



TTAAAGGGCATCGCACCCCTGCAGCTGGGTAAGTGCAACATCGCGGGATGGCTGCTGGGC



AACCCCGAGTGTGATCCCCTGCTTCCAGTGCGGTCTTGGTCTTACATTGTCGAAACACCC



AACTCTGAAAACGGAATTTGTTACCCTGGCGACTTCATCGACTACGAAGAGCTTAGAGAG



CAGCTATCGAGCGTGAGTTCTTTTGAAAGATTTGAGATCTTCCCAAAGGAAAGCTCTTGG



CCCAACCATAATACTAATGGCGTCACAGCCGCCTGCTCACATGAAGGGAAGTCTTCTTTC



TACAGGAATCTGTTGTGGTTGACGGAGAAGGAGGGAAGTTATCCAAAGCTTAAAAATTCC



TACGTGAACAAGAAGGGTAAAGAGGTCCTGGTGCTCTGGGGCATCCACCATCCTCCGAAC



TCCAAAGAACAGCAGAATCTGTATCAGAACGAAAATGCATATGTCAGTGTGGTGACAAGT



AATTATAACCGCCGCTTTACCCCCGAGATCGCCGAACGCCCGAAGGTACGGGACCAAGCG



GGTCGGATGAACTACTATTGGACCCTGCTAAAGCCTGGGGACACTATCATCTTCGAGGCC



AACGGTAACCTGATCGCTCCCATGTATGCGTTTGCCCTGAGCAGAGGATTCGGCTCTGGA



ATCATAACGAGCAACGCCTCAATGCATGAATGCAACACTAAGTGTCAAACTCCCTTGGGC



GCAATAAACTCATCCTTGCCATATCAGAACATCCACCCAGTCACCATCGGGGAGTGCCCT



AAATATGTGCGTTCAGCCAAGTTACGCATGGTAACGGGACTCCGGAATAACCCCAGCATT



CAATCTCGAGGGCTTTTTGGAGCTATCGCAGGATTCATTGAAGGGGGCTGGACTGGGATG



ATCGATGGATGGTATGGGTACCATCATCAGAACGAGCAGGGCTCCGGCTACGCAGCCGAT



CAGAAGAGCACTCAGAACGCCATCAATGGCATCACAAACAAAGTCAACACTGTGATTGAA



AAAATGAATATACAGTTTACCGCAGTGGGTAAGGAATTCAACAAGCTGGAGAAACGGATG



GAAAATCTAAACAAGAAAGTGGATGATGGCTTTCTCGACATCTGGACCTACAACGCCGAA



CTGCTGGTCCTGCTGGAAAATGAGCGCACACTGGATTTCCACGACTCGAACGTCAAGAAT



CTATACGAGAAAGTGAAATCCCAGCTCAAGAATAATGCCAAGGAGATCGGCAACGGATGC



TTCGAATTTTACCATAAATGCGACAACGAGTGTATGGAGTCCGTCCGAAACGGGACATAC



GACTATCCCAAGTATTCAGAAGAGTCAAAGCTTAACCGCGAAAAGGTGGATGGCGTTAAG



CTGGAATCTATGGGTATTTACCAGATACTGGCCATTTATAGCACTGTGGCTAGCTCATTA



GTGCTGCTGGTGTCGCTGGGAGCGATTTCCTTTTGGATGTGTAGCAACGGGAGTTTACAG



TGCCGGATTTGCATC





494
ATGAAGGCTAACCTCCTGGTGCTGCTGTGTGCCCTGGCTGCAGCGGACGCCGACACGATC



TGTATCGGATACCATGCTAATAATTCTACCGACACTGTAGACACCGTGCTGGAAAAGAAT



GTTACAGTGACCCATAGTGTTAATCTCCTCGAAGATTCACACAACGGCAAGCTCTGCCGT



CTCAAAGGAATAGCACCTCTTCAGCTGGGCAAGTGTAACATCGCCGGGTGGCTTCTGGGC



AACCCCGAATGTGATCCCCTTCTGCCAGTCCGCTCATGGTCCTATATTGTGGAAACCCCT



AATTCCGAGAACGGAATTTGTTATCCCGGAGACTTTATTGATTATGAGGAACTTAGAGAA



CAACTGTCTTCGGTCTCGTCCTTTGAGAGGTTCGAGATTTTCCCTAAGGAGAGCTCCTGG



CCCAATCACAACACTAACGGTGTGACCGCCGCCTGCTCGCATGAGGGGAAGTCCTCTTTC



TACCGCAACCTCCTGTGGCTGACAGAGAAGGAGGGGTCCTATCCCAAACTAAAAAACTCA



TACGTGAACAAAAAGGGAAAAGAGGTCTTGGTTCTCTGGGGCATCCATCACCCACCAAAC



AGTAAGGAGCAGCAAAATCTGTACCAGAATGAAAACGCATATGTTAGCGTAGTGACCTCT



AACTATAACAGGCGGTTTACTCCAGAGATTGCCGAGCGGCCCAAAGTGCGAGACCAGGCA



GGAAGGATGAACTATTATTGGACTTTGTTAAAACCCGGAGACACAATTATCTTCGAGGCA



AACGGGAACTTGATCGCACCCATGTACGCCTTCGCACTGAGCAGGGGTTTCGGCTCCGGC



ATCATCACTTCTAATGCCTCTATGCACGAGTGTAATACGAAGTGTCAGACCCCATTGGGA



GCCATCAACTCCAGTCTGCCCTATCAGAACATCCATCCGGTGACTATAGGCGAATGCCCC



AAGTACGTCAGGTCCGCTAAGCTCCGCATGGTCACCGGACTTAGGAACAACCCGAGTATT



CAGAGCCGAGGCCTGTTCGGAGCCATCGCAGGGTTCATAGAGGGAGGGTGGACCGGGATG



ATAGATGGATGGTATGGCTACCATCATCAAAACGAACAGGGCAGCGGATATGCAGCTGAT



CAGAAGTCCACCCAGAACGCCATAAACGGAATCACCAACAAAGTGAACACCGTCATAGAA



AAAATGAACATACAGTTCACCGCCGTGGGCAAAGAATTCAATAAACTTGAAAAACGGATG



GAAAATTTGAATAAGAAGGTGGATGACGGCTTCCTGGATATCTGGACTTACAATGCGGAG



CTGCTCGTGCTTCTGGAGAACGAGAGAACGCTCGACTTCCACGATTCTAACGTTAAGAAC



CTGTATGAGAAAGTTAAAAGTCAGCTCAAAAATAACGCGAAGGAAATCGGGAACGGCTGC



TTTGAATTTTACCATAAATGCGATAATGAGTGCATGGAATCCGTGCGAAACGGCACGTAC



GACTATCCAAAGTATTCAGAGGAATCAAAATTGAACAGAGAAAAGGTCGATGGTGTGAAA



CTGGAGAGTATGGGGATATATCAAATCCTTGCGATCTACTCTACTGTGGCTTCTTCCCTG



GTCCTGCTGGTGTCCTTGGGGGCAATTTCATTTTGGATGTGTTCTAATGGGAGTTTACAG



TGCAGGATCTGCATA





495
ATGAAAGCCAATCTTCTGGTTCTGCTCTGCGCTCTAGCTGCTGCCGATGCTGACACTATT



TGTATAGGCTACCACGCAAATAATTCGACGGATACTGTCGACACGGTCCTGGAAAAAAAT



GTCACAGTGACTCATTCAGTTAATCTCTTGGAGGATTCTCACAATGGAAAGTTGTGTAGA



CTGAAGGGCATTGCTCCATTGCAGCTTGGGAAGTGTAATATCGCGGGCTGGTTACTGGGC



AACCCTGAATGCGACCCCCTCTTGCCTGTCCGGTCCTGGTCTTATATCGTGGAGACACCA



AATTCTGAGAATGGAATCTGCTATCCGGGTGACTTTATCGATTACGAGGAGCTTCGGGAG



CAGCTGTCTTCAGTGTCCAGTTTTGAAAGATTTGAGATATTTCCTAAGGAGAGCTCCTGG



CCAAATCATAATACCAATGGCGTGACAGCCGCATGTTCACACGAAGGAAAAAGCTCCTTC



TATCGGAACCTGCTCTGGCTTACAGAAAAGGAAGGCTCTTACCCCAAACTCAAGAACAGT



TACGTGAATAAGAAAGGTAAAGAGGTTCTAGTACTCTGGGGCATCCACCACCCGCCAAAC



AGCAAGGAGCAACAGAACCTCTATCAGAACGAGAATGCCTACGTGTCCGTGGTCACATCA



AACTATAACCGCAGGTTTACACCAGAAATTGCAGAGCGGCCTAAAGTCCGTGATCAGGCA



GGCAGGATGAACTATTACTGGACTTTGCTGAAGCCGGGAGACACCATTATCTTCGAGGCG



AATGGGAACCTCATTGCCCCAATGTACGCCTTCGCGCTCTCTCGCGGCTTTGGCTCAGGA



ATTATCACGTCAAATGCTTCTATGCACGAGTGTAATACAAAATGTCAGACCCCTCTGGGC



GCCATAAACTCTTCCCTGCCTTATCAAAATATTCACCCAGTGACTATTGGGGAGTGCCCC



AAATACGTTAGAAGCGCTAAACTGCGTATGGTAACGGGTTTGCGGAACAACCCAAGTATC



CAGAGCCGCGGCCTGTTTGGCGCCATTGCTGGTTTTATTGAGGGGGGTTGGACAGGAATG



ATCGATGGATGGTACGGCTACCACCATCAGAATGAACAGGGGAGTGGGTACGCCGCCGAC



CAAAAGTCCACACAGAATGCGATCAACGGGATCACTAACAAGGTGAACACCGTGATTGAG



AAGATGAACATACAGTTTACCGCAGTCGGAAAGGAATTCAACAAACTTGAAAAACGCATG



GAGAATCTGAATAAAAAAGTGGACGACGGATTTTTAGATATATGGACCTATAATGCCGAA



TTGCTGGTGCTCTTAGAAAACGAACGAACGCTGGACTTCCACGATTCTAACGTTAAAAAC



CTTTATGAGAAGGTTAAGAGCCAGTTGAAGAACAACGCGAAGGAAATCGGAAACGGATGC



TTCGAATTTTACCACAAGTGTGACAACGAGTGTATGGAATCTGTTAGAAATGGCACCTAC



GATTATCCAAAGTACTCAGAAGAAAGCAAACTTAACAGGGAAAAGGTGGATGGTGTGAAA



CTGGAGTCCATGGGTATCTACCAGATACTTGCAATCTACTCTACGGTTGCTTCAAGCTTG



GTGCTGCTTGTGAGCTTGGGAGCCATCTCATTTTGGATGTGTTCAAATGGCAGCTTACAG



TGTAGGATCTGCATA
















TABLE 17







Codon Optimized Sequences Encoding H7 Hemagglutinin








SEQ



ID



NO.
Nucleic Acid Sequence





496
ATGAATACACAGATCCTTGTATTTGCCCTGATCGCAATCATTCCTACTAATGCTGACAAG



ATTTGCCTCGGCCACCATGCGGTTAGTAATGGGACCAAAGTGAACACACTGACGGAGAGA



GGAGTAGAGGTAGTTAACGCCACCGAGACTGTGGAGAGAACTAACATCCCACGGATTTGT



TCCAAGGGTAAACGTACTGTGGATCTGGGGCAGTGCGGCTTGTTGGGTACCATCACTGGA



CCGCCACAGTGCGACCAGTTTCTGGAGTTTTCCGCCGACCTGATTATAGAACGCCGAGAA



GGCAGCGATGTCTGTTACCCCGGTAAATTCGTGAATGAAGAAGCCCTCCGCCAAATCCTG



CGTGAGAGTGGGGGCATTGACAAAGAGGCGATGGGCTTTACATACAGCGGGATACGCACC



AACGGCGCGACGTCAGCCTGCCGCAGGAGTGGAAGTTCTTTCTATGCCGAGATGAAGTGG



CTGTTGTCTAATACTGATAATGCAGCCTTCCCCCAGATGACAAAGTCGTACAAGAACACC



AGAAAGTCACCCGCACTCATTGTGTGGGGTATTCACCATTCTGTCTCTACTGCTGAGCAG



ACGAAACTGTATGGTTCTGGGAACAAGCTCGTGACCGTGGGGTCCAGCAACTATCAGCAG



AGCTTTGTGCCCTCCCCAGGAGAGAGGCCACAGGTGAATGGGTTGTCAGGCCGTATCGAT



TTCCACTGGCTTATGTTGAATCCAAACGACACAGTGACATTTTCTTTCAACGGCGCCTTC



ATTGCACCAGACAGAGCTAGCTTTCTGCGAGGGAAGAGTATGGGTATCCAGTCTGGTGTG



CAGGTCGACGCTAACTGTGAGGGGGATTGCTACCATAGCGGGGGAACAATTATTTCAAAC



CTGCCCTTCCAGAATATTGACAGCAGGGCAGTGGGAAAGTGCCCCCGCTATGTGAAACAG



AGATCTTTGTTGCTGGCCACCGGCATGAAGAACGTTCCCGAAATTCCTAAGGGCCGGGGG



CTTTTTGGGGCGATAGCCGGGTTCATTGAAAACGGGGTGGAGGGGCTAATCGATGGTTGG



TACGGTTTTAGGCATCAAAACGCCCAGGGCGAAGGCACTGCGGCCGACTACAAATCCACA



CAGAGCGCCATCGACCAAATCACTGGGAAACTTAACCGACTTATTGAGAAAACAAATCAA



CAGTTTGAGCTGATTGATAACGAATTTAATGAGGTAGAGAAGCAGATCGGCAATGTAATA



AACTGGACAAGGGACAGCATTACTGAAGTCTGGAGCTACAACGCCGAGTTGCTCGTCGCG



ATGGAGAATCAGCATACCATCGATTTAGCCGACTCAGAGATGGATAAGCTGTATGAACGC



GTAAAGAGGCAGCTGCGCGAGAACGCTGAAGAGGACGGGACTGGCTGCTTCGAAATTTTC



CACAAATGCGATGATGATTGTATGGCTTCCATCCGGAACAATACCTACGACCATTCTAAG



TACCGTGAAGAGGCCATGCAGAATAGGATCCAGATTGACCCAGTGAAGCTGAGCTCGGGT



TATAAAGACGTGATTTTGTGGTTCAGTTTTGGCGCCTCTTGTTTTATCCTTCTGGCAATT



GTTATGGGGTTGGTTTTCATCTGCGTCAAGAACGGCAACATGCGCTGTACTATTTGTATC





497
ATGAATACCCAGATTCTCGTCTTCGCACTGATAGCTATAATTCCAACCAATGCCGACAAG



ATATGCTTGGGACACCATGCGGTGTCTAACGGCACAAAGGTGAATACTCTGACAGAGAGA



GGAGTGGAGGTGGTTAACGCTACAGAGACTGTGGAAAGGACGAATATACCAAGGATATGC



TCCAAGGGCAAGAAGACCGTCGACCTCGGCCAGTGTGGCCTGCTTGGCACTATCACAGGT



CCCCCTCAATGCGATCAATTTCTGGAATTCTCTGCTGATCTGATAATCGAGCGCCGCGAG



GGGTCTGACGTATGCTATCCCGGGAAATTCGTGAATGAGGAGGCTCTGAGACAGATATTG



CGGGAGTCGGGGGGCATCGATAAAGAAGCTATGGGATTCACTTACTCGGGGATCAGAACA



AACGGAGCTACATCTGCGTGTCGGCGGTCTGGCAGCTCGTTTTATGCCGAGATGAAGTGG



CTGCTCTCCAATACAGACAATGCCGCATTCCCACAAATGACGAAAAGCTATAAAAATACT



CGCAAGTCACCCGCACTAATCGTGTGGGGCATCCACCACAGCGTGTCCACCGCAGAGCAG



ACCAAATTGTATGGTAGCGGCAATAAGCTGGTTACAGTGGGATCCTCCAACTACCAACAG



TCCTTCGTCCCAAGCCCAGGGGCCCGACCGCAAGTTAACGGTCAGTCCGGACGCATTGAT



TTTCACTGGCTGATGCTTAACCCAAACGACACAGTTACCTTTTCGTTTAACGGCGCTTTC



ATTGCCCCAGATCGGGCCTCTTTTCTGCGGGGTAAGAGCATGGGAATCCAGTCGGGGGTA



CAGGTCGACGCGAATTGTGAAGGCGATTGTTACCATTCTGGGGGCACTATTATATCAAAT



CTTCCATTCCAGAATATTGACTCGCGCGCTGTGGGCAAATGCCCCAGGTACGTTAAGCAG



CGATCACTGCTCCTCGCCACAGGTATGAAAAATGTTCCAGAGATTCCCAAGGGCAGGGGG



CTGTTCGGTGCAATCGCCGGCTTTATAGAAAATGGGTGGGAGGGACTCATCGATGGTTGG



TACGGTTTTAGGCATCAAAACGCCCAGGGGGAGGGGACGGCTGCCGATTACAAGTCTACC



CAGTCAGCTATAGACCAGATCACTGGGAAACTAAACAGGCTGATCGAGAAAACCAACCAG



CAGTTCGAACTGATTGACAACGAGTTCAACGAGGTTGAAAAGCAGATTGGTAACGTGATT



AACTGGACCAGAGACTCTATCACCGAGGTCTGGAGCTACAATGCAGAACTACTTGTGGCT



ATGGAAAACCAGCATACAATTGATCTTGCTGACTCTGAGATGGACAAGCTTTATGAGAGG



GTGAAGAGACAGCTTCGGGAGAACGCTGAGGAGGATGGAACCGGTTGTTTCGAGATCTTT



CACAAATGCGATGACGATTGCATGGCTAGCATTAGGAATAACACCTATGACCACTCTAAA



TACAGAGAGGAGGCTATGCAGAATCGCATCCAGATCGACCCAGTGAAGCTGTCCTCTGGA



TACAAGGACGTAATCCTGTGGTTCTCATTTGGGGCTTCGTGCTTCATCTTGCTGGCGATT



GTTATGGGCTTAGTGTTTATCTGCGTTAAAAACGGGAACATGCGGTGTACAATCTGTATC





498
ATGAACACACAGATTCTGGTCTTTGCCTTGATCGCAATAATTCCAACTAATGCCGACAAA



ATTTGTTTAGGTCATCACGCCGTTTCAAATGGAACTAAGGTCAACACCCTGACCGAGAGG



GGCGTCGAGGTCGTGAATGCCACAGAAACTGTGGAGAGAACCAACATCCCTCGCATCTGT



AGCAAGGGCAAGAAGACTGTCGATCTTGGACAGTGCGGTCTCCTGGGAACGATTACAGGC



CCCCCACAGTGCGACCAATTCCTAGAATTCTCTGCCGACTTAATCATCGAAAGGCGTGAG



GGATCTGACGTGTGCTATCCGGGAAAGTTCGTGAATGAGGAGGCCCTACGGCAGATTCTG



CGGAAATCCGGAGGTATAGACAAAGAGGCAATGGGCTTCACCTACAGTGGGATACGCACA



AATGGGGCCACATCCACTTGTCGGAGAAGCGGCTCTTCCTTTTATGCCGAGATGAAGTGG



CTCTTATCCAACACAGACAATGCCGCCTTCCCTCAGATGACGAAGAGCTACAAAAACACC



AGGAAGTCTCCAGCAATCATTGTTTGGGGCATCCACCATAGCGTCTCCACCGCTGAGCAA



ACCAAATTATATGGGTCCGGGAATAAATTGGTCACAGTCGGTAGCTCCAACTACCAGCAG



TCATTTGTCCCCTCACCGGGGGCTCGCCCACAAGTAAATGGTTTGTCTGGCAGAATCGAC



TTTCATTGGCTCATGCTCAATCCAAACGACACGGTGACTTTCAGCTTTAACGGGGCATTT



ATTGCCCCCGACCGAGCATGTTTTCTTAGAGGCAAAAGCATGGGGATTCAGAGCGGAGTC



CAGGTCGACGCGGATTGCGAGGGTGACTGCTACCACTCAGGGGGTACCATTATCTCCAAC



CTTCCTTTTCAGAATATCGATTCGAGAGCTGTGGGCAAGTGCCCTCGGTATGTTAAACAG



CGATCCCTCCTTCTGGCCACTGGTATGAAGAACGTGCCTGAGATACCCAAAGGGAGGGGC



CTGTTTGGGGCTATCGCTGGATTTATTGAGAATGGTTGGGAGGGCCTTATCGACGGCTGG



TACGGCTTTAGGCACCAGAACGCGCAGGGCGAAGGCACAGCTGCCGACTACAAAAGCACC



CAGAGCGCGATTGACCAGATCACCGGCAAATTGAACAGGCTTATCGAAAAAACGAACCAA



CAGTTTGAGCTAATTGACAATGAGTTTAACGAGGTCGAGAGGCAGATTGGGAACGTCATC



AACTGGACAAGAGACAGCATTACCGAGGTGTGGTCTTACAATGCAGAGTTGCTAGTGGCC



ATGGAAAACCAACATACGATCGACCTCGCGGATTCTGAGATGGATAAGCTCTATGAAAGG



GTGAAAAGGCAGCTGCGGGAAAATGCTGAGGAAGACGGAACAGGATGTTTTGAAATCTTC



CACAAATGTGATGATGACTGTATGGCCTCTATAAGGAACAACACCTATGATCATTCCAAG



TATCGAGAAGAGGCCATGCAGAACCGTATCCAGATTGACCCTGTAAAACTCAGTTCAGGG



TACAAGGATGTGATCCTGTGGTTCAGCTTTGGCGCAAGCTGTTTCATTCTTCTCGCGATT



GTGATGGGGCTAGTGTTCATTTGTGTGAAAAATGGAAATATGAGATGTACCATTTGTATC





499
ATGAACACCCAGATTCTGGTCTTCGCTCTGATTGCTATTATCCCAACCAATGCAGACAAG



ATCTGTCTGGGGCACCATGCTGTGTCGAACGGCACGAAAGTGAACACACTGACCGAAAGA



GGAGTCGAGGTGGTGAACGCGACCGAGACAGTGGAGCGGACAAACATCCCACGTATCTGC



TCCAAGGGCAAGCGTACAGTGGACTTGGGGCAATGTGGCCTCCTTGGAACGATCACAGGA



CCACCGCAGTGCGACCAGTTTCTGGAGTTTTCTGCCGATTTAATCATCGAAAGGCGGGAG



GGTTCCGACGTTTGTTACCCGGGGAAGTTCGTTAACGAGGAAGCCCTGAGACAGATCCTA



CGTGAGAGCGGCGGTATCGACAAGGAGGCTATGGGCTTTACATATAGCGGAATTAGAACA



AACGGCGCTACCAGCGCCTGCCGCCGCAGCGGTTCATCTTTTTATGCCGAAATGAAGTGG



CTGCTCTCCAACACCGACAACGCCGCTTTTCCACAGATGACGAAATCCTATAAGAATACC



AGGAAAAGTCCAGCTCTGATTGTGTGGGGGATACACCACTCTGTGTCAACAGCGGAACAG



ACAAAGCTCTATGGAAGCGGAAACAAACTCGTAACGGTCGGCAGTTCCAACTATCAGCAA



TCCTTTGTGCCAAGTCCAGGCGCGCGTCCTCAGGTGAACGGCCTAAGTGGGAGAATCGAT



TTCCATTGGTTAATGCTTAATCCAAATGACACCGTGACCTTTAGCTTTAACGGCGCCTTT



ATTGCTCCCGACCGAGCTTCTTTCCTTAGAGGTAAGTCAATGGGTATCCAGAGCGGCGTG



CAGGTTGACGCAAACTGTGAAGGCGATTGTTACCACTCCGGAGGCACTATCATTAGCAAC



TTGCCATTTCAGAACATAGATTCACGCGCTGTGGGAAAGTGCCCTAGGTACGTGAAGCAG



AGGTCCCTGTTGCTCGCTACGGGCATGAAGAACGTGCCAGAGATTCCCAAAGGCAGAGGG



TTGTTCGGTGCCATTGCTGGTTTCATTGAGAATGGTTGGGAGGGCCTGATCGACGGGTGG



TACGGTTTCCGTCACCAGAATGCTCAAGGGGAGGGTACAGCAGCCGACTATAAATCCACC



CAGAGCGCAATCGATCAAATTACCGGCAAGCTAAATAGGCTGATTGAAAAAACTAATCAG



CAGTTCGAGCTCATAGACAATGAGTTCAACGAAGTGGAAAAGCAGATTGGCAACGTCATC



AATTGGACCAGAGATTCCATCACCGAGGTGTGGTCTTATAATGCCGAGCTGTTGGTTGCC



ATGGAAAATCAGCATACAATAGACCTGGCCGACTCCGAAATGGATAAACTGTACGAGAGG



GTTAAACGCCAACTGCGTGAGAATGCAGAGGAAGACGGAACAGGTTGTTTCGAGATCTTT



CACAAATGCGACGACGACTGCATGGCCTCCATAAGGAATAATACATATGATCATAGCAAA



TACAGGGAGGAGGCAATGCAAAACCGGATTCAGATTGATCCTGTGAAGCTGAGCAGCGGC



TACAAGGACGTTATTCTTTGGTTCAGTTTCGGTGCATCATGCTTCATACTCCTGGCAATA



GTGATGGGTCTGGTGTTCATCTGCGTGAAAAACGGAAATATGAGGTGCACCATATGCATC





500
ATGAATACCCAAATACTCGTCTTTGCTCTCATCGCTATCATTCCTACGAATGCCGACAAA



ATATGCCTAGGACATCACGCCGTGAGCAATGGGACAAAGGTGAATACCTTAACCGAAAGA



GGCGTGGAGGTCGTGAACGCCACAGAGACTGTGGAGCGCACCAATATACCTAGAATCTGC



TCAAAGGGCAAGAAAACAGTGGACCTAGGACAGTGTGGGCTTCTGGGGACGATCACTGGG



CCACCACAGTGCGACCAGTTCCTGGAGTTCAGCGCGGACCTGATCATCGAACGCCGAGAG



GGCTCTGATGTGTGCTACCCTGGCAAGTTTGTGAACGAGGAGGCTCTTAGGCAGATTCTC



AGGGAATCCGGCGGAATTGACAAGGAAGCTATGGGCTTCACTTATAGTGGAATCCGCACC



AATGGGGCAACGTCCGCTTGTAGGAGATCCGGGAGCAGTTTTTATGCAGAAATGAAATGG



CTGCTTAGTAACACGGACAACGCCGCTTTTCCGCAGATGACTAAGTCCTACAAGAACACC



CGCAAATCACCAGCTCTGATTGTGTGGGGGATTCACCATTCCGTGAGCACAGCCGAGCAG



ACAAAGTTGTATGGCTCTGGAAATAAACTCGTGACTGTGGGCAGTTCGAACTACCAGCAG



TCTTTTGTGCCTTCTCCCGGAGCCCGTCCCCAGGTCAACGGGCAGTCCGGAAGAATTGAT



TTCCACTGGTTGATGCTCAACCCGAATGATACAGTGACTTTTAGCTTCAACGGCGCTTTT



ATTGCCCCTGATCGTGCCAGCTTCCTTAGGGGCAAATCCATGGGGATTCAGTCAGGAGTT



CAGGTAGATGCCAATTGTGAGGGAGATTGTTACCACTCAGGGGGTACGATCATCAGCAAC



TTGCCATTTCAGAACATCGACAGTCGGGCAGTGGGCAAATGCCCACGTTACGTGAAGCAA



CGGAGTCTCCTGTTAGCCACAGGGATGAAAAATGTTCCAGAGATCCCTAAGGGCCGGGGA



CTGTTCGGGGCCATTGCCGGATTTATCGAGAATGGATGGGAGGGACTTATTGATGGTTGG



TACGGCTTTCGGCATCAGAATGCCCAAGGGGAGGGCACAGCTGCCGACTATAAATCAACC



CAGTCTGCAATAGATCAAATCACCGGTAAGCTGAATCGCCTTATCGAAAAAACGAACCAA



CAATTCGAGCTGATCGATAACGAATTCAATGAAGTGGAGAAACAGATTGGGAATGTTATT



AACTGGACAAGAGACAGCATAACCGAAGTCTGGTCCTATAATGCCGAGTTACTTGTGGCC



ATGGAAAACCAGCATACGATTGACTTAGCCGACTCCGAGATGGACAAGTTGTATGAGCGG



GTGAAGAGACAGTTACGGGAGAACGCCGAAGAGGACGGGACTGGTTGTTTTGAAATCTTC



CATAAGTGTGACGACGACTGCATGGCCAGTATTCGCAATAACACCTACGACCATAGCAAG



TACAGGGAAGAAGCCATGCAGAATCGTATTCAGATCGATCCTGTCAAACTTAGTAGTGGG



TACAAGGACGTTATCCTGTGGTTTTCTTTTGGGGCCTCCTGTTTCATTCTTCTGGCTATT



GTAATGGGACTGGTTTTCATATGTGTGAAAAATGGTAACATGCGGTGCACTATATGTATC





501
ATGAATACTCAGATTCTAGTGTTCGCTTTGATAGCTATAATCCCAACCAACGCCGACAAA



ATATGCCTGGGGCACCACGCAGTATCCAACGGGACCAAGGTCAATACCCTGACCGAACGG



GGTGTGGAAGTCGTGAACGCCACAGAGACCGTTGAGAGAACAAACATCCCTAGAATTTGT



AGCAAAGGGAAGAGGACTGTCGACTTGGGGCAGTGCGGGTTACTGGGAACAATCACTGGC



CCACCCCAGTGTGACCAGTTCCTCGAGTTCTCTGCTGATCTTATCATTGAGAGAAGAGAG



GGCAGTGACGTGTGTTATCCTGGAAAATTCGTAAACGAGGAGGCGCTTAGGCAGATTCTG



CGCGAATCAGGAGGTATCGATAAAGAGGCAATGGGGTTTACTTACAGCGGTATCCGAACC



AACGGCGCTACATCTGCATGCCGCAGGTCTGGCTCATCTTTCTATGCAGAGATGAAGTGG



TTGCTCTCTAACACCGATAATGCGGCATTTCCTCAGATGACCAAGAGCTACAAGAACACC



AGAAAATCCCCCGCGTTGATCGTGTGGGGCATCCACCATTCAGTGTCCACCGCTGAGCAG



ACAAAACTCTACGGATCTGGGAACAAGTTGGTGACTGTGGGGTCCTCTAACTACCAGCAA



TCGTTTGTGCCATCCCCAGGGGCTAGACCCCAGGTCAACGGTCTCTCTGGCCGGATCGAC



TTCCACTGGCTTATGCTTAACCCAAACGATACCGTCACCTTTAGCTTTAATGGTGCTTTC



ATTGCCCCCGACCGGGCAAGCTTCTTACGAGGCAAGAGTATGGGAATACAGAGTGGGGTT



CAAGTGGATGCCAACTGCGAGGGCGACTGTTACCACAGCGGCGGCACCATAATTTCAAAT



CTGCCGTTCCAGAATATAGACTCTCGAGCTGTTGGGAAGTGCCCCCGATACGTAAAGCAG



CGCTCTCTGTTACTGGCCACCGGCATGAAAAATGTTCCTGAGATACCGAAGGGACGTGGC



CTCTTCGGGGCCATCGCCGGGTTCATCGAGAACGGCTGGGAAGGACTGATCGATGGATGG



TACGGATTCAGGCATCAGAATGCTCAGGGAGAAGGGACGGCTGCAGATTATAAGTCTACA



CAGTCCGCCATCGATCAGATCACCGGTAAGCTTAATAGAATCATAGAGAAGACGAACCAG



CAGTTCGAGCTGATCGATAACGAGTTTAATGAGGTCGAAAAGCAGATTGGCAACGTGATA



AATTGGACAAGAGACAGTATTACTGAAGTGTGGTCCTACAACGCCGAGCTTTTGGTGGCC



ATGGAAAACCAACACACCATCGACTTAGCAGATTCCGAGATGGATAAACTTTACGAGCGA



GTAAAAAGACAGCTCAGGGAGAATGCTGAAGAAGACGGCACAGGATGTTTCGAGATTTTC



CACAAGTGTGATGACGATTGCATGGCATCAATTCGCAACAACACTTACGATCATAGCAAG



TATCGCGAGGAGGCCATGCAGAACCGCATCCAAATTGATCCTGTCAAGCTAAGTTCCGGG



TATAAAGACGTGATTTTGTGGTTTTCTTTTGGCGCTAGCTGCTTTATTCTACTGGCTATT



GTCATGGGCTTGGTTTTCATCTGCGTGAAAAATGGCAATATGCGCTGCACTATATGTATC





502
ATGAATACACAAATTCTGGTCTTCGCCTTGATTGCCATTATACCAACTAATGCCGATAAG



ATTTGCCTCGGGCACCATGCCGTCTCCAATGGCACAAAAGTCAACACACTGACTGAACGA



GGGGTCGAGGTGGTCAACGCCACTGAAACCGTGGAAAGGACCAACATCCCCCGCATTTGC



AGCAAGGGTAAAAAAACGGTAGACCTGGGACAGTGTGGGCTGCTAGGTACTATTACCGGC



CCCCCACAATGTGACCAATTCTTAGAGTTCTCCGCTGACTTGATAATTGAACGGAGAGAG



GGTTCTGACGTGTGCTACCCTGGGAAGTTTGTAAATGAAGAAGCCCTTCGACAGATTCTC



AGGGAGTCCGGGGGTATTGATAAGGAGGCCATGGGATTTACGTACAGCGGAATTCGGACT



AATGGGGCCACTTCGGCCTGCCGGCGCTCTGGTTCCTCCTTTTATGCAGAGATGAAATGG



CTCCTATCCAACACGGATAACGCCGCCTTCCCACAGATGACAAAATCCTACAAGAACACT



CGGAAGAGCCCAGCGCTGATTGTGTGGGGTATTCACCATAGCGTGTCCACTGCCGAGCAG



ACGAAGCTGTACGGAAGTGGCAACAAATTGGTCACTGTAGGCTCATCTAATTACCAGCAG



AGCTTTGTTCCTTCCCCTGGGGCAAGGCCACAAGTGAATGGCCAAAGTGGTAGAATCGAT



TTCCACTGGCTCATGTTGAATCCTAATGACACGGTAACTTTCAGTTTCAACGGCGCTTTC



ATTGCACCCGACCGGGCTTCATTTCTCCGGGGGAAGTCCATGGGGATCCAGTCAGGAGTC



CAGGTCGATGCTAATTGTGAAGGCGATTGTTACCACTCCGGTGGGACCATCATTAGCAAT



CTGCCATTTCAGAACATCGATTCCAGAGCAGTCGGCAAGTGCCCTAGATATGTGAAGCAG



AGGAGCCTGCTGCTAGCTACGGGTATGAAAAATGTGCCAGAGATCCCAAAGGGGGGGGGT



CTTTTCGGTGCCATAGCTGGATTTATCGAGAATGGCTGGGAGGGTCTGATCGACGGATGG



TACGGGTTCAGGCATCAGAATGCCCAGGGGGAGGGCACTGCCGCCGACTATAAGTCTACA



CAAAGCGCTATTGACCAAATTACCGGTAAGCTGAACAGACTGATCGAGAAGACAAACCAG



CAGTTCGAGCTCATCGATAATGAATTCAACGAGGTAGAAAAGCAAATCGGCAACGTGATT



AACTGGACCAGGGATTCTATCACTGAGGTGTGGTCATACAACGCGGAGCTGCTCGTTGCC



ATGGAAAATCAGCACACTATTGACCTGGCCGACAGCGAAATGGACAAGCTGTACGAAAGA



GTGAAACGACAGCTGCGGGAGAACGCCGAAGAGGACGGGACTGGTTGTTTCGAAATCTTC



CATAAGTGCGATGACGACTGTATGGCTTCAATCAGGAACAACACATACGACCACTCTAAG



TACAGAGAGGAGGCTATGCAGAATCGTATCCAGATTGACCCTGTAAAACTCTCCTCTGGG



TACAAAGACGTGATCCTGTGGTTTTCGTTCGGCGCATCCTGCTTCATCCTGCTCGCGATC



GTCATGGGATTAGTGTTCATTTGCGTCAAAAATGGCAATATGAGGTGTACCATTTGCATC





503
ATGAATACTCAGATCCTAGTGTTTGCTCTCATTGCTATAATCCCCACAAATGCTGACAAG



ATCTGCTTGGGCCATCACGCCGTGAGTAACGGCACTAAGGTGAATACGCTGACGGAACGG



GGTGTAGAAGTTGTAAACGCCACCGAAACAGTCGAAAGGACAAACATCCCGCGCATCTGC



AGTAAAGGTAAAAAGACCGTTGACCTCGGCCAATGCGGACTGCTGGGGACTATCACCGGA



CCCCCCCAATGTGATCAATTTCTGGAGTTCAGTGCGGACTTGATAATCGAAAGACGGGAA



GGTTCCGATGTGTGCTATCCAGGCAAGTTCGTTAATGAGGAAGCACTCCGGCAAATTCTT



CGGGAAAGCGGGGGCATAGACAAGGAAGCCATGGGCTTTACTTACAGCGGAATCCGCACA



AACGGAGCAACATCCGCTTGCAGGAGAAGTGGTAGTTCTTTTTATGCCGAGATGAAATGG



TTGCTGAGCAATACCGACAACGCAGCCTTTCCACAGATGACCAAGAGCTACAAAAATACA



AGAAAGTCCCCAGCTCTGATTGTGTGGGGAATACACCATAGCGTTAGCACAGCCGAACAA



ACAAAGCTGTACGGTTCAGGAAATAAACTTGTGACGGTAGGATCCAGCAATTATCAGCAA



TCTTTCGTGCCATCACCAGGCGCTCGGCCTCAGGTCAACGGGCAGTCGGGCCGTATAGAT



TTTCATTGGCTGATGCTGAATCCTAATGATACTGTGACCTTTAGCTTTAACGGGGGGTTC



ATAGCCCCCGATCGGGCATCTTTTCTCAGGGGTAAAAGCATGGGTATTCAGAGTGGAGTG



CAGGTTGACGCCAATTGCGAGGGAGATTGCTATCATTCCGGGGGGACCATTATTTCCAAC



CTCCCCTTCCAGAACATCGACAGCCGAGCTGTCGGCAAATGCCCCAGGTATGTGAAACAA



CGCAGCCTGTTGTTAGCAACAGGGATGAAGAATGTTCCTGAAATTCCAAAAGGGCGAGGT



CTGTTCGGCGCTATCGCAGGGTTCATTGAGAACGGTTGGGAGGGCCTGATCGATGGCTGG



TATGGCTTTAGGCACCAAAACGCACAGGGCGAAGGGACTGCCGCAGACTACAAATCTACA



CAGTCAGCGATTGATCAAATCACTGGCAAACTGAACCGCCTCATTGAGAAGACCAACCAG



CAGTTCGAACTGATAGACAATGAGTTCAATGAGGTTGAAAAGCAGATAGGTAATGTGATA



AATTGGACCAGAGATAGTATAACTGAAGTCTGGTCCTATAACGCCGAGTTACTTGTCGCT



ATGGAGAACCAGCACACAATTGACCTGGCGGACAGCGAGATGGATAAGCTGTACGAACGC



GTAAAAAGACAACTGCGCGAGAATGCGGAGGAGGACGGCACCGGGTGTTTCGAGATCTTT



CACAAGTGTGATGATGATTGTATGGCCTCCATTAGAAACAACACCTATGATCACTCCAAA



TACCGGGAGGAAGCAATGCAGAACCGCATACAGATTGACCCCGTCAAGTTGAGTTCCGGG



TATAAAGACGTGATACTCTGGTTCAGTTTTGGTGCCTCTTGCTTTATCCTGCTTGCCATC



GTGATGGGACTGGTGTTTATTTGCGTTAAAAACGGGAATATGCGTTGTACGATTTGTATA





504
ATGAATACCCAGATTCTTGTGTTCGCCCTCATTGCCATCATCCCCACCAATGCCGACAAG



ATTTGCTTGGGACATCACGCTGTGAGTAATGGCACAAAAGTAAATACGTTAACCGAACGC



GGGGTTGAAGTGGTGAATGCTACAGAGACGGTAGAGCGCACAAACATCCCGAGAATTTGC



TCCAAAGGCAAAAAGACTGTTGACCTTGGCCAGTGCGGGCTGCTGGGTACGATTACTGGG



CCACCTCAGTGCGATCAGTTCCTAGAATTTTCAGCAGATTTAATCATCGAAAGACGTGAA



GGATCAGATGTGTGTTATCCCGGAAAGTTCGTGAATGAGGAGGCTTTGAGACAGATCTTG



CGTGAATCTGGGGGCATAGATAAGGAAGCCATGGGGTTTACTTATTCTGGAATCCGCACT



AATGGGGCCACCAGCGCATGTAGGCGCTCCGGATCCTCATTCTATGCCGAGATGAAGTGG



CTTCTCAGTAACACAGATAATGCCGCCTTCCCCCAAATGACAAAGAGCTACAAGAATACA



CGGAAAAGCCCCGCCCTGATCGTATGGGGGATTCATCATTCTGTTAGCACTGCCGAGCAA



ACCAAACTGTACGGCTCAGGAAATAAGCTCGTGACGGTAGGGTCATCAAACTACCAGCAG



AGCTTCGTACCTTCCCCCGGCGCTAGACCTCAGGTCAACGGTCAGTCCGGACGAATTGAT



TTCCACTGGTTAATGCTCAACCCAAATGACACCGTCACATTCAGTTTTAACGGTGCCTTT



ATTGCTCCTGACAGAGCCTCTTTTCTGAGGGGCAAGTCCATGGGCATCCAGAGCGGGGTA



CAGGTCGACGCCAATTGCGAGGGCGACTGCTACCATTCAGGGGGGACGATCATTAGTAAC



TTACCCTTTCAAAACATTGATTCACGGGCCGTAGGCAAGTGTCCGAGATACGTCAAGCAG



CGGAGCTTGCTGTTGGCAACTGGCATGAAAAACGTTCCCGAAATCCCTAAGGGCCGAGGT



CTTTTTGGGGCAATTGCGGGCTTCATAGAGAATGGTTGGGAGGGACTGATCGATGGGTGG



TATGGCTTCAGACATCAGAACGCACAGGGTGAGGGTACCGCTGCTGACTATAAGAGCACC



CAGAGCGCAATAGATCAGATCACTGGCAAGCTTAACCGACTTATCGAAAAGACCAACCAG



CAGTTTGAATTGATTGACAACGAATTTAACGAAGTTGAGAAGCAAATTGGGAACGTTATT



AATTGGACAAGGGATTCCATCACAGAGGTTTGGAGTTACAATGCGGAGTTATTAGTGGCA



ATGGAGAACCAACATACTATTGACCTTGCGGATAGCGAGATGGACAAGCTGTACGAGAGG



GTCAAGCGCCAGTTACGGGAAAACGCGGAAGAGGATGGAACTGGATGTTTCGAGATCTTC



CACAAATGCGATGACGATTGCATGGCGTCGATCCGAAACAATACCTACGATCACAGTAAA



TACAGGGAAGAGGCAATGCAGAACCGAATTCAGATTGATCCCGTGAAGCTCAGCTCAGGG



TACAAGGACGTGATTCTGTGGTTTTCATTTGGAGCTAGCTGCTTTATACTGCTGGCTATT



GTTATGGGCTTGGTATTCATCTGTGTGAAGAATGGTAACATGAGGTGTACAATTTGCATT





505
ATGAATACTCAGATCCTGGTGTTTGCTCTGATAGCTATCATCCCCACCAACGCCGATAAG



ATTTGCCTGGGCCACCACGCAGTGAGTAACGGGACAAAAGTCAACACTCTAACTGAGCGC



GGCGTTGAAGTTGTAAATGCCACTGAAACTGTTGAGAGAACTAATATACCCCGCATTTGC



TCAAAAGGCAAGAGGACTGTGGATCTCGGCCAGTGTGGGCTTCTGGGGACCATAACTGGT



CCGCCCCAATGTGACCAGTTCTTGGAGTTTTCCGCAGACCTAATTATCGAGCGTCGCGAA



GGCTCCGATGTGTGCTACCCCGGCAAGTTTGTCAATGAAGAAGCCCTGAGGCAGATTCTG



CGAGAAAGCGGGGGTATAGACAAAGAAGCTATGGGCTTTACTTATAGCGGAATTCGTACA



AACGGCGCTACATCCGCCTGTCGACGGTCTGGTTCTAGCTTCTATGCTGAGATGAAATGG



TTGCTTAGCAACACAGACAATGCCGCTTTCCCCCAGATGACTAAAAGTTATAAAAATACC



CGGAAGAGCCCCGCACTTATCGTATGGGGGATCCATCACAGTGTGTCGACTGCCGAACAG



ACCAAGCTCTACGGGAGCGGCTCCAAGCTGGTGACAGTGGGGTCTTCTAATTACCAACAA



TCCTTTGTCCCTTCCCCTGGCGCCCGCCCCCAAGTGAATGGGCTAAGCGGAAGGATTGAC



TTTCATTGGCTGATGCTGAATCCCAACGATACAGTGACGTTCAGCTTTAACGGGGCGTTT



ATTGCCCCTGACCGTGCAAGTTTTCTCCGCGGGAAATCCATGGGCATCCAAAGCGGCGTC



CAAGTGGATGCAAACTGCGAAGGAGACTGCTATCACTCTGGAGGAACTATTATTTCTAAC



CTGCCTTTCCAGAACATCGACTCAAGGGCCGTGGGGAAATGCCCGCGCTATGTTAAACAG



AGAAGCCTGTTGCTTGCCACAGGTATGAAGAACGTGCCCGAGATCCCTAAGGGCAGAGGG



CTGTTCGGCGCAATCGCAGGGTTCATTGAAAACGGATGGGAGGGCCTCATCGACGGATGG



TACGGTTTTCGGCACCAAAACGCACAGGGGGAGGGCACAGCGGCGGATTATAAGAGCACT



CAGAGTGCCATAGATCAGATTACGGGGAAGCTCAATAGACTTATAGAGAAGACCAATCAG



CAATTCGAGCTGATCGATAACGAGTTCAATGAGGTAGAAAAGCAGATTGGGAATGTCATC



AACTGGACAAGAGATAGTATAACAGAGGTGTGGAGCTACAACGCCGAGTTACTTGTGGCC



ATGGAAAACCAGCACACAATCGACCTGGCTGATAGCGAAATGGACAAGCTGTATGAAAGA



GTCAAGAGACAGCTTCGAGAAAACGCAGAGGAGGACGGAACCGGCTGCTTCGAGATTTTT



CACAAATGTGACGATGATTGCATGGCGTCAATCCGGAACAACACCTATGACCACTCTAAG



TATCGAGAGGAGGCGATGCAGAACCGGATACAGATCGATCCTGTTAAGCTTTCATCAGGT



TACAAGGACGTAATCCTGTGGTTCTCGTTCGGCGCATCCTGCTTTATCCTTCTGGCAATT



GTGATGGGGCTCGTATTCATCTGCGTGAAAAATGGCAATATGAGATGTACTATTTGCATT





506
ATGAATACACAGATCCTTGTGTTCGCACTGATCGCGATTATCCCCACCAACGCAGACAAG



ATCTGTTTAGGCCACCATGCTGTGAGCAATGGGACAAAAGTCAACACGCTGACAGAGCGG



GGAGTGGAGGTGGTAAACGCTACTGAAACGGTCGAGAGAACTAACATTCCTAGAATTTGT



TCAAAAGGGAAAAGGACCGTGGATCTGGGCCAGTGTGGGCTGCTGGGAACAATCACTGGG



CCACCACAATGCGATCAGTTTTTAGAGTTCTCGGCCGACCTAATCATAGAGCGCAGAGAG



GGCTCCGATGTATGCTATCCCGGGAAGTTTGTGAATGAAGAAGCTTTAAGGCAGATTCTT



AGAGAATCCGGTGGGATTGACAAGGAGGCAATGGGGTTTACATACTCCGGTATTAGAACA



AACGGGGCCACCTCCGCGTGCAGGAGAAGCGGCTCCTCTTTTTATGCTGAGATGAAATGG



CTGCTGTCAAACACCGACAACGCCGCATTTCCCCAAATCACCAAGTCCTACAAGAATACA



AGAAAGTCTCCAGCCCTGATTGTTTGGGGGATACACCACTCAGTGTCCACCGCTGAACAG



ACCAAGTTGTATGGTAGCGGAAACAAGCTGGTGACCGTCGGGTCCTCAAATTATCAGCAG



TCATTTGTCCCATCTCCGGGCGCTAGGCCTCAGGTGAATGGGCTGAGTGGACGCATTGAC



TTCCACTGGCTTATGCTGAATCCTAATGACACAGTTACATTTAGTTTCAACGGGGCATTT



ATTGCGCCAGATAGAGCCAGTTTCTTGCGCGGCAAATCTATGGGAATCCAGAGCGGCGTT



CAAGTGGACGCCAACTGTGAGGGGGACTGCTACCACAGCGGCGGGACAATTATCAGCAAC



CTGCCATTCCAGAATATTGATTCACGGGCTGTGGGAAAGTGTCCTAGGTACGTCAAACAG



CGGTCTCTGCTGTTAGCAACCGGAATGAAGAATGTACCCGAGATCCCTAAAGGCCGAGGG



TTGTTCGGCGCAATTGGGGGCTTCATTGAGAATGGTTGGGAGGGTCTCATCGATGGTTGG



TACGGCTTCAGACACCAGAATGCCCAAGGCGAAGGAACTGCAGCCGACTATAAGTCAACT



CAAAGCGCAATCGACCAGATCACAGGGAAACTGAATCGCTTGATCGAAAAGACCAACCAG



CAATTCGAGCTGATCGACAATGAGTTTAACGAGGTCGAGAAGCAGATCGGAAATGTGATT



AATTGGACTCGAGACTCAATTACCGAGGTTTGGAGTTACAATGCCGAACTGCTGGTGGCC



ATGGAGAATCAACATACCATAGATCTCGCCGATAGCGAGATGGATAAACTGTATGAACGA



GTTAAGCGACAACTGAGAGAAAACGCCGAAGAAGACGGAACCGGGTGCTTTGAAATCTTC



CACAAATGCGATGATGATTGTATGGCTTCAATTCGCAACAACACCTACGATCACAGCAAG



TACCGAGAAGAGGCCATGCAAAACCGGATTCAAATCGATCCAGTGAAGCTGAGTTCTGGA



TATAAGGATGTGATTCTGTGGTTTTCATTTGGGGCTAGCTGTTTCATTCTTCTTGCCATC



GTGATGGGTCTCGTGTTTATTTGTGTCAAGAATGGGAACATGCGCTGCACGATATGCATC





507
ATGAACACCCAAATTCTAGTTTTCGCCCTTATCGCCATCATACCGACAAACGCAGACAAA



ATATGTCTCGGACACCACGCGGTGAGTAATGGCACCAAGGTGAACACTCTTACCGAGCGA



GGGGTGGAGGTGGTGAATGCAACAGAAACCGTGGAGCGCACCAACATCCCCCGGATTTGT



TCAAAGGGAAAAAAGACAGTCGACCTGGGGCAGTGTGGGCTCCTGGGCACTATCACTGGG



CCCCCGCAGTGCGACCAATTCCTGGAGTTTAGCGCAGACCTGATCATCGAAAGAAGGGAG



GGGTCAGACGTGTGTTACCCGGGAAAGTTCGTGAACGAAGAGGCACTTCGCCAGATATTA



AGAGAGAGCGGCGGGATTGATAAAGAAGCTATGGGCTTCACCTATTCTGGCATTAGGACC



AATGGCGCCACAAGTGCCTGTAGGAGATCAGGCTCGAGCTTCTACGCTGAGATGAAATGG



CTCCTGTCGAACACAGACAACGCCGCTTTTCCTCAGATGACGAAATCCTATAAAAACACG



CGGAAGTCTCCTGCGCTCATTGTGTGGGGAATTCATCACAGTGTGTCTACCGCTGAGCAG



ACAAAGCTTTACGGTTCCGGAAATAAATTAGTGACAGTTGGCTCTAGTAACTATCAGCAA



AGTTTCGTACCATCCCCGGGAGCGAGACCGCAGGTAAATGGACAGTCCGGGCGGATAGAT



TTCCATTGGCTCATGCTGAATCCTAATGACACCGTCACATTCAGCTTTAACGGGGCATTC



ATCGCACCCGATCGAGCTAGTTTTCTTCGCGGCAAGTCTATGGGAATTCAATCTGGCGTA



CAGGTGGATGCCAATTGCGAGGGTGATTGCTACCACTCTGGGGGTACCATCATCTCGAAC



CTCCCTTTTCAAAACATCGATAGCAGAGCCGTGGGCAAGTGCCCTCGATATGTTAAGCAG



AGAAGCCTGCTGCTCGCAACCGGCATGAAGAACGTGCCTGAGATTCCTAAGGGCCGCGGC



TTATTCGGCGCCATTGCTGGCTTCATCGAAAATGGCTGGGAAGGTTTAATCGATGGATGG



TATGGGTTCCGCCATCAGAACGCTCAAGGTGAGGGCACTGCCGCCGATTACAAAAGCACC



CAGAGTGCAATCGACCAGATTACTGGTAAGCTTAATCGACTAATTGAGAAAACCAACCAG



CAGTTCGAACTGATTGATAACGAGTTTAATGAAGTCGAGAAGCAGATTGGAAACGTTATC



AATTGGACCCGAGACAGTATAACTGAGGTGTGGAGCTACAACGCCGAGCTCCTCGTGGCT



ATGGAGAACCAACATACAATCGATCTTGCAGATTCTGAAATGGATAAGCTATACGAAAGA



GTAAAGCGACAGCTCCGGGAAAACGCAGAGGAAGACGGAACTGGATGTTTCGAGATTTTT



CACAAGTGCGACGACGATTGCATGGCAAGCATTAGAAATAACACATACGACCACTCAAAG



TACCGCGAGGAGGCGATGCAGAATAGGATACAGATCGACCCTGTAAAGCTGAGCTCTGGG



TACAAGGACGTGATCTTGTGGTTTTCTTTCGGCGCATCATGCTTCATCTTGCTGGCAATC



GTGATGGGCCTGGTCTTTATTTGCGTAAAGAACGGCAATATGCGCTGTACAATCTGTATC





508
ATGAATACTCAGATACTGGTGTTCGCACTCATCGCAATTATACCCACTAATGCCGATAAG



ATTTGTTTAGGACATCACGCCGTCAGTAACGGAACTAAGGTTAACACACTAACAGAGCGA



GGCGTCGAAGTGGTTAATGCAACTGAGACGGTCGAGCGCACAAACATCCCTCGTATTTGC



AGCAAAGGAAAGAAAACCGTCGATCTGGGACAGTGCGGACTCCTGGGGACCATAACCGGC



CCTCCCCAGTGCGATCAGTTTCTGGAGTTCTCAGCAGATCTTATAATCGAGCGACGGGAA



GGTTCCGACGTATGTTATCCCGGTAAATTCGTCAACGAAGAAGCCCTGAGACAGATCCTG



CGGGAGAGTGGAGGAATTGACAAGGAGGCCATGGGATTTACCTACAGCGGCATTAGAACG



AATGGGGCCACATCTGCCTGCCGACGCAGCGGCAGCTCATTCTACGCCGAGATGAAATGG



TTACTGTCCAATACCGACAACGCCGCGTTCCCGCAGATGACCAAATCTTACAAGAACACT



CGAAAATCCCCCGCACTTATTGTGTGGGGCATCCACCATAGTGTGTCAACCGCTGAGCAG



ACTAAACTCTACGGTTCTGGTAACAAACTCGTGACTGTGGGAAGCTCAAACTACCAGCAA



AGCTTTGTGCCCTCTCCCGGGGCCAGGCCACAGGTGAACGGACAGTCCGGACGCATAGAC



TTCCACTGGCTGATGCTAAATCCGAACGACACCGTCACCTTCAGTTTTAATGGGGCTTTC



ATCGCCCCTGACAGAGCTAGCTTCCTGCGCGGTAAGAGCATGGGTATTCAGAGCGGGGTG



CAGGTCGACGCCAACTGCGAAGGTGATTGCTATCATTCAGGGGGCACAATTATCTCCAAC



CTCCCATTTCAGAACATCGATAGCCGCGCAGTCGGTAAGTGTCCACGATACGTTAAACAA



AGGTCACTGCTCCTTGCCACTGGCATGAAAAACGTCCCGGAGATCCCGAAGGGCCGCGGA



CTCTTTGGGGCCATCGCTGGGTTCATTGAAAATGGTTGGGAGGGGCTCATTGACGGATGG



TATGGCTTTAGGCACCAGAACGCCCAAGGAGAGGGGACCGCAGCCGATTATAAGAGCACA



CAGTCTGCCATTGACCAGATAACCGGTAAACTTAACCGGTTAATCGAAAAAACTAACCAG



CAGTTCGAATTAATCGACAACGAATTTAATGAAGTCGAGAAACAGATCGGCAACGTCATC



AACTGGACCCGAGATAGCATAACTGAAGTGTGGTCCTACAACGCCGAGCTGCTCGTGGCT



ATGGAGAATCAGCATACCATCGACTTGGCCGACAGTGAAATGGATAAGCTGTACGAGAGA



GTTAAGCGCCAGCTGAGAGAGAACGCAGAAGAGGACGGGACCGGCTGCTTTGAGATTTTC



CATAAGTGCGATGACGACTGTATGGCAAGCATTCGCAATAATACTTACGATCACTCCAAA



TATAGGGAGGAGGCCATGCAAAACCGCATTCAGATTGATCCGGTGAAGTTGTCAAGTGGA



TATAAGGATGTGATTCTCTGGTTCTCCTTCGGGGCCTCCTGTTTTATTCTTCTCGCAATC



GTTATGGGCTTGGTCTTCATCTGCGTAAAAAATGGGAATATGAGATGTACTATCTGTATC





509
ATGAACACACAAATTCTTGTATTTGCCCTTATAGCAATCATTCCAACCAACGCAGACAAG



ATATGCCTGGGGCACCACGCCGTCTCTAACGGTACAAAGGTAAACACACTAACCGAACGC



GGTGTCGAGGTAGTGAATGCAACTGAGACCGTGGAGCGGACCAACATACCAAGAATCTGC



TCCAAAGGGAAGAGAACGGTGGATCTAGGACAGTGCGGGCTGCTCGGGACTATCACTGGA



CCACCTCAGTGTGATCAATTTTTAGAGTTCTCGGCAGACTTAATCATCGAACGGCGGGAA



GGATCTGATGTTTGCTACCCTGGCAAGTTTGTTAATGAAGAGGCGCTGCGACAGATTTTG



CGCGAATCCGGTGGTATCGATAAAGAAGCAATGGGCTTCACTTATAGTGGCATTCGGACC



AATGGAGCCACAAGCGCATGCCGAAGGAGCGGGTCCAGCTTTTACGCTGAAATGAAATGG



CTCTTGAGTAATACAGATAACGCCGCCTTTCCTCAAATGACAAAAAGCTATAAGAATACG



CGAAAAAGCCCTGCTCTAATCGTCTGGGGTATCCACCACTCTGTGTCTACAGCCGAACAA



ACCAAGCTGTATGGCAGCGGCTCAAAGCTGGTAACAGTGGGATCAAGCAATTACCAGCAG



AGTTTTGTGCCTAGCCCTGGAGCTAGACCGCAGGTGAACGGCCTTTCAGGTCGGATAGAC



TTTCACTGGCTTATGTTAAATCCAAATGACACGGTGACCTTCTCTTTCAACGGGGCATTT



ATCGCACCAGATAGGGCATCTTTTCTGCGGGGGAAGAGTATGGGCATCCAATCCGGAGTG



CAGGTTGATGCAAATTGCGAGGGGGATTGTTATCACTCCGGCGGTACAATAATTAGTAAC



CTCCCATTTCAGAATATTGATAGTCGTGCCGTCGGAAAATGTCCTCGCTATGTCAAGCAG



AGATCGCTGTTACTTGCCACCGGCATGAAAAATGTGCCCGAAATCCCAAAGGGCCGAGGT



CTGTTCGGGGCTATCGCAGGCTTCATTGAAAATGGATGGGAAGGCCTGATCGACGGGTGG



TACGGCTTCCGTCATCAGAACGCACAGGGGGAAGGGACTGCAGCGGATTATAAGTCCACC



CAAAGCGCTATTGACCAGATCACCGGCAAGCTCAATCGGCTCATAGAAAAAACTAATCAA



CAGTTTGAGTTGATAGATAATGAGTTTAACGAGGTCGAGAAGCAGATTGGGAATGTGATC



AATTGGACCAGAGACTCAATAACTGAGGTGTGGTCATACAATGCGGAGTTGTTGGTCGCT



ATGGAAAATCAACACACAATCGACCTGGCTGACTCAGAAATGGATAAGCTGTACGAGCGG



GTCAAGAGACAGCTGCGCGAGAATGCCGAGGAAGATGGAACAGGTTGCTTTGAAATTTTC



CATAAATGCGATGATGACTGTATGGCAAGTATTCGGAACAATACTTACGATCACAGTAAG



TATAGAGAAGAAGCAATGCAAAACAGAATTCAGATTGATCCGGTGAAGCTGAGCTCAGGA



TACAAAGATGTTATCCTATGGTTTTCTTTTGGGGCCTCATGCTTTATCTTATTGGCCATA



GTTATGGGGCTAGTATTTATCTGCGTAAAATCAAGGAATATGAGGTGCACCATCTGCATT





510
ATGAATACACAGATCTTGGTTTTTGCCCTCATCGCCATTATCCCCACAAATGCCGACAAA



ATTTGCTTGGGCCACCACGCCGTGTCCAATGGTACAAAAGTCAATACACTGACCGAGAGG



GGAGTGGAGGTGGTGAATGCCACAGAAACCGTTGAAAGAACGAATATTCCTAGAATTTGT



TCTAAAGGGAAAAGAACCGTTGATCTCGGGCAATGCGGTCTGTTAGGCACAATCACAGGC



CCTCCCCAGTGTGATCAATTTCTTGAGTTCAGTGCGGATCTTATCATTGAGAGACGGGAA



GGGTCTGATGTCTGTTACCCCGGCAAGTTTGTGAACGAGGAAGCCCTGCGCCAGATCCTC



AGAGAATCTGGGGGTATCGATAAGGAAGCTATGGGGTTTACTTATTCCGGGATCAGGACT



AATGGGGCCACCAGCGCCTGCCGGCGGTCCGGCAGCTCATTCTACGCCGAGATGAAGTGG



CTGCTGTCCAATACCGACAATGCGGCCTTTCCGCAGATGACCAAGAGCTATAAAAACACG



CGCAAATCACCCGCTTTAATCGTCTGGGGGATACATCATTCAGTGAGCACTGCCGAGCAA



ACCAAGCTGTATGGGAGCGGCAGTAAATTGGTTACTGTAGGTAGCTCTAACTACCAGCAG



TCTTTCGTCCCAAGCCCAGGAGCCCGTCCGCAGGTGAATGGACTCAGTGGAAGGATTGAT



TTTCATTGGCTAATGCTCAACCCGAACGATACTGTGACGTTTTCATTTAATGGCGCATTT



ATCGCGCCCGATCGAGCCAGCTTCCTCCGGGGTAAGAGTATGGGGATCCAATCAGGAGTG



CAGGTCGATGCTAACTGCGAGGGAGACTGTTACCATTCCGGCGGCACTATTATCAGCAAT



CTGCCCTTCCAGAATATCGACTCCAGAGCCGTGGGAAAGTGTCCAAGGTACGTGAAACAG



AGGAGCTTACTGCTTGCCACAGGGATGAAGAATGTCCCCGAGATTCCCAAAGGAAGGGGG



CTGTTCGGAGCCATCGCAGGGTTCATTGAGAACGGGTGGGAAGGCTTAATCGATGGCTGG



TACGGCTTCAGACACCAAAATGCACAGGGCGAAGGAACCGCCGCCGATTACAAGTCAACG



CAATCCGCTATAGATCAGATAACCGGAAAGCTGAACAGACTCATCGAAAAAACAAACCAA



CAGTTCGAACTTATAGACAACGAATTCAACGAGGTGGAAAAACAGATCGGGAACGTTATC



AATTGGACACGAGACTCAATCACAGAGGTATGGTCCTACAACGCTGAACTCCTGGTTGCG



ATGGAGAATCAGCACACCATTGACTTAGCCGACTCTGAGATGGATAAACTGTACGAGAGA



GTGAAAAGGCAGCTCCGAGAGAACGCAGAAGAGGATGGTACAGGATGCTTCGAAATCTTT



CACAAATGCGACGATGATTGTATGGCCAGCATCAGAAATAATACATATGACCATTCCAAA



TATCGGGAAGAAGCAATGCAAAACCGGATCCAGATCGATCCTGTTAAACTCAGCAGCGGT



TACAAGGACGTGATTCTGTGGTTCTCCTTCGGCGCATCATGTTTTATTCTTCTTGCTATT



GTGATGGGACTAGTATTTATATGCGTGAAGAATGGCAACATGAGATGTACCATTTGCATC





511
ATGAATACCCAAATCCTTGTATTCGCTCTGATCGCAATCATTCCAACCAATGCTGATAAA



ATCTGCTTAGGACACCACGCTGTGAGCAATGGTACAAAGGTCAATACACTGACAGAGCGG



GGCGTAGAAGTGGTCAACGCCACCGAGACGGTGGAAAGGACCAATATCCCTAGGATTTGC



TCGAAGGGCAAGAGAACAGTAGACCTGGGGCAATGTGGATTGTTGGGGACTATTACGGGA



CCGCCCCAGTGTGATCAGTTTCTGGAGTTCAGCGCTGATCTCATCATCGAGCGCCGAGAG



GGATCCGACGTGTGCTACCCAGGAAAATTCGTTAACGAGGAAGCATTAAGACAGATTTTA



CGTGAATCGGGTGGCATTGATAAAGAAGCCATGGGGTTTACTTACAGTGGAATTAGAACC



AATGGAGCCACCTCGGCTTGCCGGAGATCTGGGTCTAGCTTTTACGCAGAAATGAAGTGG



CTGCTGTCTAACACGGATAATGCCGCGTTCCCGCAGATGACCAAAAGTTATAAAAATACC



AGAAAGAGCCCTGCATTAATTGTCTGGGGCATTCACCACTCTGTTTCCACGGCCGAACAG



ACAAAATTGTATGGAAGCGGAAACAAGCTGGTCACAGTCGGATCTAGCAACTACCAGCAG



AGCTTTGTGCCCAGTCCAGGGGCCCGCCCTCAGGTCAATGGGCTTTCTGGGAGAATTGAT



TTTCACTGGCTGATGTTGAACCCCAACGACACTGTGACCTTTAGCTTCAATGGCGCGTTT



ATTGCGCCCGACAGAGCCTCCTTTTTACGGGGGAAAAGCATGGGAATACAATCTGGTGTG



CAGGTGGATGCAAATTGCGAAGGAGACTGCTATCACTCCGGGGGTACCATTATTAGCAAT



CTCCCATTCCAGAACATCGACTCCAGAGCCGTTGGTAAATGCCCCAGGTATGTCAAGCAG



CGTAGTCTCTTGTTGGCCACAGGAATGAAAAACGTGCCTGAGATCCCCAAAGGGCGCGGC



CTATTTGGGGCAATTGCCGGCTTTATCGAGAACGGATGGGAGGGCCTGATCGACGGTTGG



TATGGCTTTCGCCATCAGAATGCTCAGGGGGAAGGCACAGCTGCAGACTACAAGAGCACC



CAGAGCGCCATCGATCAAATCACCGGCAAGCTCAACCGGATCATCGAGAAGACAAATCAG



CAATTTGAATTAATCGACAACGAGTTCAATGAGGTAGAAAAGCAGATAGGAAACGTGATC



AACTGGACCAGGGATAGCATTACTGAAGTCTGGTCATACAATGCCGAACTCCTGGTGGCA



ATGGAGAACCAGCACACTATTGATCTTGCCGACTCTGAGATGGACAAACTGTACGAGCGC



GTGAAGCGACAGCTGAGGGAAAACGCTGAGGAAGACGGTACTGGCTGCTTTGAAATCTTC



CACAAATGCGACGACGATTGCATGGCATCCATACGGAACAACACTTATGATCACTCAAAG



TATCGGGAGGAAGCAATGCAGAATAGAATTCAAATCGATCCCGTTAAACTGAGCTCCGGC



TACAAGGATGTGATTCTCTGGTTTAGCTTCGGAGCATCATGCTTTATCCTCCTAGCAATT



GTAATGGGTCTGGTGTTCATATGCGTAAAGAATGGCAATATGCGCTGTACTATCTGTATT





512
ATGAACACGCAAATTCTAGTGTTTGCTCTAATTGCCATCATACCCACAAACGCCGATAAA



ATCTGCCTTGGGCATCACGCAGTAAGTAACGGTACCAAGGTGAACACGCTCACAGAGCGC



GGGGTCGAGGTCGTGAATGCCACCGAAACAGTGGAACGCACTAACATCCCTCGAATCTGT



TCAAAAGGTAAGCGGACTGTGGATCTGGGACAGTGTGGCCTGCTTGGTACGATCACCGGT



CCTCCCCAATGCGATCAGTTCCTGGAGTTCTCAGCAGACTTAATCATCGAGCGCAGAGAG



GGTAGCGATGTCTGTTACCCCGGAAAGTTTGTGAAGGAAGAAGCCCTTCGCCAGATTCTC



AGAGAGTCAGGAGGCATTGATAAGGAAGCCATGGGGTTTACCTACAGCGGTATCCGTACC



AACGGAGCCACCTCTGCCTGCCGACGCTCAGGTTCTAGCTTCTACGCTGAAATGAAATGG



TTACTGAGCAATACCGATAACGCCGCATTCCCCCAGATGACAAAAAGCTACAAGAATACC



CGCAAAAGCCCTGCCCTTATAGTTTGGGGGATACATCACTCCGTGTCCACCGCAGAACAG



ACCAAGCTGTACGGCAGCGGCAACAAATTGGTGACCGTGGGGAGTAGTAATTATCAACAG



AGCTTTGTGCCCTCGCCTGGGGCCAGACCTCAGGTCAATGGACTTAGTGGAAGGATTGAT



TTCCACTGGCTTATGCTCAATCCTAATGATACCGTCACATTCAGCTTCAACGGGGCGTTC



ATCGCACCCGATCGCGCAAGCTTCCTGCGTGGGAAGAGTATGGGCATCCAATCTGGGGTT



CAAGTGGATGCAAATTGTGAGGGCGATTGTTACCACAGCGGCGGGACGATCATCTCCAAC



CTCCCCTTCCAGAATATTGATTCTCGTGCCGTTGGGAAATGTCCTAGATATGTGAAGCAG



CGTTCCCTCCTGCTGGCTACAGGCATGAAGAACGTTCCGGAAATCCCCAAGGGCAGAGGA



CTGTTTGGCGCCATTGCAGGATTTATTGAGAATGGATGGGAGGGCCTCATCGATGGTTGG



TACGGATTCAGACACCAGAACGCTCAGGGGGAAGGAACAGCCGCCGATTATAAGTCTACC



CAGTCGGCTATCGACCAAATCACCGGAAAACTGAACAGGCTGATAGAGAAAACTAACCAG



CAGTTCGAGTTGATCGACAACGAGTTCAACGAAGTGGAGAAACAGATCGGCAACGTCATT



AACTGGACACGCGACTCAATTACAGAGGTGTGGTCCTACAACGCTGAGCTGCTGGTAGCA



ATGGAGAACCAGCATACCATCGACCTGGCTGATTCTGAAATGGATAAGCTGTATGAACGG



GTCAAGCGTCAACTGCGCGAAAACGCCGAAGAGGATGGAACAGGCTGCTTCGAAATTTTT



CATAAATGCGATGACGACTGCATGGCAAGCATCCGGAACAACACATACGATCACTCAAAA



TACCGCGAGGAGGCTATGCAGAATCGCATTCAGATTGATCCTGTGAAGTTATCCTCCGGC



TACAAAGATGTCATCCTCTGGTTCAGTTTCGGCGCGTCTTGCTTCATCCTCCTAGCAATC



GTGATGGGTCTCGTTTTCATCTGTGTGAAGAACGGGAATATGAGATGCACTATTTGCATA





513
ATGAATACCCAGATCCTTGTGTTTGCTCTGATCGCCATCATTCCCACAAACGCCGACAAA



ATTTGCCTCGGTCACCATGCTGTGTCAAACGGTACTAAAGTCAACACATTGACAGAGAGG



GGCGTGGAGGTGGTGAATGCAACCGAGACCGTTGAGCGAACAAATATCCCTCGCATCTGC



TCCAAGGGCAAGAAAACTGTGGATTTGGGCCAATGTGGGCTTTTGGGAACCATTACTGGG



CCTCCTCAGTGTGATCAGTTCCTCGAGTTCTCTGCCGACCTGATTATTGAACGCCGAGAA



GGTAGCGATGTCTGTTACCCAGGCAAATTCGTCAACGAAGAGGCACTTCGCCAGATACTG



AGAGAGAGTGGAGGCATTGATAAAGAAGCTATGGGGTTTACCTATTCTGGGATAAGGACC



AACGGGGCCACCAGTGCTTGTAGACGTAGTGGCAGCAGCTTCTACGCGGAAATGAAATGG



CTCCTGTCAAATACAGACAATGCTGCTTTTCCTCAGATGACTAAATCGTACAAAAACACG



CGGAAGAGCCCCGCCTTAATCGTGTGGGGAATCCACCACTCCGTGTCCACAGCGGAACAG



ACCAAACTTTACGGCTCCGGGAATAAGCTAGTGACCGTGGGCAGCTCCAACTATCAACAA



AGTTTCGTCCCTTCCCCCGGTGCGAGACCGCAGGTCAACGGACAGTCAGGGAGGATCGAT



TTCCACTGGCTGATGTTAAACCCTAATGACACTGTGACTTTCTCCTTCAATGGAGCGTTC



ATTGCACCGGATCGAGCGTCTTTTCTCCGGGGAAAGTCTATGGGTATCCAGTCTGGCGTG



CAGGTGGATGCCAATTGCGAGGGAGATTGCTACCACTCCGGGGGCACTATCATCTCGAAT



CTCCCCTTCCAGAACATCGACAGCCGGGCCGTGGGTAAATGCCCACGGTATGTCAAGCAA



AGATCCTTACTGCTCGCCACAGGGATGAAGAACGTGCCTGAGATCCCTAAGGGCCGGGGG



CTGTTTGGAGCCATCGCTGGGTTCATTGAAAACGGTTGGGAAGGCCTCATTGACGGATGG



TATGGCTTCAGGCACCAGAACGCTCAGGGGGAGGGGACCGCCGCCGACTACAAGAGTACG



CAATCTGCTATAGATCAGATCACTGGTAAACTCAACCGCTTGATCGAGAAAACCAATCAG



CAGTTCGAGCTTATTGACAACGAGTTTAACGAGGTAGAGAAGCAGATTGGAAATGTCATC



AATTGGACTAGAGACTCTATCACAGAGGTGTGGAGCTATAATGCCGAATTGTTGGTGGCA



ATGGAAAACCAGCACACCATCGACCTGGCCGACAGCGAAATGGACAAGTTGTATGAACGC



GTTAAACGTCAGTTGAGGGAGAACGCCGAGGAGGACGGGACGGGTTGCTTTGAAATCTTT



CATAAGTGCGATGACGACTGTATGGCTTCTATCCGCAATAACACTTATGACCACAGTAAG



TACCGGGAAGAAGCTATGCAAAACAGAATACAGATCGACCCAGTTAAATTATCAAGTGGC



TATAAAGATGTGATCCTCTGGTTCAGCTTTGGAGCCTCCTGTTTCATTTTATTGGCCATA



GTCATGGGCCTCGTATTTATCTGCGTGAAAAATGGCAACATGCGCTGCACCATCTGCATT





514
ATGAACACTCAGATCCTAGTGTTTGCTCTGATAGCGATCATACCCACCAATGCAGACAAA



ATCTGTCTGGGCCATCATGCAGTCTCTAATGGAACCAAAGTGAACACCCTAACTGAGAGG



GGCGTCGAGGTGGTGAATGCGACCGAAACTGTTGAAAGGACCAATATTCCCAGAATCTGC



TCAAAGGGAAAAAAAACGGTGGACCTGGGGCAGTGTGGATTACTAGGCACGATCACCGGG



CCTCCTCAGTGTGATCAATTTCTGGAGTTCAGCGCAGATCTTATTATTGAGAGAAGAGAG



GGCTCTGACGTGTGCTACCCAGGCAAGTTCGTGAACGAGGAGGCTCTGCGGCAGATCCTA



CGTGAGAGCGGAGGCATAGACAAGGAGGCAATGGGATTTACCTATAGCGGGATACGGACA



AATGGCGCAACGTCCGCATGTCGCCGGAGTGGGTCTTCCTTTTACGCGGAGATGAAGTGG



CTGCTGAGCAACACCGACAATGCCGCGTTTCCTCAGATGACAAAATCATATAAGAACACC



CGAAAGTCCCCAGCACTCATTGTTTGGGGGATCCACCACAGTGTAAGCACCGCCGAGCAG



ACTAAACTATACGGCAGCGGAAATAAACTTGTCACCGTCGGCTCCTCCAATTACCAACAG



TCCTTCGTCCCTTCACCGGGTGCCAGGCCCCAGGTGAACGGACAATCCGGGCGTATTGAC



TTTCACTGGCTGATGTTGAATCCAAACGACACCGTGACGTTTTCGTTCAACGGCGCATTT



ATTGCCCCCGATCGGGCGAGCTTCCTGCGGGGAAAATCCATGGGCATCCAGAGTGGGGTC



CAAGTGGACGCAAACTGTGAGGGCGACTGCTACCACTCCGGTGGAACAATCATTAGCAAT



CTTCCCTTTCAGAACATTGACTCTCGGGCCGTAGGCAAGTGTCCGCGCTACGTGAAACAG



CGCTCTCTGCTATTGGCTACAGGCATGAAGAATGTACCAGAGATACCTAAGGGACGAGGC



CTCTTTGGGGCCATCGCCGGCTTCATCGAGAATGGGTGGGAAGGCCTGATTGACGGTTGG



TATGGCTTTCGCCACCAGAATGCACAGGGTGAGGGAACGGCAGCCGATTACAAGTCCACG



CAGAGTGCCATCGATCAGATTACCGGTAAATTAAACCGGCTCATTGAGAAAACTAACCAG



CAGTTCGAACTGATCGATAATGAGTTTAATGAGGTGGAGAAGCAAATTGGCAACGTGATT



AATTGGACCAGGGACAGTATAACGGAAGTGTGGTCCTATAATGCAGAATTGCTGGTGGCC



ATGGAAAACCAGCACACGATCGATCTAGCTGATTCTGAGATGGACAAACTGTATGAGCGT



GTTAAGCGACAGCTTCGCGAAAATGCAGAGGAAGATGGCACAGGCTGCTTTGAGATATTC



CACAAATGCGACGATGACTGTATGGCTTCAATACGTAATAATACATACGACCACTCAAAA



TACCGTGAAGAGGCCATGCAAAATCGCATCCAGATCGATCCTGTGAAACTATCATCAGGC



TATAAAGACGTAATTCTTTGGTTTTCTTTCGGCGCAAGTTGCTTCATTCTTCTCGCCATT



GTGATGGGACTTGTCTTCATATGTGTGAAAAACGGAAATATGCGCTGCACCATCTGTATC





515
ATGAACACTCAAATTCTAGTCTTCGCCCTGATCGCAATCATCCCTACTAATGCCGACAAG



ATCTGTCTGGGACACCACGCAGTTTCAAACGGGACAAAGGTGAACACCCTGACCGAGCGG



GGGGTAGAAGTGGTTAACGCAACTGAGACCGTGGAACGTACCAATATACCCAGGATATGT



AGCAAGGGTAAAAAGACTGTCGATCTCGGTCAGTGTGGACTCCTGGGAACCATCACCGGA



CCTCCCCAGTGTGATCAGTTCCTGGAGTTCAGCGCAGATTTAATCATCGAACGTCGCGAA



GGATCCGACGTCTGCTATCCGGGTAAGTTTGTAAACGAGGAGGCTCTGAGACAAATCCTC



AGAGAAAGTGGGGGCATAGACAAGGAGGCAATGGGGTTCACTTATTCTGGGATTAGGACA



AATGGCGCCACTAGCGCTTGCCGCCGAAGTGGCAGTTCCTTCTACGCCGAGATGAAGTGG



TTGCTTAGCAATACTGATAATGCTGCTTTCCCCCAGATGACGAAGTCTTACAAAAATACT



CGTAAGAGCCCCGCGCTGATCGTGTGGGGGATCCACCACAGTGTGAGCACTGCCGAGCAA



ACCAAGCTGTATGGGTCTGGGAATAAATTAGTGACCGTGGGCTCTAGTAACTACCAGCAG



TCATTCGTTCCAAGTCCCGGCGCACGGCCTCAGGTTAATGGCCAGTCTGGCCGGATTGAC



TTTCATTGGCTCATGCTGAATCCCAATGACACGGTGACATTCTCCTTTAACGGAGCATTT



ATCGCACCAGACAGGGCTTCCTTCCTTCGCGGAAAATCCATGGGAATTCAGAGCGGGGTC



CAGGTCGATGCTAATTGTGAAGGGGATTGTTACCACTCTGGAGGCACAATTATTAGCAAT



CTGCCCTTCCAAAACATCGACTCCCGTGCTGTGGGCAAATGTCCACGCTACGTCAAGCAG



AGATCATTACTTCTTGCTACAGGTATGAAAAACGTGCCGGAAATCCCTAAGGGGAGAGGA



CTTTTCGGTGCCATAGCTGGATTCATAGAGAACGGATGGGAAGGGCTCATTGACGGCTGG



TATGGCTTCAGACATCAGAACGCTCAGGGAGAGGGAACTGCTGCTGACTACAAGAGTACC



CAGTCAGCTATCGACCAGATTACTGGGAAATTGAACCGCCTGATTGAAAAGACTAACCAG



CAGTTCGAGCTCATCGACAATGAATTCAATGAAGTGGAGAAGCAGATCGGTAATGTCATC



AATTGGACTCGGGATTCAATTACAGAGGTGTGGTCTTACAATGCAGAGCTGCTGGTTGCC



ATGGAAAACCAGCATACCATTGACCTGGCAGACAGTGAAATGGATAAACTGTACGAGAGG



GTTAAACGGCAATTGCGCGAAAATGCCGAGGAAGACGGGACAGGATGTTTTGAGATCTTT



CATAAATGCGATGACGACTGTATGGCTTCGATTCGAAACAATACTTACGACCACTCAAAG



TATAGAGAAGAAGCAATGCAGAACCGGATTCAAATCGACCCTGTTAAGCTGTCATCCGGC



TATAAGGATGTAATTCTCTGGTTCAGCTTTGGTGCATCATGTTTTATACTCCTCGCCATC



GTGATGGGCCTTGTATTCATCTGCGTCAAGAACGGGAATATGAGATGCACCATTTGTATT





516
ATGAACACACAGATCCTCGTTTTTGCCTTGATCGCAATCATCCCAACAAACGCAGACAAA



ATCTGTCTGGGTCACCACGCCGTCAGTAACGGGACTAAGGTGAACACCCTCACGGAGGGG



GGAGTCGAGGTCGTGAATGCTACTGAGACCGTGGAGCGTACCAACATCCCCAGGATTTGC



AGCAAAGGAAAGCGGACCGTAGACCTCGGGCAATGTGGGCTGTTAGGCACAATCACTGGC



CCTCCCCAGTGTGACCAGTTTCTTGAGTTCTCTGCTGACTTAATCATCGAGCGTCGAGAA



GGGTCAGATGTCTGCTATCCTGGCAAATTTGTGAATGAGGAAGCACTTCGGCAGATTTTG



AGAGAATCGGGCGGCATCGATAAGGAGGCTATGGGCTTCACCTACTCTGGGATTAGGACC



AATGGGGCCACCAGTGCCTGTAGGCGCTCAGGCAGTTCCTTTTACGCTGAGATGAAGTGG



CTACTGAGTAATACGGATAACGCCGCCTTCCCTCAGATGACTAAGAGCTACAAGAACACC



AGAAAATCTCCTGCCTTGATAGTGTGGGGAATACACCACAGCGTATCCACCGCAGAACAA



ACCAAGTTGTATGGGAGCGGAAACAAGTTGGTCACCGTTGGATCATCGAATTACCAGCAG



AGCTTTGTGCCTTCTCCCGGCGCTCGGCCCCAGGTGAACGGGCTGAGTGGTCGTATCGAC



TTCCATTGGCTTATGCTTAACCCGAATGACACCGTAACGTTCAGCTTCAATGGCGCTTTT



ATTGCACCCGACCGCGCGTCATTCCTACGCGGAAAGTCCATGGGGATCCAGTCTGGTGTG



CAGGTGGACGCCAATTGTGAGGGCGATTGCTATCACTCCGGAGGGACAATTATCTCGAAT



CTCCCGTTCCAGAACATTGACAGCCGGGCTGTCGGGAAGTGCCCGCGCTATGTGAAACAG



AGGTCCCTCCTTCTTGCAACTGGCATGAAAAACGTTCCCGAGATCCCAAAGGGCCGTGGA



CTGTTTGGAGCCATCGCTGGCTTCATAGAGAACGGCTGGGAGGGCCTGATTAATGGTTGG



TACGGCTTTAGACACCAAAATGCCCAGGGAGAAGGCACCGCCGCAGACTACAAATCGACT



CAGTCCGCAATTGATCAGATTACCGGGAAACTCAACCGGCTCATCGAAAAGACTAACCAG



CAGTTTGAATTGATTGACAACGAGTTCAATGAGGTGGAGAAGCAGATCGGGAATGTCATC



AACTGGACACGGGACTCAATAACCGAAGTGTGGTCATACAATGCGGAGCTGCTTGTCGCC



ATGGAAAATCAGCACACAATCGACCTAGCAGACTCTGAAATGGACAAGCTGTATGAGAGA



GTGAAGCGACAATTACGTGAAAATGCGGAGGAGGACGGAACTGGCTGCTTCGAGATCTTC



CACAAGTGTGATGACGATTGCATGGCCTCTATCCGCAACAACACTTACGATCATAGCAAA



TACAGGGAGGAAGCCATGCAGAACCGGATCCAGATTGATCCTGTGAAGCTGTCTAGTGGC



TATAAAGACGTAATCCTCTGGTTCAGCTTCGGCGCAAGCTGCTTCATCCTTCTCGCCATA



GTGATGGGCTTAGTGTTTATATGCGTGAAGAACGGGAACATGCGCTGTACCATTTGTATC





517
ATGAATACTCAAATCCTCGTCTTTGCACTCATAGCAATTATCCCTACCAACGCTGATAAG



ATTTGTTTGGGGCATCACGCCGTCTCCAACGGGACTAAGGTAAATACATTGACGGAAAGA



GGGGTGGAAGTTGTGAATGCCACTGAGACTGTGGAGCGGACCAACATCCCCCGTATATGT



TCAAAAGGAAAACGCACAGTCGACTTGGGTCAGTGCGGACTCCTGGGGACTATTACCGGG



CCACCTCAGTGCGACCAATTTCTGGAATTCAGCGCGGACCTGATCATTGAGCGCCGAGAG



GGAAGTGACGTATGCTACCCTGGGAAGTTTGTTAATGAGGAAGCACTAAGGCAAATACTG



CGGGAATCGGGCGGAATTGATAAGGAAGCTATGGGCTTCACGTACAGCGGAATTAGAACC



AACGGGGCTACGAGTGCGTGTAGACGGTCCGGTAGTTCCTTTTACGCCGAAATGAAATGG



CTCCTAAGCAATACGGACAACGCCGCATTTCCTCAGATCACAAAATCATACAAGAACACT



AGGAAGAGTCCCGCCCTTATTGTGTGGGGAATTCATCACAGTGTGAGTACTGCCGAACAG



ACTAAGCTCTATGGCTCAGGAAATAAGCTCGTCACCGTTGGGTCCAGTAACTATCAGCAG



TCTTTTGTCCCGTCACCTGGGGCCAGACCTCAAGTCAACGGCTTGAGTGGACGTATCGAT



TTTCATTGGCTGATGCTGAACCCAAATGACACTGTCACTTTTAGCTTCAATGGGGCTTTT



ATCGCTCCAGATCGGGCATCCTTCCTGCGTGGGAAATCCATGGGAATTCAATCAGGTGTC



CAGGTGGATGCTAATTGCGAGGGGGACTGCTATCACTCAGGGGGGACTATTATATCCAAT



CTGCCCTTTCAGAACATCGATTCCAGGGCGGTGGGCAAATGTCCTAGATATGTAAAACAG



AGGTCTCTGCTTCTGGCGACAGGCATGAAGAATGTTCCTGAAATCCCCAAGGGCAGGGGC



CTGTTCGGGGCCATTGCAGGCTTTATCGAGAACGGCTGGGAGGGGCTAATCGACGGCTGG



TACGGCTTTCGACATCAGAACGCTCAGGGTGAAGGCACGGCTGCCGATTATAAGTCGACG



CAGTCAGCCATTGATCAAATCACTGGCAAACTTAATCGCCTCATAGAGAAGACCAATCAG



CAGTTTGAACTCATCGATAACGAGTTCAACGAGGTGGAAAAACAAATTGGTAACGTCATC



AATTGGACCAGGGACAGTATTACAGAGGTTTGGTCCTACAACGCCGAATTGTTGGTGGCA



ATGGAAAATCAGCATACTATCGACCTGGCTGACAGCGAAATGGACAAGCTCTATGAACGG



GTAAAGAGGCAGTTACGGGAGAACGCTGAGGAGGACGGCACTGGGTGTTTCGAGATCTTT



CATAAATGCGATGATGACTGCATGGCTTCTATCCGTAATAACACGTATGATCACTCCAAG



TATCGGGAAGAGGCCATGCAGAACCGGATCCAAATCGATCCCGTAAAGTTGTCATCCGGC



TACAAAGACGTAATTTTGTGGTTTTCTTTCGGAGCTTCCTGTTTCATACTGCTAGCTATC



GTAATGGGGTTGGTGTTCATCTGCGTGAAGAATGGAAACATGAGGTGTACCATCTGTATC





518
ATGAACACCCAGATCCTCGTCTTCGCTCTAATCGCCATAATCCCCACTAATGCCGACAAA



ATTTGTCTCGGACACCACGCCGTTAGCAACGGGACAAAAGTTAACACACTTACTGAGAGA



GGGGTCGAGGTTGTAAATGCTACAGAAACCGTGGAGAGGACTAATATTCCAAGAATTTGT



TCAAAGGGAAAAAAGACAGTGGATCTTGGCCAGTGCGGGCTGCTGGGGACAATCACAGGA



CCACCCCAGTGCGACCAATTTCTGGAATTCTCTGCAGACCTGATTATTGAACGCCGTGAG



GGGAGTGACGTTTGCTATCCCGGGAAGTTTGTTAACGAAGAGGCTCTTAGACAAATCCTC



CGCGAATCTGGGGGGATCGATAAAGAGGCCATGGGGTTTACCTACTCCGGCATTAGGACT



AATGGAGCTACCTCCGCCTGTAGGAGGTCTGGAAGCTCATTTTACGCAGAAATGAAATGG



TTGCTCAGCAACACCGACAATGCAGCGTTTCCGCAAATGACCAAGAGTTACAAGAACACC



CGAAAGTCTCCTGCGTTGATTGTGTGGGGCATTCACCATTCAGTTTCCACTGCAGAGCAG



ACAAAACTGTACGGTTCAGGAAACAAGCTGGTAACCGTGGGATCTTCCAACTATCAGCAG



AGCTTCGTGCCCTCGCCCGGAGCCCGCCCTCAGGTGAACGGACAGAGTGGAAGGATCGAC



TTCCACTGGCTGATGTTGAATCCCAACGATACCGTGACTTTCTCTTTCAACGGTGCATTT



ATAGCCCCTGACCGCGCTTCCTTTCTCCGAGGAAAAAGCATGGGCATCCAGTCTGGAGTG



CAGGTTGACGCAAATTGCGAAGGCGACTGTTACCATAGTGGCGGCACAATAATTTCTAAC



CTTCCCTTTCAAAATATTGACAGCCGCGCAGTAGGTAAGTGTCCTAGATACGTGAAGCAG



AGGAGCCTACTGCTCGCCACTGGCATGAAAAATGTGCCGGAGATCCCTAAGGGCAGAGGG



CTGTTCGGCGCCATCGCCGGCTTCATCGAAAATGGATGGGAGGGGTTGATAGACGGTTGG



TACGGCTTCCGGCATCAGAACGCCCAGGGTGAGGGGACCGCCGCTGATTATAAAAGTACC



CAGTCTGCTATCGATCAGATCACCGGGAAGCTCAACCGTCTTATTGAGAAGACCAATCAG



CAATTCGAACTCATCGACAACGAGTTTAACGAGGTTGAAAAGCAAATTGGAAATGTGATT



AATTGGACACGGGATTCAATAACCGAAGTCTGGTCGTACAACGCAGAGCTACTTGTGGCA



ATGGAGAACCAGCACACCATAGACCTTGCCGACTCCGAAATGGATAAGTTGTATGAAAGA



GTGAAACGCCAGCTGCGGGAGAATGCCGAGGAAGATGGGACAGGATGTTTTGAGATCTTT



CACAAGTGCGACGATGATTGCATGGCCTCCATTCGAAACAATACTTATGACCATAGCAAA



TACAGAGAGGAGGCCATGCAGAACCGGATTCAAATCGATCCTGTTAAGTTATCTTCAGGT



TACAAGGATGTCATCCTTTGGTTCTCGTTTGGAGCCAGCTGCTTCATATTGCTGGCTATC



GTGATGGGTCTGGTGTTTATCTGCGTTAAGAACGGCAATATGAGATGTACGATCTGTATT





519
ATGAACACTCAGATTCTGGTCTTTGCCCTGATTGCTATCATCCCAACCAACGCAGACAAG



ATCTGTCTGGGACACCATGCCGTATCTAACGGAACCAAGGTTAACACGTTGACCGAGCGC



GGCGTTGAAGTCGTCAATGCCACTGAGACCGTGGAGCGAACAAACATTCCCAGAATCTGT



AGCAAGGGCAAACGGACTGTGGACCTGGGCCAGTGTGGGTTGTTGGGAACAATCACAGGA



CCTCCACAGTGTGATCAGTTCCTGGAGTTTAGTGCAGACCTTATCATCGAACGCAGAGAA



GGTTCCGACGTCTGTTACCCTGGGAAATTTGTAAATGAGGAGGCCTTGAGACAGATCCTT



AGGGAATCTGGAGGAATCGACAAGGAGGCCATGGGCTTTACCTATAGCGGAATAAGGACC



AATGGCGCCACTTCCGCCTGTAGGAGAAGCGGTTCATCATTCTATGCAGAGATGAAGTGG



TTGTTAAGTAACACGGATAATGCTGCGTTTCCACAGATGACCAAGTCCTACAAGAATACC



CGAAAATCCCCCGCACTCATTGTCTGGGGAATACACCACAGCGTCTCAACAGCTGAGCAA



ACAAAACTCTATGGATCCGGGAATAAGCTCGTGACCGTAGGCTCATCAAACTACCAGCAG



TCGTTCGTGCCATCTCCAGGGGCCCGGCCTCAGGTCAACGGTCTGTCAGGACGCATTGAT



TTTCACTGGCTGATGCTTAATCCCAACGATACCGTCACATTCTCCTTCAATGGGGCGTTT



ATTGCGCCTGACAGAGCTAGCTTTTTGCGAGGTAAGTCTATGGGCATACAGTCTGGGGTG



CAAGTGGACGCGAATTGCGAGGGGGACTGCTATCATTCCGGAGGCACCATCATCTCCAAC



CTCCCATTTCAAAATATCGACAGTAGGGCGGTGGGGAAGTGCCCCCGTTACGTAAAACAG



CGCTCCCTCCTGCTGGCCACAGGGATGAAGAATGTTCCAGAAATACCAAAAGGAAGGGGT



CTGTTTGGTGCCATCGCAGGCTTCATCGAAAACGGATGGGAGGGGCTGATTGATGGTTGG



TACGGATTTAGACACCAGAATGCCCAGGGCGAAGGAACTGCCGCTGATTATAAGAGCACA



CAGTCAGCTATAGACCAGATCACTGGGAAGCTAAACAGAATCATTGAAAAGACGAACCAG



CAGTTCGAACTAATCGACAATGAGTTCAACGAGGTGGAAAAGCAGATTGGGAACGTGATA



AATTGGACACGCGACTCCATAACGGAAGTGTGGAGCTACAATGCGGAGCTGCTGGTGGCT



ATGGAGAATCAGCACACCATCGACCTTGCGGATAGTGAAATGGATAAACTCTACGAGCGT



GTTAAGCGGCAATTGCGGGAGAACGCCGAGGAGGATGGGACCGGGTGCTTCGAGATTTTC



CACAAATGTGATGATGACTGTATGGCCTCCATACGCAATAATACCTACGACCATAGCAAA



TATCGGGAGGAAGCCATGCAGAACCGAATCCAAATAGACCCAGTGAAGCTGAGTTCCGGC



TATAAAGATGTGATTCTCTGGTTTAGCTTTGGAGCAAGCTGTTTTATCCTGTTAGCGATT



GTGATGGGTTTAGTGTTCATTTGTGTGAAAAACGGTAACATGCGATGCACCATTTGTATC





520
ATGAATACCCAGATCCTTGTCTTTGCCCTGATAGCCATTATTCCCACCAACGCAGATAAA



ATTTGCCTCGGGCACCACGCTGTGAGCAACGGCACAAAGGTGAATACTCTGACAGAACGG



GGTGTAGAGGTGGTTAATGCAACAGAGACAGTGGAGCGCACAAACATCCCCAGAATCTGC



TCTAAGGGCAAGCGGACTGTGGATTTAGGGCAATGTGGACTGCTAGGTACTATCACCGGG



CCTCCACAGTGTGACCAGTTTTTGGAGTTCTCTGCCGATCTTATCATCGAGCGTCGAGAG



GGGAGTGATGTGTGCTACCCAGGCAAATTTGTGAACGAGGAAGCCCTTCGGCAGATCCTG



AGAGAGTCCGGCGGCATCGACAAAGAGGCCATGGGTTTTACCTATTCAGGAATCCGAACC



AACGGAGCCACCTCCGCCTGTAGGCGGAGTGGGTCTAGCTTTTATGCAGAAATGAAATGG



TTGCTGTCCAACACCGATAATGCAGCTTTCCCACAGATAACAAAGTCTTACAAAAATACG



CGCAAGTCCCCAGCGCTAATTGTGTGGGGCATTCATCACAGCGTGTCTACTGCGGAGCAG



ACCAAGCTGTACGGGAGCGGGAATAAATTGGTCACAGTCGGGAGCTCGAACTACCAGCAA



AGCTTCGTTCCTAGCCCCGGGGCAAGGCCTCAGGTGAACGGACTGAGCGGCAGAATTGAC



TTCCACTGGTTGATGCTTAATCCTAACGATACAGTGACCTTTAGCTTCAATGGAGCGTTC



ATTGCCCCTGATCGCGCCTCCTTTCTCCGGGGGAAAAGTATGGGGATTCAATCCGGGGTG



CAGGTTGACGCTAATTGTGAGGGTGATTGCTACCACTCCGGGGGCACCATTATAAGCAAT



TTACCGTTTCAGAATATTGACTCTCGAGCCGTGGGGAAATGTCCCCGGTACGTCAAGCAA



AGGTCTTTGCTGCTGGCTACCGGCATGAAAAACGTACCCGAGATCCCAAAAGGACGCGGC



CTCTTCGGTGCAATCGCCGGCTTTATAGAGAATGGATGGGAAGGGCTTATTGACGGGTGG



TATGGGTTCCGCCATCAGAATGCGCAAGGCGAAGGAACTGCCGCCGATTACAAGAGTACA



CAGTCCGCCATCGATCAAATTACTGGCAAACTAAATAGACTCATCGAGAAGACAAACCAG



CAGTTTGAACTCATTGACAACGAATTCAACGAGGTAGAGAAACAGATTGGCAACGTCATC



AATTGGACACGGGACAGTATCACAGAAGTCTGGTCCTACAACGCAGAGCTTCTCGTTGCT



ATGGAAAATCAGCACACCATTGACCTGGCTGACTCCGAGATGGACAAGTTGTATGAGCGT



GTGAAAAGGCAGTTGCGTGAAAACGCCGAGGAAGACGGCACAGGTTGTTTTGAGATCTTT



CACAAATGCGACGACGATTGTATGGCAAGCATAAGAAACAATACTTATGACCACAGTAAA



TATCGAGAGGAAGCCATGCAGAACAGAATCCAAATCGACCCTGTGAAACTAAGCTCAGGC



TACAAGGACGTGATCCTCTGGTTCTCCTTTGGTGCTTCCTGCTTTATTCTCCTTGCCATC



GTCATGGGCCTCGTGTTCATCTGCGTTAAGAACGGTAATATGCGGTGTACTATTTGTATC





521
ATGAATACCCAGATTCTCGTTTTTGCCCTAATAGCTATCATTCCTACAAATGCCGATAAA



ATTTGCTTGGGCCATCATGCCGTGAGCAACGGGACTAAGGTTAACACCCTGACTGAGCGG



GGCGTAGAGGTGGTTAACGCCACAGAGACAGTGGAACGGACGAACATTCCAAGAATTTGT



TCAAAGGGCAAGAAAACGGTGGACCTCGGGCAATGTGGTCTGCTAGGCACTATAACAGGA



CCTCCTCAGTGCGATCAGTTTCTGGAATTCAGTGCAGATCTGATCATCGAGCGTCGAGAG



GGATCAGATGTCTGTTATCCTGGGAAGTTCGTCAATGAGGAGGCACTGAGACAGATACTC



AGAGAGAGCGGAGGCATTGATAAGGAAGCTATGGGTTTTACCTATTCTGGTATTAGAACT



AACGGAGCCACAAGTGCCTGTCGTCGGTCGGGCTCTTCGTTTTACGCTGAGATGAAGTGG



CTGCTGAGTAATACTGACAATGCAGCGTTCCCCCAGATGACTAAGAGTTATAAAAACACC



CGTAAAAGCCCAGCACTGATCGTGTGGGGAATTCATCATTCAGTCTCTACAGCCGAGCAG



ACCAAGCTCTACGGGTCTGGCAACAAGCTCGTTACAGTAGGATCTAGCAACTATCAACAG



AGCTTTGTACCATCCCCTGGAGCTCGTCCACAAGTGAACGGTCAGTCGGGCCGTATCGAC



TTTCACTGGCTGATGCTGAATCCTAATGACACGGTGACTTTCAGTTTCAATGGAGCCTTC



ATCGCACCAGACCGCGCAAGCTTTCTACGCGGGAAGAGTATGGGGATTCAGTCCGGCGTT



CAAGTGGACGCCAATTGCGAAGGGGACTGTTACCATAGGGGGGGCACCATCATTAGTAAC



CTCCCATTTCAAAACATCGATTCTCGCGCCGTGGGGAAATGTCCTAGATACGTGAAACAG



CGCAGCCTGCTCCTCGCAACTGGCATGAAGAATGTTCCAGAGATTCCGAAGGGGCGGGGT



CTCTTTGGCGCCATCGCCGGGTTCATCGAAAACGGGTGGGAGGGACTGATCGATGGCTGG



TATGGCTTCCGACATCAAAACGCACAGGGTGAGGGCACAGCTGCCGATTATAAATCCACG



CAGAGCGCAATCGATCAGATCACCGGCAAACTGAACAGGCTGATCGAGAAAACTAATCAG



CAGTTCGAGCTTATCGATAATGAATTCAATGAAGTGGAGAAGCAGATTGGGAATGTGATT



AATTGGACTCGGGACTCTATTACTGAAGTGTGGAGTTACAACGCCGAGCTCTTGGTTGCT



ATGGAGAATCAGCATACAATTGACTTGGCAGATTCCGAGATGGATAAGCTCTACGAGCGT



GTCAAGCGGCAACTGAGAGAGAACGCCGAAGAGGATGGGACGGGGTGCTTCGAGATTTTC



CATAAGTGCGACGATGATTGTATGGCCAGTATCAGAAATAATACATATGACCATAGCAAA



TACAGAGAGGAAGCAATGCAGAACCGGATCCAGATTGATCCGGTGAAGCTCTCTAGCGGA



TATAAGGATGTTATCCTGTGGTTTTCTTTTGGAGCCTCCTGTTTCATTCTGCTGGCCATT



GTAATGGGACTAGTCTTCATATGTGTAAAAAACGGCAATATGAGGTGCACTATTTGTATT





522
ATGAACACACAGATCCTGGTATTCGCGCTCATCGCAATTATACCAACAAATGCCGATAAG



ATATGCTTGGGACATCACGCCGTATCCAACGGTACCAAAGTGAATACACTGACCGAACGT



GGCGTAGAGGTGGTGAACGCCACTGAGACGGTTGAGCGCACCAACATCCCCCGCATCTGC



TCCAAGGGAAAACGCACCGTCGACCTGGGACAGTGTGGGCTGCTCGGCACAATCACGGGT



CCTCCTCAGTGTGACCAATTCTTGGAGTTCAGCGCAGATCTAATTATAGAGAGGCGGGAG



GGAAGCGATGTGTGCTATCCTGGCAAATTTGTCAACGAGGAAGCCCTTCGCCAGATTCTT



CGGGAGTCCGGCGGAATCGATAAAGAGGCTATGGGGTTTACATATAGTGGAATCCGCACC



AATGGCGCCACGTCGGCCTGTAGGAGGAGCGGATCCAGTTTCTATGCCGAGATGAAATGG



CTCCTCAGTAATACTGATAATGCTGCGTTCCCCCAGATAACCAAATCGTACAAAAATACA



CGGAAGTCTCCCGCGCTGATTGTATGGGGCATACACCACTCCGTATCGACTGCCGAACAG



ACTAAGCTCTACGGCTCTGGGAACAAGTTAGTGACCGTCGGCTCGAGCAATTACCAGCAG



AGTTTTGTCCCATCACCAGGGGCAAGACCTCAGGTGAACGGGCTTTCAGGGAGGATTGAC



TTCCACTGGCTGATGCTGAACCCAAATGACACTGTCACCTTTTCGTTCAACGGGGCATTT



ATCGCCCCAGACAGGGCCTCATTCCTTAGAGGCAAATCTATGGGCATTCAAAGCGGGGTT



CAGGTGGACGCGAACTGTGAGGGCGACTGTTATCATAGCGGTGGCACTATTATCTCCAAC



CTGCCCTTTCAGAATATAGACAGTAGAGCCGTGGGTAAGTGCCCACGGTATGTGAAGCAA



AGGTCCCTGCTCCTCGCTACGGGGATGAAGAATGTGCCAGAGATTCCTAAGGGTCGCGGC



CTGTTCGGAGCAATAGCGGGTTTTATAGAAAATGGTTGGGAAGGATTAATAGATGGGTGG



TACGGGTTTAGGCACCAGAATGCTCAGGGAGAGGGTACGGCAGCTGATTATAAGTCTACA



CAATCTGCCATCGACCAGATCACCGGAAAGCTCAACAGACTTATCGAAAAAACTAACCAG



CAGTTCGAATTGATCGACAATGAATTTAATGAAGTGGAGAAGCAGATAGGTAACGTGATT



AACTGGACTCGGGACTCAATCACTGAAGTTTGGAGTTACAACGCAGAGCTCCTGGTCGCC



ATGGAGAACCAGCATACCATAGATCTCGCTGACAGTGAGATGGACAAACTGTACGAAAGA



GTGAAGCGTCAGCTCAGAGAGAATGCGGAGGAAGATGGGACCGGATGCTTCGAAATTTTT



CACAAGTGTGACGACGACTGTATGGCCAGCATAAGGAATAACACTTATGATCATTCTAAG



TATCGTGAGGAGGCAATGCAGAACAGGATTCAAATTGATCCGGTTAAGCTTTCTTCAGGA



TACAAGGACGTCATTCTGTGGTTCTCCTTCGGGGCATCTTGCTTTATTTTACTTGCAATC



GTGATGGGGTTAGTCTTTATCTGCGTGAAAAATGGGAACATGAGGTGTACTATCTGCATC





523
ATGAATACACAGATCCTGGTCTTTGCTCTGATCGCAATTATTCCTACGAATGCAGACAAG



ATTTGCCTTGGACACCACGCCGTATCTAACGGCACCAAAGTCAATACCCTGACCGAGCGG



GGCGTTGAAGTTGTTAATGCCACCGAAACAGTAGAACGCACTAATATACCACGCATTTGC



TCGAAAGGGAAAAAGACCGTTGACCTCGGCCAGTGCGGCCTGCTTGGCACAATCACAGGA



CCACCACAGTGTGACCAATTTCTCGAATTTTCCGCTGATCTGATAATAGAGAGGCGGGAA



GGGAGCGACGTGTGTTATCCAGGGAAGTTCGTTAACGAGGAAGCACTTAGGCAAATACTG



CGGGAAAGCGGTGGCATCGATAAAGAGGCCATGGGCTTTACCTACAGTGGTATTAGGACA



AACGGCGCGACATCCGCGTGTAGGAGAAGCGGCTCATCCTTCTACGCTGAAATGAAGTGG



CTGTTAAGTAATACCGATAATGCGGCTTTCCCGCAAATGACTAAGAGTTACAAAAACACT



AGAAAGTCTCCAGCTCTGATTGTTTGGGGGATTCATCATTCTGTGAGTACAGCCGAACAG



ACCAAGTTGTACGGCTCCGGAAACAAGCTGGTGACTGTAGGCTCTTCTAATTATCAACAG



TCTTTTGTACCTAGTCCGGGTGCCCGCCCACAGGTAAACGGGCAGTCAGGCAGAATCGAT



TTCCACTGGCTCATGCTGAATCCAAACGATACCGTCACCTTCAGTTTCAATGGAGCATTT



ATAGCACCGGACCGCGCGTCATTCCTACGGGGTAAATCCATGGGCATTCAGAGCGGGGTT



CAAGTAGATGCCAACTGTGAGGGCGACTGCTATCACTCTGGCGGTACGATCATAAGCAAC



CTTCCGTTTCAAAATATCGACAGCCGTGCTGTTGGCAAATGCCCCCGTTACGTGAAGCAG



AGAAGCCTTCTGTTGGCTACTGGAATGAAGAATGTGCCCGAGATTCCTAAGGGAAGAGGC



CTCTTCGGAGCGATCGCTGGATTTATAGAAAATGGCTGGGAAGGACTAATCGACGGCTGG



TATGGGTTTAGACACCAGAACGCACAGGGGGAGGGCACTGCTGCGGATTATAAGTCGACA



CAGTCCGCGATCGACCAGATCACCGGTAAACTCAATCGGCTCATTGAGAAGACAAACCAA



CAGTTCGAGTTGATCGATAATGAATTTAATGAAGTGGAAAAGCAGATAGGAAATGTGATC



AACTGGACACGGGACAGCATTACCGAAGTATGGAGTTACAATGCAGAGCTGCTGGTTGCT



ATGGAGAACCAGCACACGATTGATTTGGCCGATTCGGAAATGGACAAGCTTTACGAGCGG



GTGAAAAGGCAACTCCGCGAAAATGCTGAAGAGGATGGGACTGGCTGTTTCGAGATTTTT



CACAAGTGCGACGACGATTGCATGGCCAGCATAAGGAATAATACATATGACCACTCCAAA



TACAGGGAAGAAGCAATGCAGAACAGAATCCAGATCGACCCTGTGAAGTTGAGTAGTGGA



TACAAGGATGTCATCCTGTGGTTTTCTTTTGGCGCCTCATGCTTCATTCTGCTGGCAATT



GTAATGGGCCTGGTGTTCATTTGTGTGAAAAACGGAAATATGAGGTGTACAATCTGTATC





524
ATGAACACGCAAATTTTGGTCTTCGCATTGATTGCAATTATTCCTACGAACGCAGACAAG



ATCTGTCTAGGACACCACGCTGTGTCAAACGGAACAAAAGTGAACACGCTGACCGAGCGG



GGGGTCGAAGTGGTGAATGCAACTGAAACTGTAGAACGAACTAACATCCCAAGAATTTGT



AGCAAAGGAAAGAAGACAGTTGACCTGGGTCAGTGCGGACTGCTCGGTACCATCACCGGT



CCGCCGCAGTGCGACCAATTTTTAGAGTTCTCTGCAGACTTAATCATCGAGCGCAGAGAG



GGCTCAGATGTCTGCTACCCCGGTAAGTTCGTGAACGAGGAGGCGCTTCGTCAGATTCTG



CGAAAGAGTGGCGGGATCGACAAGGAGGCTATGGGCTTCACTTACTCAGGCATTCGTACG



AATGGCGCCACATCCACCTGCAGGCGGAGCGGGTCTAGTTTTTACGCCGAGATGAAGTGG



TTGTTATCGAACACCGACAATGCGGCCTTCCCCCAGATGACAAAATCATACAAAAATACG



CGCAAGTCACCCGCTATAATTGTGTGGGGCATTCACCACAGCGTCTCTACGGCCGAACAG



ACGAAATTATACGGGTCTGGGAACAAACTGGTGACAGTCGGCAGCAGTAACTACCAGCAA



TCTTTCGTGCCATCGCCAGGAGCCCGCCCGCAGGTCAATGGGTTATCTGGACGGATAGAC



TTCCATTGGCTGATGCTTAACCCAAACGACACTGTTACCTTTAGCTTCAATGGGGCTTTT



ATCGCGCCTGATAGAGCTTGCTTCCTGAGAGGAAAGTCAATGGGAATCCAGTCAGGTGTG



CAGGTGGACGCGGATTGTGAAGGTGATTGCTACCACAGTGGGGGGACAATCATTAGTAAT



CTGCCATTCCAGAATATTGATTCACGTGCAGTAGGAAAATGTCCACGATATGTTAAGCAA



AGGTCGTTGCTACTCGCTACTGGTATGAAAAACGTACCAGAAATACCTAAGGGAAGGGGA



CTATTTGGTGCAATTGCAGGGTTCATCGAGAACGGCTGGGAGGGCCTCATAGACGGATGG



TATGGTTTCCGGCACCAGAACGCACAGGGCGAAGGCACAGCAGCCGATTACAAGTCCACA



CAGAGCGCAATCGACCAGATCACAGGCAAACTCAATAGGCTCATAGAAAAGACCAATCAG



CAGTTTGAGCTCATTGACAACGAATTCAATGAAGTGGAGCGGCAGATAGGAAACGTGATA



AATTGGACCCGGGATAGCATTACGGAGGTCTGGTCCTATAACGCGGAGCTGCTGGTGGCC



ATGGAGAATCAGCACACCATTGACCTGGCCGATAGCGAAATGGATAAGCTGTATGAGCGC



GTGAAGAGGCAGCTGCGGGAGAACGCTGAAGAGGACGGCACGGGCTGTTTTGAGATTTTC



CACAAGTGTGATGACGACTGCATGGCCTCCATCCGAAACAACACCTATGACCATTCCAAA



TACCGGGAAGAGGCAATGCAAAATAGAATACAGATCGATCCTGTGAAGCTGTCCAGCGGC



TATAAAGACGTTATTCTGTGGTTCTCTTTCGGGGCATCCTGTTTTATACTCTTAGCTATC



GTTATGGGCCTGGTCTTTATTTGCGTGAAGAACGGCAACATGCGGTGCACGATTTGCATC





525
ATGAACACCCAGATCCTGGTTTTCGCTTTAATCGCGATTATACCCACAAACGCTGATAAG



ATCTGCCTTGGGCATCATGCCGTGAGTAATGGTACAAAGGTCAATACACTCACTGAGAGA



GGCGTCGAGGTCGTGAATGCTACTGAAACCGTCGAGAGAACAAATATACCCAGGATTTGC



AGTAAAGGCAAGAAAACAGTAGATCTCGGTCAGTGCGGGTTGCTCGGGACCATCACTGGG



CCACCTCAGTGCGACCAATTCTTGGAGTTTTCCGCCGACCTCATTATTGAGCGCCGGGAA



GGCAGTGACGTCTGTTACCCCGGGAAATTCGTTAATGAGGAGGCCCTGAGACAGATCCTC



CGGGAGAGCGGGGGAATTGACAAGGAGGCCATGGGGTTCACCTATTCTGGAATTAGGACT



AACGGCGCCACATCCGCGTGTCGCCGGTCTGGGTCATCTTTCTACGCCGAGATGAAATGG



TTGCTCAGCAATACCGATAACGCCGCCTTTCCTCAGATGACCAAGTCATACAAAAACACA



CGAAAGTCACCCGCACTGATAGTGTGGGGCATACACCACAGCGTTTCAACTGCCGAACAG



ACAAAATTGTACGGATCTGGCAATAAGCTGGTCACCGTGGGCTCCAGTAACTACCAGCAA



AGCTTCGTCCCCTCCCCCGGTGCTAGGCCACAAGTCAATGGCCAGTCCGGTAGAATCGAC



TTCCATTGGCTAATGCTAAACCCCAATGACACTGTGACATTTTCTTTTAACGGAGCATTC



ATCGCCCCGGATAGGGCCAGCTTTCTCAGGGGCAAATCAATGGGGATTCAGAGTGGGGTG



CAAGTTGATGCTAATTGTGAGGGTGATTGCTATCATTCAGGGGGAACCATTATCAGCAAT



TTGCCCTTCCAGAACATAGACTCACGCGCCGTCGGTAAGTGCCCTCGCTATGTCAAGCAA



AGGTCCCTGCTGCTGGCCACTGGAATGAAGAACGTGCCCGAGATCCCAAAGGGCAGGGGC



TTATTCGGGGCCATTGCAGGTTTCATCGAAAACGGCTGGGAAGGACTAATAGATGGGTGG



TACGGCTTTCGTCACCAGAACGCACAAGGGGAGGGGACAGCTGCTGATTATAAAAGTACT



CAGAGCGCTATCGACCAGATTACAGGTAAGCTGAATCGGTTAATCGAGAAGACCAACCAG



CAGTTCGAACTTATTGACAATGAGTTCAATGAGGTGGAGAAGCAGATTGGCAATGTGATT



AATTGGACGCGGGATAGTATTACCGAGGTCTGGTCCTATAACGCCGAGTTGCTAGTGGCA



ATGGAAAACCAGCACACGATAGATCTTGCAGACAGCGAAATGGATAAGTTGTACGAAAGG



GTGAAACGGCAACTAAGGGAAAACGCTGAGGAAGATGGGACAGGATGCTTCGAGATCTTC



CACAAATGTGACGATGACTGTATGGCCAGTATTAGAAATAACACATATGACCATTCCAAA



TATCGGGAAGAGGCTATGCAAAATCGCATCCAGATTGATCCCGTAAAACTCTCCTCGGGA



TACAAAGACGTGATCCTGTGGTTCTCCTTCGGAGCCTCTTGTTTCATCCTACTCGCCATC



GTTATGGGGTTAGTGTTCATCTGTGTGAAGAATGGCAATATGAGGTGTACAATCTGCATT





526
ATGAATACCCAGATCCTTGTTTTCGCCCTCATCGCCATAATTCCCACCAACGCAGATAAA



ATCTGTCTCGGCCACCACGCAGTGAGCAATGGCACTAAGGTCAATACCCTCACTGAACGA



GGTGTCGAGGTTGTCAACGCCACTGAAACGGTAGAGAGAACGAACATCCCCCGCATATGC



AGTAAAGGCAAGAAAACTGTGGATCTCGGACAGTGCGGCCTGCTGGGCACCATTACCGGC



CCGCCCCAGTGCGATCAATTCCTGGAATTTTCTGCAGACCTCATCATCGAACGTCGGGAA



GGGAGTGACGTGTGTTACCCCGGGAAATTCGTAAATGAGGAGGCTCTTCGCCAGATTCTG



AGGGAAAGTGGGGGTATTGATAAGGAAGCAATGGGCTTTACCTATTCCGGAATTAGAACC



AATGGCGCCACCTCCGCATGTAGACGGTCTGGTTCATCATTCTACGCTGAGATGAAGTGG



CTGCTGTCCAACACTGACAACGCTGCATTTCCTCAGATGACTAAAAGTTACAAAAACACT



CGCAAATCCCCTGCCCTTATTGTTTGGGGCATTCATCATAGTGTAAGTACAGCCGAACAA



ACCAAACTGTATGGCTCAGGGAATAAATTAGTTACCGTGGGTTCATCCAACTACCAGCAG



TCTTTCGTCCCTTCTCCAGGCGCTCGCCCACAAGTTAATGGGCAATCTGGGCGAATCGAT



TTCCACTGGTTGATGCTGAACCCCAACGACACCGTTACCTTCAGTTTTAACGGCGCATTT



ATTGCCCCCGACCGCGCAAGTTTTCTGAGGGGCAAATCAATGGGGATCCAATCTGGCGTC



CAGGTGGATGCCAACTGCGAAGGCGACTGTTATCATTCCGGTGGAACAATAATCTCTAAT



TTGCCGTTTCAGAACATTGATTCAAGAGCCGTGGGCAAGTGCCCACGGTACGTAAAACAG



CGCTCCTTACTCCTTGCTACAGGGATGAAGAACGTGCCGGAGATCCCTAAAGGCCGAGGA



CTCTTTGGTGCTATTGCAGGGTTTATAGAAAATGGCTGGGAGGGACTGATTGATGGGTGG



TACGGATTCCGACACCAGAATGCCCAAGGCGAGGGTACCGCTGCAGACTACAAAAGTACC



CAGAGTGCTATCGACCAGATCACCGGGAAGTTAAATCGTTTGATAGAAAAAACAAATCAA



CAATTCGAGCTGATTGACAATGAGTTCAACGAGGTGGAGAAACAAATAGGAAACGTAATC



AATTGGACTCGTGACAGTATAACCGAAGTCTGGAGCTACAATGCGGAGCTACTCGTCGCT



ATGGAAAATCAGCATACAATCGATCTGGCGGACAGCGAGATGGATAAGCTGTACGAACGC



GTGAAGAGACAACTGAGAGAAAACGCCGAGGAAGATGGCACAGGCTGCTTCGAGATTTTC



CATAAGTGCGATGACGATTGCATGGCGAGTATTAGGAATAACACATATGATCACTCAAAG



TATCGCGAGGAGGCGATGCAAAACAGGATCCAGATTGACCCCGTGAAATTGTCTTCTGGC



TACAAGGACGTGATACTCTGGTTTTCCTTCGGGGCCTCCTGTTTCATTCTGCTGGCGATT



GTGATGGGGCTGGTGTTTATATGTGTGAAAAATGGGAATATGAGATGTACTATTTGCATT





527
ATGAACACCCAGATCCTTGTGTTCGCACTGATAGCGATTATACCAACCAACGCCGACAAG



ATCTGCTTAGGGCACCACGCTGTAAGTAATGGTACTAAGGTGAATACGCTGACTGAAAGA



GGTGTGGAAGTGGTGAACGCCACAGAAACCGTAGAAAGGACCAACATCCCCAGAATCTGC



AGCAAGGGGAAGCGGACCGTAGACCTGGGACAATGTGGACTTCTGGGAACAATTACTGGC



CCTCCACAGTGCGACCAGTTCTTGGAGTTTAGCGCCGACCTCATTATCGAGCGACGGGAA



GGCAGCGATGTATGTTATCCAGGCAAATTTGTGAACGAAGAAGCTCTCAGGCAGATTCTG



CGGGAATCCGGCGGCATTGATAAAGAGGCTATGGGCTTTACCTACAGGGGGATCCGTACA



AACGGGGCAACCTCTGCCTGTCGGAGATCTGGCTCAAGCTTTTATGCCGAGATGAAATGG



CTCCTGTCTAATACTGACAATGCTGCTTTCCCACAGATGACGAAGTCCTATAAAAACACC



CGGAAGTCCCCCGCCTTAATTGTATGGGGCATCCATCATTCCGTTAGCACAGCCGAACAG



ACCAAGCTTTATGGATCTGGAAACAAGCTGGTGACCGTGGGCTCAAGTAACTATCAACAG



TCATTCGTGCCTTCACCTGGAGCCCGCCCGCAGGTCAATGGCCTTAGCGGACGGATTGAC



TTTCATTGGCTTATGCTGAATCCCAATGATACAGTGACGTTCAGCTTCAACGGCGCCTTC



ATAGCCCCCGACCGTGCCAGTTTTCTTCGGGGAAAGAGCATGGGGATCCAAAGTGGCGTG



CAGGTGGACGCCAATTGCGAAGGCGATTGCTATCATTCAGGCGGAACAATTATCAGTAAC



CTGCCGTTTCAGAATATTGACAGTCGAGCAGTTGGGAAGTGTCCAAGGTACGTGAAACAG



CGCAGCCTCCTTTTAGCCACAGGCATGAAGAATGTCCCAGAGATTCCGAAGGGCCGTGGG



CTGTTTGGTGCTATTGCAGGTTTTATCGAAAATGGCTGGGAAGGACTTATTGACGGCTGG



TATGGGTTTAGGCATCAGAATGCCCAGGGTGAAGGCACTGCCGCCGACTATAAGAGCACG



CAAAGCGCGATCGATCAGATTACTGGCAAGTTAAATAGACTGATCGAAAAAACCAACCAA



CAGTTTGAGTTGATTGATAACGAGTTTAATGAGGTCGAAAAGCAGATTGGGAACGTGATA



AACTGGACCCGGGACAGCATAACCGAAGTATGGAGCTACAATGCAGAGCTGCTTGTGGCT



ATGGAGAATCAGCACACAATCGATCTGGCAGACAGTGAGATGGACAAACTCTACGAGAGG



GTCAAGCGGCAGCTCCGGGAAAATGCCGAGGAAGATGGTACCGGATGCTTTGAGATTTTC



CATAAGTGTGACGATGATTGTATGGCCTCCATTCGCAATAACACCTATGATCACTCAAAG



TATAGGGAGGAGGCAATGCAAAATCGCATCCAGATCGACCCCGTGAAGCTTAGCTCCGGA



TATAAGGACGTGATCTTGTGGTTCTCTTTTGGTGCCTCCTGCTTCATCCTTCTGGCCATT



GTGATGGGATTGGTATTTATTTGCGTGAAGAATGGCAATATGCGATGCACAATTTGCATC





528
ATGAATACACAGATACTGGTGTTTGCGCTGATTGCCATTATTCCAACAAATGCTGATAAA



ATCTGCCTGGGGCATCACGCAGTTTCAAATGGCACCAAAGTGAACACACTTACCGAGCGA



GGCGTGGAGGTGGTGAATGCCACTGAAACAGTGGAGCGTACCAATATCCCTCGTATCTGT



AGCAAGGGTAAACGGACTGTCGATCTGGGCCAGTGTGGTTTACTGGGGACAATTACAGGC



CCCCCTCAGTGTGATCAGTTCTTAGAGTTTTCAGCTGATCTGATCATAGAACGGAGAGAA



GGCAGCGACGTGTGTTACCCTGGCAAGTTCGTGAATGAGGAGGCCCTGCGCCAAATCCTG



AGAGAGTCTGGGGGGATAGATAAAGAAGCGATGGGGTTCACTTATTCTGGCATCCGAACC



AATGGCGCTACGAGCGCATGCCGCAGATCTGGCTCTAGCTTTTACGCTGAGATGAAATGG



CTCCTCTCTAATACGGACAATGCTGCATTTCCCCAGATGACCAAATCTTACAAGAATACC



CGTAAGTCCCCAGCTCTCATCGTGTGGGGAATCCACCACTCTGTGAGTACTGCCGAGCAG



ACAAAGCTCTACGGCTCTGGAAATAAGTTGGTGACCGTAGGTTCATCCAATTATCAACAG



TCATTCGTGCCTAGTCCCGGTGCTCGGCCCCAAGTGAACGGCCTCTCCGGGAGGATTGAC



TTCCATTGGCTGATGCTGAACCCTAACGATACAGTGACATTTTCATTTAACGGCGCGTTT



ATAGCTCCTGACCGAGCTTCCTTTCTCCGAGGTAAGAGCATGGGCATCCAGAGTGGGGTA



CAAGTCGATGCGAATTGCGAGGGCGATTGTTACCACAGTGGTGGCACTATCATTTCCAAC



CTTCCTTTTCAGAACATTGACTCACGGGCGGTCGGCAAATGTCCTCGCTACGTGAAGCAA



AGGTCCCTTCTGCTGGCCACAGGGATGAAAAACGTGCCTGAGATCCCCAAGGGGGGGGGT



CTCTTTGGGGCCATCGCAGGATTTATAGAAAATGGGTGGGAGGGACTCATTAATGGCTGG



TACGGATTTAGACACCAGAACGCCCAAGGGGAGGGCACTGCCGCCGATTATAAATCCACT



CAGAGCGCTATCGATCAAATAACAGGTAAACTGAATCGGTTAATTGAGAAAACCAATCAA



CAGTTTGAACTGATAGATAACGAGTTTAATGAAGTGGAGAAGCAGATTGGAAACGTGATC



AACTGGACCAGAGACTCCATTACTGAGGTTTGGTCGTATAACGCGGAGCTGCTCGTCGCT



ATGGAGAATCAACATACCATCGACCTGGCTGATAGTGAGATGGACAAGCTGTACGAGCGC



GTTAAAAGACAGCTGCGTGAGAACGCTGAAGAGGATGGTACAGGATGTTTTGAGATCTTT



CACAAGTGTGATGACGACTGCATGGCTAGTATCCGAAACAATACATACGACCACAGCAAA



TATAGAGAAGAGGCCATGCAAAATCGTATACAAATTGATCCCGTGAAACTATCCTCCGGC



TACAAGGATGTGATCTTGTGGTTTTCCTTTGGCGCATCTTGCTTCATCCTGCTGGCAATT



GTAATGGGATTGGTCTTTATCTGCGTGAAGAACGGCAATATGCGGTGTACTATCTGCATC





529
ATGAACACTCAGATCCTCGTGTTTGCCTTGATCGCCATCATACCAACGAATGCAGATAAG



ATCTGCCTGGGACACCATGCTGTATCAAATGGCACTAAGGTGAACACCCTGACTGAGCGG



GGCGTTGAAGTGGTGAACGCCACTGAAACGGTGGAAAGGACCAATATCCCCAGAATTTGC



TCAAAGGGCAAAAAAACTGTTGACCTCGGCCAGTGCGGCCTCTTAGGGACGATAACCGGT



CCCCCTCAGTGTGATCAGTTCCTGGAGTTCTCAGCCGATCTGATCATTGAAAGAAGAGAA



GGCTCGGACGTGTGTTATCCGGGCAAGTTCGTGAACGAAGAAGCCCTGCGCCAGATCCTC



CGCGAAAGCGGGGGCATCGACAAGGAAGCCATGGGTTTCACCTACTCTGGAATTCGCACC



AACGGGGCCACTTCCGCATGCCGACGGTCCGGTTCGAGCTTTTACGCTGAGATGAAGTGG



CTTTTATCAAACACAGATAACGCGGCTTTCCCGCAGATGACCAAGTCCTATAAGAACACA



AGAAAGTCTCCGGCCCTGATTGTCTGGGGGATCCACCATAGTGTTTCTACTGCGGAGCAG



ACAAAACTTTATGGTAGCGGGAACAAACTGGTCACCGTCGGCTCCTCCAATTACCAGCAG



AGTTTTGTTCCCTCCCCCGGGGCACGACCCCAAGTCAATGGGCAAAGTGGCAGGATAGAT



TTCCACTGGTTGATGCTCAACCCCAATGACACCGTGACATTTAGCTTTAACGGAGCTTTT



ATCGCACCAGACCGGGCATCATTCCTGCGTGGCAAGAGTATGGGTATTCAAAGTGGGGTT



CAGGTAGACGCAAACTGCGAGGGCGACTGTTATCACAGTGGGGGGACCATTATCAGCAAC



CTACCGTTTCAGAATATCGATAGTAGGGCAGTGGGGAAATGCCCTCGATATGTGAAGCAA



CGGTCCCTGCTCCTGGCTACGGGAATGAAAAACGTCCCAGAGATTCCCAAGGGCCGGGGC



CTTTTCGGCGCGATTGCTGGCTTTATTGAGAATGGGTGGGAGGGATTAATCGACGGGTGG



TATGGCTTTAGGCACCAGAACGCTCAGGGCGAAGGTACGGCCGCAGATTACAAGTCCACC



CAGTCCGCCATCGACCAGATTACAGGCAAGCTCAACCGTTTAATTGAGAAAACCAATCAG



CAGTTCGAGCTCATCGATAACGAGTTCAATGAGGTGGAGAAACAGATTGGCAACGTGATA



AACTGGACTAGGGACTCAATCACAGAGGTCTGGAGCTATAATGCCGAGCTGCTAGTTGCC



ATGGAAAACCAGCATACAATCGATCTTGCCGACTCCGAAATGGACAAACTATATGAGAGA



GTCAAACGTCAGCTAAGAGAGAATGCAGAAGAGGATGGCACGGGTTGCTTCGAAATTTTC



CACAAGTGTGACGACGACTGCATGGCCAGCATTAGAAACAACACATACGATCATAGCAAG



TATAGGGAGGAGGCGATGCAGAACAGGATTCAGATTGATCCCGTCAAGCTCTCTTCTGGC



TATAAGGATGTCATTCTGTGGTTTTCTTTCGGCGCCTCATGTTTCATCCTGCTTGCAATC



GTGATGGGATTAGTTTTCATTTGTGTAAAGAACGGCAATATGCGGTGTACAATCTGCATC





530
ATGAATACTCAAATCCTGGTCTTCGCCCTTATTGCGATCATACCTACCAACGCCGATAAG



ATCTGCTTGGGGCACCATGCCGTCTCAAACGGCACCAAGGTCAACACTCTTACAGAACGG



GGTGTAGAAGTGGTTAATGCCACTGAGACTGTCGAACGAACAAACATCCCTCGAATCTGC



AGCAAAGGGAAACGGACTGTCGATCTTGGCCAGTGTGGGCTCCTGGGTACCATAACGGGG



CCTCCCCAGTGCGACCAATTCTTAGAGTTCTCGGCCGATTTAATAATAGAACGCAGAGAG



GGATCAGACGTATGTTACCCGGGCAAATTCGTCAATGAGGAGGCACTCCGGCAGATCCTG



AGGGAGAGCGGCGGAATTGACAAAGAGGCCATGGGATTCACTTATAGTGGGATTCGTACC



AATGGCGCTACAAGTGCCTGCCGTAGATCCGGGTCGAGTTTTTATGCCGAAATGAAGTGG



CTACTGTCCAATACAGATAACGCTGCGTTCCCTCAGATGACTAAGTCTTACAAGAATACC



AGGAAAAGCCCTGCCCTTATTGTGTGGGGAATTCACCATTCGGTGAGCACCGCGGAACAA



ACAAAACTGTACGGCAGTGGGAACAAGCTCGTGACGGTAGGGTCCTCTAACTACCAACAA



AGTTTCGTCCCATCCCCAGGAGCTAGACCTCAGGTGAACGGGTTAAGCGGGCGAATTGAT



TTCCATTGGCTGATGCTGAACCCCAACGACACAGTGACATTTAGCTTCAATGGCGCCTTC



ATAGCTCCAGACAGAGCTTCCTTTCTGAGAGGCAAAAGTATGGGAATTCAGTCTGGAGTC



CAAGTGGATGCCAACTGCGAGGGGGACTGTTATCATTCTGGCGGGACCATTATCTCTAAC



CTACCATTCCAGAATATAGACAGTAGGGCCGTAGGGAAGTGTCCCCGCTATGTAAAGCAG



CGGAGTCTGCTGCTGGCAACAGGTATGAAGAACGTGCCCGAAATCCCCAAGGGCCGCGGA



CTCTTTGGGGCTATCGCTGGGTTCATTGAGAACGGATGGGAAGGCCTCATCGATGGGTGG



TATGGTTTTCGTCACCAGAACGCTCAGGGGGAAGGCACCGCCGCTGACTATAAATCTACT



CAATCGGCCATCGACCAGATTACAGGGAAGCTGAATCGTCTAATCGAGAAAACCAATCAG



CAATTCGAGCTTATTGACAATGAGTTCAATGAAGTGGAGAAACAGATTGGAAATGTTATA



AACTGGACCCGGGACAGCATAACTGAGGTGTGGAGTTACAACGCGGAGCTCCTCGTTGCC



ATGGAGAACCAGCACACCATAGATCTGGCCGATAGCGAAATGGACAAGCTGTACGAGCGG



GTTAAGCGTCAACTGCGAGAGAATGCCGAAGAAGATGGCACCGGATGCTTTGAAATATTC



CACAAATGCGATGATGACTGTATGGCTTCTATACGTAATAACACTTACGATCATAGCAAG



TACCGAGAGGAGGCTATGCAAAACAGGATACAGATCGACCCCGTGAAACTTTCATCAGGC



TATAAGGACGTTATACTGTGGTTCTCGTTCGGGGCAAGTTGCTTCATTCTGCTCGCCATT



GTCATGGGCCTGGTTTTTATCTGTGTGAAGAACGGCAATATGCGGTGTACCATTTGCATC





531
ATGAATACCCAGATCTTGGTTTTCGCACTGATCGCAATTATCCCAACAAACGCAGACAAA



ATTTGTCTTGGTCATCATGCCGTTTCCAACGGGACTAAAGTTAACACCCTCACGGAACGC



GGAGTAGAGGTGGTCAACGCTACAGAAACCGTGGAGCGTACGAACATCCCTCGCATATGT



TCCAAAGGAAAGAAGACTGTCGATCTGGGACAGTGCGGCCTATTAGGGACCATCACCGGC



CCTCCTCAGTGCGATCAATTCCTTGAGTTTTCCGCGGATCTCATAATAGAGCGCAGGGAG



GGTTCCGACGTCTGTTACCCTGGCAAGTTTGTGAATGAGGAAGCCTTACGGCAAATCTTG



AGGAAGTCTGGCGGTATTGACAAGGAAGCGATGGGTTTTACTTATTCCGGCATCAGGACA



AATGGGGCTACTTCTACTTGTCGGAGGAGTGGAAGCAGCTTCTATGCCGAGATGAAGTGG



CTTCTGAGCAACACTGACAATGCCGCCTTTCCCCAGATGACAAAATCATACAAAAACACA



CGCAAATCGCCCGCAATCATTGTCTGGGGCATTCATCATTCTGTCTCAACCGCCGAGCAG



ACTAAACTCTATGGCTCAGGAAATAAATTAGTGACCGTGGGATCCAGCAATTACCAGCAA



AGTTTCGTGCCTTCCCCAGGCGCAAGACCGCAGGTTAACGGCCTCTCTGGACGCATCGAC



TTTCATTGGCTCATGCTTAACCCCAATGATACAGTGACATTCTCCTTCAATGGAGCTTTT



ATCGCTCCGGACCGTGCTTGTTTCCTTCGAGGCAAGTCCATGGGAATTCAAAGTGGCGTT



CAGGTTGACGCCGACTGCGAAGGTGACTGCTATCATAGCGGAGGCACTATCATCAGCAAT



CTTCCATTCCAGAACATTGACTCGCGAGCCGTGGGAAAGTGCCCAAGGTATGTCAAGCAG



AGGAGCCTGCTGCTGGCTACCGGCATGAAAAACGTCCCCGAAATTCCAAAAGGCCGTGGT



TTGTTTGGCGCCATTGCCGGTTTTATCGAGAACGGATGGGAGGGACTGATTGACGGCTGG



TACGGCTTCAGACACCAGAACGCGCAGGGAGAAGGGACGGCGGCCGATTATAAGAGCACT



CAGAGCGCTATCGATCAGATTACCGGTAAATTGAATAGACTGATCGAAAAGACCAACCAG



CAATTTGAACTCATTGACAATGAGTTCAACGAGGTGGAACGGCAGATAGGAAATGTCATT



AACTGGACACGAGATTCTATTACTGAGGTGTGGAGTTACAACGCGGAGCTCCTAGTCGCC



ATGGAGAACCAGCATACAATCGACCTGGCCGACAGCGAAATGGACAAGCTGTATGAAAGA



GTAAAGAGGCAGCTGCGGGAGAACGCCGAGGAGGATGGAACCGGTTGTTTTGAGATCTTT



CACAAATGCGACGATGACTGCATGGCAAGCATCCGGAACAACACTTATGACCACAGCAAG



TATAGGGAGGAGGCCATGCAGAATAGAATCCAGATCGACCCAGTCAAGTTAAGCAGTGGC



TACAAAGATGTTATCCTCTGGTTCTCTTTTGGAGCCTCATGTTTCATTCTTCTAGCAATC



GTGATGGGTCTCGTCTTTATTTGTGTCAAAAATGGAAATATGCGCTGTACCATTTGTATT





532
ATGAACACTCAGATCCTTGTCTTTGCGCTAATTGCAATTATTCCAACGAATGCAGACAAA



ATCTGCCTGGGCCATCACGCTGTTTCCAACGGAACAAAGGTGAACACACTCACGGAAAGG



GGCGTCGAAGTGGTGAATGCCACGGAGACTGTTGAGAGGACCAACATCCCCAGGATCTGT



AGCAAAGGAAAGCGGACAGTTGACCTGGGCCAGTGTGGCCTTCTTGGTACCATCACCGGA



CCTCCCCAATGCGACCAGTTTCTGGAGTTTAGCGCAGACCTTATCATCGAGCGGCGCGAG



GGGAGCGACGTCTGTTACCCGGGCAAGTTCGTAAATGAAGAGGCGCTAAGGCAGATCCTT



AGGGAATCCGGGGGTATAGACAAAGAGGCAATGGGCTTTACCTACAGCGGAATCCGGACT



AATGGCGCCACCTCCGCTTGTAGGCGTTCAGGATCTAGTTTCTACGCTGAGATGAAGTGG



TTGTTGAGTAATACCGATAATGCGGCCTTCCCTCAGATGACCAAATCCTATAAAAATACA



AGAAAAAGCCCAGCCCTGATCGTATGGGGGATCCACCATTCTGTATCTACCGCAGAACAG



ACTAAGCTCTACGGGTCTGGGTCCAAATTGGTAACTGTAGGGAGCTCTAATTATCAACAG



AGCTTTGTTCCGAGTCCTGGCGCCAGGCCCCAGGTGAACGGTCTGTCCGGGAGAATTGAT



TTTCACTGGCTCATGCTCAATCCTAATGATACGGTTACCTTCAGCTTTAATGGAGCGTTC



ATCGCACCCGATAGGGCTTCATTTTTACGTGGCAAGTCCATGGGAATCCAGTCAGGAGTC



CAGGTCGACGCTAATTGCGAGGGTGATTGCTACCACAGCGGAGGAACTATCATTTCGAAC



CTCCCCTTTCAGAATATTGATTCTAGGGCCGTCGGTAAATGTCCAAGATATGTGAAGCAA



AGGTCTTTGCTACTCGCCACTGGAATGAAAAACGTGCCTGAAATCCCTAAAGGCCGGGGC



CTGTTTGGCGCAATCGCTGGATTTATCGAGAATGGTTGGGAGGGACTGATTGACGGCTGG



TATGGATTCCGGCACCAAAACGCTCAGGGGGAAGGCACTGCTGCCGATTACAAGTCCACT



CAATCCGCGATTGACCAAATAACCGGTAAGCTGAATAGGCTGATCGAGAAGACAAATCAG



CAGTTTGAGCTCATCGATAACGAGTTTAATGAAGTAGAAAAGCAGATTGGGAACGTTATT



AATTGGACAAGAGATAGTATAACCGAGGTGTGGAGCTATAATGCGGAGCTCCTGGTGGCC



ATGGAAAATCAGCATACAATAGACCTCGCCGATAGCGAAATGGATAAATTATACGAGAGA



GTGAAGCGGCAGCTGAGGGAAAACGCTGAGGAGGACGGAACTGGCTGTTTTGAGATCTTT



CATAAGTGCGATGATGACTGTATGGCCAGCATTCGGAACAACACCTACGATCATTCTAAG



TATAGGGAGGAGGCAATGCAGAACCGAATCCAAATAGATCCTGTTAAGCTGTCTAGCGGA



TATAAAGACGTGATACTTTGGTTCAGCTTCGGGGCCAGCTGTTTCATTCTGCTTGCTATC



GTCATGGGACTTGTATTTATCTGCGTGAAGTCCAGAAACATGAGGTGCACTATATGTATC





533
ATGAACACTCAAATCCTGGTGTTCGCGCTGATCGCCATCATACCTACCAATGCTGACAAA



ATCTGCTTGGGCCACCACGCCGTTAGCAATGGAACCAAAGTGAACACGTTGACGGAAAGA



GGAGTGGAGGTGGTGAATGCCACGGAAACAGTGGAGCGGACAAACATCCCCCGGATCTGT



AGTAAAGGGAAAAAGACGGTTGATCTCGGCCAGTGCGGCCTCCTGGGGACAATAACCGGG



CCTCCTCAATGTGACCAGTTCCTGGAATTCTCAGCCGATTTAATCATAGAGCGGCGGGAG



GGGAGTGATGTGTGTTATCCAGGGAAATTCGTGAATGAAGAAGCCTTGAGACAGATCCTT



CGCGAAAGTGGAGGAATCGACAAGGAGGCCATGGGCTTTACTTATAGTGGAATCAGAACC



AACGGCGCCACGTCCGCATGCCGACGCAGCGGTTCTAGCTTCTATGCCGAAATGAAGTGG



CTGCTCTCCAATACCGATAATGCAGCCTTCCCCCAAATGACGAAATCTTACAAGAATACC



CGCAAAAGTCCTGCTTTGATTGTCTGGGGCATCCACCACAGCGTCTCTACTGCCGAACAA



ACAAAGTTATACGGATCAGGCAACAAACTGGTCACCGTAGGTTCCAGCAACTACCAACAG



TCATTTGTCCCGAGCCCTGGAGCCCGCCCACAGGTGAAGGGGCAGTCCGGCCGAATTGAC



TTTCACTGGCTGATGCTCAACCCGAACGATACTGTGACCTTCAGCTTCAATGGCGCGTTC



ATTGCACCTGACCGTGCATCATTCTTGAGGGGCAAAAGCATGGGGATCCAGTCTGGAGTC



CAGGTCGACGCAAATTGCGAAGGAGATTGTTATCACAGCGGGGGCACGATTATCTCAAAT



CTCCCCTTTCAAAATATAGATAGCCGAGCAGTTGGCAAATGCCCTCGCTACGTGAAACAA



AGGAGCCTGCTCCTGGCTACCGGGATGAAGAACGTACCTGAAATCCCCAAGGGACGCGGA



CTTTTCGGCGCTATTGCTGGGTTCATAGAAAACGGCTGGGAAGGGTTGATCGACGGCTGG



TATGGCTTCAGACACCAGAATGCTCAGGGAGAAGGCACAGCAGCCGACTACAAATCAACC



CAGTCTGCCATCGATCAGATTACAGGAAAGCTGAATCGGCTCATCGAGAAAACTAACCAG



CAGTTCGAACTCATCGACAATGAGTTTAACGAGGTCGAAAAACAGATTGGTAATGTGATC



AACTGGACTAGGGACTCCATTACAGAGGTTTGGTCCTATAATGCCGAGCTTTTGGTTGCC



ATGGAAAACCAACATACCATCGACCTGGCCGATAGCGAGATGGACAAGTTGTACGAGAGG



GTAAAAAGGCAGCTCAGAGAAAACGCCGAGGAAGATGGAACCGGTTGTTTCGAAATTTTT



CATAAGTGCGATGACGACTGTATGGCTTCAATTCGAAACAATACTTACGATCACAGCAAG



TACCGCGAAGAGGCCATGCAGAATAGGATTCAGATTGATCCTGTTAAGTTGTCATCCGGC



TATAAGGATGTAATCTTATGGTTTAGTTTCGGCGCTAGCTGCTTCATACTGCTGGCAATC



GTGATGGGGCTGGTATTTATATGCGTCAAAAATGGGAATATGCGCTGTACCATCTGCATC





534
ATGAATACTCAAATCTTGGTCTTTGCACTGATCGCCATTATTCCTACTAACGCCGATAAA



ATTTGCTTGGGTCATCACGCCGTGTCAAATGGCACTAAAGTTAATACCTTAACAGAGCGC



GGAGTAGAGGTGGTGAATGCAACGGAGACTGTTGAGCGGACCAATATACCCCGCATTTGT



AGTAAAGGCAAGAAAACAGTGGACCTGGGCCAATGCGGGTTGCTTGGGACGATCACCGGC



CCCCCGCAGTGCGATCAGTTCTTAGAATTCTCCGCTGACCTAATCATCGAAAGACGGGAG



GGCAGCGATGTGTGTTATCCTGGCAAATTCGTCAACGAGGAAGCCCTCAGGCAGATTCTT



CGCAAGTCAGGGGGTATTGATAAGGAGGCGATGGGATTCACATACTCCGGAATTCGAACA



AACGGCGCTACAAGTACTTGTAGGAGGAGCGGGAGTTCATTCTACGCAGAGATGAAGTGG



CTGCTCAGCAACACCGACAACGCAGCGTTCCCACAGATGACCAAAAGCTATAAAAATACC



CGAAAGAGTCCCGCAATCATCGTATGGGGAATTCATCACAGTGTCTCTACCGCTGAGCAG



ACCAAGTTGTATGGCTCCGGCAACAAGCTCGTTACCGTTGGCAGCTCAAATTACCAACAG



TCCTTCGTCCCCTCCCCAGGGGCAAGGCCCCAAGTCAACGGCCTGTCCGGCAGAATTGAC



TTCCACTGGCTCATGCTAAACCCCAATGATACGGTCACCTTCAGTTTTAATGGGGCATTC



ATCGCACCCGACAGAGCCTGTTTTCTGCGAGGTAAATCAATGGGTATACAATCCGGGGTC



CAGGTCGACGCTGACTGCGAGGGCGACTGCTATCATTCGGGAGGCACCATTATTTCCAAC



CTGCCTTTCCAGAACATTGATTCCAGAGCCGTGGGCAAGTGTCCTCGGTACGTGAAACAA



CGATCTCTGCTTCTGGCTACCGGAATGAAGAACGTGCCCGAGATCCCCAAGGGACGAGGC



CTGTTCGGGGCCATTGCCGGATTTATTGAGAATGGCTGGGAGGGTCTCATCGATGGATGG



TACGGCTTCAGGCACCAGAACGCACAAGGTGAAGGCACAGCTGCTGATTACAAATCCACC



CAGAGTGCAATTGACCAGATCACCGGAAAACTCAATAGACTGATTGAAAAAACCAACCAA



CAGTTTGAATTGATTGATAATGAGTTTAACGAAGTCGAACGGCAGATTGGTAATGTGATC



AATTGGACCCGGGATTCCATTACAGAGGTTTGGTCCTACAACGCCGAGCTGCTCGTCGCA



ATGGAAAATCAGCACACCATAGATCTGGCCGACTCCGAGATGGACAAGCTTTACGAAAGG



GTGAAGAGACAGCTCAGGGAGAACGCCGAAGAGGACGGAACAGGGTGTTTCGAAATCTTC



CATAAGTGCGACGATGATTGTATGGCTTCTATCCGGAACAACACCTATGATCACTCCAAA



TATAGAGAGGAAGCAATGCAGAACAGGATTCAAATCGACCCTGTCAAACTCTCAAGTGGG



TACAAGGACGTAATCCTATGGTTCAGCTTTGGCGCCAGCTGTTTTATTCTGCTGGCAATC



GTGATGGGTTTGGTGTTTATCTGCGTCAAGAATGGCAACATGAGGTGTACCATTTGCATC





535
ATGAATACACAGATCCTGGTCTTCGCCCTTATCGCTATCATCCCCACAAACGCCGACAAG



ATATGCCTGGGCCACCACGCCGTTAGCAACGGCACCAAAGTAAACACTCTCACTGAAAGG



GGTGTGGAAGTTGTGAACGCAACAGAAACCGTAGAACGCACGAACATTCCAAGAATTTGC



TCAAAGGGGAAACGTACAGTCGATCTAGGACAGTGCGGCCTGCTCGGCACCATAACCGGG



CCCCCCCAATGCGATCAATTTCTGGAGTTCTCTGCCGATCTTATCATCGAGCGTCGGGAA



GGGAGCGATGTGTGCTACCCCGGCAAATTTGTGAACGAGGAGGCCCTCAGACAGATCTTA



AGAGAGTCTGGAGGGATTGACAAAGAGGCCATGGGGTTCACATACTCCGGCATACGTACG



AATGGGGCCACGAGTGCTTGTCGGAGGAGCGGTTCAAGTTTCTACGCGGAGATGAAATGG



CTGCTGAGCAATACCGATAACGCCGCCTTCCCCCAGATGACCAAAAGTTATAAAAATACA



AGGAAATCACCCGCCCTTATCGTTTGGGGAATTCATCACTCCGTCAGTACCGCCGAACAG



ACTAAGCTCTATGGATCGGGTTCAAAGCTAGTGACCGTGGGCTCAAGCAATTACCAGCAA



TCCTTTGTACCAAGCCCTGGGGCCCGTCCCCAAGTGAACGGATTAAGCGGTAGGATTGAC



TTCCATTGGTTGATGCTCAATCCGAATGATACGGTGACCTTCAGTTTCAACGGGGGGTTC



ATAGCTCCTGATCGCGCGAGCTTCCTCCGGGGAAAATCGATGGGAATTCAGTCAGGCGTT



CAGGTGGACGCCAATTGTGAAGGAGACTGCTACCATAGCGGAGGGACTATAATTTCCAAT



CTGCCTTTTCAGAACATTGACTCCCGCGCTGTGGGGAAGTGTCCCCGGTACGTGAAGCAA



CGCTCCCTGCTTCTCGCCACAGGCATGAAGAACGTACCTGAGATTCCTAAGGGCCGGGGG



CTTTTCGGCGCGATTGCTGGATTCATCGAAAACGGCTGGGAAGGTTTAATAGATGGCTGG



TATGGCTTCAGGCACCAGAATGCACAGGGCGAGGGGACCGCGGCCGACTATAAGTCTACC



CAAAGTGCTATTGATCAGATAACCGGAAAGCTTAACCGCCTGATCGAGAAAACCAATCAA



CAGTTTGAACTTATCGACAACGAATTCAACGAGGTTGAGAAGCAGATTGGGAACGTCATT



AATTGGACCCGAGATTCGATCACAGAGGTGTGGAGCTACAACGCCGAGCTGCTGGTCGCG



ATGGAAAATCAGCATACAATCGACTTGGCCGATAGTGAGATGGACAAACTATACGAGAGA



GTGAAACGGCAGCTGAGGGAGAACGCCGAAGAGGACGGCACCGGGTGCTTTGAGATTTTT



CACAAGTGCGATGACGATTGTATGGCTTCCATCAGGAATAATACTTACGACCACAGTAAG



TATCGCGAAGAGGCTATGCAAAACCGCATTCAGATCGACCCCGTCAAACTCTCATCGGGC



TATAAAGATGTGATACTCTGGTTTTCTTTTGGTGCATCATGCTTCATTCTTTTGGCAATA



GTGATGGGGCTGGTGTTCATCTGCGTAAAGAACGGTAACATGAGATGCACTATCTGTATT





536
ATGAATACACAGATCTTAGTGTTTGCTTTAATAGCTATTATTCCAACCAATGCCGATAAA



ATCTGTCTGGGACACCACGCCGTGAGCAATGGGACGAAAGTGAACACTCTTACCGAACGA



GGAGTCGAGGTTGTCAATGCTACGGAAACTGTGGAAAGGACCAACATCCCAAGGATCTGC



AGCAAAGGCAAAAAAACTGTAGATCTGGGGCAGTGTGGACTGCTGGGGACCATTACCGGA



CCCCCCCAGTGCGACCAGTTCTTGGAGTTTTCCGCCGATCTGATTATTGAGCGGCGCGAG



GGGTCTGATGTGTGCTATCCTGGTAAATTTGTCAACGAAGAGGCGCTGCGACAAATTCTC



CGCAAAAGTGGGGGAATCGACAAGGAAGCCATGGGCTTCACATACTCTGGCATTCGAACA



AATGGGGCCACTTCCACATGCAGGCGGTCTGGGTCTTCATTTTATGCCGAGATGAAGTGG



CTTCTTTCTAATACTGACAACGCCGCCTTCCCCCAAATGACCAAGTCCTACAAAAACACC



CGGAAGTCCCCAGCCATTATCGTCTGGGGAATCCATCACAGCGTTTCTACAGCCGAACAG



ACCAAGCTCTACGGATCAGGAAACAAACTGGTTACAGTGGGTAGCAGCAACTATCAGCAG



TCGTTCGTTCCTTCTCCTGGGGCGCGGCCGCAAGTAAACGGGCTCAGTGGGCGTATCGAT



TTCCACTGGCTGATGCTGAACCCAAACGACACAGTCACCTTCAGCTTTAATGGAGCCTTC



ATCGCCCCTGATAGGGCCTGCTTTCTGCGGGGAAAATCCATGGGCATCCAAAGCGGAGTG



CAGGTCGACGCCGATTGCGAAGGGGACTGCTACCATTCTGGTGGGACCATCATCTCCAAC



CTCCCATTTCAGAACATTGACTCCCGGGCGGTCGGAAAATGCCCACGTTACGTGAAGCAG



CGCAGTCTCTTACTCGCCACTGGGATGAAGAACGTGCCCGAAATTCCAAAGGGGCGTGGT



CTGTTTGGGGCGATTGCCGGCTTCATTGAGAACGGCTGGGAGGGGCTTATCGACGGCTGG



TACGGATTCCGTCACCAGAATGCCCAGGGTGAGGGCACCGCAGCAGACTATAAAAGCACA



CAGAGCGCCATTGACCAAATCACTGGGAAGCTGAATCGCCTGATTGAGAAAACTAACCAG



CAGTTTGAACTCATAGATAATGAATTTAACGAAGTCGAAAGGCAGATTGGCAACGTAATT



AATTGGACTCGCGACTCAATCACTGAGGTCTGGAGTTACAATGCAGAACTGCTTGTCGCT



ATGGAGAACCAGCATACCATTGACCTGGCTGATAGCGAGATGGATAAACTGTACGAAAGG



GTGAAGCGACAGCTCCGCGAGAACGCAGAGGAGGACGGGACCGGCTGTTTCGAGATCTTT



CACAAGTGTGACGACGACTGTATGGCTTCGATTCGGAACAACACCTATGACCACTCCAAA



TATAGGGAAGAGGCTATGCAGAATAGGATCCAAATCGATCCTGTGAAGCTGAGCTCCGGC



TACAAAGACGTAATCCTGTGGTTCTCTTTTGGCGCCTCGTGTTTTATCCTACTCGCCATC



GTCATGGGTTTAGTTTTTATCTGCGTAAAAAATGGAAATATGAGATGTACTATCTGCATC





537
ATGAACACGCAGATCCTTGTCTTCGCCCTGATTGCCATTATACCCACTAACGCCGATAAA



ATTTGCTTGGGCCACCACGCCGTGTCCAATGGAACAAAAGTGAATACTTTGACCGAGAGG



GGTGTCGAAGTCGTCAACGCCACCGAGACTGTCGAACGGACAAATATACCGCGTATCTGT



TCTAAAGGGAAGCGAACCGTGGACCTGGGTCAATGCGGACTGCTGGGGACTATTACAGGG



CCCCCTCAGTGCGATCAGTTTCTGGAATTTAGCGCTGACCTCATTATTGAAAGGAGGGAG



GGATCAGATGTGTGTTACCCAGGTAAGTTTGTCAATGAGGAAGCCCTCCGACAGATTCTC



AGGGAATCTGGAGGCATTGATAAAGAGGCTATGGGGTTCACCTATTCAGGCATCAGGACC



AATGGGGCTACCAGCGCTTGCCGCCGGAGCGGATCATCTTTTTATGCCGAGATGAAATGG



CTACTGTCAAACACCGACAACGCCGCATTCCCACAGATGACCAAGAGTTACAAGAATACA



CGCAAGTCACCCGCCCTCATCGTCTGGGGCATCCATCATTCCGTGAGCACAGCCGAGCAG



ACGAAGCTCTACGGATCGGGCAGCAAGCTCGTAACCGTCGGGAGCTCTAACTATCAGCAA



TCTTTTGTGCCCTCCCCCGGAGCCCGGCCACAGGTCAATGGACTATCCGGGCGCATCGAT



TTCCACTGGCTGATGTTGAACCCGAACGACACCGTGACATTTTCATTCAATGGGGCATTC



ATCGCGCCAGACCGCGCGTCCTTTCTGAGGGGAAAGTCCATGGGTATCCAGTCTGGTGTA



CAGGTGGATGCCAACTGTGAGGGTGACTGCTACCATAGTGGAGGAACAATTATCTCCAAC



TTGCCATTCCAAAACATCGACAGTAGAGCTGTTGGTAAATGTCCCAGGTACGTGAAGCAA



AGGTCATTGCTGCTGGCCACTGGGATGAAGAATGTGCCCGAAATTCCAAAAGGAAGGGGG



CTTTTCGGGGCAATCGCCGGCTTCATTGAGAATGGCTGGGAAGGCCTCATCGACGGGTGG



TACGGGTTTAGGCATCAAAACGCGCAGGGGGAGGGGACAGCTGCTGATTACAAGAGTACA



CAGAGCGCAATCGACCAGATCACCGGGAAACTAAATCGCCTCATCGAGAAGACTAATCAG



CAGTTCGAACTGATCGACAACGAGTTCAACGAGGTCGAAAAACAGATTGGTAACGTCATT



AACTGGACCAGAGATTCCATAACCGAAGTCTGGTCCTATAACGCAGAACTGCTGGTAGCC



ATGGAGAACCAGCACACTATCGACCTGGCAGACTCGGAAATGGATAAACTGTACGAGAGG



GTGAAGCGGCAGCTCCGGGAGAACGCTGAAGAAGATGGTACCGGCTGTTTCGAAATTTTT



CACAAATGTGACGATGATTGTATGGCCTCTATACGCAACAATACCTACGATCACTCCAAA



TACAGGGAGGAGGCTATGCAGAATCGTATCCAGATCGATCCGGTAAAACTGAGTAGCGGA



TATAAGGATGTGATCCTGTGGTTCAGCTTCGGGGCTAGTTGCTTTATTCTGTTGGCAATT



GTGATGGGCCTGGTGTTCATTTGCGTCAAAAATGGCAACATGCGCTGCACCATTTGTATC





538
ATGAACACCCAAATATTAGTGTTCGCATTGATTGCGATTATCCCAACCAACGCAGATAAG



ATCTGCTTGGGACATCACGCTGTCAGCAACGGGACCAAGGTGAACACGTTGACAGAGAGG



GGCGTAGAAGTGGTCAACGCCACTGAGACAGTGGAACGCACCAACATACCGCGGATCTGC



TCCAAGGGAAAGCGCACGGTGGATCTTGGCCAGTGCGGCCTGCTGGGTACGATAACTGGA



CCTCCCCAGTGCGACCAGTTCCTGGAGTTCTCCGCCGACCTCATCATCGAAAGGAGAGAA



GGTAGCGATGTCTGCTACCCAGGGAAATTCGTTAACGAAGAGGCCCTTAGACAAATCCTG



AGAGAATCTGGCGGGATCGATAAGGAGGCAATGGGATTTACTTACTCAGGAATTAGGACT



AACGGGGCTACCTCTGCGTGCCGACGGTCCGGTTCGAGCTTCTATGCCGAGATGAAATGG



CTTTTGAGCAACACCGATAATGCTGCTTTTCCCCAGATGACTAAGTCCTATAAGAATACC



AGAAAAAGCCCCGCCTTAATTGTGTGGGGCATCCACCACTCAGTGAGTACAGCCGAACAA



ACGAAACTGTACGGCTCTGGTTCCAAGTTGGTCACAGTCGGATCCTCAAATTATCAGCAG



AGCTTCGTACCCTCTCCGGGTGCGAGACCACAGGTGAACGGCCTGAGTGGTCGGATTGAC



TTCCACTGGCTCATGCTGAACCCCAACGATACCGTAACTTTCTCTTTCAACGGAGCCTTT



ATAGCTCCTGATAGAGCTTCTTTTCTGCGTGGGAAGTCCATGGGGATCCAGAGCGGCGTG



CAGGTGGACGCGAACTGTGAGGGTGACTGCTATCACTCAGGAGGAACAATTATCTCGAAT



CTTCCTTTTCAAAACATCGACTCCCGAGCCGTCGGAAAATGCCCTCGCTATGTGAAACAG



CGGAGCTTGTTGCTCGCCACGGGGATGAAGAACGTCCCTGAAATACCGAAGGGGGGGGGC



CTGTTTGGAGCAATCGCAGGATTTATCGAGAACGGGTGGGAAGGGCTTATTGATGGGTGG



TATGGCTTCCGCCACCAAAACGCTCAAGGCGAGGGGACTGCTGCTGATTATAAATCGACA



CAGTCTGCTATTGACCAGATTACAGGAAAGCTCAACCGATTGATAGAAAAGACTAACCAG



CAGTTTGAGCTGATCGATAATGAATTTAACGAGGTGGAGAAGCAGATCGGGAATGTGATC



AACTGGACCAGAGATTCCATCACTGAAGTTTGGAGTTACAACGCCGAGCTCCTGGTGGCT



ATGGAAAATCAGCATACCATCGACCTCGCTGACAGTGAGATGGACAAGCTCTATGAAAGA



GTTAAGCGACAGCTGCGAGAGAATGCCGAGGAGGATGGTACAGGCTGCTTTGAGATTTTC



CACAAGTGTGATGATGACTGTATGGCCTCAATACGGAATAATACATATGATCACTCCAAG



TATCGGGAGGAAGCCATGCAGAACCGTATCCAGATCGACCCTGTGAAACTGAGCTCTGGA



TACAAGGATGTCATACTCTGGTTCTCATTCGGTGCTTCTTGTTTTATTCTGCTGGCCATT



GTGATGGGCCTCGTGTTTATATGCGTAAAGTCCCGCAACATGAGATGCACCATCTGTATC





539
ATGAATACTCAGATACTGGTATTCGCTCTCATTGCTATTATTCCTACGAACGCAGATAAG



ATTTGCCTAGGCCATCATGCTGTCTCTAACGGCACTAAGGTCAACACCCTGACCGAGCGC



GGAGTGGAGGTAGTTAACGCAACTGAAACAGTCGAACGCACCAATATTCCCAGAATCTGC



TCGAAGGGAAAGAAGACCGTCGATCTGGGGCAATGTGGGCTTCTCGGCACCATCACGGGC



CCTCCACAGTGTGACCAGTTTCTGGAATTTTCCGCCGACCTGATCATAGAGCGCCGGGAA



GGATCCGATGTGTGTTATCCCGGGAAGTTCGTGAACGAGGAAGCACTGCGACAGATCCTG



AGGGAGTCCGGCGGGATTGACAAGGAGGCCATGGGCTTCACTTATAGCGGTATACGTACC



AACGGTGCAACCAGTGCTTGCAGGCGATCCGGGTCCTCCTTCTACGCTGAGATGAAGTGG



CTCCTCTCCAATACAGACAACGCCGCCTTTCCACAGATGACTAAAAGTTATAAGAACACA



CGCAAGTCCCCCGCGCTGATCGTGTGGGGGATTCATCATAGCGTGAGCACCGCGGAGCAG



ACAAAACTCTACGGAAGCGGTAACAAGCTGGTAACAGTGGGATCTTCTAACTACCAACAG



AGTTTCGTGCCTTCCCCAGGTGCGCGCCCCCAGGTAAACGGACAGAGTGGGAGAATCGAC



TTCCACTGGCTGATGCTGAATCCCAACGATACTGTCACCTTTAGTTTTAATGGTGCATTT



ATCGCCCCTGATAGAGCATCCTTCTTACGGGGGAAGAGTATGGGGATTCAGTCAGGCGTG



CAGGTTGACGCTAACTGCGAGGGCGATTGTTACCACTCGGGGGGGACTATAATCTCGAAC



CTTCCCTTTCAAAACATAGATAGCCGGGCCGTGGGCAAATGTCCGAGATACGTGAAACAG



AGGAGTCTGTTGCTGGCTACGGGCATGAAGAACGTGCCAGAAATTCCTAAGGGCCGCGGT



CTGTTCGGAGCAATCGCAGGGTTCATCGAGAATGGCTGGGAAGGGCTGATCGATGGTTGG



TATGGATTCAGACACCAGAACGCGCAGGGGGAGGGAACAGCCGCTGACTATAAATCCACA



CAGAGCGCTATAGATCAAATCACAGGGAAACTTAACAGGCTGATCGAGAAAACAAACCAG



CAGTTTGAGTTGATTGATAATGAGTTCAACGAGGTGGAGAAGCAAATCGGCAACGTCATC



AATTGGACTCGCGATTCTATCACTGAGGTATGGAGCTACAATGCAGAGCTGCTCGTAGCG



ATGGAGAATCAGCATACAATTGATCTGGCCGACTCCGAAATGGACAAGCTGTATGAGCGC



GTAAAGAGACAACTTAGAGAAAATGCCGAGGAAGATGGCACTGGCTGCTTCGAAATCTTT



CATAAATGCGATGATGACTGTATGGCATCTATCAGAAACAACACTTATGACCACTCCAAG



TATAGGGAAGAAGCTATGCAGAATAGAATCCAGATCGATCCCGTAAAACTTAGTTCCGGG



TACAAGGACGTTATTCTTTGGTTTTCTTTCGGCGCAAGCTGTTTCATCCTTCTTGCAATC



GTAATGGGTCTCGTCTTCATCTGCGTTAAAAATGGCAACATGCGTTGCACAATTTGCATT





540
ATGAATACCCAGATCCTGGTCTTTGCGCTGATCGCTATTATCCCAACTAACGCCGATAAA



ATCTGCCTGGGCCACCACGCTGTCAGCAATGGCACAAAGGTAAATACCCTAACAGAGCGG



GGGGTGGAAGTCGTTAATGCTACTGAGACCGTGGAACGAACAAATATTCCTAGGATCTGT



TCCAAGGGCAAGCGCACTGTGGACTTGGGTCAGTGCGGCTTACTTGGTACAATCACTGGG



CCGCCACAGTGCGACCAGTTTCTCGAGTTCTCGGCCGATCTGATCATAGAAAGAAGGGAG



GGCAGCGACGTGTGCTACCCCGGCAAGTTTGTTAACGAGGAGGCACTGCGGCAGATCCTG



AGAGAAAGCGGAGGCATCGACAAAGAGGCAATGGGGTTCACCTACTCTGGCATTAGGACT



AACGGTGCAACTTCTGCCTGCCGGAGAAGCGGTTCTTCCTTCTACGCCGAAATGAAGTGG



CTGCTGTCCAATACTGACAACGCTGCCTTTCCTCAGATGACAAAGAGTTACAAAAACACA



CGGAAAAGCCCAGCTCTGATCGTGTGGGGCATCCACCATAGTGTAAGCACAGCTGAACAG



ACGAAGCTGTACGGGTCTGGCAATAAACTTGTCACAGTTGGATCGTCCAATTACCAACAG



AGCTTCGTCCCCAGTCCAGGTGAGAGACCTCAGGTTAACGGCCTCTCGGGGAGAATCGAC



TTCCACTGGCTGATGCTTAACCCCAACGACACAGTAACCTTCTCCTTTAACGGCGCCTTT



ATTGCTCCTGATAGGGCCTCCTTTTTGAGAGGAAAAAGTATGGGCATCCAAAGCGGGGTG



CAGGTGGACGCCAACTGTGAAGGCGACTGCTACCACTCGGGGGGCACCATAATATCCAAC



CTACCTTTTCAGAATATTGACTCTCGGGCCGTGGGGAAGTGTCCTCGTTACGTGAAGCAG



CGAAGCCTCCTACTCGCAACCGGCATGAAGAACGTCCCAGAGATCCCAAAGGGTCGGGGC



CTGTTCGGTGCCATTGCCGGGTTTATAGAAAACGGGTGGGAAGGCCTGATCGATGGCTGG



TATGGCTTCCGCCATCAGAACGCACAGGGTGAGGGCACAGCAGCAGACTATAAAAGCACT



CAATCGGCCATCGACCAGATCACGGGGAAGTTAAATAGGCTGATTGAAAAGACAAACCAA



CAATTCGAACTTATTGATAACGAGTTTAACGAAGTGGAGAAGCAGATAGGAAACGTTATC



AATTGGACGCGAGATTCCATAACAGAAGTTTGGTCATATAATGCCGAGCTCCTAGTCGCC



ATGGAAAATCAGCACACTATTGATCTGGCTGATTCCGAGATGGATAAATTATATGAGAGA



GTGAAGCGCCAGCTTAGGGAAAACGCCGAAGAGGACGGAACTGGGTGTTTCGAGATCTTT



CATAAATGCGATGATGACTGCATGGCCTCTATTCGGAATAACACATACGATCACTCCAAG



TATCGGGAGGAGGCGATGCAGAACAGAATTCAGATTGATCCAGTGAAGCTGTCCAGCGGA



TACAAAGACGTGATACTATGGTTCAGCTTTGGTGCTAGTTGCTTTATCCTGTTGGCGATC



GTCATGGGCCTGGTATTCATTTGCGTGAAGAATGGTAACATGCGCTGCACCATATGTATT





541
ATGAACACACAGATACTGGTGTTCGCACTGATAGCCATAATACCTACCAATGCTGATAAA



ATTTGTCTTGGTCACCATGCCGTCAGCAATGGAACAAAAGTCAATACTCTGACAGAGAGG



GGAGTCGAAGTGGTGAACGCAACAGAGACGGTAGAACGGACAAACATTCCAAGAATCTGT



TCCAAAGGTAAGAGGACGGTCGATCTCGGACAGTGCGGCCTATTAGGAACTATTACTGGT



CCTCCGCAGTGCGACCAGTTTCTGGAATTTAGCGCAGACTTGATTATAGAGCGGCGAGAA



GGGTCCGATGTATGCTATCCCGGCAAATTCGTGAATGAGGAGGCCCTGCGACAGATTTTG



AGAGAAAGCGGGGGGATTGATAAAGAAGCGATGGGGTTTACATATTCAGGCATCAGGACC



AATGGCGCTACCTCAGCTTGCCGAAGAAGTGGTAGCTCTTTTTATGCCGAAATGAAGTGG



CTTCTTTCAAACACTGATAACGCAGCCTTCCCACAGATGACCAAGAGCTACAAGAATACT



CGTAAATCACCAGCCCTAATTGTGTGGGGTATCCACCATTCAGTCTCTACCGCAGAACAA



ACAAAACTGTACGGCAGCGGGAACAAGCTAGTGACCGTTGGATCCAGCAATTACCAGCAA



AGCTTTGTCCCTTCCCCCGGCGCACGTCCACAGGTAAACGGCTTGAGCGGGAGAATTGAT



TTCCACTGGCTAATGCTAAATCCCAACGATACCGTTACTTTTAGCTTCAATGGGGCTTTC



ATTGCCCCAGATAGAGCCTCTTTCCTGAGAGGTAAAAGTATGGGCATCCAATCCGGGGTG



CAGGTGGATGCGAATTGTGAAGGCGATTGTTACCACAGGGGGGGGACCATTATTTCCAAC



TTACCCTTCCAAAACATCGATTCGCGAGCAGTGGGCAAATGTCCCCGGTATGTCAAGCAG



AGGTCGCTGTTGCTGGCCACCGGCATGAAAAATGTCCCTGAGATTCCAAAAGGTCGCGGT



TTGTTTGGCGCTATTGCGGGATTTATCGAGAACGGCTGGGAGGGGCTGATTGACGGGTGG



TACGGGTTCAGACACCAGAACGCTCAGGGCGAGGGAACCGCTGCGGATTATAAAAGCACG



CAGTCGGCCATAGACCAGATCACAGGCAAGCTCAATAGGCTCATCGAGAAGACGAATCAG



CAATTCGAATTGATAGATAACGAATTCAACGAGGTGGAGAAACAGATTGGGAATGTGATC



AATTGGACAAGGGATTCAATTACGGAAGTGTGGTCCTATAACGCCGAGCTGCTCGTGGCC



ATGGAGAATCAGCATACAATCGATCTGGCCGACAGTGAGATGGATAAACTCTACGAACGT



GTGAAGCGGCAGCTACGCGAGAACGCCGAGGAAGATGGGACAGGCTGTTTTGAGATCTTC



CACAAGTGCGACGACGACTGTATGGCGTCAATCCGCAATAACACATACGACCACAGCAAG



TACCGAGAGGAAGCCATGCAAAACAGGATCCAAATCGATCCTGTAAAGCTTTCCTCTGGG



TATAAAGACGTCATTCTTTGGTTCTCTTTTGGAGCCAGTTGCTTCATCCTTCTAGCCATT



GTGATGGGGCTGGTATTCATCTGCGTGAAAAATGGGAATATGCGATGTACCATATGCATT





542
ATGAATACCCAGATCCTCGTTTTTGCTCTGATCGCAATTATTCCCACTAATGCAGACAAA



ATCTGTCTCGGTCATCATGCTGTGTCTAATGGAACGAAGGTCAATACCCTGACCGAACGC



GGTGTCGAAGTGGTCAATGCGACAGAAACTGTAGAACGAACCAATATCCCTAGGATTTGT



TCCAAGGGGAAGAAGACTGTTGACTTGGGGCAATGCGGGCTCCTAGGCACCATTACGGGC



CCCCCCCAATGTGACCAGTTCCTAGAGTTTAGCGCAGATCTGATCATCGAAAGAAGGGAA



GGCTCCGATGTGTGCTATCCCGGGAAGTTCGTGAATGAAGAGGCGCTGAGGCAGATTCTC



AGAGAGAGCGGCGGTATTGAGAAAGAAGCTATGGGATTTACATATAGCGGGATTCGCGCA



AACGGCGCAACTAGTGCGTGTCGACGCAGCGGTTCTTCTTTCTATGCCGAGATGAAGTGG



TTACTAAGCAACACCGATAACGCCGCGTTCCCCCAGATGACCAAGTCTTATAAGAACACA



CGCAAATCCCCCGCGCTCATTGTGTGGGGAATTCACCACAGCGTCTCTACTGCAGAGCAG



ACAAAACTGTACGGTTCAGGGAATAAGCTCGTAACTGTAGGGTCAAGTAACTACCAGCAG



TCCTTTGTCCCTTCTCCAGGGGCTCGGCCTCAGGTCAATGGGCTGAGCGGCCGGATCGAT



TTCCACTGGCTGATGCTGAATCCCAACGACACCGTGACTTTCTCTTTCAACGGGGCCTTT



ATCGCCCCAGATCGGGCCAGCTTTCTGAGAGGGAAGTCAATGGGAATCCAGTCTGGAGTC



CAGGTGGATGCGAACTGTGAAGGGGATTGCTACCACAGCGGCGGGACTATCATCTCCAAC



CTTCCATTCCAAAACATTGACTCTCGCGCCGTTGGCAAGTGTCCACGATACGTCAAGCAG



AGGTCTCTGCTCCTGGCTACCGGAATGAAGAATGTGCCCGAGATACCCAAAGGCCGTGGC



CTGTTCGGCGCGATAGCTGGCTTTATTGAAAACGGATGGGAGGGATTGATAGACGGCTGG



TACGGCTTTCGCCATCAGAACGCGCAGGGCGAAGGAACCGCCGCCGATTATAAATCAACA



CAGTCAGCTATCGACCAGATAACCGGCAAGCTGAACCGATTAATTGAAAAAACAAACCAG



CAGTTTGAACTGATCGATAATGAATTCAACGAAGTGGAAAAACAGATTGGGAATGTTATA



AATTGGACTCGGGACTCCATCACTGAAGTTTGGTCTTACAATGCCGAATTACTGGTTGCC



ATGGAAAATCAACACACTATCGATCTCGCGGACAGCGAAATGGACAAGCTTTACGAACGC



GTTAAACGGCAGCTTCGTGAGAATGCGGAAGAGGATGGAACGGGCTGCTTCGAGATCTTC



CATAAATGCGACGACGATTGTATGGCCTCAATTAGGAATAACACCTACGATCACAGCAAG



TACCGGGAGGAGGCCATGCAGAACCGCATTCAAATTGATCCCGTCAAACTCTCGAGCGGG



TATAAAGATGTGATCTTGTGGTTCTCTTTTGGTGCTTCCTGCTTTATCCTACTGGCCATT



GTCATGGGACTGGTGTTCATCTGCGTCAAAAACGGGAACATGCGCTGTACCATCTGTATT





543
ATGAACACCCAGATCCTTGTCTTTGCTCTGATTGCTATCATCCCTACAAATGCGGACAAG



ATTTGTCTGGGTCATCATGCAGTATCCAACGGAACCAAAGTCAACACCCTAACCGAACGC



GGCGTAGAAGTGGTCAACGCCACCGAGACCGTGGAACGCACAAATATTCCTAGGATCTGC



TCAAAAGGTAAAAAGACAGTGGATTTGGGCCAGTGTGGTCTGCTGGGGACTATAACTGGC



CCCCCCCAATGCGATCAGTTCCTTGAATTTAGCGCCGATCTCATTATAGAACGGCGGGAG



GGCAGCGATGTTTGCTATCCAGGAAAGTTTGTCAATGAAGAAGCACTAAGGCAGATTCTG



AGAGAATCTGGAGGAATCGACAAGGAGGCCATGGGATTCACGTACTCCGGCATTCGCACA



AATGGGGCCACCTCAGCTTGTAGGCGCAGTGGCAGCAGCTTTTACGCGGAGATGAAGTGG



TTGCTTTCCAATACAGATAACGCTGCATTCCCCCAGATGACAAAAAGCTACAAGAATACA



CGAAAATCCCCCGCTCTGATAGTGTGGGGGATCCACCATAGTGTGTCAACCGCCGAGCAA



ACGAAGTTGTATGGCTCCGGAAACAAATTGGTGACTGTCGGTTCATCCAACTACCAGCAG



TCTTTTGTGCCTTCTCCCGGGGCCCGACCTCAGGTAAATGGTCAGAGCGGTCGGATCGAC



TTCCACTGGCTCATGCTGAATCCCAACGACACAGTTACTTTTTCATTCAATGGGGCATTC



ATTGCGCCAGACAGGGCCTCCTTTCTAAGGGGTAAGTCGATGGGAATACAGTCTGGCGTG



CAAGTAGATGCAAATTGCGAAGGGGACTGCTATCACTCTGGGGGCACGATCATCAGTAAC



CTGCCTTTTCAGAACATCGACAGCCGAGCAGTAGGAAAATGCCCACGCTACGTGAAGCAG



CGCTCACTGCTCTTAGCCACCGGGATGAAGAACGTCCCAGAAATTCCTAAAGGAAGGGGG



CTGTTCGGCGCAATTGCTGGGTTTATTGAGAATGGATGGGAGGGTCTGATCGATGGCTGG



TACGGTTTCAGACACCAGAACGCCCAAGGCGAAGGCACAGCCGCTGACTATAAGAGTACT



CAAAGTGCAATTGACCAGATTACCGGCAAGTTGAATCGTCTGATTGAAAAGACAAATCAG



CAGTTCGAACTGATAGATAATGAGTTTAATGAGGTTGAGAAACAGATAGGCAACGTGATT



AACTGGACCAGGGACTCAATCACAGAAGTGTGGAGCTACAACGCGGAATTACTAGTGGCA



ATGGAAAATCAGCATACTATCGACCTTGCAGATTCTGAAATGGACAAACTGTATGAAAGA



GTGAAACGCCAGCTCCGTGAAAATGCCGAAGAGGACGGGACCGGTTGTTTTGAGATTTTC



CATAAGTGTGACGACGATTGTATGGCAAGCATCCGTAATAATACATACGATCATTCGAAG



TATCGCGAGGAGGCAATGCAGAACAGGATACAAATCGATCCTGTAAAACTGAGTAGTGGG



TATAAAGATGTGATTTTGTGGTTCTCATTTGGCGCCTCTTGTTTCATCCTCCTCGCTATC



GTGATGGGACTGGTGTTTATCTGCGTGAAGAATGGTAACATGCGGTGCACTATATGCATC





544
ATGAATACCCAGATCCTAGTGTTTGCCCTTATTGCCATCATACCGACAAACGCCGACAAG



ATATGCCTAGGACATCACGCTGTCTCAAACGGTACCAAGGTTAACACGTTGACGGAGCGA



GGAGTTGAGGTGGTGAACGCTACTGAGACCGTGGAACGCACTAACATTCCCCGCATTTGT



AGTAAAGGCAAGAGAACTGTCGACCTGGGACAGTGCGGCCTCTTAGGGACCATCACAGGA



CCCCCGCAGTGTGACCAGTTCCTCGAATTTTCTGCTGACCTGATCATTGAGCGGAGAGAG



GGGAGCGATGTGTGCTACCCCGGAAAATTCGTAAATGAAGAAGCACTGCGACAGATTCTG



CGGGAGAGTGGCGGAATTGATAAGGAAGCTATGGGGTTTACATACAGGGGGATCAGGACT



AACGGAGCGACCAGCGCTTGCAGGCGGTCAGGAAGTTCTTTCTATGCAGAAATGAAGTGG



CTGCTGTCCAACACGGACAATGCTGCTTTCCCCCAGATGACTAAATCCTACAAAAATACT



CGAAAATCTCCCGCCCTTATTGTTTGGGGGATCCATCACAGCGTGTCGACCGCCGAACAG



ACAAAGCTCTATGGAAGCGGTAACAAGCTTGTGACCGTTGGATCTTCCAATTATCAGCAG



TCCTTTGTCCCCTCTCCTGGTGCCAGACCCCAGGTTAATGGCCTAAGCGGGCGCATCGAC



TTTCATTGGCTCATGCTGAACCCTAATGATACCGTTACGTTTAGTTTTAATGGCGCCTTC



ATTGCCCCTGACAGAGCATCTTTCCTGCGAGGGAAGTCAATGGGCATCCAGAGCGGTGTA



CAGGTGGACGCCAATTGTGAGGGCGATTGTTATCACTCCGGGGGAACAATTATTAGTAAT



CTGCCCTTCCAGAATATAGATTCGAGGGCGGTAGGTAAGTGTCCTCGCTACGTTAAACAA



CGCTCTCTTCTTTTGGCCACTGGGATGAAGAACGTACCTGAAATACCTAAGGGTCGCGGG



CTCTTTGGCGCGATCGCAGGCTTCATTGAAAACGGCTGGGAGGGTTTAATCAACGGGTGG



TACGGTTTCCGACACCAGAACGCTCAGGGGGAAGGTACCGCTGCAGATTACAAGTCCACT



CAATCAGCTATTGATCAGATCACGGGCAAGCTGAACAGGCTCATCGAAAAGACCAATCAG



CAATTCGAACTCATCGATAACGAGTTCAACGAGGTGGAGAAGCAAATTGGAAATGTAATA



AATTGGACGCGCGATTCTATTACAGAAGTGTGGTCCTACAACGCGGAACTCTTAGTGGCA



ATGGAGAACCAGCATACTATTGACCTGGCTGACTCAGAAATGGATAAGCTGTACGAAAGG



GTGAAAAGACAGTTGAGGGAAAATGCTGAGGAAGATGGGACGGGATGCTTTGAGATTTTC



CATAAGTGCGATGATGACTGCATGGCAAGCATCCGTAACAACACATATGACCATTCTAAG



TACCGGGAGGAAGCCATGCAAAATCGCATACAGATCGACCCTGTGAAGCTCAGTTCTGGC



TACAAAGATGTGATCCTGTGGTTTTCGTTCGGAGCCAGCTGCTTTATCCTACTTGCAATA



GTCATGGGTCTTGTGTTCATATGCGTAAAGAATGGCAACATGAGGTGTACCATCTGTATC





545
ATGAACACCCAGATTCTGGTGTTTGCCCTGATTGCTATAATTCCAACCAATGCGGACAAA



ATCTGCCTGGGCCACCACGCCGTGTCGAACGGCACGAAAGTGAATACCTTAACGGAAAGA



GGCGTTGAAGTTGTGAATGCAACAGAAACTGTAGAAAGAACTAATATTCCTAGAATCTGT



TCTAAGGGGAAAAAAACGGTGGACTTAGGCCAGTGTGGTCTGCTAGGGACTATCACCGGC



CCCCCTCAATGTGACCAGTTCCTGGAGTTCAGCGCCGACCTCATTATAGAAAGAAGAGAA



GGATCAGACGTGTGCTACCCTGGCAAATTCGTAAACGAGGAGGCCCTCCGGCAGATCCTC



CGCGAATCCGGTGGAATCGACAAGGAAGCCATGGGATTTACCTATTCTGGTATTCGGACC



AACGGCGCCACGAGTGCTTGTCGGCGGTCAGGGTCTTCCTTTTACGCAGAGATGAAGTGG



CTCCTGTCCAATACTGACAATGCCGCATTCCCTCAAATGACTAAGTCCTATAAAAATACC



AGAAAATCTCCTGCACTTATCGTGTGGGGCATTCATCACTCTGTCAGTACTGCCGAGCAG



ACCAAGCTATACGGGAGCGGTAACAAGCTTGTGACAGTAGGGTCATCCAACTATCAGCAA



AGCTTTGTACCGTCCCCTGGGGCACGTCCCCAGGTGAACGGCCAGTCCGGGGGGATCGAC



TTCCACTGGTTGATGCTGAATCCTAACGATACCGTGACCTTCTCTTTCAACGGGGCATTT



ATCGCACCAGACAGGGCTTCCTTTCTGCGCGGAAAGTCCATGGGCATCCAGTCCGGCGTG



CAGGTCGATGCAAACTGCGAGGGTGATTGCTACCATTCTGGGGGGACAATAATCTCTAAT



CTGCCTTTTCAGAACATTGACAGTCGAGCGGTGGGCAAGTGTCCCAGGTACGTGAAACAA



CGCTCCCTTCTGTTGGCAACAGGGATGAAGAACGTGCCTGAGATCCCGAAAGGCCGTGGA



TTATTTGGCGCTATTGCTGGCTTCATTGAGAATGGATGGGAGGGCTTAATCGACGGTTGG



TACGGCTTCCGGCATCAGAATGCACAGGGCGAAGGAACAGCTGCCGACTATAAATCCACC



CAGTCCGCAATCGATCAGATAACCGGCAAGCTGAACCGGCTCATTGAGAAAACAAATCAG



CAGTTCGAGCTCATAGACAATGAGTTTAACGAGGTAGAGAAACAGATTGGTAATGTCATT



AACTGGACACGGGATAGCATCACGGAAGTTTGGAGCTATAATGCTGAGCTCTTGGTCGCT



ATGGAGAACCAGCATACGATTGACTTGGCAGACTCTGAGATGGATAAGCTTTATGAGCGC



GTGAAGAGGCAACTTAGAGAGAACGCTGAGGAGGACGGTACTGGGTGCTTCGAGATATTC



CATAAGTGCGACGATGACTGCATGGCCAGCATTAGAAACAACACATATGATCACTCCAAG



TATCGTGAAGAAGCCATGCAGAATCGGATTCAGATTGATCCAGTGAAGCTGTCCTCCGGC



TACAAGGATGTGATCCTGTGGTTCTCGTTCGGTGCTAGCTGCTTCATATTGTTAGCTATC



GTTATGGGCCTCGTGTTCATCTGCGTGAAGAACGGTAACATGCGTTGCACTATCTGCATA





546
ATGAACACTCAAATTCTGGTGTTCGCACTCATTGCCATCATACCAACTAACGCTGACAAG



ATATGCTTGGGCCATCACGCCGTGAGCAATGGGACAAAGGTAAACACCCTCACAGAAAGA



GGCGTCGAAGTGGTTAATGCTACAGAGACAGTCGAGAGGACAAACATCCCCCGTATTTGT



TCCAAGGGTAAGAAAACTGTTGATCTGGGCCAGTGTGGGTTGTTAGGAACCATCACCGGA



CCCCCGCAATGTGATCAATTCCTGGAATTTTCTGCGGATCTGATTATTGAGAGGCGCGAA



GGCAGCGATGTGTGTTATCCCGGAAAGTTTGTTAACGAAGAAGCACTGCGGCAGATTCTG



CGAGAATCCGGTGGCATCGACAAAGAGGCTATGGGCTTTACTTATTCCGGCATCAGGACG



AATGGAGCCACCTCTGCCTGCCGCCGGTCAGGGAGTTCCTTCTATGCAGAGATGAAGTGG



CTGCTCTCCAATACAGATAATGCCGCATTCCCTCAGATGACGAAATCTTATAAAAACACA



CGGAAGAGTCCCGCACTGATCGTCTGGGGAATTCACCACTCCGTGAGCACTGCAGAGCAA



ACCAAGCTGTACGGGTCAGGGAACAAGTTAGTGACAGTCGGAAGCTCTAATTATCAACAG



TCGTTCGTGCCAAGTCCTGGGGCCCGACCGCAGGTGAATGGTCAGTCAGGGCGTATCGAT



TTCCACTGGTTAATGCTGAATCCAAACGACACCGTGACCTTCTCCTTTAATGGCGCCTTT



ATTGCACCCGATAGAGCTTCCTTTTTAAGAGGAAAATCCATGGGAATTCAAAGTGGTGTG



CAGGTAGATGCGAATTGCGAGGGAGATTGTTATCACTCCGGTGGGACCATTATCTCCAAC



CTCCCTTTCCAGAACATCGACTCGCGAGCTGTGGGCAAGTGCCCAAGATACGTTAAGCAG



AGATCGCTTCTGTTGGCCACCGGAATGAAGAACGTTCCTGAAATTCCTAAGGGCCGCGGA



TTATTCGGCGCCATTGCAGGCTTTATAGAAAACGGTTGGGAGGGCCTTATCGATGGATGG



TATGGCTTCAGACACCAGAATGCACAAGGGGAGGGGACTGCCGCCGACTATAAGTCGACC



CAGAGCGCAATTGATCAGATTACTGGGAAGCTTAATAGACTCATCGAGAAAACAAACCAA



CAGTTCGAACTCATTGACAACGAGTTTAATGAGGTTGAGAAGCAGATCGGTAATGTCATC



AACTGGACAAGAGACAGCATCACTGAGGTGTGGTCCTATAATGCTGAGCTGCTGGTAGCT



ATGGAGAACCAACACACAATTGATCTCGCCGACTCAGAGATGGACAAGTTGTACGAGCGC



GTCAAGAGGCAATTAAGAGAAAACGCCGAGGAGGATGGGACCGGCTGTTTTGAGATCTTC



CATAAATGCGATGATGACTGTATGGCTAGCATCCGAAACAACACTTATGACCACTCCAAA



TATCGGGAAGAAGCAATGCAGAATCGAATTCAAATTGACCCAGTTAAACTCAGTTCCGGA



TATAAGGACGTTATCCTCTGGTTCAGCTTCGGAGCATCTTGCTTTATACTGCTGGCAATC



GTTATGGGACTCGTGTTCATCTGTGTCAAGAACGGTAACATGAGATGTACTATCTGCATT





547
ATGAACACACAAATCTTGGTCTTTGCTCTCATTGCAATAATACCGACAAATGCCGATAAA



ATCTGTCTAGGACACCACGCTGTATCCAATGGAACAAAGGTCAATACCTTGACAGAGCGC



GGCGTAGAGGTGGTAAATGCCACAGAGACAGTCGAGCGAACAAATATTCCCCGCATATGT



TCCAAAGGTAAAAAGACCGTTGACCTCGGGCAGTGCGGATTACTGGGAACAATCACGGGC



CCCCCACAGTGTGACCAATTTCTGGAGTTCAGTGCCGATTTAATCATAGAGCGCAGGGAA



GGTTCCGACGTCTGTTATCCTGGCAAGTTTGTAAACGAGGAGGCCTTACGGCAAATACTG



AGGGAGTCAGGCGGCATCGAGAAGGAAGCCATGGGCTTCACCTATTCCGGAATTCGGGCG



AACGGCGCAACCTCGGCCTGCCGACGGAGCGGAAGCTCATTTTACGCCGAGATGAAGTGG



CTGCTTTCCAACACTGACAACGCAGCTTTCCCTCAAATGACAAAGTCGTATAAGAACACA



AGAAAATCTCCTGCCCTCATTGTTTGGGGCATACACCATTCCGTGTCAACAGCAGAACAG



ACAAAACTCTACGGCTCGGGTAACAAGCTCGTGACAGTCGGTTCCAGTAATTACCAGCAG



TCCTTTGTACCTTCCCCCGGTGCACGGCCCCAGGTGAACGGCCTCTCTGGCAGGATTGAT



TTCCACTGGCTGATGCTGAATCCTAACGATACAGTCACTTTTAGCTTTAATGGAGCTTTC



ATTGCACCCGACCGCGCCAGCTTTTTGAGGGGAAAATCCATGGGGATCCAATCCGGAGTG



CAGGTGGATGCTAACTGCGAAGGCGATTGTTATCATAGTGGGGGGACCATAATCAGTAAC



CTCCCTTTTCAGAATATCGACTCCCGCGCAGTAGGAAAATGCCCTAGGTACGTGAAACAG



CGCTCCTTACTGCTCGCCACGGGCATGAAGAATGTTCCTGAGATACCAAAAGGGGGGGGC



CTGTTTGGGGCTATTGCGGGATTCATTGAAAACGGGTGGGAGGGGTTGATCGATGGCTGG



TACGGGTTCAGGCACCAGAATGCCCAGGGTGAAGGAACAGCAGCCGACTACAAGTCTACG



CAGTCTGCTATCGATCAGATTACCGGCAAGCTAAACCGCTTAATTGAAAAAACCAACCAA



CAGTTCGAACTGATCGACAATGAGTTTAACGAAGTGGAAAAGCAGATAGGGAACGTGATT



AATTGGACCAGAGACAGTATTACCGAGGTGTGGTCGTATAATGCCGAACTGTTGGTAGCT



ATGGAGAACCAGCACACGATAGATCTGGCAGACAGTGAAATGGATAAGCTGTATGAGAGA



GTAAAGCGGCAACTCCGGGAAAATGCAGAAGAGGATGGCACAGGATGCTTCGAGATATTC



CATAAGTGTGATGACGATTGTATGGCCAGCATCAGAAACAATACCTACGACCACTCAAAA



TACCGCGAAGAGGCCATGCAGAATAGGATTCAAATTGACCCAGTGAAGCTCTCCTCGGGA



TACAAAGATGTGATCTTGTGGTTCAGCTTCGGCGCCTCCTGTTTTATCCTCCTGGCGATA



GTGATGGGACTCGTCTTTATTTGCGTTAAGAACGGGAACATGAGGTGCACCATATGCATC





548
ATGAACACCCAGATCCTAGTGTTTGCACTTATCGCCATCATCCCGACTAATGCGGACAAG



ATCTGCCTGGGCCATCACGCTGTGTCTAATGGAACCAAGGTGAATACGCTGACGGAACGA



GGAGTGGAGGTGGTAAATGCTACGGAAACAGTCGAGAGAACCAACATCCCACGGATCTGC



TCTAAGGGAAAAAAGACCGTTGATCTGGGCCAATGCGGTCTACTCGGTACCATTACCGGA



CCACCACAATGCGACCAGTTTCTCGAATTCAGCGCCGACTTGATCATAGAAAGGCGCGAG



GGATCGGATGTGTGCTACCCTGGCAAATTCGTGAATGAGGAGGCCCTCCGCCAGATCCTT



AGAGAATCAGGTGGCATCGATAAGGAAGCTATGGGCTTCACATACTCGGGCATAAGAACA



AATGGCGCTACCAGCGCCTGTCGACGCTCGGGCAGCTCCTTTTATGCCGAGATGAAGTGG



TTGCTCAGTAACACAGATAACGCAGCCTTCCCACAGATGACAAAGTCTTACAAGAATACC



CGTAAAAGCCCAGCCCTTATTGTGTGGGGAATACACCATAGCGTGAGCACGGCAGAGCAG



ACGAAACTGTATGGTAGCGGGAACAAACTCGTTACGGTCGGGAGCTCAAACTACCAGCAG



TCTTTTGTACCTTCACCCGGCGCTCGCCCACAGGTTAACGGTCAGTCGGGGAGAATCGAT



TTCCACTGGCTGATGCTGAACCCAAATGACACCGTCACCTTCTCCTTCAACGGAGCCTTC



ATTGCCCCAGATCGCGCCTCTTTTCTTAGAGGCAAGTCCATGGGCATCCAATCAGGCGTC



CAGGTCGATGCCAATTGTGAAGGCGACTGTTATCATTCCGGAGGCACAATTATAAGCAAC



CTGCCCTTCCAGAACATCGACAGTCGAGCTGTCGGTAAGTGCCCTCGTTACGTGAAGCAG



CGGAGTCTCCTCTTAGCTACAGGAATGAAAAATGTCCCAGAGATCCCTAAAGGACGCGGT



CTCTTTGGGGCCATAGCTGGATTCATCGAAAACGGCTGGGAAGGCCTGATCGACGGCTGG



TACGGCTTCAGACACCAGAATGCACAAGGGGAAGGAACCGCTGCTGATTATAAGAGTACC



CAGTCAGCTATCGACCAAATAACCGGTAAGCTTAACCGACTGATTGAGAAAACAAACCAG



CAATTTGAGCTCATTGATAATGAGTTTAATGAGGTGGAAAAGCAGATTGGCAATGTCATT



AACTGGACCCGCGACTCGATTACAGAAGTGTGGTCTTATAACGCGGAGTTACTTGTCGCC



ATGGAAAATCAGCACACCATCGACTTGGCCGACTCTGAAATGGACAAACTGTACGAGCGA



GTCAAGCGACAACTGAGGGAGAACGCCGAGGAAGACGGGACCGGTTGTTTTGAGATATTT



CACAAATGCGACGATGACTGCATGGCCTCGATCAGGAACAATACTTACGACCACTCCAAG



TACAGGGAAGAAGCGATGCAAAACAGGATACAGATAGATCCTGTTAAGCTCTCCAGTGGG



TATAAAGACGTGATCCTGTGGTTCAGCTTCGGAGCATCCTGTTTTATCCTTTTGGCCATC



GTAATGGGATTAGTCTTCATCTGCGTGAAGAATGGGAACATGCGGTGCACCATCTGTATA





549
ATGAATACCCAGATATTGGTATTTGCCCTGATAGCGATCATTCCAACTAACGCAGATAAG



ATATGCCTCGGCCACCACGCTGTGTCGAATGGGACTAAGGTGAATACCCTGACTGAAAGA



GGTGTCGAGGTGGTCAACGCTACCGAAACAGTGGAAAGGACCAACATACCGAGAATCTGC



AGCAAAGGTAAAAAGACTGTAGACCTCGGCCAGTGCGGCCTTCTGGGGACCATTACTGGA



CCTCCCCAATGCGATCAGTTCCTGGAGTTCTCTGCCGACCTCATCATTGAGCGGAGAGAG



GGAAGCGATGTGTGCTACCCCGGCAAATTTGTGAATGAGGAGGCTCTGAGACAGATTTTG



AGGGAGAGTGGCGGGATCGAAAAGGAGGCAATGGGGTTTACCTACTCAGGAATCAGGGCC



AACGGAGCAACCTCTGCATGCAGAAGGTCCGGGTCCTCCTTCTACGCAGAGATGAAATGG



CTGTTAAGCAATACGGATAATGCCGCCTTCCCTCAGATGACTAAGTCCTATAAAAATACC



CGTAAGAGTCCAGCACTCATAGTCTGGGGCATTCACCATTCCGTCTCTACAGCAGAGCAG



ACTAAACTCTATGGAAGCGGGAACAAACTCGTGACCGTCGGCTCGAGCAACTATCAACAA



TCTTTCGTTCCATCTCCCGGAGCCAGACCCCAGGTGAACGGGCTATCGGGACGGATCGAC



TTCCACTGGCTGATGTTAAACCCCAATGATACGGTCACCTTTAGCTTCAATGGTGCATTC



ATCGCTCCAGACCGGGCCTCGTTTCTCAGAGGAAAATCTATGGGAATCCAGAGTGGTGTG



CAGGTGGACGCCAACTGCGAGGGTGATTGTTATCATTCTGGGGGCACTATCATCTCAAAC



CTCCCATTCCAGAACATAGATTCAAGAGCAGTTGGAAAGTGTCCAAGATATGTGAAGCAG



CGCTCTCTGCTTTTGGCCACCGGCATGAAAAATGTTCCTGAGATACCGAAAGGACGGGGC



CTATTTGGCGCGATCGCAGGATTCATCGAAAATGGATGGGAGGGACTGATCGACGGTTGG



TATGGCTTCCGCCACCAGAATGCCCAGGGGGAAGGTACCGCAGCTGACTATAAATCAACG



CAGTCCGCCATCGATCAGATAACTGGCAAACTGAATAGGCTAATAGAAAAGACTAACCAG



CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTGGAGAAGCAGATTGGCAACGTTATT



AACTGGACCCGGGACTCCATCACGGAGGTGTGGTCTTACAACGCAGAGTTACTAGTAGCA



ATGGAGAATCAGCACACTATAGACCTAGCCGATAGTGAAATGGACAAACTATATGAGAGA



GTCAAACGCCAACTGCGGGAGAACGCCGAAGAAGATGGAACAGGATGTTTCGAGATTTTC



CACAAATGTGATGATGATTGCATGGCGTCTATCCGCAATAATACTTACGATCATTCAAAG



TACCGCGAAGAGGCCATGCAGAACCGAATCCAGATTGATCCCGTGAAGCTTTCCTCCGGA



TACAAAGATGTAATCCTGTGGTTCTCATTCGGCGCTTCCTGTTTCATCTTACTGGCAATC



GTCATGGGGCTGGTTTTCATTTGCGTCAAAAACGGCAATATGAGATGTACTATTTGCATC





550
ATGAACACCCAGATCCTGGTTTTTGCCTTGATCGCAATTATTCCTACCAATGCGGACAAA



ATTTGCCTTGGGCACCACGCCGTTTCCAATGGCACAAAGGTCAACACTTTGACCGAACGG



GGAGTGGAAGTGGTGAACGCTACAGAAACCGTTGAGCGGACTAACATTCCCAGGATCTGT



AGTAAGGGCAAGCGCACCGTGGACCTGGGCCAGTGCGGATTGTTAGGCACCATCACCGGC



CCACCCCAGTGCGACCAGTTCCTGGAATTTAGTGCAGATTTAATCATAGAACGAAGAGAG



GGTTCTGATGTGTGTTACCCGGGGAAATTCGTGAACGAAGAGGCCCTCCGCCAGATTTTG



AGAGAGAGCGGAGGCATAGATAAAGAAGCAATGGGCTTTACCTATAGCGGGATCCGGACT



AATGGAGCTACCTCTGCATGTCGGCGTAGTGGAAGTTCTTTCTATGCTGAGATGAAATGG



CTCCTTTCTAACACAGACAATGCTGCATTTCCACAAATGACAAAATCCTATAAAAATACT



CGGAAATCCCCAGCCCTGATCGTTTGGGGAATCCACCATTCAGTTTCGACTGCAGAACAG



ACTAAATTGTATGGGTCCGGGTCTAAGCTGGTAACAGTTGGAAGTTCCAATTACCAGCAA



AGCTTCGTCCCCTCGCCAGGTGCACGCCCACAGGTGAAGGGGCTAAGCGGGCGTATTGAT



TTCCACTGGTTAATGCTGAATCCAAACGACACTGTCACGTTCAGCTTTAACGGAGCGTTC



ATCGCTCCTGACCGCGCCAGTTTCCTGCGAGGTAAATCAATGGGCATCCAGTCAGGTGTT



CAGGTAGATGCCAACTGTGAGGGGGATTGCTATCATTCTGGGGGGACTATTATTAGTAAC



CTGCCCTTCCAGAATATAGATTCTCGGGCCGTCGGCAAGTGTCCAAGGTACGTTAAACAG



CGCAGTCTGTTACTTGCCACTGGAATGAAGAACGTTCCCGAGATCCCAAAGGGCCGAGGT



CTGTTCGGGGCCATCGCCGGCTTTATCGAGAATGGATGGGAAGGGTTGATTGATGGATGG



TATGGTTTCCGTCACCAAAATGCCCAGGGAGAGGGGACAGCTGCTGACTATAAGTCCACC



CAGAGTGCAATAGACCAAATCACAGGGAAACTGAATAGACTTATCGAAAAGACCAACCAG



CAGTTTGAGTTGATTGATAACGAATTCAATGAAGTCGAGAAACAGATTGGGAATGTCATT



AATTGGACACGAGACTCCATCACAGAGGTGTGGTCCTACAATGCCGAATTGTTGGTGGCC



ATGGAGAATCAACATACTATCGATCTGGCAGACTCAGAAATGGACAAGCTGTATGAGCGA



GTGAAGAGGCAGCTGAGAGAGAACGCCGAAGAAGATGGAACCGGGTGCTTTGAGATTTTT



CATAAGTGTGACGACGATTGTATGGCAAGTATCCGCAATAATACCTACGACCACTCCAAG



TATAGAGAGGAAGCCATGCAGAACCGGATTCAGATTGATCCAGTGAAACTCAGTTCCGGC



TATAAAGACGTGATCCTGTGGTTTAGCTTCGGCGCCTCCTGTTTCATCCTGTTGGCCATT



GTCATGGGGCTGGTCTTTATCTGTGTCAAGTCCCGAAACATGCGATGCACAATCTGCATC





551
ATGAACACTCAAATTCTAGTGTTCGCACTGATTGCCATTATCCCAACTAACGCCGACAAA



ATCTGTTTGGGCCACCATGCTGTTAGCAACGGTACCAAAGTGAATACCCTGACCGAAAGA



GGCGTTGAAGTAGTAAACGCCACTGAAACCGTTGAGAGGACAAACATTCCACGGATTTGT



AGCAAAGGAAAGAAAACTGTCGATCTGGGGCAATGTGGACTGCTGGGCACCATCACTGGC



CCTCCCCAGTGTGACCAGTTTCTGGAGTTTTCCGCAGATTTAATCATAGAGCGCAGAGAA



GGAAGTGACGTGTGCTACCCTGGGAAATTCGTTAATGAAGAAGCCCTCCGGCAGATCCTA



AGAGAATCTGGGGGTATCGAAAAGGAGGCAATGGGATTCACGTACTCGGGGATCCGTGCT



AACGGAGCAACTTCCGCATGCCGGAGGTCAGGGTCATCTTTTTATGCTGAAATGAAATGG



TTGCTGTCAAATACCGATAACGCCGCGTTCCCGCAAATGACAAAGAGCTACAAAAATACC



CGCAAGAGTCCCGCGCTCATCGTGTGGGGCATCCATCATAGCGTGTCCACTGCTGAGCAG



ACCAAACTTTATGGTAGTGGGAACAAGCTGGTCACGGTCGGATCAAGCAATTACCAGCAG



TCCTTCGTACCAAGCCCGGGGGCCCGGCCCCAGGTGAACGGCCTGTCAGGACGCATCGAC



TTTCACTGGTTGATGTTGAACCCGAATGATACAGTGACTTTTTCATTCAACGGCGCTTTT



ATCGCACCAGACAGGGCCTCCTTTCTCCGCGGGAAGAGCATGGGCATCCAGAGTGGTGTG



CAGGTTGACGCGAATTGCGAGGGAGACTGTTATCACTCAGGCGGAACAATTATCAGCAAT



CTTCCTTTCCAAAACATTGATTCGAGAGCCGTCGGGAAGTGCCCCAGGTACGTCAAGCAG



CGAAGTCTGCTTTTAGCTACAGGAATGAAGAACGTGCCCGAGATACCCAAAGGCAGGGGA



CTGTTCGGCGCAATCGCTGGCTTTATTGAGAACGGATGGGAAGGTCTGATCGATGGCTGG



TATGGATTTAGGCACCAGAACGCTCAGGGCGAGGGCACTGCAGCCGATTATAAGAGCACG



CAGTCTGCCATAGACCAAATCACCGGGAAACTCAACAGGCTGATCGAGAAGACCAACCAG



CAATTTGAGCTCATTGACAATGAATTTAATGAAGTGGAGAAGCAGATCGGCAATGTTATT



AATTGGACACGAGACTCTATTACTGAAGTGTGGTCTTACAATGCCGAGCTGCTTGTTGCA



ATGGAGAATCAGCATACAATCGATCTGGCCGATTCAGAGATGGACAAGCTGTACGAAAGG



GTGAAACGGCAGCTACGGGAGAACGCTGAGGAGGATGGCACAGGGTGCTTTGAGATTTTC



CATAAGTGCGACGACGATTGTATGGCGAGTATACGCAATAACACCTACGATCATTCAAAG



TATCGCGAGGAAGCCATGCAGAACCGCATTCAGATCGATCCCGTGAAGTTGTCCTCTGGC



TACAAAGACGTCATTCTGTGGTTCAGCTTTGGAGCATCCTGTTTCATCCTCCTGGCAATC



GTGATGGGACTCGTGTTTATCTGCGTCAAAAACGGCAATATGAGGTGCACCATCTGTATT





552
ATGAATACACAGATCTTGGTTTTCGCTCTGATCGCCATCATACCGACCAATGCTGACAAA



ATCTGTCTGGGTCACCATGCAGTGAGCAACGGTACCAAAGTCAATACATTGACCGAGCGT



GGCGTCGAAGTTGTTAATGCCACAGAAACAGTCGAGCGAACCAATATTCCGAGAATTTGC



TCCAAGGGGAAGAAGACCGTGGACCTAGGCCAGTGTGGACTGCTGGGTACAATTACTGGG



CCACCACAGTGTGATCAGTTCCTGGAGTTCAGCGCAGATCTGATCATCGAACGGAGAGAG



GGATCAGATGTATGCTATCCTGGTAAATTCGTAAACGAAGAGGCCCTGCGACAGATTCTA



AGAAAAAGCGGAGGCATCGATAAGGAAGCTATGGGGTTCACATATTCAGGCATCAGAACT



AATGGTGCCACTTCCACTTGCCGACGAAGCGGGAGTAGCTTCTACGCAGAAATGAAATGG



CTTCTATCAAACACGGACAACGCGGCCTTTCCTCAGATGACCAAATCCTATAAGAACACC



AGAAAAAGCCCCGCAATCATCGTATGGGGAATTCATCACTCTGTGAGTACCGCCGAGCAG



ACAAAGCTTTACGGCTCCGGAAACAAGCTGGTGACCGTTGGGAGTAGCAATTACCAGCAG



TCTTTCGTACCATCCCCCGGTGCGAGACCCCAAGTTAACGGCCTTTCAGGACGCATTGAT



TTCCACTGGCTGATGTTGAATCCGAACGACACCGTGACGTTCTCCTTCAACGGGGCATTC



ATTGCACCCGATAGAGCCTGTTTCCTCAGGGGAAAATCCATGGGCATACAGAGCGGGGTG



CAGGTGGACGCCGACTGTGAGGGAGACTGCTACCACTCTGGTGGTACGATCATAAGCAAC



CTCCCATTCCAGAATATCGATTCTAGGGCGGTGGGTAAATGTCCAAGATATGTGAAGCAG



CGGTCTCTTCTGCTGGCCACCGGCATGAAAAACGTTCCTGAGATTCCCAAAGGCAGAGGG



CTGTTCGGCGCAATCGCCGGCTTTATAGAAAACGGATGGGAGGGCCTGATCGATGGGTGG



TACGGATTCAGACACCAGAATGCCCAGGGCGAAGGTACAGCTGCAGATTACAAAAGCACA



CAGTCAGCCATTGACCAAATCACAGGCAAACTGAATCGCCTCATTGAGAAAACGAATCAG



CAGTTCGAGCTCATTGATAACGAGTTCAACGAGGTCGAAAGACAAATTGGTAATGTGATC



AACTGGACGAGGGACTCAATCACTGAGGTGTGGTCTTATAATGCAGAGCTGTTGGTGGCT



ATGGAGAATCAACACACAATTGACCTGGCGGATTCTGAAATGGATAAACTGTACGAACGA



GTCAAGCGTCAGCTGAGGGAGAACGCTGAGGAAGACGGGACTGGATGCTTCGAAATTTTC



CATAAATGCGATGACGATTGCATGGCCTCTATCCGAAACAATACATACGATCATAGTAAG



TACAGAGAAGAGGCCATGCAGAACAGAATCCAGATTGACCCGGTGAAACTGTCATCGGGA



TACAAGGACGTCATCCTCTGGTTTTCTTTTGGTGCCTCTTGCTTCATATTACTGGCAATT



GTTATGGGACTGGTCTTCATATGTGTTAAGAATGGTAACATGCGGTGTACAATATGCATC





553
ATGAACACTCAAATCCTCGTTTTCGCTCTGATTGCTATTATTCCTACTAATGCCGATAAG



ATTTGTCTGGGCCACCATGCAGTTTCCAATGGAACCAAGGTTAACACCCTGACGGAGCGT



GGTGTTGAGGTGGTTAATGCAACTGAAACTGTTGAGCGTACCAATATCCCTAGAATATGC



AGTAAGGGGAAAAAAACTGTGGACCTCGGCCAATGTGGCCTGCTGGGCACCATCACAGGG



CCGCCCCAATGTGATCAATTTTTAGAATTTAGCGCAGACCTGATTATCGAGCGCCGAGAA



GGTAGCGACGTGTGCTACCCTGGCAAGTTTGTGAATGAGGAAGCCCTGAGACAAATTCTT



AGGGAGTCAGGAGGCATCGACAAGGAAGCCATGGGCTTTACCTATAGGGGGATCAGAACA



AATGGCGCAACTTCAGCCTGTAGGCGCTCGGGGTCCTCTTTCTACGCAGAGATGAAATGG



CTGCTCAGCAATACAGACAATGCTGCTTTCCCTCAGATGACCAAGTCCTACAAAAATACC



CGGAAGTCGCCCGCTTTGATCGTTTGGGGAATTCACCATTCTGTCAGCACGGCCGAGCAG



ACTAAGCTATACGGGTCCGGTAACAAACTGGTGACAGTCGGCAGCAGCAATTACCAGCAG



TCTTTCGTGCCCTCCCCAGGCGCAAGGCCCCAGGTAAATGGTCAGTCTGGACGCATAGAT



TTTCACTGGCTCATGCTCAACCCCAATGACACAGTTACCTTTTCCTTCAATGGAGCCTTT



ATCGCCCCGGATCGCGCCAGTTTTCTGCGGGGTAAATCCATGGGGATCCAGTCAGGGGTG



CAGGTCGACGCTAACTGCGAGGGAGATTGTTACCACTCAGGAGGAACCATCATCAGCAAT



TTGCCCTTCCAGAATATCGATTCTAGGGCAGTGGGCAAGTGTCCAAGGTACGTAAAGCAG



CGATCCCTCCTGCTGGCCACCGGTATGAAAAATGTGCCAGAGATCCCTAAAGGTAGGGGG



CTCTTCGGGGCTATCGCGGGCTTCATCGAGAATGGGTGGGAGGGACTCATCGATGGATGG



TACGGCTTCAGACACCAGAACGCACAAGGCGAGGGGACAGCAGCTGATTATAAATCCACC



CAGTCCGCTATCGACCAGATTACAGGGAAACTGAATCGGCTCATCGAGAAGACCAACCAG



CAGTTCGAGCTGATTGACAATGAGTTCAATGAGGTTGAAAAGCAGATTGGCAACGTCATC



AATTGGACTCGTGACAGCATCACCGAGGTTTGGTCCTACAACGCCGAGCTGCTCGTCGCC



ATGGAGAATCAACACACTATAGACTTGGCCGACTCAGAAATGGATAAGCTATATGAGAGA



GTTAAGCGACAGTTACGCGAGAACGCAGAAGAAGACGGTACCGGATGCTTTGAAATCTTT



CACAAATGCGACGACGACTGTATGGCATCAATAAGAAACAACACCTACGATCACTCAAAG



TACCGCGAGGAGGCCATGCAAAACCGGATCCAAATAGACCCCGTTAAGTTGTCCAGGGGG



TATAAGGACGTGATTTTGTGGTTCTCTTTTGGGGCCTCCTGTTTCATTCTTCTGGCTATC



GTGATGGGCCTGGTGTTCATATGTGTTAAGAATGGTAACATGAGATGTACTATCTGTATT





554
ATGAATACACAAATTCTGGTCTTCGCTCTGATCGCCATAATTCCCACCAACGCTGATAAG



ATCTGTCTGGGCCACCACGCCGTCTCCAATGGTACTAAAGTAAACACTCTCACTGAGCGC



GGCGTTGAAGTGGTCAATGCTACCGAGACTGTGGAGCGGACAAACATCCCAAGGATTTGC



TCTAAGGGAAAGAGAACTGTGGACTTGGGCCAGTGTGGATTACTGGGCACAATTACAGGC



CCTCCCCAGTGCGATCAGTTCTTGGAGTTTAGTGCCGACCTAATAATTGAACGCAGAGAG



GGATCTGACGTGTGCTATCCAGGGAAATTTGTTAATGAAGAGGCACTCCGCCAGATTCTG



CGAGAGTCCGGCGGGATCGACAAAGAGGCCATGGGATTCACGTATTCGGGCATCAGGACC



AATGGCGCGACCTCCGCGTGTCGACGGAGCGGCAGTAGCTTTTATGCTGAGATGAAGTGG



CTCCTCAGTAACACCGACAACGCTGCTTTCCCTCAGATGACCAAGTCATACAAGAATACC



CGGAAATCCCCTGCACTTATCGTGTGGGGAATCCATCATTCCGTTAGTACCGCCGAGCAA



ACTAAACTGTACGGGAGTGGCAACAAGCTTGTGACTGTGGGCTCATCGAATTATCAACAG



TCGTTCGTCCCATCACCAGGCGCTAGGCCACAGGTTAATGGACTGTCGGGGCGCATCGAT



TTTCACTGGTTAATGTTAAACCCTAATGACACCGTTACGTTTAGCTTCAATGGTGCCTTT



ATCGCCCCCGACCGGGCCAGCTTCCTCCGTGGAAAGTCCATGGGAATTCAGTCAGGCGTA



CAAGTGGATGCCAACTGTGAAGGCGATTGCTACCATTCTGGAGGAACCATTATTAGCAAC



CTGCCCTTCCAGAACATTGATAGCAGGGCAGTAGGTAAATGTCCCCGGTATGTGAAACAA



AGAAGCCTGCTGCTCGCCACTGGCATGAAAAACGTCCCTGAGATCCCGAAAGGTAGAGGC



TTGTTCGGGGCAATTGCCGGGTTCATTGAAAACGGATGGGAAGGACTGATTGACGGATGG



TATGGGTTCCGGCACCAAAATGCTCAGGGAGAAGGGACCGCAGCCGATTATAAGTCAACC



CAAAGCGCCATTGACCAGATTACCGGAAAGCTTAACCGGCTCATCGAAAAGACAAATCAG



CAGTTTGAGCTGATCGACAACGAATTTAATGAGGTGGAGAAGCAGATCGGAAACGTGATT



AATTGGACTAGGGACAGCATCACCGAGGTCTGGTCTTATAACGCCGAACTGCTGGTAGCG



ATGGAAAATCAACACACCATCGACCTGGCTGACTCAGAGATGGATAAGCTGTATGAAAGG



GTCAAACGTCAGCTTCGTGAAAATGCTGAAGAGGATGGCACAGGTTGCTTCGAAATCTTC



CATAAGTGTGATGATGATTGTATGGCTAGTATTAGGAACAACACATACGACCATTCCAAA



TATCGGGAGGAAGCTATGCAAAACCGGATCCAAATCGACCCAGTTAAACTGTCTTCCGGC



TACAAAGATGTTATTCTCTGGTTCAGTTTTGGTGCATCCTGCTTTATACTCCTTGCCATC



GTAATGGGCCTGGTGTTTATCTGCGTCAAGAACGGAAACATGCGATGCACGATCTGTATC





555
ATGAACACTCAGATCCTCGTATTCGCCTTGATCGCTATTATTCCAACTAACGCCGATAAA



ATCTGCCTTGGCCACCATGCCGTTAGCAACGGTACTAAAGTGAATACTCTTACAGAGAGG



GGCGTCGAGGTCGTAAATGCCACTGAAACAGTTGAGCGAACAAACATTCCTCGAATTTGT



TCTAAGGGAAAAAGAACAGTCGACCTCGGCCAGTGCGGATTGCTGGGAACCATTACGGGG



CCTCCCCAGTGCGATCAGTTTCTGGAGTTTTCCGCCGACCTGATCATAGAGCGGCGCGAG



GGTTCCGACGTGTGCTACCCAGGAAAATTTGTCAACGAAGAAGCACTACGACAGATCTTG



AGAGAGAGCGGAGGGATTGACAAGGAAGCAATGGGATTCACTTATAGCGGCATCAGGACT



AATGGTGCGACCTCTGCTTGCAGACGTTCCGGGTCATCCTTCTACGCAGAGATGAAGTGG



TTACTAAGCAATACCGATAACGCAGCTTTTCCCCAGATGACCAAGTCCTACAAGAATACA



CGGAAAAGCCCCGCTTTGATCGTTTGGGGTATCCATCACTCTGTGAGCACCGCAGAACAG



ACAAAGTTGTACGGATCGGGAAGTAAGCTTGTCACCGTGGGCTCGTCCAACTACCAACAG



TCTTTTGTACCTTCTCCAGGGGCTCGTCCACAAGTCAACGGCCTGTCTGGGAGAATCGAC



TTTCACTGGCTCATGTTAAATCCCAATGACACAGTCACCTTCTCCTTTAATGGCGCCTTC



ATTGCACCCGACCGTGCCTCATTCCTGAGAGGTAAGTCCATGGGAATTCAGAGCGGTGTC



CAGGTCGACGCTAACTGCGAGGGGGACTGCTATCACTCCGGGGGGACAATTATCAGTAAT



TTGCCCTTTCAGAATATTGATTCAAGAGCTGTTGGAAAGTGCCCACGCTACGTAAAGCAG



AGAAGCCTCCTATTGGCCACAGGAATGAAGAACGTGCCGGAGATCCCCAAGGGTCGCGGT



TTGTTTGGCGCCATCGCTGGCTTTATTGAAAACGGATGGGAGGGTTTGATTGATGGCTGG



TATGGGTTCAGGCATCAGAACGCCCAGGGAGAAGGTACCGCAGCAGACTACAAGAGCACA



CAGTCCGCCATTGACCAGATTACTGGTAAGCTGAACAGATTGATCGAAAAGACTAACCAG



CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTGGAAAAGCAGATCGGGAATGTGATC



AATTGGACCCGGGATTCAATCACCGAGGTGTGGAGCTATAATGCCGAGCTGCTCGTAGCC



ATGGAGAATCAACATACAATAGATCTCGCTGACTCCGAAATGGATAAGCTCTACGAGCGC



GTAAAACGGCAGCTGCGCGAAAACGCTGAAGAAGATGGAACTGGATGCTTCGAGATCTTT



CATAAGTGCGACGATGATTGTATGGCCTCCATTAGAAATAATACCTATGACCATAGCAAG



TACAGGGAAGAGGCCATGCAAAATAGAATCCAGATCGATCCCGTCAAACTAAGTTCGGGG



TATAAGGATGTGATCCTATGGTTTTCCTTTGGTGCTAGCTGTTTCATTCTGTTAGCCATC



GTCATGGGGCTTGTGTTCATATGTGTGAAAAATGGTAACATGCGGTGCACAATTTGTATA





556
ATGAATACACAGATCTTAGTATTTGCGCTAATCGCTATTATCCCTACCAATGCTGATAAG



ATCTGTCTGGGCCACCACGCCGTTTCCAATGGCACTAAAGTGAACACTCTCACTGAGCGC



GGCGTCGAGGTGGTCAACGCCACCGAGACAGTTGAGAGAACAAACATACCTCGCATCTGT



AGTAAAGGCAAGAAGACTGTCGATCTGGGCCAGTGTGGGCTGCTGGGAACGATAACCGGT



CCCCCTCAGTGTGATCAGTTTCTGGAATTCTCTGCAGACCTGATTATCGAAAGACGAGAA



GGGAGCGACGTGTGTTACCCCGGAAAGTTTGTTAATGAGGAAGCACTGCGCCAGATCCTT



CGGGAATCTGGGGGCATCGATAAGGAAGCGATGGGCTTCACTTATAGTGGGATTCGCACC



AACGGGGCTACGTCCGCTTGCCGGCGGAGCGGTTCGTCTTTTTACGCGGAAATGAAGTGG



CTGCTCAGCAATACCGATAACGCCGCCTTCCCGCAGATGACAAAAAGCTATAAGAATACC



CGGAAAAGTCCGGCACTCATAGTGTGGGGGATCCACCATAGCGTTAGCACGGCGGAGCAG



ACAAAGCTCTATGGGAGTGGAAATAAGCTGGTGACCGTCGGCTCTTCAAATTACCAGCAA



TCATTTGTGCCCTCTCCCGGCGCCCGTCCTCAAGTGAACGGACAGTCAGGAAGGATTGAC



TTCCACTGGCTCATGTTGAACCCTAATGACACAGTGACATTTTCGTTTAACGGAGCATTC



ATCGCCCCTGACAGAGCTAGTTTCCTCAGAGGGAAGAGTATGGGGATCCAGAGCGGGGTA



CAGGTGGATGCAAACTGTGAGGGGGACTGCTATCATTCTGGTGGGACCATCATTTCGAAC



CTGCCATTCCAGAACATTGACTCTCGCGCTGTTGGCAAATGTCCTAGGTACGTTAAGCAA



AGATCATTGCTGCTCGCAACGGGCATGAAAAACGTGCCGGAAATCCCTAAAGGTCGGGGT



CTCTTCGGCGCCATCGCCGGATTCATTGAGAATGGCTGGGAGGGACTCATCGACGGGTGG



TATGGGTTCCGGCATCAGAACGCACAGGGCGAGGGGACTGCCGCTGACTACAAATCGACC



CAGTCCGCTATTGACCAGATCACCGGCAAACTCAACCGGCTGATCGAGAAGACTAACCAA



CAGTTTGAACTCATCGATAATGAGTTCAACGAGGTAGAAAAACAAATTGGAAACGTGATC



AATTGGACACGCGATTCTATTACTGAGGTCTGGAGTTATAACGCAGAGCTGCTGGTGGCT



ATGGAAAACCAGCACACCATTGATCTAGCTGACTCGGAAATGGATAAGCTGTACGAAAGG



GTGAAACGCCAGCTACGCGAAAATGCCGAGGAAGACGGTACAGGATGCTTCGAGATATTC



CACAAGTGCGACGACGACTGCATGGCCAGCATCCGCAATAACACATATGACCATTCTAAA



TACCGGGAGGAAGCCATGCAGAATCGAATCCAGATCGACCCTGTCAAATTAAGCAGTGGG



TACAAGGACGTGATCCTGTGGTTTAGCTTCGGAGCTAGTTGTTTTATATTACTCGCCATC



GTTATGGGATTGGTATTTATCTGCGTCAAGAATGGAAACATGCGCTGCACTATCTGCATC





557
ATGAACACCCAGATACTCGTCTTTGCCCTCATTGCCATAATCCCGACTAATGCGGATAAG



ATTTGTCTAGGGCATCACGCTGTATCAAACGGCACGAAAGTCAACACCTTGACCGAAAGG



GGCGTAGAGGTGGTAAACGCTACAGAAACAGTCGAGCGGACAAATATCCCAAGGATTTGC



AGCAAGGGTAAAAAGACTGTAGACTTAGGACAGTGCGGCTTACTCGGCACAATCACAGGC



CCCCCCCAATGTGATCAGTTCCTTGAATTCAGTGCAGATCTGATAATCGAAAGGAGGGAG



GGATCTGACGTGTGTTACCCAGGCAAATTCGTCAACGAGGAAGCACTCAGACAGATCTTA



AGAAAGTCCGGGGGGATAGACAAAGAAGCTATGGGTTTTACGTACAGTGGGATAAGAACC



AATGGCGCCACTAGCACCTGTAGGAGGAGTGGGTCGTCCTTCTATGCTGAAATGAAGTGG



CTGCTGTCCAATACTGACAATGCAGCCTTTCCTCAGATGACAAAGAGCTACAAGAATACA



AGGAAAAGCCCGGCAATTATAGTATGGGGAATCCACCATTCAGTCAGCACCGCTGAACAA



ACTAAGCTGTATGGCTCCGGCAATAAGCTCGTCACAGTGGGGAGCTCAAATTATCAGCAG



TCATTCGTGCCAAGCCCAGGGGCGCGGCCGCAAGTTAACGGCCTCTCCGGAAGAATTGAT



TTTCATTGGTTAATGCTTAATCCTAACGACACGGTTACCTTCAGCTTTAACGGCGCTTTC



ATCGCTCCCGACAGGGCTTGTTTTCTCCGCGGCAAGTCTATGGGAATCCAGTCCGGGGTG



CAGGTCGACGCGGATTGTGAAGGAGACTGCTACCACAGTGGGGGCACTATAATCTCAAAT



CTGCCATTCCAGAATATCGACAGTCGCGCCGTGGGGAAGTGTCCGAGATACGTTAAGCAA



CGATCACTGCTACTGGCCACCGGTATGAAAAATGTGCCAGAGATTCCCAAAGGGAGAGGC



CTGTTTGGTGCCATCGCCGGGTTTATCGAGAACGGGTGGGAAGGCTTGATTGACGGCTGG



TACGGATTTCGGCACCAAAACGCCCAAGGGGAAGGTACCGCTGCCGATTACAAGAGCACC



CAAAGTGCCATTGACCAGATTACGGGGAAACTGAACAGACTGATCGAGAAAACGAATCAA



CAATTCGAACTGATAGATAACGAATTTAACGAAGTCGAGCGACAGATCGGGAATGTGATC



AACTGGACTAGGGATTCTATTACCGAGGTATGGAGCTATAATGCTGAGCTTCTTGTGGCA



ATGGAAAATCAACACACAATAGATTTAGCGGATAGTGAGATGGACAAGCTCTACGAACGG



GTAAAAAGACAGTTGAGAGAGAATGCCGAGGAGGACGGGACAGGCTGTTTTGAAATCTTC



CATAAGTGTGACGATGATTGTATGGCGAGCATCCGAAACAATACTTACGATCACAGCAAA



TACCGTGAGGAGGCGATGCAGAATAGAATCCAGATAGATCCGGTTAAACTGTCCAGCGGG



TACAAGGATGTGATCCTGTGGTTCTCATTCGGCGCTTCATGTTTCATTTTGCTGGCAATT



GTGATGGGACTCGTGTTCATATGTGTGAAAAACGGCAATATGCGCTGCACTATTTGCATC





558
ATGAATACACAGATCCTAGTGTTCGCACTCATAGCTATAATCCCTACAAATGCCGACAAG



ATATGTCTTGGCCACCACGCTGTGTCAAACGGGACAAAAGTTAACACCTTGACAGAGCGG



GGCGTCGAGGTCGTTAACGCCACCGAGACTGTGGAAAGAACAAATATACCCCGGATTTGT



TCAAAAGGGAAGAGAACTGTCGACCTGGGGCAGTGCGGACTCCTGGGGACTATCACTGGA



CCTCCACAATGCGACCAGTTCCTCGAGTTCTCTGCCGATCTCATCATTGAGAGGCGAGAG



GGGTCCGATGTGTGTTACCCAGGGAAATTTGTGAATGAGGAAGCCCTTCGGCAGATACTT



CGTGAAAGCGGGGGCATCGATAAAGAGGCCATGGGTTTTACGTATTCTGGAATTCGCACC



AACGGGGCCACAAGTGCATGTCGGAGGAGCGGATCATCATTCTATGCAGAGATGAAATGG



CTGCTTTCTAACACCGATAATGCCGCTTTCCCGCAGATGACAAAAAGTTATAAAAATACC



AGGAAATCCCCCGCTCTAATTGTGTGGGGGATTCATCACAGCGTTTCCACTGCCGAACAG



ACTAAGCTGTACGGTTCGGGCAGCAAGCTGGTGACAGTGGGTTCATCAAACTACCAACAG



TCCTTCGTGCCTTCTCCAGGCGCGCGGCCGCAGGTTAACGGACTCTCTGGCAGAATCGAC



TTTCATTGGTTGATGCTGAATCCCAACGACACCGTCACCTTCTCCTTTAACGGTGCATTT



ATCGCCCCAGATCGTGCTTCATTTCTACGCGGCAAAAGCATGGGGATTCAGTCCGGCGTC



CAGGTAGATGCAAACTGTGAGGGCGACTGTTACCACTCAGGCGGAACAATTATTAGCAAC



CTGCCATTTCAGAATATTGACTCTCGCGCCGTGGGGAAATGCCCAAGATATGTCAAGCAG



CGGAGCCTGCTCCTGGCCACTGGGATGAAGAATGTGCCAGAAATACCAAAGGGTAGAGGT



CTGTTCGGCGCCATCGCTGGCTTTATAGAGAATGGATGGGAGGGACTGATCGATGGCTGG



TACGGATTCAGACATCAAAACGCCCAAGGTGAAGGAACCGCTGCCGATTACAAGTCTACC



CAAAGTGCTATAGATCAGATAACCGGCAAGCTTAATAGGCTCATTGAGAAAACAAATCAG



CAGTTCGAGCTGATCGACAACGAGTTCAACGAGGTGGAGAAGCAGATTGGAAACGTGATT



AATTGGACGCGCGATAGCATCACAGAGGTGTGGTCCTATAACGCAGAGCTGCTGGTGGCT



ATGGAGAACCAGCACACTATCGATCTGGCCGACTCCGAAATGGACAAGCTGTACGAGAGG



GTGAAGCGGCAGTTGCGAGAGAATGCCGAGGAGGACGGGACAGGCTGCTTTGAGATCTTT



CACAAGTGCGACGATGATTGTATGGCTTCAATCCGCAATAACACATACGATCATTCCAAA



TACAGGGAGGAAGCTATGCAGAACCGAATCCAGATAGATCCAGTGAAGCTCTCTAGTGGC



TACAAGGACGTGATTCTGTGGTTCAGTTTCGGTGCTAGCTGTTTTATTCTGCTTGCAATA



GTAATGGGGTTGGTGTTTATCTGTGTTAAGTCACGGAACATGCGCTGCACCATATGCATC





559
ATGAACACACAGATCCTAGTTTTCGCGCTGATCGCAATCATACCTACAAATGCTGACAAG



ATTTGCCTAGGACATCACGCCGTGTCTAATGGAACCAAAGTAAACACTCTGACTGAGCGC



GGGGTAGAGGTCGTGAATGCAACAGAAACGGTAGAGCGGACAAATATCCCTAGGATATGC



AGTAAAGGCAAGCGTACAGTAGATCTCGGCCAGTGTGGCCTACTCGGAACAATCACCGGT



CCTCCCCAGTGCGACCAGTTCCTTGAATTCAGTGCTGATCTGATCATTGAAAGGGGGGAG



GGGTCCGATGTATGTTACCCTGGGAAGTTTGTCAATGAAGAGGCACTGCGCCAAATCCTG



AGAGAGTCAGGAGGCATAGACAAAGAGGCTATGGGATTTACATACAGTGGGATAAGAACT



AACGGCGCGACCAGCGCCTGCAGGAGGTCCGGGTCGTCTTTCTATGCCGAAATGAAATGG



CTCCTTTCTAATACAGATAACGCAGCCTTTCCCCAGATCACTAAATCATACAAGAATACT



AGGAAGTCACCCGCACTCATCGTTTGGGGCATACATCACTCGGTCAGCACCGCCGAACAG



ACTAAATTATACGGTTCAGGGAACAAGCTCGTAACCGTGGGCTCGTCTAACTATCAACAG



AGTTTCGTTCCGTCCCCCGGGGCGAGACCGCAGGTGAATGGCCTCTCCGGGCGAATCGAT



TTTCATTGGCTGATGCTGAACCCCAACGATACCGTAACCTTTTCGTTCAACGGGGCTTTC



ATCGCTCCGGATAGAGCATCATTTCTGCGCGGGAAGTCCATGGGCATTCAGAGCGGTGTT



CAAGTCGACGCCAACTGTGAGGGAGACTGTTATCACAGGGGGGGGACCATCATCAGCAAC



CTCCCGTTTCAGAATATTGACTCAAGGGCGGTCGGAAAGTGTCCACGTTACGTCAAGCAG



CGGAGTCTCCTGTTAGCGACAGGCATGAAGAATGTCCCTGAAATTCCTAAAGGCCGGGGC



CTATTTGGTGCCATCGCCGGTTTCATCGAGAACGGGTGGGAAGGTCTGATCGATGGTTGG



TATGGCTTCCGCCACCAGAATGCGCAAGGGGAAGGAACCGCGGCGGACTACAAAAGTACT



CAGTCCGCAATCGATCAGATCACAGGTAAGTTGAATAGGCTTATCGAGAAGACAAACCAG



CAGTTTGAGCTTATAGACAACGAATTCAATGAGGTGGAAAAGCAAATTGGAAATGTAATC



AATTGGACCAGGGATAGCATCACCGAAGTGTGGAGCTACAATGCCGAGCTGTTGGTGGCA



ATGGAGAACCAACATACAATCGACCTAGCCGATAGTGAGATGGACAAGCTGTATGAGCGG



GTGAAGCGGCAGCTGAGGGAAAATGCGGAGGAAGACGGAACTGGGTGTTTCGAGATTTTC



CACAAGTGTGATGACGATTGTATGGCCTCAATTCGGAACAACACATACGATCATTCCAAG



TATCGAGAAGAGGCCATGCAAAACCGGATTCAGATTGACCCCGTCAAGTTATCCTCCGGG



TACAAGGACGTTATTCTCTGGTTTAGCTTTGGAGCCAGTTGCTTCATTCTGTTGGCAATT



GTGATGGGTCTTGTATTCATCTGTGTGAAAAATGGGAATATGCGCTGCACCATCTGTATC





560
ATGAACACGCAAATCTTGGTGTTCGCACTGATCGCCATTATTCCAACCAATGCTGACAAG



ATTTGCCTTGGTCACCACGCGGTTAGCAACGGGACCAAAGTGAACACCCTGACCGAGCGA



GGGGTGGAGGTAGTGAACGCAACCGAGACAGTGGAGAGAACTAATATACCCCGGATCTGT



AGCAAGGGTAAGAGAACGGTGGATCTTGGGCAGTGTGGCTTGTTGGGGACTATCACAGGC



CCTCCTCAGTGCGACCAGTTCTTGGAATTTTCTGCCGACCTTATCATTGAGCGCAGAGAG



GGGTCAGATGTCTGTTATCCTGGAAAATTTGTGAACGAAGAGGCTCTTCGGCAGATACTG



CGCGAATCAGGCGGCATTGACAAAGAAGCCATGGGGTTTACCTATAGCGGAATCAGGACT



AACGGCGCCACCTCCGCCTGCAGGAGGAGTGGGAGCAGCTTCTACGCTGAAATGAAGTGG



TTGCTCTCTAACACAGACAATGCTGCATTCCCTCAGATTACCAAGAGTTATAAGAACACA



CGCAAATCTCCCGCGCTGATCGTGTGGGGCATTCATCACAGCGTTAGCACGGCCGAGCAG



ACAAAACTGTACGGCTCGGGAAATAAACTTGTGACGGTTGGCAGCAGCAACTATCAGCAG



TCCTTCGTTCCTTCTCCAGGCGCGCGCCCCCAGGTGAATGGGTTGTCTGGGAGAATCGAC



TTTCACTGGCTAATGCTTAATCCTAACGACACGGTGACTTTCTCATTTAACGGAGCTTTC



ATCGCACCAGACCGCGCATCCTTTCTGAGAGGGAAATCGATGGGCATCCAATCCGGGGTG



CAGGTCGATGCGAACTGCGAGGGTGATTGTTATCACTCCGGGGGCACCATAATCAGCAAC



CTGCCTTTCCAGAATATCGACTCCCGGGCAGTAGGAAAGTGCCCACGATATGTGAAGCAG



AGGAGCTTGCTGCTGGCTACAGGCATGAAGAATGTCCCAGAAATCCCCAAGGGGAGAGGT



CTATTTGGGGCCATCGCTGGCTTTATAGAGAACGGGTGGGAAGGTCTGATTGACGGGTGG



TACGGCTTTAGGCACCAGAACGCCCAGGGCGAAGGAACAGCTGCCGACTATAAATCTACA



CAGAGCGCCATTGATCAGATAACTGGCAAGTTAAACCGGCTCATCGAGAAGACTAATCAG



CAATTTGAGCTTATCGATAACGAATTCAATGAAGTAGAGAAACAAATCGGGAATGTGATC



AACTGGACTCGAGATTCAATAACGGAGGTATGGTCCTACAACGCCGAACTGCTCGTTGCT



ATGGAGAACCAGCACACCATCGATCTGGCAGACAGCGAGATGGATAAGCTCTACGAGAGA



GTCAAGCGACAGTTACGTGAAAATGCCGAAGAAGATGGAACCGGTTGCTTTGAGATATTT



CATAAATGCGATGATGATTGCATGGCTTCGATTCGGAATAACACATATGACCACAGCAAG



TACAGGGAAGAAGCGATGCAAAACCGCATTCAGATCGACCCAGTCAAACTAAGCTCTGGA



TACAAAGACGTTATACTGTGGTTCTCCTTTGGAGCCAGCTGCTTCATCCTGCTCGCCATA



GTGATGGGACTGGTGTTTATCTGCGTGAAAAACGGAAACATGAGGTGTACCATTTGTATC





561
ATGAACACACAGATTCTCGTCTTCGCACTCATTGCCATCATCCCTACAAACGCGGACAAA



ATTTGCCTTGGGCACCACGCCGTGAGCAACGGCACAAAAGTCAACACATTGACAGAGCGA



GGCGTAGAGGTCGTTAATGCCACCGAAACGGTAGAAAGGACGAACATTCCTAGGATATGT



AGTAAAGGAAAGCGTACTGTAGATTTAGGACAGTGTGGCTTGCTGGGAACTATCACAGGA



CCCCCACAATGCGACCAGTTCCTAGAGTTTAGCGCCGATCTGATAATTGAACGTAGGGAG



GGAAGCGACGTATGCTACCCAGGGAAATTTGTGAAGGAGGAGGCCCTCCGACAGATTCTG



AGAGAGTCCGGGGGAATCGACAAGGAAGCCATGGGATTCACCTATTCGGGCATAAGAACC



AACGGCGCAACATCCGCTTGCCGGAGGTCCGGGAGTAGTTTTTATGCTGAGATGAAGTGG



CTGCTTTCCAACACCGATAACGCCGCCTTTCCTCAGATGACGAAATCCTATAAGAATACA



AGAAAAAGCCCGGCACTCATCGTGTGGGGCATCCATCACAGCGTCTCCACGGCAGAGCAG



ACTAAACTCTACGGATCTGGAAATAAACTGGTAACAGTGGGGTCAAGTAACTACCAACAG



TCGTTCGTGCCATCCCCTGGCGCTCGGCCTCAGGTTAACGGGCTGTCCGGTAGGATTGAT



TTCCATTGGCTGATGTTAAACCCAAACGACACCGTGACCTTCAGTTTTAACGGCGCTTTT



ATTGCTCCCGACAGGGCAAGTTTCTTGAGGGGCAAGAGCATGGGAATCCAGTCTGGTGTG



CAGGTCGATGCCAACTGTGAGGGAGATTGTTATCATAGCGGAGGTACGATTATCTCTAAT



CTACCTTTTCAAAATATCGACTCCAGGGCGGTCGGGAAATGTCCTCGCTACGTCAAGCAG



AGGTCACTGCTTCTGGCAACCGGAATGAAGAACGTGCCCGAAATCCCAAAGGGCAGAGGT



CTGTTTGGCGCTATAGCCGGGTTCATTGAGAACGGATGGGAGGGTTTAATAGACGGGTGG



TATGGATTCCGCCACCAAAATGCCCAGGGGGAAGGGACAGCTGCCGATTACAAGTCAACA



CAGAGCGCGATCGATCAGATCACAGGAAAGTTGAACAGGTTGATAGAGAAAACAAATCAA



CAGTTTGAGCTGATCGATAATGAGTTCAATGAGGTCGAGAAGCAAATTGGGAACGTAATA



AATTGGACACGAGATTCCATAACTGAAGTGTGGTCTTACAATGCTGAACTGCTCGTGGCG



ATGGAAAACCAACACACGATTGATTTGGCCGATTCCGAGATGGATAAACTGTATGAACGT



GTGAAGCGTCAACTTCGTGAAAATGCCGAAGAGGACGGTACCGGATGCTTCGAGATCTTC



CACAAGTGTGATGATGATTGCATGGCCAGTATCAGGAATAACACATATGACCATTCCAAA



TACCGCGAAGAGGCCATGCAGAATCGTATTCAGATTGACCCCGTTAAGCTGAGTTCCGGT



TACAAAGATGTCATTCTCTGGTTTTCTTTTGGCGCCTCATGTTTCATTCTGCTAGCCATT



GTGATGGGGCTTGTCTTTATCTGTGTCAAGAACGGTAACATGAGGTGTACCATCTGTATC





562
ATGAATACCCAGATTCTGGTGTTCGCGTTAATAGCCATTATCCCAACTAACGCTGATAAG



ATATGTCTGGGCCATCACGCTGTGAGCAATGGAACTAAGGTGAACACTCTGACCGAGAGG



GGTGTGGAGGTAGTGAATGCTACCGAGACAGTAGAGCGGACTAACATTCCCAGGATTTGC



TCTAAGGGCAAGCGCACCGTCGACCTGGGACAGTGCGGGTTGCTAGGTACGATAACTGGT



CCACCACAATGTGATCAATTCTTGGAATTTTCTGCTGACCTCATTATAGAGAGGAGGGAG



GGCTCCGATGTGTGCTACCCCGGGAAATTCGTCAACGAAGAAGCACTGCGTCAGATTTTG



AGAGAATCGGGGGGTATTGACAAGGAGGCCATGGGTTTTACCTACTCCGGCATTCGTACT



AACGGAGCCACCAGTGCCTGCAGGCGGAGCGGGAGTAGCTTCTACGCTGAGATGAAATGG



CTTCTAAGCAACACTGATAACGCCGCTTTCCCCCAGATGACTAAATCTTACAAAAACACA



CGGAAGAGTCCCGCTCTGATAGTATGGGGAATACACCATTCAGTCTCTACAGCCGAGCAG



ACTAAGCTTTATGGAAGCGGGAACAAACTGGTGACCGTCGGTTCATCTAATTACCAGCAG



TCTTTCGTGCCCTCTCCTGGGGCCAGGCCCCAGGTGAATGGGCTGTCTGGCCGCATTGAT



TTCCACTGGTTAATGCTGAATCCCAATGATACCGTGACCTTTTCTTTCAATGGCGCTTTC



ATTGCTCCTGATAGAGCCTCATTTCTGAGAGGGAAGTCGATGGGGATACAGTCTGGGGTC



CAGGTCGACGCTAATTGCGAAGGCGATTGCTACCACTCTGGGGGGACAATTATAAGTAAT



TTGCCGTTCCAGAATATCGATAGTAGAGCTGTGGGGAAATGCCCCCGCTACGTAAAGCAG



CGTTCCCTTTTGCTTGCCACAGGTATGAAAAACGTGCCCGAAATTCCAAAAGGAAGAGGA



CTATTTGGTGCCATTGCGGGGTTCATCGAAAACGGATGGGAGGGCCTGATCGATGGGTGG



TACGGCTTCAGACATCAAAATGCTCAGGGGGAAGGAACTGCAGCGGACTATAAATCTACC



CAGTCTGCCATCGATCAGATCACTGGCAAACTAAATCGACTTATCGAGAAAACAAACCAG



CAGTTTGAGCTTATCGATAACGAGTTCAACGAGGTAGAAAAGCAGATTGGAAACGTCATT



AACTGGACTCGGGATTCAATCACAGAAGTATGGAGTTACAACGCTGAGCTTTTAGTGGCC



ATGGAAAATCAGCATACGATTGATCTCGCCGACTCCGAGATGGATAAGCTGTACGAACGT



GTGAAGCGCCAGCTCAGAGAGAATGCAGAGGAGGACGGGACTGGCTGCTTCGAGATCTTT



CATAAATGTGACGATGACTGCATGGCAAGCATTCGAAATAACACATACGATCATAGTAAG



TATCGGGAGGAGGCTATGCAAAATCGGATTCAAATTGATCCGGTGAAGCTGTCGAGTGGC



TACAAGGATGTGATTTTATGGTTTTCATTCGGGGCCTCCTGCTTCATCCTACTGGCCATA



GTGATGGGCCTGGTGTTTATCTGCGTGAAAAATGGTAATATGCGGTGCACCATCTGCATC





563
ATGAATACTCAAATTTTAGTTTTCGCTCTTATTGCCATCATTCCAACTAACGCTGATAAA



ATCTGCCTGGGCCACCACGCCGTCAGCAATGGGACCAAGGTAAACACACTCACCGAACGC



GGCGTGGAAGTAGTGAATGCGACCGAAACTGTTGAGCGCACCAACATTCCACGAATATGT



TCCAAGGGTAAGAAAACCGTGGATCTGGGGCAATGTGGCCTTCTGGGGACGATAACAGGA



CCACCCCAGTGTGACCAGTTTCTGGAGTTTTCCGCAGACCTGATCATCGAACGTAGGGAG



GGAAGCGACGTCTGTTATCCCGGCAAGTTCGTTAATGAGGAGGCCCTTCGACAAATCCTG



CGCGAAAGCGGTGGGATAGACAAAGAAGCCATGGGCTTCACATACAGCGGGATCAGAACC



AACGGCGCCACAAGTGCCTGCAGGCGATCTGGCTCGTCCTTCTACGCGGAGATGAAGTGG



CTGCTGTCAAACACCGACAATGCCGCTTTTCCCCAGATGACAAAAAGCTACAAAAACACC



CGAAAAAGCCCTGCATTAATAGTCTGGGGCATCCACCACAGCGTGTCTACCGCCGAACAA



ACGAAGCTGTATGGTTCCGGAAACAAACTAGTGACGGTGGGCTCATCAAATTATCAGCAG



TCCTTCGTGCCTTCCCCAGGGGCCAGGCCTCAGGTGAATGGACAATCCGGGCGAATTGAT



TTTCATTGGCTCATGTTGAACCCCAACGACACTGTAACGTTTTCTTTCAACGGTGCGTTT



ATCGCTCCAGATAGGGCCTCCTTCCTCCGAGGAAAAAGTATGGGTATCCAGAGTGGCGTG



CAGGTGGATGCCAATTGCGAGGGTGACTGCTACCACTCTGGCGGTACAATTATCTCTAAT



CTGCCCTTCCAGAACATAGACAGCCGTGCGGTCGGGAAGTGCCCCCGCTACGTTAAGCAA



CGGTCTTTATTGCTTGCCACTGGTATGAAGAACGTGCCAGAGATACCAAAAGGGAGAGGG



CTCTTTGGCGCCATCGCTGGATTTATAGAGAACGGGTGGGAGGGCCTGATTGACGGGTGG



TACGGATTCCGCCATCAGAACGCCCAAGGTGAAGGCACCGCCGCCGACTACAAGAGCACC



CAGAGCGCCATTGATCAGATCACGGGAAAACTGAATAGGCTGATTGAAAAGACAAATCAG



CAGTTCGAGCTGATAGACAACGAATTTAACGAAGTAGAAAAACAAATCGGCAACGTGATC



AACTGGACAAGAGACTCCATCACTGAAGTGTGGAGCTATAATGCCGAGTTACTCGTGGCA



ATGGAGAATCAGCATACTATTGATCTGGCCGATTCGGAAATGGACAAGCTGTACGAACGC



GTCAAGCGGCAACTGCGGGAGAATGCCGAGGAGGACGGTACCGGTTGTTTCGAGATTTTT



CATAAATGTGATGACGACTGCATGGCCTCAATTAGAAACAACACATATGATCACAGCAAG



TATCGGGAAGAAGCTATGCAAAACCGGATTCAGATCGACCCAGTTAAGCTGAGTAGCGGG



TATAAGGACGTAATCCTCTGGTTTTCTTTCGGCGCCTCCTGTTTTATTTTATTAGCGATC



GTGATGGGTCTGGTGTTTATCTGCGTCAAAAATGGTAATATGAGGTGTACTATATGTATC





564
ATGAACACTCAGATTCTAGTATTTGCACTTATTGCCATCATACCAACCAACGCTGACAAG



ATCTGTCTCGGCCATCATGCGGTCAGTAACGGTACAAAGGTCAATACACTGACAGAACGT



GGGGTAGAGGTCGTAAACGCAACCGAGACCGTGGAGAGAACCAATATTCCTCGAATATGT



TCCAAAGGCAAGAGGACTGTTGATTTAGGACAGTGCGGGCTGCTGGGAACTATAACAGGG



CCCCCACAATGTGATCAATTCCTCGAGTTCTCAGCCGACCTCATTATCGAGAGACGCGAG



GGATCTGATGTGTGCTACCCTGGCAAATTCGTGAACGAGGAGGCCCTGCGCCAGATCTTG



CGGGAAAGCGGTGGAATCGATAAGGAGGCCATGGGGTTTACTTATAGCGGCATAAGGACC



AACGGCGCCACCTCTGCATGCAGGAGGAGCGGCAGTAGCTTCTACGCAGAGATGAAATGG



CTGCTGTCTAATACCGACAATGCCGCGTTCCCTCAAATGACTAAAAGCTACAAGAATACG



CGCAAGTCTCCAGCCCTGATCGTGTGGGGCATCCATCACAGTGTCTCAACTGCAGAACAG



ACCAAACTTTACGGTTCAGGCAACAAACTCGTCACCGTCGGCTCTTCTAATTATCAACAG



AGTTTCGTGCCTAGCCCAGGCGAGCGACCCCAGGTGAACGGTCTTTCCGGTCGGATCGAT



TTTCACTGGCTCATGCTCAACCCGAACGATACTGTGACTTTCAGTTTCAACGGGGCCTTC



ATTGCTCCGGATCGGGCATCATTTCTGAGGGGCAAGTCTATGGGCATCCAGTCCGGCGTG



CAGGTGGACGCTAACTGCGAAGGTGATTGTTACCACTCGGGTGGCACAATCATTTCTAAT



CTACCCTTCCAGAACATTGACTCAAGAGCTGTCGGGAAGTGTCCACGATACGTGAAGCAG



AGATCCCTGCTCCTCGCCACAGGGATGAAGAATGTCCCAGAGATTCCTAAAGGGCGCGGC



CTGTTCGGAGCTATAGCGGGGTTCATTGAGAATGGGTGGGAAGGCCTAATTGACGGTTGG



TATGGTTTTAGGCATCAGAATGCCCAGGGCGAGGGTACCGCCGCAGATTATAAAAGTACT



CAGTCTGCCATCGATCAAATCACCGGGAAGCTAAACCGGTTGATCGAAAAAACTAACCAG



CAGTTTGAGCTGATTGACAACGAATTTAACGAGGTGGAGAAACAGATCGGCAACGTAATT



AATTGGACGCGGGATAGCATCACAGAAGTCTGGAGCTATAATGCAGAGCTCCTGGTGGCG



ATGGAGAATCAGCACACTATCGACTTGGCTGATTCGGAAATGGATAAGCTGTATGAGAGG



GTGAAACGTCAGCTGCGGGAGAATGCCGAAGAAGATGGTACCGGGTGTTTCGAAATATTC



CATAAATGTGACGATGATTGTATGGCCAGCATCCGAAATAACACATATGACCATTCTAAA



TACAGAGAAGAGGCCATGCAGAATCGAATACAAATCGACCCTGTGAAACTGTCCTCCGGA



TATAAAGATGTTATCCTTTGGTTTAGCTTCGGCGCCTCTTGCTTTATACTGTTGGCAATC



GTGATGGGCTTGGTATTTATTTGTGTCAAGAATGGCAATATGCGCTGTACGATCTGCATT





565
ATGAACACCCAGATCTTGGTGTTTGCTCTTATTGCAATCATCCCTACTAACGCCGATAAA



ATCTGTCTGGGTCACCATGCCGTCAGTAATGGAACCAAGGTAAACACACTGACGGAGAGG



GGCGTGGAGGTGGTTAACGCAACCGAAACAGTTGAGCGGACGAATATCCCCCGGATATGT



AGTAAGGGAAAGAAAACTGTCGATCTGGGACAGTGCGGCCTACTAGGAACCATCACTGGG



CCTCCCCAGTGTGACCAGTTCCTGGAATTTTCTGCCGACCTGATTATCGAACGCCGTGAG



GGATCCGACGTGTGCTATCCAGGTAAATTCGTGAATGAAGAAGCACTTAGGCAGATCCTT



CGTGAATCTGGGGGCATCGATAAGGAAGCTATGGGGTTTACTTATTCCGGTATTAGGACC



AACGGGGCAACAAGCGCCTGCAGACGAAGTGGTTCGTCATTTTACGCCGAGATGAAATGG



CTGTTGTCCAACACTGACAATGCTGCTTTTCCCCAAATGACCAAAAGCTATAAAAACACT



CGGAAATCACCCGCCCTCATCGTATGGGGGATCCACCATTCTGTTTCTACTGCAGAACAG



ACAAAACTGTACGGGAGCGGCAATAAGCTGGTGACCGTGGGGTCCTCCAATTATCAACAG



TCTTTTGTCCCGTCCCCAGGAGCGAGACCACAGGTCAATGGACAGTCAGGCCGAATCGAC



TTCCACTGGCTTATGCTTAATCCAAACGACACCGTCACCTTTAGTTTCAATGGCGCCTTC



ATCGCCCCAGACAGAGCCTCATTCCTGCGCGGGAAATCGATGGGCATTCAGTCGGGAGTC



CAAGTGGACGCAAACTGCGAAGGTGACTGTTACCATAGTGGGGGCACAATCATCAGTAAC



CTGCCCTTTCAGAACATAGATTCCCGCGCCGTAGGAAAGTGTCCCCGGTATGTGAAACAG



AGATCATTGTTGCTGGCAACAGGGATGAAAAATGTACCCGAAATTCCCAAAGGGCGAGGG



CTGTTTGGAGCCATTGCCGGTTTTATCGAGAACGGGTGGGAGGGCCTGATCGATGGGTGG



TACGGTTTCAGACACCAGAACGCCCAGGGCGAAGGGACCGCTGCAGATTACAAGTCGACC



CAATCCGCGATAGATCAGATCACTGGTAAACTCAATCGACTCATTGAAAAGACAAATCAA



CAGTTCGAGCTGATTGATAACGAGTTCAACGAAGTCGAAAAGCAGATAGGGAACGTGATC



AATTGGACACGCGACTCCATCACCGAAGTGTGGAGTTACAATGCAGAGCTGTTGGTAGCG



ATGGAGAACCAGCATACTATTGACCTGGCCGATTCAGAAATGGACAAGCTGTACGAGCGC



GTCAAGCGGCAACTGCGAGAGAATGCTGAAGAGGATGGAACCGGATGCTTCGAAATCTTC



CACAAGTGCGATGACGACTGCATGGCCTCCATCAGGAACAATACATACGATCACTCAAAG



TACCGGGAGGAGGCCATGCAGAACCGTATTCAGATCGACCCCGTAAAACTGAGCTCCGGC



TACAAGGATGTAATCTTGTGGTTCAGCTTCGGCGCTTCATGCTTTATTTTACTGGCCATC



GTCATGGGACTTGTCTTTATCTGTGTTAAGAACGGGAATATGCGGTGCACCATCTGCATC





566
ATGAATACACAGATACTGGTGTTTGCCCTCATTGCAATCATTCCAACCAATGCCGACAAG



ATTTGCCTGGGCCATCACGCTGTGTCCAACGGCACCAAGGTGAACACCCTTACAGAACGC



GGGGTGGAGGTGGTCAACGCAACCGAGACCGTGGAGAGAACCAATATTCCAAGGATCTGC



TCGAAGGGAAAGAAGACCGTAGATCTGGGACAGTGTGGGCTGCTCGGCACAATAACCGGC



CCCCCGCAGTGTGATCAGTTCTTGGAGTTCAGCGCTGATCTGATTATCGAGCGGAGGGAG



GGATCCGACGTCTGTTACCCCGGGAAGTTCGTGAATGAAGAAGCTCTTAGACAGATCCTT



CGCGAATCTGGCGGAATTGACAAGGAAGCTATGGGCTTCACTTATTCTGGAATAAGAACC



AACGGCGCAACCTCCGCCTGTAGGCGCAGCGGATCCAGCTTTTATGCCGAGATGAAATGG



TTGTTGTCCAATACTGACAATGCCGCTTTCCCCCAGATGACCAAGTCCTACAAGAATACT



CGAAAAAGCCCAGCTTTGATCGTCTGGGGCATCCACCATTCTGTCTCCACCGCGGAGCAG



ACCAAGCTTTATGGCTCTGGTAACAAGCTGGTGACTGTGGGAAGCAGCAATTACCAGCAA



AGTTTCGTGCCTAGTCCCGGGGCCCGCCCACAGGTAAACGGCCAGTCAGGGAGAATAGAC



TTCCACTGGCTGATGCTGAACCCTAATGACACGGTGACATTTAGCTTTAATGGTGCTTTC



ATCGCTCCCGATCGCGCCAGTTTTCTCAGAGGGAAGTCGATGGGAATCCAATCCGGTGTC



CAAGTGGACGCCAATTGTGAGGGAGACTGCTATCATAGCGGGGGAACAATCATATCTAAT



CTTCCATTTCAGAACATTGATTCTCGAGCAGTTGGAAAGTGCCCCCGGTACGTGAAGCAA



CGAAGCCTGCTCCTTGCAACCGGCATGAAGAATGTGCCCGAGATCCCAAAGGGACGGGGC



CTATTCGGGGCCATCGCCGGGTTCATCGAGAATGGTTGGGAGGGACTAATCGATGGATGG



TATGGCTTTCGGCACCAGAACGCTCAGGGCGAAGGAACCGCAGCAGACTACAAATCAACA



CAGTCCGCCATAGACCAGATCACAGGTAAACTCAACCGCCTGATAGAGAAAACAAATCAG



CAATTTGAACTTATCGACAATGAGTTCAACGAAGTGGAGAAACAAATAGGAAACGTAATT



AACTGGACCAGGGACTCAATCACCGAAGTGTGGAGCTATAATGCCGAGCTCCTGGTGGCT



ATGGAGAATCAGCATACTATCGACTTAGCTGACAGCGAGATGGACAAGCTGTATGAACGG



GTCAAACGGCAGCTTAGGGAGAATGCTGAAGAGGATGGCACTGGCTGCTTCGAGATCTTC



CACAAATGCGATGATGACTGTATGGCCTCTATTAGGAATAATACGTACGACCATTCTAAA



TACAGGGAGGAGGCTATGCAGAACCGGATTCAGATTGATCCAGTTAAGCTGTCTAGCGGT



TATAAAGATGTGATTTTGTGGTTCTCCTTTGGCGCCAGCTGTTTCATCTTGCTAGCAATA



GTTATGGGCCTAGTGTTTATCTGCGTGAAGAACGGCAATATGAGATGTACAATCTGCATC





567
ATGAACACACAGATCCTGGTATTTGCTCTTATCGCTATCATCCCGACCAACGCCGATAAG



ATCTGTCTTGGCCACCACGCCGTTTCGAATGGCACCAAGGTGAATACTCTTACCGAACGA



GGAGTGGAAGTTGTGAACGCCACGGAAACAGTTGAACGCACCAACATCCCGAGGATCTGT



TCCAAAGGCAAGAAAACGGTTGACCTGGGCCAGTGTGGACTGTTGGGGACTATCACCGGG



CCCCCACAGTGTGATCAGTTCCTGGAGTTTTCTGCTGACCTGATTATTGAAAGACGGGAG



GGGTCAGACGTGTGTTACCCCGGCAAGTTCGTCAATGAGGAAGCTCTTCGACAGATTTTA



AGGGAATCGGGCGGAATTGACAAGGAAGCCATGGGGTTCACCTACTCTGGGATTCGTACC



AACGGTGCTACCTCCGCTTGTCGAAGGTCTGGCAGTAGCTTCTACGCGGAGATGAAATGG



CTCCTGTCAAACACAGACAATGCCGCGTTCCCTCAAATGACTAAGTCATACAAAAACACT



CGTAAGTCCCCGGCTCTCATAGTGTGGGGCATCCACCATAGTGTGAGCACAGCGGAGCAG



ACCAAATTGTACGGAAGCGGCAACAAGCTTGTGACTGTGGGTTCCTCCAACTACCAACAG



AGTTTCGTGCCAAGCCCGGGCGCTCGCCCTCAGGTCAACGGCCAGTCCGGCAGAATTGAC



TTCCACTGGCTCATGCTCAACCCAAACGACACAGTTACATTTAGTTTCAATGGAGCGTTC



ATAGCACCTGATCGCGCTTCTTTTCTGAGAGGAAAATCCATGGGGATTCAGAGTGGTGTG



CAAGTAGATGCTAACTGCGAGGGCGACTGTTACCACTCTGGCGGTACTATCATCTCCAAC



CTCCCATTTCAAAACATAGATTCTCGTGCGGTGGGCAAATGTCCGAGGTACGTGAAACAG



CGATCACTCCTGCTAGCCACCGGAATGAAAAACGTGCCCGAGATCCCGAAGGGCCGGGGC



CTGTTCGGTGCCATCGCAGGGTTTATCGAAAACGGGTGGGAAGGCCTGATCGATGGGTGG



TATGGGTTTCGGCATCAGAACGCACAGGGAGAAGGAACAGCTGCTGACTACAAAAGCACA



CAGTCTGCCATCGACCAAATTACAGGTAAACTCAATAGGCTCATTGAGAAGACCAATCAG



CAGTTCGAGCTCATTGACAATGAGTTTAACGAGGTCGAAAAGCAAATCGGGAATGTAATA



AATTGGACCCGCGACAGTATCACAGAAGTCTGGAGTTACAACGCAGAGCTGCTCGTGGCT



ATGGAGAACCAGCACACAATTGACTTGGCTGACTCCGAAATGGATAAGTTGTACGAACGA



GTAAAGCGCCAGCTGCGCGAGAACGCTGAAGAGGACGGGACGGGGTGTTTCGAAATTTTC



CACAAATGTGACGATGATTGCATGGCCTCTATCCGCAACAATACCTACGACCACAGCAAG



TACCGCGAGGAGGCCATGCAGAACCGCATCCAAATCGACCCTGTGAAGTTGTCTTCCGGA



TACAAGGATGTGATCCTGTGGTTCTCCTTTGGGGCCAGTTGCTTTATCCTTCTCGCAATT



GTGATGGGACTCGTCTTTATCTGCGTGAAAAACGGTAACATGCGCTGTACAATTTGTATA





568
ATGAACACCCAGATCCTAGTCTTTGCTCTGATTGCGATCATCCCCACCAATGCGGATAAG



ATCTGCCTCGGACACCACGCCGTCTCTAATGGCACGAAAGTCAACACCTTAACAGAAAGG



GGGGTGGAGGTGGTTAATGCCACCGAGACAGTCGAACGAACGAATATTCCCAGAATTTGT



TCTAAAGGAAAACGCACCGTGGACTTAGGGCAGTGCGGCCTCCTCGGCACTATTACCGGC



CCTCCACAGTGTGACCAGTTCTTAGAGTTCAGCGCCGACCTGATCATAGAGCGAAGGGAA



GGGTCTGACGTGTGCTATCCTGGCAAATTTGTGAATGAGGAGGCCTTGAGACAGATTCTT



AGGGAGTCGGGCGGTATAGACAAGGAAGCTATGGGCTTTACATACAGTGGGATCCGGACA



AATGGCGCGACAAGCGCATGTAGGAGAAGCGGAAGCAGCTTTTACGCTGAGATGAAGTGG



CTACTCTCCAATACCGATAATGCCGCCTTCCCACAAATGACAAAATCCTATAAGAACACC



AGGAAGTCCCCAGCCCTCATCGTCTGGGGAATTCACCACTCCGTCTCTACAGCAGAACAA



ACTAAACTCTACGGTTCCGGAAATAAGCTCGTTACTGTCGGCAGCTCCAATTACCAGCAG



TCATTCGTCCCAAGTCCCGGAGCAAGACCTCAGGTTAATGGCCTCAGCGGAAGAATCGAC



TTCCACTGGTTGATGTTAAACCCGAACGACACAGTGACATTCTCCTTTAACGGAGCCTTC



ATCGCACCGGATCGGGCCTCTTTTTTAAGGGGAAAGAGCATGGGCATTCAGTCCGGGGTG



CAGGTCGATGCTAACTGTGAAGGCGATTGTTATCATAGCGGAGGCACCATCATCTCAAAT



CTGCCTTTTCAGAACATTGACTCCAGAGCTGTAGGAAAGTGTCCTCGCTATGTGAAACAA



AGGTCTCTTCTGCTGGCAACTGGAATGAAGAATGTGCCAGAGATTCCTAAGGGTCGGGGA



CTATTTGGAGCCATAGCCGGCTTTATAGAAAATGGATGGGAGGGCCTGATAGACGGTTGG



TACGGGTTCCGCCATCAGAATGCCCAAGGTGAGGGTACGGCCGCAGACTATAAGTCTACA



CAGAGCGCCATTGATCAGATAACCGGAAAGCTGAACCGTCTGATAGAGAAAACCAACCAG



CAATTTGAACTTATTGATAACGAGTTCAACGAGGTTGAGAAGCAGATCGGCAATGTTATT



AACTGGACAAGAGATTCGATCACCGAAGTTTGGTCATACAACGCCGAACTGCTGGTAGCC



ATGGAGAACCAGCACACAATCGACCTCGCAGATAGTGAGATGGACAAACTGTACGAGCGT



GTGAAGAGACAGCTGAGAGAGAACGCGGAGGAAGACGGCACTGGCTGTTTCGAGATTTTC



CATAAGTGCGATGACGATTGCATGGCCTCCATTAGGAATAATACCTATGACCATTCCAAA



TACCGTGAAGAAGCCATGCAAAACCGGATCCAGATTGACCCCGTCAAGCTTTCGTCAGGG



TATAAAGATGTGATCCTGTGGTTCTCTTTCGGCGCCAGTTGCTTCATCCTGCTCGCAATC



GTGATGGGACTCGTGTTCATATGTGTCAAAAACGGCAACATGCGCTGTACGATCTGCATA





569
ATGAACACTCAGATCCTTGTCTTTGCCCTAATAGCAATAATTCCAACAAATGCCGATAAA



ATCTGTTTGGGTCATCACGCCGTCTCAAACGGAACAAAGGTGAACACACTGACAGAACGG



GGTGTCGAGGTGGTCAATGCCACCGAAACTGTCGAACGCACTAATATTCCCAGAATATGC



TCGAAGGGTAAGAGGACGGTAGACTTGGGCCAGTGTGGCCTGCTTGGTACCATCACTGGC



CCTCCCCAGTGTGACCAATTCCTGGAGTTTAGCGCGGACCTGATAATTGAGAGACGTGAG



GGTAGCGATGTTTGCTATCCTGGAAAGTTCGTCAATGAAGAGGCCCTGAGGCAGATCCTA



CGAGAATCCGGCGGGATCGATAAAGAAGCTATGGGATTTACCTACTCCGGGATCAGGACA



AACGGGGCAACTTCGGCATGTCGGCGGTCTGGCAGCTCATTTTATGCTGAGATGAAATGG



TTGCTCTCAAACACCGATAACGCCGCTTTCCCACAAATCACCAAGTCCTACAAGAACACA



AGGAAGTCCCCCGCTTTGATTGTCTGGGGCATCCACCACAGCGTGTCAACTGCTGAGCAG



ACCAAGTTATACGGCTCAGGCAACAAACTCGTTACCGTGGGATCTTCGAATTATCAACAG



AGTTTTGTGCCATCCCCTGGTGCTAGGCCGCAAGTTAATGGTCTTAGTGGGCGTATAGAC



TTCCACTGGCTTATGCTGAATCCGAACGATACCGTCACCTTTTCATTCAACGGTGCTTTC



ATAGCCCCCGATCGCGCCTCTTTCCTCAGGGGGAAGTCTATGGGTATTCAGTCAGGTGTG



CAGGTGGATGCGAATTGTGAGGGAGATTGTTACCACTCCGGGGGCACCATAATAAGCAAT



CTTCCCTTTCAAAATATCGACTCTCGGGGGGTCGGAAAATGTCCGCGCTATGTGAAGCAG



CGGAGTCTCCTGCTGGCAACAGGGATGAAAAATGTGCCCGAGATTCCTAAAGGAAGAGGT



TTGTTTGGTGCGATCGCTGGTTTTATCGAGAATGGGTGGGAGGGCTTAATCGACGGTTGG



TATGGGTTTAGACACCAGAACGCCCAGGGAGAGGGTACCGCAGCCGACTATAAGAGTACA



CAGAGCGCAATCGACCAGATCACAGGCAAACTCAACCGCCTAATTGAGAAAACTAACCAG



CAATTCGAGTTAATCGACAATGAGTTCAACGAGGTAGAAAAGCAAATAGGCAACGTCATT



AATTGGACCCGGGACAGTATAACAGAGGTCTGGAGCTATAATGCCGAGCTGTTGGTGGCC



ATGGAAAACCAGCACACGATCGACCTGGCAGACAGCGAAATGGACAAGCTGTACGAGAGA



GTTAAGCGCCAGTTGCGCGAGAACGCCGAGGAAGATGGCACCGGGTGCTTCGAAATCTTT



CACAAGTGCGATGACGACTGCATGGCTTCTATTCGAAATAATACTTATGATCATAGCAAG



TATAGAGAAGAAGCCATGCAGAATAGGATCCAGATCGACCCAGTAAAGTTGTCTTCTGGC



TACAAGGATGTGATACTGTGGTTCTCCTTTGGGGCTAGTTGCTTTATTTTGCTGGCTATT



GTTATGGGTCTGGTGTTCATTTGTGTGAAGAATGGGAACATGCGCTGCACGATATGTATC





570
ATGAATACCCAGATCCTGGTGTTCGCACTGATCGCCATTATACCCACCAACGCCGACAAG



ATCTGCCTTGGCCACCACGCTGTTTCTAATGGAACGAAGGTCAATACTCTGACCGAGAGG



GGGGTGGAAGTCGTGAACGCTACAGAGACTGTTGAAAGGACAAATATTCCGCGCATTTGC



AGCAAAGGGAAGCGAACCGTGGATTTGGGCCAATGTGGCCTCCTTGGCACTATTACAGGC



CCACCTCAGTGTGATCAGTTTCTGGAATTCTCCGCTGACCTCATTATAGAACGGAGAGAA



GGATCAGACGTTTGTTACCCTGGCAAATTCGTGAATGAGGAGGCCTTGAGACAGATACTC



AGGGAGTCCGGCGGCATCGACAAGGAAGCAATGGGTTTCACCTACAGCGGCATTCGCACC



AACGGCGCCACCTCCGCCTGCCGCCGCAGCGGGTCTAGCTTTTATGCCGAAATGAAATGG



CTCTTAAGTAATACAGACAACGCTGCCTTTCCCCAGATGACAAAATCATACAAGAACACA



AGAAAATCACCCGCACTTATAGTTTGGGGGATCCATCACTCCGTGTCCACCGCTGAGCAG



ACTAAGTTGTACGGGAGTGGAAACAAACTGGTTACGGTGGGTAGTTCTAACTATCAGCAG



TCCTTTGTGCCTTCGCCCGGAGCTCGCCCACAGGTTAACGGTCTGAGCGGTCGCATCGAC



TTCCACTGGCTAATGCTGAACCCTAACGATACCGTGACATTCTCTTTTAATGGAGCTTTC



ATCGCCCCCGACCGCGCTTCCTTTTTGAGGGGGAAGTCCATGGGTATCCAGAGCGGAGTG



CAGGTGGACGCCAATTGCGAGGGAGATTGTTATCATTCTGGGGGCACCATTATCTCTAAT



TTACCGTTTCAGAATATCGACTCAAGAGCAGTGGGCAAGTGCCCTCGATACGTGAAGCAG



CGCAGCCTGCTTCTTGCTACAGGAATGAAAAACGTCCCGGAGATTCCCAAGGGGGGGGGC



CTGTTCGGCGCCATCGCAGGCTTCATAGAGAACGGTTGGGAGGGACTGATTGATGGATGG



TACGGGTTCCGCCATCAGAACGCCCAGGGCGAAGGAACCGCTGCGGACTACAAGTCCACC



CAGTCCGCAATCGACCAGATAACGGGCAAGTTGAATAGGCTCATCGAAAAAACGAACCAA



CAATTCGAGCTTATTGATAACGAGTTTAACGAAGTAGAAAAGCAGATTGGGAATGTGATA



AACTGGACCAGAGATAGCATCACCGAGGTGTGGAGCTATAATGCAGAACTGCTAGTAGCT



ATGGAAAATCAGCACACAATCGACTTAGCCGATAGTGAGATGGACAAATTGTATGAGCGA



GTAAAAAGACAATTAAGAGAAAACGCAGAGGAGGATGGCACCGGTTGTTTCGAAATCTTT



CACAAATGTGATGACGACTGTATGGCCTCAATTCGGAACAACACCTACGACCACAGCAAA



TACAGAGAAGAGGCCATGCAGAATCGCATACAGATAGATCCAGTCAAACTGTCATCTGGG



TACAAGGACGTTATATTATGGTTCTCTTTCGGGGCAAGCTGCTTCATCCTTCTGGCTATC



GTGATGGGCTTGGTCTTCATCTGCGTCAAGAATGGAAACATGCGCTGCACCATCTGCATC





571
ATGAATACCCAGATCCTGGTTTTCGCCCTGATCGCTATCATTCCTACTAACGCAGATAAG



ATCTGCCTGGGGCACCATGCAGTCAGCAACGGGACCAAGGTGAACACACTGACTGAGCGT



GGAGTCGAGGTCGTCAATGCGACTGAGACAGTAGAGCGGACGAACATACCCAGAATCTGC



AGCAAAGGGAAACGGACGGTAGACCTCGGCCAGTGCGGTCTCCTGGGTACCATCACAGGT



CCACCCCAATGCGATCAGTTTCTGGAGTTCTCCGCCGACCTCATCATCGAACGGCGCGAG



GGGTCCGATGTCTGCTACCCTGGTAAATTCGTCAATGAAGAGGCTCTCCGTCAGATTCTT



CGGGAATCAGGGGGGATTGACAAGGAAGCTATGGGATTTACATACTCCGGTATACGAACC



AACGGAGCTACCAGTGCTTGCCGACGGTCAGGGTCATCATTCTACGCCGAGATGAAATGG



CTTCTCTCGAACACTGATAATGCTGCGTTTCCACAAATTACCAAAAGCTACAAAAACACC



CGGAAGTCCCCTGCACTGATCGTGTGGGGAATTCACCACAGCGTCTCTACGGCTGAACAG



ACCAAACTGTACGGATCAGGCAACAAGTTGGTGACTGTCGGGTCATCCAATTATCAGCAG



AGTTTCGTTCCCAGCCCTGGCGCAAGACCTCAGGTGAACGGCTTGTCCGGGAGGATTGAT



TTTCACTGGCTCATGCTGAATCCTAATGACACTGTTACCTTTTCTTTTAATGGGGCTTTT



ATTGCACCGGACCGAGCAAGTTTTCTACGCGGAAAGTCCATGGGGATACAGAGTGGGGTG



CAGGTGGATGCTAATTGCGAGGGCGATTGTTATCACAGGGGCGGCACCATAATATCAAAC



CTGCCCTTCCAGAACATCGACTCCAGGGCCGTGGGCAAGTGTCCAAGATACGTCAAACAA



AGATCTCTGCTGCTGGCCACTGGGATGAAAAACGTCCCAGAAATCCCAAAAGGGAGGGGG



CTCTTCGGAGCCATAGCCGGGTTTATCGAAAATGGATGGGAAGGTCTGATAGACGGGTGG



TACGGTTTCAGACATCAGAACGCACAGGGCGAGGGAACAGCCGCCGACTACAAGAGCACC



CAGAGTGCAATCGATCAGATCACTGGTAAGCTTAATAGGCTGATCGAAAAGACTAATCAA



CAATTTGAGCTGATAGACAATGAATTCAACGAAGTTGAAAAGCAGATAGGTAATGTAATC



AATTGGACCCGAGATTCAATAACTGAAGTCTGGAGCTACAATGCCGAACTGTTGGTGGCT



ATGGAGAACCAACATACGATTGACCTGGCCGACTCCGAGATGGACAAGCTGTATGAGCGG



GTAAAGAGACAGCTGAGGGAGAATGCCGAGGAAGATGGCACCGGATGTTTCGAGATTTTT



CACAAGTGTGATGACGACTGCATGGCGTCTATCCGGAATAACACCTACGACCACTCAAAA



TATCGGGAAGAAGCGATGCAGAATCGAATTCAGATCGACCCAGTCAAACTGTCGAGTGGC



TATAAAGATGTGATACTGTGGTTTAGCTTCGGGGCATCTTGTTTCATTCTGCTGGCTATT



GTGATGGGCCTCGTGTTCATTTGCGTTAAGAATGGGAATATGCGATGCACCATTTGTATC





572
ATGAATACTCAAATACTTGTCTTTGCACTAATCGCTATCATACCCACTAATGCCGATAAA



ATCTGCTTAGGACACCATGCTGTGTCCAACGGAACTAAAGTGAACACTCTGACGGAGCGA



GGCGTCGAAGTTGTCAACGCAACCGAGACTGTGGAGCGCACGAATATCCCCCGAATCTGC



TCGAAAGGAAAGAAGACTGTTGACCTTGGTCAATGCGGATTACTGGGAACCATCACAGGA



CCCCCCCAATGCGACCAGTTTCTGGAATTTAGTGCTGATCTTATAATCGAGCGCCGGGAA



GGTAGCGACGTTTGTTATCCGGGAAAGTTTGTAAACGAGGAGGCTCTGAGACAGATCCTG



CGCGAGTCAGGGGGGATCGACAAGGAGGCCATGGGCTTTACCTACTCTGGAATCAGAACA



AATGGCGCTACTTCCGCTTGTCGGCGCTCTGGAAGCAGCTTCTATGCTGAAATGAAATGG



CTGCTGTCCAACACCGACAATGCAGCCTTTCCTCAGATGACTAAATCTTACAAAAATACC



CGGAAATCCCCAGCTCTGATAGTGTGGGGTATCCATCACTCAGTCAGTACTGCTGAACAA



ACCAAGTTATATGGCTCCGGCAATAAGCTAGTAACCGTGGGAAGCTCCAACTACCAACAG



TCTTTCGTGCCCTCACCCGGCGCAAGACCCCAGGTGAACGGCCAGTCAGGTCGCATTGAT



TTCCACTGGTTGATGCTTAACCCAAATGACACCGTTACCTTTTCCTTCAATGGCGCCTTT



ATAGCGCCCGACAGAGCTTCATTCCTTAGAGGCAAGTCTATGGGTATCCAATCCGGAGTC



CAGGTAGACGCAAACTGTGAGGGAGACTGCTATCATTCCGGTGGAACCATCATATCGAAT



TTGCCTTTCCAGAACATCGATAGCCGGGCGGTCGGCAAGTGCCCTAGATACGTTAAACAA



AGGAGCCTGCTCTTAGCAACAGGTATGAAGAACGTCCCAGAGATTCCAAAGGGCCGAGGA



CTGTTCGGTGCAATAGCTGGCTTTATCGAGAATGGGTGGGAGGGGCTCATCGATGGTTGG



TATGGGTTCAGACACCAGAATGCCCAGGGCGAAGGAACCGCTGCTGACTACAAAAGCACA



CAGAGCGCTATAGATCAGATAACAGGCAAGCTTAACCGGCTGATCGAGAAAACGAATCAG



CAGTTCGAACTCATTGATAATGAGTTCAACGAAGTGGAGAAGCAGATTGGTAATGTCATC



AACTGGACTAGAGATAGTATAACAGAAGTGTGGTCTTATAACGCCGAACTCCTGGTCGCA



ATGGAAAATCAACATACCATTGACCTGGCTGATTCGGAGATGGACAAACTTTATGAGCGG



GTGAAGAGGCAGCTCCGAGAGAATGCAGAAGAGGACGGCACAGGGTGCTTTGAGATCTTC



CATAAGTGCGACGATGATTGCATGGCTTCCATCAGGAATAATACTTATGACCACTCCAAG



TACCGGGAGGAAGCCATGCAAAATCGGATCCAAATAGATCCAGTGAAGCTTTCGTCAGGA



TATAAGGACGTGATCTTGTGGTTTAGCTTCGGGGCCTCTTGTTTCATCCTCCTGGCGATT



GTCATGGGACTTGTATTCATTTGTGTGAAGAACGGAAACATGCGCTGCACCATTTGCATA





573
ATGAACACACAGATCCTTGTGTTCGCCCTTATCGCAATAATTCCCACAAACGCCGACAAA



ATATGCCTGGGTCACCACGCCGTAAGCAATGGCACCAAAGTTAACACCCTCACCGAGCGT



GGGGTGGAGGTGGTGAACGCCACCGAGACCGTTGAAAGGACAAACATTCCACGAATTTGT



AGTAAGGGCAAACGGACTGTAGATCTGGGTCAGTGTGGGCTGCTGGGCACTATCACCGGC



CCACCACAGTGCGACCAATTCCTAGAATTCTCAGCTGATTTAATCATCGAAAGGCGCGAG



GGGTCTGACGTCTGTTACCCGGGAAAATTTGTGAACGAAGAGGCCCTGCGACAGATTCTG



CGTGAGTCCGGGGGAATCGACAAAGAGGCGATGGGATTTACCTATTCAGGCATACGGACC



AATGGAGCTACTTCTGCATGCCGGAGGAGCGGCTCGTCTTTCTACGCTGAAATGAAGTGG



TTGCTGAGTAATACCGACAACGCAGCCTTCCCCCAGATGACAAAGAGCTACAAGAACACA



CGCAAGTCACCCGCACTCATAGTCTGGGGGATTCATCACTCAGTCAGTACCGCGGAGCAG



ACCAAGCTCTACGGTAGCGGCAACAAGCTGGTCACAGTTGGTTCTAGTAATTACCAGCAG



TCCTTTGTTCCCTCCCCCGGCGCCCGTCCCCAAGTCAACGGGCTCTCGGGCAGAATCGAC



TTCCACTGGCTCATGTTGAACCCCAACGATACTGTGACATTCTCTTTTAATGGTGCTTTT



ATCGCGCCGGACAGGGCCTCTTTCTTACGCGGCAAGAGCATGGGTATACAGTCTGGAGTC



CAGGTTGATGCTAATTGCGAAGGCGACTGTTATCATTCAGGAGGCACCATCATATCAAAC



CTGCCCTTCCAAAATATAGATAGTCGGGCTGTGGGTAAATGCCCTAGGTACGTCAAGCAG



AGAAGTCTTCTGCTCGCCACTGGCATGAAAAACGTACCAGAGATTCCTAAAGGAAGAGGC



CTATTTGGAGCAATTGCCGGCTTTATCGAGAATGGGTGGGAAGGCCTTATAAACGGGTGG



TATGGCTTCAGGCACCAGAACGCCCAGGGGGAGGGTACCGCCGCCGATTACAAGAGCACT



CAGAGTGCCATAGACCAGATTACTGGAAAATTAAATAGACTGATTGAGAAAACAAACCAG



CAGTTTGAACTGATTGACAATGAATTCAATGAGGTGGAGAAGCAGATTGGGAACGTGATC



AATTGGACCCGGGACTCTATTACTGAGGTATGGAGCTATAACGCTGAGCTTTTGGTGGCC



ATGGAGAACCAACATACGATTGATCTGGCAGATAGCGAAATGGATAAGCTTTATGAGCGT



GTTAAGAGGCAGCTCCGCGAAAATGCCGAAGAGGATGGTACGGGATGCTTCGAGATTTTC



CATAAATGCGACGACGATTGCATGGCTAGCATTAGGAACAACACCTATGACCACAGTAAA



TATAGAGAGGAGGCCATGCAAAATCGCATTCAGATAGACCCTGTCAAGTTGAGCTCGGGG



TATAAGGACGTCATACTTTGGTTTAGTTTTGGGGCGAGCTGTTTTATTTTGCTGGCCATA



GTTATGGGTCTGGTCTTTATTTGTGTAAAGAACGGGAATATGCGTTGCACCATTTGCATA





574
ATGAACACCCAAATATTAGTGTTCGCCCTCATAGCAATCATTCCCACAAATGCTGATAAG



ATTTGCCTTGGTCATCATGCTGTGAGTAACGGGACCAAGGTGAACACTCTTACGGAGCGC



GGGGTTGAAGTTGTTAACGCTACCGAGACCGTTGAAAGAACCAACATCCCACGAATCTGC



AGCAAGGGGAAGCGGACCGTGGACTTGGGACAGTGTGGGTTGTTGGGGACTATCACCGGG



CCCCCTCAGTGCGACCAGTTCCTCGAATTCAGCGCCGATCTGATCATAGAGCGACGGGAG



GGGAGTGACGTTTGCTACCCCGGTAAATTCGTGAAGGAAGAAGCCCTGAGACAGATTCTA



CGGGAGTCTGGCGGCATAGATAAAGAGGCTATGGGTTTCACATATAGCGGCATCCGCACA



AACGGAGCCACTTCTGCCTGCAGGAGATCTGGCTCCTCTTTTTACGCTGAAATGAAATGG



TTACTGTCCAACACCGACAATGCCGCCTTTCCCCAAATGACCAAGTCATACAAGAATACC



CGGAAATCCCCAGCTTTGATCGTTTGGGGTATCCATCACTCAGTTTCTACCGCGGAGCAG



ACTAAACTCTATGGCTCTGGAAATAAGCTGGTGACAGTGGGCTCTTCCAATTATCAGCAG



TCGTTTGTTCCGTCCCCTGGCGCTAGACCACAGGTGAACGGCCTGTCCGGGCGAATCGAT



TTCCACTGGCTGATGCTGAACCCGAACGACACCGTCACATTTAGCTTCAATGGAGCCTTC



ATTGCTCCCGATCGAGCTTCTTTCCTGCGGGGCAAATCAATGGGCATACAATCGGGTGTG



CAGGTGGACGCCAATTGTGAGGGAGACTGTTACCATTCAGGCGGCACCATTATTAGCAAT



CTACCATTCCAGAATATAGACTCCCGGGCTGTTGGCAAGTGCCCCCGGTATGTTAAACAG



CGGTCCCTGCTCCTGGCTACCGGTATGAAGAATGTTCCGGAAATCCCGAAGGGGCGCGGA



CTCTTCGGCGCTATCGCGGGTTTTATCGAGAACGGGTGGGAGGGCCTTATCGATGGGTGG



TACGGCTTCCGGCACCAGAATGCCCAGGGAGAAGGCACCGCCGCCGACTATAAGTCAACA



CAGTCCGCAATTGACCAAATCACCGGTAAGCTGAATCGCTTAATTGAGAAAACCAACCAA



CAATTCGAACTGATTGATAACGAATTCAACGAGGTCGAAAAGCAGATCGGGAATGTGATC



AACTGGACCCGCGATAGCATTACCGAGGTCTGGTCTTACAACGCAGAACTTCTCGTTGCG



ATGGAGAATCAACACACTATTGATCTGGCTGACTCCGAGATGGACAAGCTGTACGAGCGC



GTGAAGCGCCAGCTGCGGGAAAATGCAGAAGAGGATGGCACTGGCTGCTTCGAGATCTTC



CACAAGTGCGATGATGATTGCATGGCATCGATCAGGAACAATACATACGACCACTCGAAG



TACAGAGAGGAGGCTATGCAGAACCGAATACAGATAGATCCAGTTAAACTATCATCCGGG



TACAAGGACGTTATCCTGTGGTTCTCATTTGGAGCATCCTGCTTCATTCTTCTCGCAATC



GTCATGGGACTGGTTTTCATCTGTGTGAAGAACGGCAACATGCGGTGCACCATCTGCATC





575
ATGAATACCCAGATATTAGTATTTGCCCTTATAGCCATCATCCCTACTAACGCGGACAAA



ATCTGCCTGGGACACCATGCCGTTTCTAACGGTACAAAAGTCAACACCTTAACGGAACGG



GGGGTGGAAGTGGTTAATGCTACAGAGACCGTTGAACGCACCAACATCCCCCGCATTTGC



TCCAAAGGGAAGAAAACTGTGGACCTAGGTCAGTGTGGCCTGTTGGGTACTATCACCGGC



CCACCTCAATGCGACCAGTTTCTGGAGTTCAGCGCCGATCTGATCATCGAAAGAAGAGAG



GGTAGCGACGTTTGTTATCCTGGAAAGTTTGTTAATGAAGAGGCTCTGAGACAGATTTTG



CGAGAATCCGGGGGAATCGACAAGGAAGCCATGGGCTTTACATACTCTGGTATTAGGACC



AACGGTGCCACTTCTGCCTGCAGACGGAGCGGTAGTTCTTTTTACGCCGAAATGAAATGG



CTATTGTCTAATACGGATAACGCTGCATTTCCTCAGATGACGAAATCATACAAAAATACA



AGGAAAAGCCCCGCTCTGATTGTGTGGGGTATCCACCACTCCGTATCCACAGCAGAACAA



ACAAAGCTGTATGGATCTGGTAACAAGCTCGTGACGGTGGGCTCTAGCAACTATCAGCAG



AGTTTTGTGCCATCACCTGGCGCAAGACCCCAGGTCAACGGCCAGTCCGGCCGAATCGAC



TTCCACTGGCTTATGCTAAACCCCAACGACACGGTGACTTTCAGTTTTAACGGCGCCTTT



ATCGCTCCTGATCGCGCTTCTTTCCTTAGGGGTAAATCTATGGGGATACAATCAGGAGTG



CAGGTAGACGCTAACTGCGAAGGAGACTGCTATCACTCTGGAGGAACGATAATCTCCAAT



TTACCCTTCCAGAACATAGACAGTCGGGCCGTCGGGAAATGCCCCAGGTACGTGAAGCAG



CGGTCTCTTCTGCTCGCGACTGGCATGAAAAACGTTCCCGAGATACCCAAGGGAAGGGGC



CTGTTCGGCGCAATTGCTGGGTTCATTGAAAACGGCTGGGAGGGCCTTATTGATGGTTGG



TACGGATTCAGACACCAGAATGCACAGGGCGAGGGCACAGCCGCCGATTATAAGTCAACG



CAGTCAGCGATAGACCAGATAACCGGGAAATTGAACCGTCTGATTGAGAAAACAAACCAG



CAATTCGAATTGATTGATAACGAGTTTAATGAGGTGGAAAAGCAGATTGGAAACGTCATT



AACTGGACACGAGATTCAATTACAGAGGTGTGGAGCTATAACGCGGAGTTGCTGGTCGCT



ATGGAAAACCAACATACTATAGATCTTGCCGATTCCGAGATGGACAAACTCTATGAGAGA



GTCAAACGACAATTAAGGGAAAACGCCGAGGAAGATGGCACCGGATGCTTCGAAATCTTC



CATAAGTGCGATGACGACTGTATGGCATCTATTCGCAACAACACGTACGATCACTCGAAA



TATCGGGAAGAGGCCATGCAGAATAGGATCCAGATTGACCCTGTCAAATTGAGCAGCGGC



TACAAGGATGTTATTCTGTGGTTCAGTTTCGGCGCCTCCTGTTTCATCTTACTCGCTATT



GTCATGGGCTTAGTGTTCATCTGTGTCAAGAATGGCAATATGCGGTGCACTATATGCATT





576
ATGAACACTCAGATTCTGGTGTTCGCCCTAATTGCCATTATTCCCACCAATGCCGACAAA



ATTTGCCTGGGCCATCATGCCGTCTCGAACGGTACCAAAGTCAATACCCTGACAGAGCGC



GGCGTGGAGGTGGTGAATGCAACTGAGACCGTCGAGAGGACTAATATCCCCAGAATTTGC



TCAAAGGGAAAGAAAACAGTGGATCTGGGTCAGTGCGGTCTCTTAGGGACTATCACTGGT



CCTCCTCAGTGCGACCAGTTTCTGGAATTTAGTGCTGATCTGATTATCGAGCGGCGCGAA



GGGTCCGACGTTTGCTACCCCGGAAAGTTTGTTAACGAGGAAGCCTTGCGGCAAATCCTG



CGGAAGTCCGGCGGCATCGACAAGGAGGCCATGGGCTTTACATACTCTGGCATCCGCACC



AACGGAGCTACCAGCACCTGTAGGAGGTCTGGTAGTTCATTCTATGCTGAGATGAAGTGG



CTGCTCAGTAATACCGACAATGCTGCTTTTCCTCAGATGACAAAATCATACAAGAACACG



AGAAAAAGCCCAGCTATTATTGTATGGGGGATTCATCATTCTGTCAGTACCGCTGAGCAG



ACTAAGCTTTACGGTAGCGGAAATAAGCTTGTCACAGTGGGGTCCAGCAATTACCAGCAG



TCGTTTGTTCCCTCCCCAGGAGCACGCCCCCAAGTCAACGGTCTATCGGGGAGGATCGAC



TTCCATTGGCTGATGCTCAATCCTAACGACACCGTGACATTCTCTTTCAATGGCGCCTTT



ATCGCACCGGACCGTGCCTGTTTTTTACGCGGTAAGTCAATGGGGATACAATCTGGAGTC



CAGGTGGACGCCGACTGTGAAGGGGACTGCTATCATTCGGGTGGTACTATTATCAGCAAT



CTGCCCTTCCAAAACATAGACTCAAGAGCTGTTGGAAAGTGCCCGAGATACGTGAAGCAA



AGGTCACTCTTGCTTGCAACCGGGATGAAGAACGTGCCTGAGATCCCGAAGGGCCGAGGG



CTGTTTGGTGCTATAGCTGGCTTCATCGAGAATGGATGGGAGGGTTTAATTGACGGCTGG



TATGGATTTCGGCACCAGAATGCACAGGGAGAAGGGACCGCCGCCGATTACAAAAGTACG



CAGAGTGCTATCGATCAGATTACCGGTAAATTGAATAGGCTGATTGAAAAAACTAACCAG



CAGTTCGAGCTGATTGATAACGAGTTCAACGAGGTCGAGAGACAGATTGGGAACGTCATT



AATTGGACGAGAGACTCAATCACGGAGGTCTGGAGCTACAATGCTGAGCTGTTAGTAGCA



ATGGAAAATCAGCACACTATTGACCTCGCCGACTCCGAGATGGACAAACTGTACGAACGG



GTGAAGCGGCAACTTCGCGAAAACGCTGAGGAAGACGGCACGGGATGTTTCGAAATCTTC



CATAAATGCGACGATGACTGCATGGCCTCTATCCGTAATAACACATATGACCATAGTAAG



TATAGGGAGGAAGCCATGCAGAATCGAATCCAGATCGACCCCGTGAAGCTGAGCTCCGGC



TACAAAGACGTCATCCTCTGGTTTAGCTTTGGGGCGTCTTGTTTCATTCTCCTCGCGATC



GTGATGGGTCTTGTCTTCATTTGCGTGAAAAACGGGAATATGAGGTGTACCATTTGTATC





577
ATGAATACCCAAATACTTGTGTTTGCCTTGATTGCCATAATTCCTACCAATGCCGACAAA



ATCTGCCTGGGCCATCATGCCGTTAGTAATGGGACTAAGGTGAACACCCTGACAGAACGT



GGCGTGGAGGTGGTCAACGCAACAGAAACCGTCGAGAGGACCAACATTCCTCGGATATGT



TCGAAGGGAAAGAAGACGGTGGACCTGGGGCAATGCGGGCTGCTCGGCACCATTACGGGT



CCACCTCAGTGTGATCAGTTTCTCGAGTTTTCTGCAGACCTCATCATTGAACGTAGAGAG



GGCTCAGACGTGTGTTACCCAGGCAAATTTGTTAACGAGGAAGCCCTGCGCCAGATCCTG



CGAGAATCTGGCGGCATTGACAAAGAGGCTATGGGATTCACGTACTCTGGTATCCGTACC



AACGGCGCCACGTCCGCCTGTAGAAGGTCAGGCTCATCTTTTTACGCCGAGATGAAATGG



CTCCTGTCTAATACGGACAATGCCGCATTTCCTCAGATGACCAAAAGTTACAAAAACACC



CGGAAGAGTCCAGCTCTGATTGTGTGGGGCATCCATCACAGCGTGTCAACTGCGGAACAG



ACCAAGCTGTATGGGTCCGGCAATAAACTGGTGACTGTGGGTTCCAGCAATTACCAGCAA



TCCTTTGTGCCCAGCCCTGGCGCTAGACCGCAAGTGAACGGGCAGAGCGGGAGGATTGAC



TTCCACTGGCTGATGCTCAATCCCAACGATACCGTAACCTTTTCATTTAACGGCGCTTTC



ATCGCCCCCGATAGAGCTAGTTTCCTACGGGGAAAAAGCATGGGTATTCAAAGTGGTGTG



CAGGTAGACGCAAATTGTGAAGGCGACTGTTACCATTCGGGTGGGACCATTATCTCCAAC



CTGCCCTTCCAGAACATTGATTCACGCGCCGTGGGAAAGTGCCCTAGGTATGTTAAACAG



AGAAGCCTGCTGTTGGCCACAGGGATGAAGAATGTGCCAGAGATTCCAAAGGGACGGGGA



CTCTTTGGTGCGATCGCAGGCTTCATCGAGAACGGTTGGGAAGGGCTGATAGATGGATGG



TACGGTTTCCGTCACCAGAACGCCCAAGGAGAGGGGACAGCCGCGGACTACAAATCAACG



CAGTCTGCCATTGACCAAATCACTGGCAAACTGAACCGGCTTATCGAGAAAACCAACCAG



CAGTTTGAACTGATAGATAATGAATTCAACGAGGTTGAGAAGCAAATTGGGAACGTCATA



AATTGGACTAGAGACTCTATCACAGAGGTGTGGTCATATAATGCAGAGCTGTTGGTGGCA



ATGGAAAACCAGCACACTATCGACCTAGCAGATTCTGAGATGGACAAGCTATATGAACGC



GTTAAGCGGCAGCTGCGGGAAAACGCAGAAGAAGACGGTACAGGTTGTTTCGAGATATTT



CACAAATGCGACGATGATTGTATGGCATCGATCAGAAATAATACGTATGACCACTCCAAA



TACCGAGAAGAGGCTATGCAGAACCGAATCCAGATTGATCCTGTAAAGCTCAGTTCTGGC



TACAAGGACGTCATTCTCTGGTTTAGCTTTGGAGCCTCCTGTTTCATTCTTTTGGCCATC



GTTATGGGCCTCGTGTTTATTTGCGTGAAAAATGGTAATATGCGGTGTACCATATGTATC





578
ATGAATACCCAAATTCTGGTTTTTGCGCTGATCGCGATCATACCGACCAACGCGGATAAA



ATTTGTCTCGGGCATCACGCCGTGAGCAATGGGACCAAGGTAAACACACTGACGGAGCGG



GGGGTGGAGGTGGTGAACGCCACAGAGACGGTCGAGCGGACAAATATTCCTCGGATATGC



TCCAAGGGCAAGAAGACTGTTGATTTAGGCCAGTGCGGCCTCCTCGGCACCATCACCGGA



CCGCCCCAGTGCGACCAGTTCCTGGAGTTTTCCGCTGACCTGATCATCGAAAGGAGAGAG



GGAAGCGATGTGTGTTACCCTGGAAAGTTTGTTAATGAGGAGGCCCTAAGACAGATTCTG



CGGGAATCCGGCGGCATCGAGAAGGAGGCCATGGGATTTACTTACAGCGGGATTAGAGCG



AACGGAGCTACATCTGCCTGTCGCAGGAGTGGATCTTCCTTCTACGCTGAGATGAAATGG



CTGCTCTCGAATACGGACAACGCCGCGTTTCCTCAAATGACTAAATCTTACAAAAACACT



CGGAAGTCCCCCGCGCTCATTGTGTGGGGAATCCACCACAGTGTGAGTACAGCCGAGCAG



ACTAAACTGTATGGCAGTGGGAATAAGCTGGTCACAGTTGGGTCCTCCAACTACCAGCAG



AGCTTCGTTCCCAGTCCGGGCGCACGCCCGCAGGTTAATGGCCTTAGCGGTAGAATCGAT



TTCCACTGGCTGATGCTGAATCCTAACGATACTGTGACTTTCAGCTTCAATGGCGCTTTT



ATTGCACCCGACAGAGCTTCTTTTCTGCGTGGCAAATCCATGGGCATTCAGTCCGGCGTG



CAGGTGGACGCCAACTGCGAAGGCGATTGTTACCACTCTGGGGGCACCATCATCTCCAAC



CTCCCTTTTCAAAACATAGACAGTCGCGCTGTGGGAAAATGTCCAAGGTACGTTAAACAA



CGGTCTCTGCTACTGGCTACCGGCATGAAGAATGTGCCCGAAATCCCCAAGGGACGGGGC



TTATTTGGCGCGATTGCCGGATTTATTGAAAATGGCTGGGAGGGCCTCATTGACGGATGG



TACGGTTTTCGACACCAGAACGCTCAGGGTGAAGGGACCGCTGCAGACTACAAATCCACG



CAGTCCGCTATCGATCAGATTACAGGAAAGCTGAACAGACTAATCGAGAAGACTAATCAG



CAGTTCGAGCTAATCGATAATGAGTTCAACGAGGTCGAAAAGCAGATTGGGAACGTCATC



AACTGGACTCGCGATAGCATCACGGAGGTATGGTCTTATAATGCAGAGTTGCTGGTGGCC



ATGGAAAATCAGCATACAATCGACTTGGCTGACTCTGAGATGGATAAATTGTATGAGAGG



GTAAAAAGGCAGTTGAGAGAGAACGCGGAGGAAGATGGCACTGGTTGCTTCGAGATCTTT



CACAAGTGTGACGACGATTGCATGGCCAGTATTAGAAATAATACATATGACCACAGCAAG



TACAGGGAGGAGGCCATGCAGAATCGTATCCAAATCGATCCCGTGAAATTGTCAAGCGGA



TATAAAGACGTTATACTATGGTTCTCCTTTGGGGCTAGTTGTTTCATTCTCCTGGCGATC



GTCATGGGCCTGGTTTTCATCTGCGTTAAGAATGGGAATATGAGATGTACTATCTGCATC





579
ATGAATACCCAGATTCTGGTGTTCGCTCTCATTGCAATAATCCCGACTAACGCTGATAAA



ATCTGTCTTGGCCACCACGCTGTGAGTAATGGAACGAAAGTCAATACGCTCACTGAGCGG



GGAGTCGAAGTTGTTAACGCTACCGAGACCGTGGAGCGGACAAACATACCGCGGATTTGC



TCAAAGGGCAAAAAGACAGTGGATCTGGGTCAGTGCGGCCTTCTCGGCACAATCACCGGG



CCCCCACAGTGTGACCAATTTCTCGAGTTTTCAGCTGATTTGATAATTGAGCGCCGGGAG



GGCAGTGATGTATGCTATCCAGGGAAGTTCGTGAATGAAGAGGCCCTCCGCCAAATTCTC



CGGGAATCTGGCGGGATTGACAAGGAAGCCATGGGGTTCACTTACTCTGGAATTCGGACT



AATGGTGCTACCAGTGCTTGCCGTAGAAGTGGTAGCAGTTTCTATGCCGAAATGAAATGG



TTGTTAAGCAATACCGATAACGCAGCATTTCCCCAGATGACAAAGTCGTACAAAAACACC



AGGAAAAGTCCTGCTCTGATCGTGTGGGGTATCCATCACTCTGTGAGTACAGCAGAACAG



ACTAAACTGTATGGATCAGGCAATAAGTTGGTGACAGTAGGCTCTTCGAATTACCAACAG



TCATTTGTCCCCAGCCCGGGAGCCCGGCCACAGGTCAACGGCCAAAGCGGACGCATCGAT



TTCCACTGGCTTATGCTGAATCCTAATGACACCGTCACATTTTCCTTCAATGGGGCCTTT



ATTGCCCCAGATCGTGCATCCTTTCTGAGAGGGAAATCCATGGGTATACAGAGCGGGGTG



CAGGTGGACGCAAACTGTGAGGGAGATTGTTACCATTCTGGCGGTACGATCATCAGCAAC



TTGCCATTCCAGAATATAGACTCCCGGGCAGTCGGTAAGTGTCCCCGGTACGTCAAACAA



AGAAGCTTGCTGCTGGCCACCGGGATGAAAAATGTTCCCGAGATCCCCAAGGGGCGTGGC



CTCTTTGGCGCAATCGCAGGGTTTATCGAGAATGGGTGGGAAGGGCTGATCGACGGCTGG



TATGGATTCAGGCACCAAAACGCACAGGGAGAAGGGACAGCCGCCGACTACAAAAGCACA



CAGAGTGCGATCGATCAAATCACAGGTAAATTGAACCGACTGATTGAGAAGACAAACCAA



CAGTTTGAGCTCATAGATAATGAGTTCAACGAGGTGGAGAAGCAGATAGGAAATGTGATC



AACTGGACAAGGGATTCCATCACTGAAGTCTGGTCCTATAATGCCGAGCTGTTGGTTGCC



ATGGAAAACCAGCATACCATTGACCTCGCCGATTCCGAAATGGATAAGCTGTACGAAAGG



GTGAAGCGGCAGTTGCGGGAGAACGCAGAAGAAGATGGAACAGGATGCTTTGAGATATTT



CACAAATGCGATGATGATTGCATGGCCTCGATACGCAACAATACCTATGACCATAGCAAG



TACCGAGAGGAGGCGATGCAAAACAGGATCCAGATTGACCCAGTGAAGCTCAGCAGTGGG



TACAAGGATGTCATTTTGTGGTTTAGCTTTGGAGCCTCATGCTTCATACTCCTCGCCATC



GTCATGGGGTTGGTATTTATCTGCGTCAAGAACGGCAATATGAGGTGTACTATCTGCATC





580
ATGAATACTCAGATTCTGGTGTTTGCGCTTATCGCTATTATACCCACTAATGCCGACAAA



ATCTGTCTGGGCCATCACGCCGTTAGCAACGGCACCAAAGTGAACACACTCACAGAACGT



GGTGTGGAAGTCGTCAATGCCACCGAGACAGTTGAGCGCACCAATATTCCTAGAATCTGT



TCCAAAGGCAAAAAAACTGTCGATCTAGGCCAATGCGGACTGCTCGGAACTATTACTGGA



CCACCGCAGTGCGATCAGTTCCTCGAGTTCAGCGCAGACCTGATCATAGAGAGGAGAGAA



GGTAGCGACGTTTGTTACCCTGGAAAATTTGTCAACGAGGAGGCGCTTCGACAGATTCTC



AGAGAGAGTGGAGGTATAGATAAGGAGGCCATGGGTTTCACGTATTCAGGTATCAGAACG



AATGGGGCAACCAGTGCCTGTCGCCGGTCAGGCAGCAGCTTCTATGCAGAGATGAAGTGG



CTCCTGTCAAACACAGACAATGCTGCATTCCCACAGATGACCAAGAGCTACAAGAACACG



CGAAAGTCACCTGCATTAATAGTCTGGGGTATCCACCACTCTGTCTCCACTGCCGAACAG



ACCAAACTTTACGGATCTGGAAATAAGCTGGTCACTGTGGGGTCTTCTAATTATCAGCAG



AGTTTTGTACCCTCGCCCGGGGCCCGGCCCCAGGTAAACGGACAGTCCGGACGGATTGAC



TTTCACTGGCTCATGCTTAACCCAAACGACACAGTGACCTTCAGTTTTAACGGCGCTTTC



ATCGCTCCCGACAGGGCCTCATTCCTGAGGGGAAAGTCGATGGGAATCCAGAGCGGGGTT



CAGGTTGATGCAAATTGCGAAGGGGATTGTTACCATTCCGGCGGAACCATTATCTCCAAC



CTGCCATTTCAGAATATAGATAGCCGCGCCGTGGGAAAGTGCCCTAGGTACGTCAAACAG



CGGTCTCTGCTCCTGGCTACAGGCATGAAAAATGTTCCGGAAATCCCAAAGGGGGGGGGA



CTCTTCGGAGCCATCGCAGGCTTCATCGAAAACGGCTGGGAGGGGTTAATCGATGGATGG



TATGGCTTCCGCCATCAGAACGCACAGGGGGAGGGCACCGCGGCCGATTATAAGAGTACC



CAGAGCGCAATAGATCAGATAACTGGTAAGTTGAATCGGTTAATTGAAAAAACTAACCAG



CAGTTCGAACTAATCGATAATGAGTTCAATGAAGTCGAGAAACAGATAGGCAACGTTATC



AATTGGACCAGGGACAGCATAACAGAAGTGTGGTCCTATAACGCCGAACTCCTCGTTGCC



ATGGAGAACCAGCATACCATTGACCTGGCTGATTCAGAGATGGATAAACTATACGAACGG



GTCAAGCGTCAATTGAGAGAGAATGCGGAAGAGGACGGGACTGGGTGCTTCGAAATCTTC



CATAAGTGTGATGACGATTGTATGGCGTCCATTCGCAATAACACCTACGATCATTCAAAA



TACCGTGAAGAGGCGATGCAGAATAGGATTCAGATCGACCCAGTGAAGCTCAGTAGTGGA



TATAAAGACGTAATTCTCTGGTTCTCTTTCGGAGCTAGCTGCTTCATTCTTCTGGCCATC



GTGATGGGACTCGTTTTCATATGTGTTAAAAATGGCAACATGCGTTGCACAATCTGTATC





581
ATGAACACTCAGATTTTAGTTTTCGCTCTAATTGCCATTATTCCTACAAATGCTGATAAA



ATATGCCTGGGACACCATGCTGTCTCCAACGGTACCAAAGTCAATACTCTTACGGAGAGG



GGGGTGGAGGTAGTGAACGCCACCGAGACAGTCGAACGTACAAATATACCTCGGATTTGC



TCCAAGGGAAAGAAGACAGTGGATCTGGGGCAATGTGGTCTGCTGGGAACTATCACAGGC



CCACCGCAGTGCGACCAGTTTCTTGAGTTTTCAGCCGACCTGATCATCGAGCGACGCGAG



GGCAGCGACGTGTGTTACCCCGGGAAGTTCGTAAACGAGGAAGCTCTCCGCCAGATCCTG



CGCGAGAGTGGAGGTATTGATAAGGAGGCCATGGGCTTTACATATTCTGGCATCCGGACC



AATGGGGCCACAAGCGCCTGTAGGAGATCTGGATCCAGTTTTTACGCCGAAATGAAATGG



CTGCTGAGCAACACAGACAATGCCGCCTTTCCTCAGATGACAAAGAGCTACAAAAACACA



AGGAAGTCACCCGCCCTTATTGTCTGGGGTATCCATCACTCTGTCAGTACAGCTGAGCAG



ACCAAGCTGTATGGTTCTGGCAATAAATTGGTTACCGTCGGGAGCAGTAACTATCAACAA



TCATTTGTTCCAAGTCCAGGAGCCCGGCCCCAGGTCAATGGTCAAAGTGGAAGGATTGAC



TTTCACTGGTTAATGCTTAATCCCAACGATACCGTGACCTTCTCATTTAATGGGGCCTTT



ATTGCTCCGGACCGTGCCAGCTTTCTCCGCGGTAAGTCCATGGGCATCCAGTCCGGCGTA



CAAGTGGATGCCAATTGCGAAGGCGACTGTTACCACTCTGGCGGCACCATCATCTCAAAC



CTTCCGTTCCAGAACATAGATAGTCGGGCCGTGGGCAAGTGCCCTAGGTATGTGAAGCAG



CGCTCATTACTGTTGGCTACTGGCATGAAAAATGTGCCAGAGATCCCTAAAGGTCGTGGT



CTTTTTGGAGCTATCGCTGGGTTCATTGAAAATGGATGGGAGGGGCTGATCGACGGTTGG



TACGGATTCCGGCATCAGAATGCACAGGGCGAAGGCACAGCCGCTGATTACAAGAGCACC



CAGTCAGCTATTGACCAGATCACAGGGAAGCTGAACCGGCTAATCGAGAAAACAAACCAA



CAATTTGAACTTATCGATAACGAATTTAATGAGGTGGAGAAACAGATAGGCAACGTGATC



AACTGGACACGGGATAGTATCACTGAGGTGTGGAGTTACAATGCCGAACTCTTGGTGGCT



ATGGAGAATCAGCATACTATCGATCTAGCGGACTCTGAGATGGACAAACTCTATGAACGA



GTGAAGAGGCAGCTTCGCGAGAACGCTGAGGAAGATGGGACAGGGTGTTTTGAAATTTTT



CATAAGTGTGATGATGATTGCATGGCATCTATCCGGAATAACACATACGACCATTCCAAG



TACCGTGAAGAGGCTATGCAAAACCGAATTCAGATAGACCCAGTGAAGCTCTCTTCCGGA



TACAAGGATGTAATTCTGTGGTTTTCATTCGGTGCATCCTGCTTCATCCTGCTTGCAATC



GTGATGGGTTTAGTGTTCATCTGTGTGAAGAATGGGAATATGAGGTGTACAATTTGCATC





582
ATGAACACGCAGATCCTGGTGTTCGCACTGATTGCAATTATTCCCACCAATGCCGATAAG



ATCTGTTTAGGACATCACGCCGTGTCCAACGGTACGAAGGTGAACACATTGACCGAGCGG



GGAGTCGAAGTGGTAAATGCAACCGAGACTGTTGAACGCACAAATATCCCAAGAATTTGT



TCAAAGGGTAAAAAAACCGTGGACCTCGGACAGTGCGGGCTGCTTGGAACGATTACAGGA



CCTCCACAATGCGACCAGTTCCTGGAATTTTCCGCTGACCTCATCATAGAACGACGGGAA



GGGTCCGACGTGTGTTATCCGGGAAAGTTCGTTAACGAGGAGGCTCTGAGGCAGATCTTG



AGGGAGAGTGGTGGCATCGACAAGGAGGCGATGGGCTTCACATACAGTGGCATCAGAACT



AACGGAGCCACCAGCGCATGTCGACGGTCTGGTAGCAGTTTTTATGCAGAGATGAAGTGG



TTGCTGAGCAATACAGATAATGCCGCATTCCCCCAAATGACAAAGTCCTATAAGAACACG



CGGAAAAGTCCTGCCCTAATTGTGTGGGGAATCCACCACTCTGTTAGTACCGCTGAGCAG



ACCAAGTTATACGGCAGCGGGAACAAGTTGGTGACAGTTGGATCTAGTAACTACCAGCAA



AGCTTCGTTCCTAGCCCGGGGGCACGTCCCCAGGTGAACGGGCAGAGTGGCCGGATCGAT



TTTCATTGGCTGATGCTCAATCCAAACGACACTGTCACATTCAGTTTTAACGGAGCCTTT



ATCGCCCCTGATAGAGCCTCATTCCTTAGGGGAAAAAGTATGGGAATCCAGTCTGGTGTA



CAGGTGGATGCCAACTGTGAAGGTGACTGTTATCATTCAGGTGGAACCATCATATCAAAC



CTGCCCTTCCAAAATATTGACTCAAGAGCAGTGGGCAAGTGCCCCCGATATGTGAAGCAG



CGATCCCTGCTGCTCGCAACTGGCATGAAGAATGTCCCGGAAATCCCTAAGGGGCGGGGC



CTTTTCGGGGCAATCGCAGGCTTCATCGAAAATGGATGGGAGGGCCTGATCGACGGATGG



TACGGTTTCCGGCATCAGAATGCTCAGGGGGAGGGGACCGCGGCTGACTATAAGTCGACA



CAATCTGCCATAGATCAGATCACGGGAAAACTGAACAGACTGATAGAGAAGACTAATCAG



CAGTTCGAACTGATCGATAACGAGTTCAATGAGGTTGAAAAGCAAATCGGGAACGTAATC



AACTGGACACGAGACAGCATTACTGAGGTGTGGTCCTACAATGCGGAATTGCTGGTGGCT



ATGGAAAATCAACACACAATCGATCTTGCCGATTCAGAGATGGACAAGCTTTACGAGAGA



GTAAAGCGACAACTGCGCGAGAATGCTGAGGAGGACGGGACTGGGTGCTTCGAGATCTTT



CACAAGTGTGACGACGACTGCATGGCCTCTATCCGGAATAATACTTATGACCATAGCAAA



TATAGAGAGGAGGCCATGCAAAACCGGATCCAGATTGATCCAGTCAAGCTCTCCAGCGGT



TATAAGGATGTGATTTTGTGGTTCAGTTTTGGCGCTTCATGCTTCATACTCTTGGCCATC



GTGATGGGCCTGGTGTTTATTTGTGTGAAGAACGGAAACATGCGGTGTACAATTTGCATC





583
ATGAATACCCAGATCCTCGTTTTCGCTCTGATCGCAATCATTCCCACAAACGCAGATAAA



ATCTGTCTGGGGCATCACGCTGTGAGCAACGGCACAAAAGTTAACACCTTAACCGAGCGC



GGCGTGGAGGTGGTTAATGCTACCGAGACCGTCGAACGGACCAATATCCCCAGGATCTGT



AGTAAAGGCAAGAAGACAGTCGACCTGGGGCAGTGTGGGCTCCTCGGGACTATCACAGGA



CCCCCTCAGTGTGATCAGTTCCTCGAGTTCTCAGCGGACCTTATTATAGAACGCCGAGAG



GGTTCTGATGTGTGTTACCCCGGCAAATTTGTGAACGAGGAGGCTCTGAGGCAAATTCTG



CGCGAAAGCGGCGGCATTGAAAAGGAAGCTATGGGGTTTACATACTCCGGAATAAGAGCC



AATGGCGCGACTTCTGCTTGTCGAAGGTCCGGAAGCTCCTTTTATGCGGAAATGAAATGG



CTATTGAGCAATACCGACAATGCTGCCTTCCCCCAGATGACCAAGAGTTATAAAAATACC



CGAAAAAGCCCCGCGCTTATCGTTTGGGGCATCCATCATTCTGTTTCTACAGCCGAACAG



ACTAAGCTTTATGGCAGCGGGAATAAGCTCGTGACCGTCGGCTCAAGTAACTATCAGCAG



TCATTCGTGCCTTCCCCGGGGGCTAGACCTCAAGTGAATGGATTATCCGGACGAATCGAC



TTCCATTGGTTGATGTTAAACCCTAATGATACTGTGACCTTCTCCTTCAACGGGGCCTTC



ATTGCTCCAGATCGTGCTAGTTTCCTGCGGGGCAAGTCCATGGGTATTCAATCCGGAGTC



CAGGTCGACGCAAACTGTGAGGGGGATTGCTACCACTCCGGAGGCACAATTATTTCTAAT



CTGCCATTTCAGAACATTGACTCCCGCGCCGTGGGGAAATGTCCAAGGTATGTGAAACAA



CGGAGCCTACTGCTCGCCACCGGAATGAAGAACGTTCCTGAAATACCTAAAGGTCGGGGT



TTGTTTGGGGCTATAGCCGGCTTCATAGAAAACGGATGGGAAGGCCTGATCGATGGCTGG



TATGGCTTTAGGCATCAAAATGCACAGGGGGAGGGCACTGCGGCTGACTATAAGAGCACC



CAGTCAGCGATTGACCAGATTACTGGCAAGCTGAATAGACTTATAGAAAAGACAAATCAG



CAATTCGAGCTGATAGACAACGAATTCAATGAGGTGGAGAAACAAATTGGTAACGTCATT



AACTGGACTCGTGACTCTATTACGGAAGTGTGGAGTTACAATGCTGAGCTCCTCGTCGCC



ATGGAAAACCAACACACTATAGATTTGGCCGATAGCGAGATGGACAAGCTGTACGAGAGG



GTAAAACGCCAGTTGAGAGAAAACGCCGAGGAAGATGGCACCGGTTGCTTTGAGATTTTC



CACAAGTGCGATGATGACTGCATGGCAAGCATCAGAAATAACACATACGATCATAGTAAA



TACAGGGAGGAAGCCATGCAAAACCGCATTCAGATCGATCCCGTCAAGCTCTCTTCGGGG



TACAAAGATGTCATCCTTTGGTTCTCATTCGGCGCATCTTGCTTTATCCTGCTGGCTATA



GTGATGGGGCTCGTGTTTATTTGCGTCAAAAATGGAAACATGCGCTGTACCATCTGTATT





584
ATGAATACTCAGATCCTGGTGTTTGCGCTCATTGCGATCATCCCAACCAACGCCGACAAA



ATATGTCTGGGACATCACGCCGTTTCCAACGGGACGAAGGTGAACACGTTGACAGAGCGC



GGAGTGGAGGTCGTGAATGCTACTGAGACCGTGGAGAGGACTAATATCCCGAGGATCTGC



AGTAAGGGCAAGAAGACTGTCGACTTAGGACAGTGTGGCCTGTTAGGCACAATCACAGGC



CCCCCTCAATGTGACCAATTTCTGGAGTTTTCTGCCGACCTCATAATCGAGCGCAGGGAA



GGCTCCGACGTGTGCTATCCGGGAAAGTTCGTCAACGAGGAAGCCCTCAGACAGATCCTT



CGCGAATCCGGCGGCATAGATAAGGAAGCTATGGGTTTCACATATTCAGGAATCCGCACG



AATGGCGCAACTTCCGCTTGCCGGCGATCAGGATCCTCTTTCTACGCAGAGATGAAGTGG



CTGCTGAGCAATACCGACAATGCCGCCTTCCCCCAAATGACAAAGTCATACAAGAATACT



CGTAAATCACCTGCCCTGATTGTGTGGGGAATCCATCACTCAGTGTCCACAGCGGAGCAG



ACCAAGCTGTACGGAAGCGGTAACAAGCTTGTTACCGTTGGCTCTAGCAATTATCAGCAG



AGCTTTGTTCCTTCACCTGGAGCCAGACCTCAAGTAAATGGGCAAAGCGGTAGAATCGAC



TTTCACTGGCTGATGCTGAATCCCAATGACACAGTCACCTTTTCGTTTAACGGCGCGTTT



ATAGCACCCGATAGGGCCAGTTTTTTGAGAGGAAAGTCAATGGGAATCCAAAGCGGCGTG



CAAGTCGATGCCAATTGTGAGGGCGACTGTTACCATAGTGGGGGAACCATTATAAGTAAT



TTACCCTTTCAGAATATTGACTCAAGGGCTGTGGGAAAATGTCCCAGGTATGTCAAGCAG



AGAAGCCTGCTGCTGGCCACCGGTATGAAGAACGTACCCGAGATTCCAAAAGGCAGAGGA



CTGTTTGGAGCAATTGCTGGGTTCATCGAGAACGGGTGGGAGGGGCTTATTGATGGCTGG



TACGGATTTAGACATCAAAATGCACAGGGGGAAGGCACTGCCGCTGATTATAAAAGTACG



CAGTCCGCGATAGACCAGATTACCGGAAAGTTGAACCGGCTGATCGAGAAAACTAATCAG



CAGTTTGAGTTGATCGACAACGAATTTAACGAGGTGGAGAAACAAATCGGCAATGTGATT



AACTGGACTAGAGACTCCATTACCGAGGTGTGGTCATATAACGCCGAATTGCTCGTGGCC



ATGGAAAACCAGCACACCATCGATCTCGCTGATAGCGAGATGGACAAACTCTACGAAAGG



GTCAAGAGACAACTCCGAGAGAACGCCGAGGAAGACGGGACTGGGTGTTTTGAGATCTTT



CATAAATGTGATGACGACTGTATGGCTTCTATCCGGAATAACACATACGACCACTCCAAA



TATCGGGAGGAAGCTATGCAAAATCGTATTCAAATTGATCCCGTCAAGCTGAGCTCCGGG



TATAAGGACGTTATCCTCTGGTTCTCCTTTGGCGCTTCCTGTTTCATCCTTCTGGCTATT



GTCATGGGGCTCGTTTTCATATGCGTTAAGAACGGGAATATGCGGTGTACGATCTGTATA





585
ATGAACACACAGATATTGGTGTTTGCTTTGATTGCAATCATTCCTACAAACGCGGATAAA



ATCTGCCTGGGCCACCATGCTGTGAGTAACGGCACCAAAGTGAATACTTTAACTGAACGC



GGTGTCGAGGTTGTGAACGCGACTGAAACGGTGGAGCGCACGAATATTCCCCGGATCTGC



AGCAAAGGCAAAAAGACTGTCGACCTTGGTCAGTGCGGGCTACTTGGGACTATCACTGGA



CCCCCACAGTGTGATCAATTCCTGGAATTTTCAGCCGATTTGATTATTGAGCGGAGAGAG



GGATCCGACGTGTGCTATCCAGGCAAGTTTGTGAACGAGGAGGCATTGCGGCAGATTCTC



AGGGAATCTGGAGGCATTGATAAGGAAGCTATGGGTTTCACCTATAGCGGTATCCGGACC



AACGGAGCTACCAGCGCGTGCCGGAGGAGCGGTAGCTCCTTTTACGCGGAGATGAAGTGG



TTGCTCTCTAACACGGACAACGCCGCCTTCCCACAGATGACCAAGAGCTACAAGAACACC



CGCAAATCACCTGCCTTAATTGTGTGGGGCATTCATCATAGTGTCTCTACGGCCGAGCAG



ACAAAACTGTATGGATCTGGCAATAAGCTTGTCACCGTCGGCAGCTCCAATTACCAGCAG



TCTTTCGTACCCAGTCCCGGTGCAAGGCCACAGGTCAACGGACAGTCGGGGCGGATTGAC



TTCCACTGGCTGATGCTCAACCCTAATGATACTGTAACCTTCAGCTTCAATGGCGCATTC



ATAGCTCCCGATCGGGCATCATTCCTGCGAGGTAAATCTATGGGGATCCAGTCCGGCGTG



CAGGTGGATGCCAACTGCGAGGGCGATTGCTATCACAGTGGTGGGACAATCATCTCTAAT



TTACCCTTCCAGAATATTGATAGCCGAGCTGTGGGGAAATGCCCAAGGTACGTCAAGCAG



CGTTCGCTTCTGTTAGCCACTGGCATGAAAAATGTGCCAGAGATACCCAAAGGCAGGGGG



TTATTTGGAGCAATTGCCGGTTTTATTGAAAATGGCTGGGAGGGACTCATCGACGGCTGG



TATGGCTTCAGACACCAAAATGCCCAGGGTGAAGGTACCGCCGCCGACTACAAGTCCACT



CAAAGTGCAATTGACCAAATAACTGGAAAGCTGAACCGGCTGATCGAAAAGACAAATCAG



CAGTTTGAGTTAATCGATAACGAGTTCAACGAGGTCGAGAAGCAGATTGGAAATGTCATT



AACTGGACAAGGGATTCCATCACTGAGGTGTGGAGCTACAACGCCGAGCTGCTCGTCGCA



ATGGAGAACCAGCATACTATTGACCTGGCAGACTCTGAAATGGATAAATTATACGAACGC



GTGAAACGCCAGCTCAGAGAAAATGCTGAAGAGGACGGGACCGGTTGTTTTGAGATTTTT



CACAAGTGCGACGACGATTGCATGGCCTCCATTAGGAACAATACATACGACCATAGTAAG



TATCGAGAGGAAGCCATGCAGAACAGGATACAGATAGACCCTGTTAAACTGTCCTCCGGG



TACAAGGATGTGATCCTTTGGTTTTCTTTTGGGGCATCCTGCTTTATTCTGCTGGCAATC



GTCATGGGCCTTGTTTTTATCTGCGTAAAGAATGGAAATATGAGATGCACAATCTGTATC





586
ATGAACACCCAGATCCTTGTATTCGCATTAATAGCTATCATTCCAACAAACGCGGACAAA



ATTTGCCTGGGGCACCATGCAGTCTCCAACGGCACTAAGGTGAATACGCTCACCGAGCGG



GGCGTGGAGGTTGTTAATGCGACGGAGACGGTTGAGCGGACGAATATCCCCCGAATTTGT



TCGAAGGGAAAACGGACAGTGGACCTGGGTCAGTGTGGGTTGCTGGGTACCATTACAGGC



CCCCCCCAGTGTGATCAGTTTCTGGAATTTTCCGCCGACCTTATTATCGAGCGGAGGGAA



GGGTCCGATGTCTGTTACCCAGGGAAGTTCGTTAACGAGGAGGCTTTGCGCCAGATACTC



CGGGAGAGTGGTGGTATTGACAAGGAGGCCATGGGGTTCACCTACAGCGGCATCAGGACT



AATGGAGCCACCTCGGCCTGTAGAAGAAGTGGATCTTCTTTCTATGCCGAGATGAAATGG



TTGCTATCTAACACTGACAACGCCGCCTTTCCACAGATGACTAAAAGTTACAAAAATACA



CGGAAAAGCCCAGCCTTAATAGTCTGGGGCATCCATCATAGTGTGTCCACCGCCGAACAG



ACTAAACTATATGGGTCCGGAAGCAAGCTTGTGACGGTGGGCTCTTCCAACTACCAGCAG



AGTTTTGTGCCCTCCCCCGGAGCACGGCCTCAGGTCAACGGCTTGAGCGGACGGATCGAC



TTTCATTGGTTAATGCTGAATCCAAATGATACAGTAACATTTTCATTTAATGGCGCCTTC



ATTGCTCCAGACAGAGCTAGTTTCTTACGGGGCAAATCAATGGGCATCCAGAGCGGGGTT



CAGGTGGATGCCAACTGTGAAGGAGATTGTTATCACAGCGGGGGGACTATCATTTCTAAT



CTCCCATTTCAGAATATCGATTCACGGGCAGTTGGCAAGTGCCCGAGATACGTCAAGCAG



CGATCTCTCCTTCTCGCAACCGGAATGAAAAACGTCCCAGAGATTCCTAAAGGCAGGGGC



CTGTTCGGCGCCATCGCCGGATTTATTGAGAACGGGGGGAGCGGGCTGATAGATGGCTGG



TACGGCTTTCGGCATCAGAATGCACAGGGCGAGGGTACGGCTGCGGACTACAAAAGTACT



CAAAGCGCAATCGACCAGATTACAGGAAAGCTGAACCGGTTAATTGAAAAGACAAACCAG



CAATTCGAGCTCATCGACAATGAGTTTAATGAAGTGGAGAAGCAGATCGGCAATGTAATC



AACTGGACCAGAGATAGTATCACTGAAGTGTGGTCCTACAACGCCGAGCTTCTGGTGGCT



ATGGAGAACCAGCATACTATCGATCTTGCGGATAGCGAGATGGATAAGCTGTACGAGCGT



GTTAAGCGACAGCTAAGAGAGAACGCGGAGGAGGACGGTACTGGGTGTTTCGAAATTTTT



CACAAGTGCGATGACGATTGTATGGCGTCTATCCGCAATAATACTTATGATCATAGTAAG



TATCGGGAAGAAGCTATGCAGAACCGCATCCAAATCGACCCCGTGAAGCTTTCAAGCGGT



TACAAAGACGTTATCTTGTGGTTCAGCTTCGGGGCGTCTTGCTTTATCCTGCTGGCGATT



GTAATGGGCTTGGTCTTTATCTGTGTGAAGTCCAGAAATATGAGATGCACCATTTGTATC





587
ATGAATACCCAAATCCTCGTGTTCGCTTTAATCGCAATCATCCCGACCAATGCCGACAAG



ATCTGCCTGGGTCACCACGCTGTCTCCAACGGCACTAAGGTGAACACCTTAACAGAGAGA



GGCGTGGAAGTAGTTAATGCTACCGAAACCGTGGAAAGGACCAACATTCCGCGGATATGT



TCTAAGGGAAAACGCACCGTAGATCTCGGCCAGTGTGGACTGCTGGGCACAATCACCGGT



CCTCCACAATGTGATCAGTTTCTTGAGTTCTCGGCCGACCTCATCATCGAAAGGAGGGAA



GGATCTGATGTGTGTTATCCCGGGAAGTTCGTGAAAGAAGAGGCCCTGCGTCAGATATTG



CGAGAGAGTGGGGGGATAGATAAGGAAGCAATGGGCTTCACATACAGCGGCATCAGAACA



AATGGCGCGACATCCGCCTGTAGAAGGTCTGGGTCTAGCTTCTACGCAGAGATGAAATGG



CTGCTCAGTAACACGGACAATGCGGCCTTCCCCCAGATGACTAAAAGCTATAAAAATACA



AGGAAGAGCCCCGCCTTGATAGTGTGGGGAATCCATCATAGTGTGAGTACCGCTGAACAG



ACGAAGCTATACGGATCAGGCAACAAGCTGGTTACTGTCGGCAGTTCTAACTACCAGCAA



TCCTTTGTGCCTTCTCCCGGCGCCCGCCCACAAGTGAATGGACTATCTGGCAGAATTGAT



TTCCACTGGCTGATGCTGAACCCCAATGACACTGTGACTTTCAGCTTTAACGGAGCCTTT



ATCGCCCCCGATAGAGCCAGTTTCCTGAGGGGCAAATCCATGGGCATCCAGTCAGGCGTG



CAGGTCGATGCCAACTGCGAGGGAGATTGTTACCATTCGGGTGGCACCATAATTAGTAAC



TTACCATTCCAGAATATTGACAGCAGAGCCGTTGGGAAATGCCCCAGGTATGTCAAGCAG



AGGTCCCTACTACTGGCCACAGGCATGAAGAATGTTCCTGAAATTCCTAAAGGCCGTGGT



CTTTTCGGAGCAATCGCAGGATTCATCGAAAACGGCTGGGAAGGACTGATTGATGGGTGG



TATGGTTTTAGGCACCAAAATGCACAGGGCGAGGGCACAGCTGCAGATTACAAGAGCACT



CAGTCAGCTATTGATCAGATTACCGGAAAGCTTAACAGGCTCATCGAAAAGACTAATCAG



CAGTTTGAACTGATCGACAACGAATTCAACGAAGTAGAGAAACAGATTGGGAACGTGATT



AATTGGACCCGAGACTCTATCACAGAGGTGTGGAGTTACAACGCAGAGTTGCTGGTAGCA



ATGGAAAACCAGCACACAATCGATCTCGCAGACAGTGAGATGGATAAACTTTACGAAAGG



GTCAAACGTCAGTTAAGAGAGAACGCGGAAGAGGATGGCACCGGTTGCTTTGAAATTTTC



CACAAATGCGATGACGACTGCATGGCGTCTATCAGAAATAACACTTACGACCATAGTAAG



TATCGGGAGGAGGCTATGCAGAACCGAATTCAGATCGATCCAGTAAAGCTCAGCAGCGGC



TACAAGGACGTCATCCTTTGGTTCTCTTTCGGGGCCAGTTGCTTCATCCTTCTCGCTATA



GTCATGGGCCTCGTGTTTATCTGCGTAAAAAATGGGAACATGAGGTGCACCATTTGCATA





588
ATGAATACACAGATATTGGTCTTCGCTCTCATCGCTATCATTCCCACCAACGCTGACAAA



ATCTGTTTAGGCCACCATGCCGTATCCAATGGCACTAAGGTCAACACACTTACTGAGCGA



GGCGTAGAGGTCGTCAACGCTACAGAAACTGTTGAGCGAACCAACATCCCCAGGATTTGC



TCTAAGGGGAAAAAGACTGTAGACCTTGGGCAGTGTGGCCTGCTGGGGACTATCACCGGG



CCACCTCAATGTGACCAATTTCTGGAGTTCTCAGCTGATCTGATTATCGAGAGGCGCGAG



GGATCTGATGTCTGTTACCCAGGTAAGTTCGTCAATGAGGAGGCGCTCCGCCAGATCCTC



CGCGAGAGTGGCGGGATCGATAAAGAGGCCATGGGCTTCACTTACTCCGGCATCAGGACC



AATGGCGCTACATCCGCCTGTAGACGGAGCGGATCCAGCTTTTACGCCGAAATGAAGTGG



CTGCTGTCCAACACAGACAACGCTGCTTTTCCACAGATGACAAAGTCTTATAAAAATACC



CGCAAATCTCCTGCCCTGATTGTGTGGGGCATTCACCACTCAGTGTCCACTGCCGAGCAG



ACTAAGTTGTACGGAAGTGGCAACAAGCTGGTGACGGTCGGCTCTTCAAACTATCAACAG



AGCTTTGTACCTTCCCCAGGGGCCCGGCCACAGGTGAACGGGCAGTCAGGAAGGATTGAT



TTCCACTGGCTGATGCTGAATCCAAATGATACTGTCACCTTCAGCTTTAATGGAGCTTTT



ATTGCCCCGGATCGCGCATCCTTCCTGCGCGGGAAGAGTATGGGGATCCAGTCCGGGGTA



CAAGTCGACGCTAACTGCGAAGGCGATTGCTACCATAGCGGAGGAACCATCATTAGTAAC



CTCCCCTTTCAGAATATTGATTCCCGTGCCGTTGGGAAATGTCCCAGATACGTCAAGCAG



AGGTCCTTGCTGCTCGCAACCGGCATGAAGAATGTGCCAGAGATTCCAAAGGGGAGAGGT



CTTTTCGGTGCTATCGCCGGCTTTATCGAGAACGGCTGGGAAGGGCTGATCGATGGCTGG



TACGGATTCCGGCATCAAAACGCGCAGGGAGAGGGAACTGCGGCCGACTACAAGTCAACT



CAGTCTGCCATCGATCAGATTACTGGTAAGCTTAACCGTCTCATCGAGAAAACCAACCAA



CAATTTGAATTAATTGATAACGAGTTTAACGAAGTGGAGAAGCAAATTGGGAATGTCATA



AACTGGACACGGGATTCTATCACCGAGGTATGGTCTTACAACGCGGAGTTGCTGGTCGCC



ATGGAGAACCAACATACCATCGATCTGGCTGACAGTGAAATGGACAAGCTGTATGAGCGG



GTGAAACGGCAGCTCCGGGAGAATGCAGAGGAAGACGGTACTGGCTGTTTCGAGATCTTC



CATAAGTGCGACGATGACTGTATGGCCTCGATTAGGAACAACACCTATGATCACAGCAAG



TATCGCGAGGAAGCGATGCAGAACCGGATTCAGATCGACCCAGTTAAACTCTCGTCGGGC



TACAAGGATGTAATCCTGTGGTTTAGCTTCGGAGCGTCGTGTTTCATCTTGTTGGCGATA



GTAATGGGCCTTGTTTTTATCTGCGTGAAGAACGGAAATATGAGATGCACTATCTGTATT





589
ATGAACACGCAGATCCTAGTGTTCGCACTTATCGCCATCATCCCTACCAATGCTGACAAA



ATTTGCCTGGGACATCATGCGGTTTCTAATGGAACCAAGGTGAATACCCTAACAGAACGG



GGGGTGGAAGTTGTCAATGCCACAGAAACGGTTGAGCGTACTAACATTCCCCGCATTTGC



TCCAAAGGAAAAAAAACTGTGGATCTGGGCCAGTGTGGACTTCTGGGCACTATTACCGGC



CCTCCTCAGTGCGACCAGTTCCTGGAGTTCTCTGCGGACCTTATTATTGAGAGACGTGAG



GGATCTGATGTGTGTTATCCAGGGAAGTTCGTAAACGAAGAGGCTCTTAGACAAATCCTG



CGGAAGAGCGGTGGCATAGATAAAGAGGCAATGGGGTTTACATACAGCGGCATAAGGACC



AACGGCGCCACATCCACTTGCAGGCGGTCCGGGTCGTCATTTTACGCCGAGATGAAATGG



TTGTTAAGTAATACAGACAACGCAGCCTTTCCGCAGATGACTAAATCTTATAAAAACACA



CGAAAATCTCCGGCGATCATTGTATGGGGCATACACCACAGTGTTAGCACTGCCGAGCAG



ACGAAACTATATGGCTCCGGAAATAAACTGGTCACCGTAGGATCCTCCAACTACCAGCAG



AGCTTCGTGCCCTCGCCTGGCGCACGGCCACAAGTTAATGGTCTCAGCGGTCGGATTGAC



TTTCACTGGCTCATGCTTAATCCTAATGACACAGTAACCTTCTCCTTTAACGGCGCCTTC



ATAGCTCCCGACAGGGCATGTTTTCTGCGCGGGAAGAGTATGGGGATCCAGTCCGGGGTC



CAGGTAGATGCAGACTGCGAAGGGGACTGCTACCACAGTGGGGGTACCATCATTAGTAAC



CTTCCCTTTCAGAATATTGACAGCAGGGCCGTCGGGAAGTGCCCCCGCTACGTGAAGCAG



CGGTCTTTGCTCCTGGCTACCGGTATGAAGAACGTGCCCGAGATACCAAAAGGCAGGGGG



CTCTTTGGTGCCATCGCCGGCTTTATCGAAAATGGATGGGAGGGCCTCATCGACGGTTGG



TACGGTTTCAGGCACCAGAATGCCCAGGGGGAAGGAACAGCTGCAGATTACAAGTCAACC



CAGTCTGCTATTGACCAGATAACAGGGAAACTGAACCGATTAATTGAGAAAACTAATCAA



CAGTTCGAGCTGATTGATAACGAGTTTAACGAGGTGGAACGCCAAATCGGGAACGTGATT



AACTGGACAAGGGATTCAATCACAGAGGTTTGGAGTTATAATGCCGAACTGCTGGTCGCC



ATGGAGAACCAGCACACTATCGATCTAGCTGATTCTGAGATGGACAAGCTCTATGAGCGC



GTCAAGCGTCAGCTCCGCGAAAACGCTGAAGAAGATGGCACTGGCTGTTTCGAGATCTTC



CACAAGTGTGACGACGACTGCATGGCCTCCATAAGGAATAACACTTATGATCACAGCAAG



TATCGAGAGGAGGCCATGCAGAACCGCATTCAGATTGATCCCGTTAAGTTAAGTTCTGGG



TATAAAGATGTCATTCTTTGGTTCTCTTTTGGTGCTTCATGTTTTATACTGCTGGCTATC



GTCATGGGACTCGTGTTCATCTGCGTCAAAAATGGGAATATGCGGTGTACCATATGCATT





590
ATGAATACGCAGATCCTGGTGTTCGCTCTAATCGCTATTATCCCTACAAACGCAGATAAG



ATCTGTTTAGGCCACCATGCAGTTTCTAATGGCACTAAGGTCAACACTCTCACTGAACGC



GGGGTGGAGGTAGTCAACGCTACAGAGACAGTTGAACGAACAAACATCCCCAGGATTTGC



TCTAAGGGTAAAAAAACAGTGGACCTGGGACAGTGCGGACTGCTCGGGACCATTACTGGG



CCACCTCAGTGTGACCAGTTCTTGGAGTTTTCCGCCGATCTAATCATCGAAAGACGAGAA



GGATCCGATGTGTGCTATCCTGGCAAGTTTGTGAATGAGGAAGCACTGCGGCAGATCTTG



CGGGAGTCTGGCGGAATTGATAAGGAAGCAATGGGTTTTACCTACTCCGGTATTCGGACA



AATGGAGCTACATCCGCATGTCGGCGGTCCGGAAGCAGTTTCTACGCCGAGATGAAGTGG



CTATTGTCAAACACAGATAACGCTGCCTTCCCCCAGATGACTAAGAGCTATAAGAACACC



CGGAAGAGCCCTGCCCTGATCGTCTGGGGCATTCATCATTCGGTCAGTACAGCCGAACAA



ACTAAGTTGTACGGCTCCGGAAACAAGTTGGTTACAGTGGGGTCTTCCAACTACCAGCAG



AGCTTTGTACCTTCCCCCGGAGCCCGACCCCAGGTCAACGGCCAGTCTGGAAGAATTGAT



TTTCATTGGCTAATGCTGAATCCTAATGATACTGTGACATTTTCATTCAATGGAGCCTTC



ATAGCACCTGATAGGGCCTCTTTCCTGCGGGGAAAAAGCATGGGTATTCAGAGTGGCGTT



CAGGTGGATGCTAATTGCGAGGGGGACTGCTATCATAGTGGTGGGACCATTATTAGCAAC



CTCCCCTTTCAGAATATAGATAGCAGGGCTGTCGGCAAATGTCCAAGGTACGTTAAGCAG



CGGAGTCTACTGTTGGCCACCGGTATGAAAAACGTCCCCGAGATCCCTAAGGGACGCGGC



CTGTTCGGCGCCATCGCCGGATTTATCGAGAACGGGTGGGAAGGCTTGATCGATGGGTGG



TATGGATTCCGACATCAGAACGCCCAGGGCGAAGGTACTGCTGCCGACTATAAATCTACG



CAGAGCGCAATAGACCAGATTACGGGGAAACTGAACAGGCTGATCGAGAAGACCAATCAG



CAGTTTGAGCTGATTGACAATGAATTCAACGAAGTTGAGAAACAGATCGGTAACGTGATA



AATTGGACTAGAGATAGTATCACCGAGGTATGGAGCTACAACGCCGAGCTGCTTGTCGCT



ATGGAAAACCAGCACACCATCGACCTTGCTGACAGTGAGATGGATAAACTCTATGAACGA



GTGAAGAGACAGTTGCGGGAAAACGCCGAAGAGGACGGTACCGGGTGCTTTGAGATATTT



CACAAGTGCGATGATGACTGTATGGCTAGTATCCGCAATAATACATATGACCATAGTAAG



TACAGAGAAGAAGCCATGCAAAACAGAATACAAATTGACCCCGTGAAGTTAAGCTCAGGA



TACAAAGATGTCATCCTTTGGTTCTCCTTCGGCGCATCATGCTTTATACTTCTCGCAATC



GTGATGGGTCTGGTTTTTATATGCGTCAAGAACGGCAATATGCGCTGTACGATCTGTATT





591
ATGAACACCCAGATTCTGGTTTTTGCATTGATCGCCATTATTCCGACTAATGCCGACAAA



ATCTGTTTGGGACACCACGCCGTGAGCAACGGCACGAAAGTCAACACACTCACAGAACGA



GGCGTGGAAGTTGTCAACGCAACCGAGACGGTTGAGCGCACCAACATCCCAAGGATCTGC



TCTAAGGGCAAGAAGACCGTGGACCTTGGGCAGTGTGGCCTGCTGGGGACAATAACCGGT



CCACCACAATGTGATCAATTCCTGGAGTTTTCAGCCGACCTCATCATAGAACGCCGGGAA



GGTTCTGACGTGTGCTACCCGGGCAAATTTGTCAACGAGGAGGCTCTCAGGCAGATCCTG



AGGGAGTCAGGCGGAATTGACAAGGAAGCCATGGGTTTCACGTACAGCGGTATTCGGACC



AATGGGGCTACATCAGCCTGTCGCAGATCTGGAAGTTCTTTTTACGCTGAAATGAAGTGG



CTGCTGTCAAATACCGATAACGCTGCATTTCCCCAGATGACAAAAAGTTATAAGAATACC



AGGAAGTCCCCCGCCTTGATCGTGTGGGGCATACACCACTCAGTGAGTACAGCCGAGCAG



ACCAAGTTGTATGGATCGGGTAACAAACTAGTCACCGTGGGCTCCAGCAATTATCAGCAG



AGTTTTGTCCCCAGCCCCGGGGCTAGACCGCAAGTCAATGGTCAGTCCGGCCGTATCGAT



TTTCACTGGCTGATGCTAAATCCCAATGACACTGTAACCTTTTCCTTTAATGGGGCATTC



ATTGCACCCGACAGGGCATCCTTTTTGCGGGGTAAGAGTATGGGTATCCAGAGTGGCGTC



CAGGTGGATGCAAACTGCGAGGGTGACTGCTACCATTCAGGAGGCACGATTATATCAAAT



CTGCCCTTTCAGAACATTGACAGTCGCGCCGTTGGCAAATGTCCAAGGTACGTGAAGCAG



AGAAGCCTCCTGCTCGCCACTGGCATGAAAAATGTGCCCGAGATTCCCAAAGGCCGGGGT



CTTTTTGGCGCAATAGCTGGTTTTATCGAGAATGGTTGGGAAGGACTCATCGACGGCTGG



TACGGATTTCGGCACCAAAACGCCCAAGGGGAAGGAACCGCCGCAGATTACAAGAGCACG



CAGTCAGCTATCGACCAGATCACCGGCAAGCTTAATCGGCTTATTGAAAAAACCAATCAA



CAATTCGAGCTGATTGACAATGAATTTAATGAAGTGGAGAAACAAATTGGGAACGTGATC



AATTGGACCAGAGACAGCATAACTGAAGTGTGGAGTTATAACGCAGAACTGCTGGTCGCT



ATGGAAAATCAACACACTATTGATCTGGCCGATAGCGAAATGGACAAGCTATACGAAAGG



GTTAAACGGCAGCTTCGCGAGAACGCCGAGGAGGACGGCACCGGCTGCTTCGAGATTTTC



CACAAGTGTGATGACGATTGTATGGCCTCCATCAGAAACAACACCTACGACCATAGCAAG



TATAGAGAAGAAGCCATGCAGAATCGCATCCAGATCGACCCCGTTAAGCTTTCATCCGGC



TATAAGGACGTTATCTTATGGTTCTCTTTTGGAGCATCATGCTTTATCCTCCTGGCTATC



GTTATGGGCCTTGTTTTCATCTGCGTTAAAAACGGGAATATGCGCTGCACCATCTGTATT





592
ATGAATACACAGATCTTAGTGTTTGCTCTTATAGCAATCATACCCACAAACGCCGATAAG



ATCTGTCTGGGGCACCATGCCGTGAGCAACGGAACTAAGGTTAACACATTAACTGAGAGA



GGTGTGGAGGTAGTTAACGCGACCGAGACTGTAGAGCGGACTAATATCCCTCGCATTTGC



AGTAAGGGCAAAAAGACCGTTGACCTTGGTCAGTGTGGGCTGCTTGGAACCATCACCGGA



CCTCCTCAGTGTGACCAGTTCCTCGAATTTTCCGCTGACCTGATTATTGAGAGAAGGGAA



GGGAGTGACGTGTGTTATCCTGGCAAATTCGTCAATGAAGAAGCGCTACGCCAGATCCTT



AGAGAGAGTGGGGGAATCGATAAGGAGGCAATGGGCTTTACATACAGTGGCATAAGAACC



AATGGCGCGACAAGTGCCTGCCGCCGGAGCGGCTCAAGTTTCTATGCTGAGATGAAATGG



TTACTCAGTAATACTGATAATGCCGCATTTCCACAGATGACTAAATCTTATAAAAATACA



CGGAAATCACCCGCACTGATTGTATGGGGTATCCACCACAGCGTCTCCACAGCGGAGCAA



ACAAAACTGTACGGCAGTGGGAACAAATTGGTTACTGTTGGGTCCTCGAATTATCAGCAG



TCTTTCGTCCCTAGCCCTGGAGCTCGCCCCCAAGTTAACGGTCAGAGCGGCAGGATAGAT



TTCCACTGGTTAATGCTAAACCCTAATGACACCGTAACCTTTTCGTTTAATGGAGCATTC



ATTGCGCCTGACCGCGCGAGCTTCTTAAGGGGAAAGTCAATGGGAATTCAATCTGGGGTC



CAAGTCGACGCAAATTGTGAGGGCGACTGCTACCACTCAGGAGGAACTATCATCTCGAAC



CTGCCTTTTCAAAACATCGATAGCAGAGCCGTTGGCAAGTGCCCTCGCTATGTGAAACAG



CGCTCACTTCTCTTAGCGACGGGAATGAAGAACGTTCCGGAGATCCCAAAGGGTCGTGGC



TTGTTTGGCGCAATAGCAGGGTTCATAGAGAACGGATGGGAAGGTCTGATTGACGGTTGG



TATGGCTTCAGACACCAGAATGCTCAGGGAGAAGGAACCGCAGCCGATTATAAATCAACA



CAGAGCGCCATAGATCAGATCACAGGAAAGTTAAATCGCCTGATCGAGAAGACGAATCAG



CAGTTCGAGCTGATCGACAACGAGTTCAACGAAGTCGAGAAACAAATTGGCAACGTGATC



AACTGGACGAGGGATAGCATTACGGAGGTGTGGTCTTATAACGCTGAACTACTTGTGGCA



ATGGAGAACCAGCATACAATCGACCTCGCTGACTCAGAAATGGATAAGCTGTACGAGAGA



GTTAAACGGCAGTTGAGAGAAAACGCAGAGGAGGATGGCACAGGCTGCTTTGAAATTTTT



CACAAGTGCGATGATGACTGCATGGCTTCCATTCGGAACAATACGTATGACCACTCTAAA



TACAGGGAAGAGGCCATGCAGAATCGCATCCAGATCGATCCTGTAAAGTTGTCCTCAGGC



TATAAAGATGTGATCCTCTGGTTTTCCTTTGGGGCATCATGTTTCATTCTGCTCGCCATC



GTGATGGGGCTGGTGTTCATTTGTGTTAAGAACGGGAATATGCGGTGCACTATCTGTATT





593
ATGAATACGCAGATACTCGTGTTTGCCCTGATCGCCATAATCCCTACGAACGCAGATAAG



ATCTGCCTCGGACACCACGCTGTTAGCAACGGAACCAAGGTTAACACTTTGACGGAGAGG



GGAGTGGAGGTCGTTAATGCCACCGAAACCGTGGAACGTACCAACATCCCCCGGATCTGT



TCCAAAGGTAAAAAGACTGTCGATCTGGGACAGTGCGGCTTACTGGGAACTATTACTGGG



CCCCCGCAGTGTGACCAATTCCTGGAATTCTCTGCAGATCTTATTATTGAGCGGAGGGAG



GGGAGCGACGTCTGCTATCCGGGGAAGTTCGTCAACGAGGAGGCCTTGAGACAGATCCTG



AGAGAATCTGGGGGCATCGATAAAGAAGCCATGGGATTTACTTATAGCGGCATAAGAACC



AATGGCGCCACATCCGCCTGCCGTAGGAGTGGCTCAAGTTTTTATGCAGAAATGAAATGG



CTACTCAGCAATACTGACAACGCTGCCTTCCCCCAGATGACAAAGAGCTATAAGAATACC



AGGAAGTCACCAGCCCTGATCGTTTGGGGCATACACCATTCCGTATCTACCGCGGAGCAA



ACAAAGCTTTATGGCTCTGGGAATAAGCTTGTAACTGTTGGCAGTAGTAATTATCAGCAG



AGCTTTGTTCCATCCCCTGGCGCCCGGCCCCAGGTGAATGGTCAAAGCGGCAGGATAGAC



TTTCACTGGCTGATGCTCAACCCCAACGATACTGTGACATTCTCCTTTAACGGAGCCTTC



ATTGCTCCCGACCGCGCCTCTTTCCTCAGGGGCAAAAGTATGGGGATTCAGTCAGGTGTT



CAGGTGGACGCAAACTGCGAAGGCGATTGCTACCACTCGGGGGGGACAATCATATCCAAC



CTGCCCTTCCAGAACATTGACAGTCGCGCCGTGGGTAAATGCCCACGGTACGTGAAACAG



CGGTCCCTGCTACTGGCTACTGGGATGAAAAACGTCCCTGAGATTCCCAAAGGCCGGGGA



CTGTTTGGCGCTATCGCGGGGTTCATAGAGAATGGGTGGGAGGGCTTGATCGACGGGTGG



TACGGTTTTAGACATCAGAACGCGCAAGGGGAGGGGACTGCTGCAGATTACAAGTCGACA



CAGTCCGCAATCGACCAGATCACCGGTAAATTGAACCGGCTGATAGAAAAGACCAACCAG



CAGTTTGAGTTGATAGACAATGAATTCAATGAGGTCGAAAAACAGATCGGTAATGTGATT



AATTGGACTCGGGATTCAATTACGGAAGTATGGTCTTACAACGCGGAGTTGTTAGTTGCA



ATGGAAAACCAGCACACGATCGATCTTGCAGACTCTGAAATGGATAAATTATACGAGCGG



GTCAAACGCCAGCTTCGGGAAAACGCCGAAGAGGATGGTACTGGATGTTTTGAGATCTTT



CATAAATGCGACGACGATTGTATGGCCAGCATTCGGAACAATACTTACGACCATTCAAAG



TACCGGGAGGAAGCCATGCAGAATAGAATCCAGATTGATCCAGTGAAACTCAGCTCGGGA



TACAAAGATGTGATTCTGTGGTTCTCCTTCGGGGCCTCTTGCTTCATACTGCTGGCTATC



GTAATGGGGCTTGTCTTCATATGTGTGAAAAACGGGAATATGAGATGCACCATTTGTATC





594
ATGAATACTCAGATACTCGTTTTTGCTTTGATAGCCATCATTCCAACTAACGCTGACAAA



ATCTGCCTAGGACACCATGCAGTGTCAAATGGCACAAAGGTGAATACTTTGACGGAGAGG



GGCGTGGAGGTGGTGAACGCAACAGAGACAGTGGAGCGCACCAACATTCCACGCATTTGT



AGTAAAGGAAAGAAGACAGTCGACCTCGGCCAGTGCGGGCTACTGGGTACGATTACTGGA



CCCCCCCAGTGTGATCAGTTTCTTGAGTTTAGCGCGGATCTGATAATTGAGCGCCGGGAG



GGTTCCGATGTCTGTTACCCCGGAAAGTTTGTGAACGAAGAAGCCCTTAGGCAAATCCTG



CGCGAGAGCGGCGGAATTGAGAAGGAAGCTATGGGGTTCACGTATAGCGGTATTCGGGCT



AACGGAGCCACTAGTGCATGTCGCCGCAGCGGCTCCTCATTCTACGCTGAGATGAAGTGG



CTGCTGTCCAATACCGACAATGCTGCTTTTCCGCAGATGACTAAGTCATACAAAAACACT



AGAAAGTCGCCCGCTTTGATTGTTTGGGGCATCCACCACAGCGTGAGTACAGCTGAGCAG



ACAAAGCTATATGGTTCAGGGAATAAATTAGTTACCGTGGGCAGCTCTAACTACCAGCAG



TCCTTTGTGCCCTCTCCCGGCGCTCGGCCTCAGGTAAATGGGCTTAGCGGCCGGATCGAC



TTTCATTGGCTGATGCTCAACCCTAATGACACAGTGACGTTCTCTTTCAATGGCGCGTTC



ATTGCCCCCGACAGGGCTTCTTTCCTACGGGGGAAAAGCATGGGTATTCAGTCAGGTGTT



CAAGTAGACGCAAACTGTGAAGGAGACTGTTACCACAGCGGGGGCACAATCATTTCAAAT



CTTCCTTTCCAGAACATAGATAGCCGGGCAGTCGGTAAATGCCCTCGGTATGTGAAACAA



AGATCCCTGTTGCTAGCAACAGGCATGAAAAACGTCCCAGAGATCCCTAAGGGACGCGGA



CTTTTCGGCGCGATCGCGGGATTTATCGAGAACGGCTGGGAAGGCCTAATCGATGGATGG



TATGGGTTTAGGCATCAGAATGCTCAGGGGGAGGGAACGGCTGCAGATTATAAATCTACT



CAGTCTGCTATCGACCAAATCACTGGGAAGCTCAATAGGCTGATTGAAAAAACAAATCAA



CAGTTCGAGCTGATAGACAATGAGTTCAACGAGGTAGAGAAGCAGATAGGTAACGTAATT



AATTGGACTCGCGACTCCATTACAGAAGTGTGGTCCTACAATGCTGAGCTGCTTGTGGCA



ATGGAAAACCAGCACACCATAGACCTGGCTGATTCAGAAATGGATAAACTGTATGAGAGG



GTGAAGAGGCAGCTCCGGGAAAACGCTGAGGAAGACGGCACAGGTTGCTTCGAAATTTTT



CATAAGTGCGATGACGACTGTATGGCTTCAATTCGAAACAATACATACGACCACTCCAAG



TATCGAGAGGAAGCCATGCAGAATCGTATCCAAATTGATCCCGTTAAACTATCATCCGGA



TATAAAGACGTCATCTTGTGGTTTTCCTTCGGGGCCTCTTGTTTCATCCTCCTCGCAATC



GTTATGGGATTGGTGTTTATCTGCGTGAAAAACGGCAACATGCGGTGCACAATATGCATT





595
ATGAACACCCAGATCTTGGTGTTCGCCCTCATTGCTATTATACCAACTAATGCGGACAAA



ATCTGCCTTGGACACCATGCCGTATCCAATGGAACCAAGGTCAATACACTGACGGAGAGG



GGAGTGGAAGTAGTGAACGCCACGGAAACAGTGGAAAGGACAAATATCCCTAGGATTTGC



TCCAAAGGCAAAAGAACAGTGGACCTGGGGCAATGCGGGCTTTTGGGTACTATTACAGGA



CCACCTCAGTGCGACCAATTCCTTGAGTTCAGCGCTGATCTGATTATAGAGAGGCGCGAG



GGGAGTGATGTTTGCTACCCCGGTAAGTTCGTAAATGAGGAGGCTCTGCGGCAGATCTTA



CGCGAAAGCGGGGGCATTGATAAGGAAGCTATGGGGTTTACCTACAGCGGCATTCGCACT



AATGGCGCGACATCTGCCTGTCGCCGTTCCGGGTCATCTTTCTATGCAGAGATGAAATGG



CTGCTCTCCAATACTGATAATGCTGCTTTCCCTCAAATGACAAAGTCTTACAAGAATACA



AGGAAGTCTCCCGCACTGATTGTGTGGGGCATCCACCACAGCGTCTCAACCGCTGAGCAG



ACTAAACTGTATGGTTCTGGGAACAAGCTCGTGACCGTCGGATCGTCTAATTATCAGCAG



AGCTTCGTCCCATCACCTGGCGCCAGACCCCAAGTGAACGGTCTGTCCGGCAGAATTGAT



TTCCACTGGCTGATGCTGAATCCCAATGACACGGTCACATTCTCATTTAATGGCGCATTC



ATTGCCCCGGATAGAGCTTCCTTTCTCAGGGGCAAGTCTATGGGAATTCAGAGCGGTGTC



CAGGTGGACGCGAATTGCGAAGGGGACTGCTATCACTCCGGCGGCACCATCATTTCTAAC



CTCCCTTTTCAGAATATTGACAGTCGCGCCGTCGGGAAATGCCCTCGCTACGTGAAGCAG



AGATCACTGCTCTTGGCCACAGGAATGAAGAACGTGCCCGAGATCCCGAAAGGGAGAGGG



CTCTTCGGAGCCATCGCTGGGTTCATTGAAAACGGATGGGAAGGCCTGATAGACGGCTGG



TACGGCTTCCGGCACCAAAACGCCCAGGGGGAAGGAACAGCCGCTGACTATAAATCTACA



CAGAGCGCGATAGACCAGATCACCGGCAAATTAAATCGTCTCATCGAAAAAACAAATCAG



CAGTTTGAGCTTATCGATAATGAATTCAACGAGGTTGAAAAGCAAATCGGGAATGTTATA



AATTGGACCCGAGACTCCATTACCGAGGTGTGGAGCTATAACGCCGAGCTGTTGGTGGCC



ATGGAGAACCAACATACAATTGATTTGGCCGACTCCGAGATGGACAAGCTGTATGAGCGG



GTTAAACGGCAACTGCGTGAGAATGCAGAAGAAGACGGCACTGGCTGCTTCGAAATCTTC



CACAAGTGCGATGATGATTGCATGGCTTCAATACGCAATAACACATACGATCACAGCAAA



TACAGGGAGGAAGCTATGCAGAATCGCATCCAGATTGATCCAGTGAAGCTGTCATCCGGA



TACAAAGATGTTATATTATGGTTCTCCTTTGGGGCTTCCTGTTTCATCCTGCTGGCAATC



GTGATGGGCCTAGTGTTCATATGCGTCAAGAATGGAAACATGAGATGCACCATCTGTATC





596
ATGAATACCCAGATACTTGTATTTGCCCTTATCGCCATAATCCCCACTAACGCCGACAAG



ATTTGTCTAGGGCACCATGCAGTATCTAATGGAACAAAAGTGAATACCCTCACAGAACGG



GGTGTTGAAGTGGTTAATGCCACCGAAACAGTCGAGAGAACTAACATTCCCAGGATTTGT



AGCAAGGGTAAGAAGACAGTTGACCTTGGGCAGTGTGGCTTACTTGGAACTATTACCGGC



CCACCACAGTGCGATCAGTTTCTGGAGTTCAGCGCAGATCTCATTATTGAGAGAAGAGAA



GGAAGCGACGTGTGCTACCCTGGCAAGTTCGTGAATGAGGAGGCCCTTCGGCAGATCCTT



AGGGAGTCCGGAGGCATTGATAAGGAGGCTATGGGTTTTACCTATTCTGGCATTCGTACC



AACGGGGCCACAAGTGCTTGTCGCCGCTCCGGTTCTTCCTTTTACGCTGAGATGAAATGG



TTGCTCAGCAACACTGACAATGCTGCTTTCCCACAGATGACAAAATCCTACAAAAATACC



AGAAAATCGCCCGCCTTGATTGTGTGGGGGATCCACCATAGTGTGTCTACCGCTGAGCAG



ACCAAGCTGTATGGTTCCGGGAATAAGCTCGTGACCGTAGGTTCTTCCAATTATCAGCAG



AGTTTCGTGCCTTCCCCCGGCGCCAGACCTCAGGTGAATGGCCAGAGCGGGAGAATAGAC



TTCCATTGGCTCATGCTGAACCCTAACGATACAGTGACCTTCAGTTTCAACGGCGCCTTC



ATCGCTCCAGACCGCGCCTCATTCCTTCGCGGCAAAAGCATGGGGATCCAGTCCGGGGTT



CAAGTAGACGCCAACTGCGAGGGTGACTGCTATCACTCCGGAGGGACGATAATCAGCAAT



CTTCCCTTCCAGAACATCGATAGCCGCGCCGTCGGTAAGTGCCCACGCTACGTTAAACAG



CGCAGCCTGCTCTTGGCTACCGGCATGAAGAACGTCCCCGAAATCCCTAAGGGCCGGGGC



CTGTTCGGGGCCATTGCGGGTTTTATTGAGAATGGCTGGGAGGGGCTGATAGACGGGTGG



TACGGATTTAGACACCAGAATGCTCAGGGGGAAGGGACCGCTGCCGATTATAAGAGCACC



CAGTCTGCTATTGACCAGATTACGGGTAAGCTGAACAGACTTATTGAAAAAACCAACCAG



CAGTTTGAGCTTATCGACAATGAATTCAACGAAGTGGAGAAGCAGATCGGGAATGTCATC



AACTGGACAAGAGATAGCATCACAGAGGTCTGGTCATATAACGCCGAACTGTTGGTGGCC



ATGGAAAATCAACACACTATAGATCTAGCCGACTCTGAAATGGATAAGTTGTACGAGCGG



GTAAAACGGCAGCTGCGGGAAAACGCTGAGGAAGATGGCACCGGATGCTTCGAGATTTTT



CATAAATGCGATGACGACTGTATGGCCTCTATCAGGAATAATACATACGATCATAGTAAG



TACCGGGAAGAAGCCATGCAGAACAGGATCCAGATAGATCCCGTTAAGCTGTCTAGGGGG



TACAAGGATGTCATCTTATGGTTCAGCTTCGGCGCCAGCTGCTTCATCCTATTGGCCATT



GTCATGGGACTAGTCTTTATCTGCGTGAAAAACGGTAATATGCGGTGTACTATCTGTATC





597
ATGAATACCCAGATCCTGGTTTTCGCGCTGATCGCAATCATACCTACTAACGCAGATAAG



ATTTGCTTGGGACATCATGCCGTGTCCAACGGCACAAAAGTCAATACCCTCACAGAGAGG



GGCGTTGAGGTGGTGAATGCTACCGAGACTGTGGAGAGGACCAATATTCCGAGAATTTGC



TCAAAAGGAAAGCGTACAGTCGACCTGGGGCAATGTGGCCTACTCGGCACCATTACAGGG



CCCCCCCAGTGTGACCAGTTTCTCGAATTTTCTGCTGACCTCATCATCGAGAGACGCGAG



GGGTCCGACGTGTGTTACCCTGGCAAATTCGTTAATGAAGAAGCCCTAAGACAAATTCTA



CGCGAGAGCGGAGGTATTGACAAAGAGGCTATGGGATTCACTTATTCTGGTATCCGCACC



AACGGCGCTACCTCCGCCTGCCGGCGCTCCGGATCCAGCTTTTATGCTGAGATGAAATGG



TTGCTGTCCAACACCGACAATGCTGCATTTCCTCAGATGACCAAATCTTATAAAAACACA



AGAAAGAGTCCTGCGTTGATTGTGTGGGGAATACACCACTCAGTAAGCACTGCCGAACAG



ACGAAGCTGTATGGTTCCGGAAACAAGCTCGTTACAGTGGGCAGTTCAAATTACCAGCAG



AGCTTTGTTCCTTCCCCAGGGGAACGACCCCAAGTTAATGGACTGTCCGGGAGAATTGAT



TTCCATTGGCTGATGCTGAACCCCAACGACACTGTGACGTTCTCCTTTAATGGGGCATTT



ATCGCCCCGGATAGAGCTTCTTTTCTGAGAGGCAAGTCAATGGGGATCCAGTCAGGGGTG



CAAGTCGATGCCAACTGCGAAGGAGATTGTTATCACTCAGGAGGCACGATTATTAGCAAT



CTGCCCTTCCAGAATATTGATTCTCGCGCCGTGGGCAAATGTCCTCGATACGTGAAGCAG



AGATCCCTGCTGCTGGCTACCGGCATGAAAAATGTACCAGAGATTCCAAAGGGGAGAGGA



CTGTTCGGTGCCATCGCCGGTTTCATAGAAAATGGGTGGGAGGGCCTGATTGATGGCTGG



TACGGTTTTAGGCACCAGAATGCTCAGGGAGAAGGGACCGCCGCAGATTATAAAAGCACT



CAGTCTGCAATCGATCAGATAACAGGTAAACTGAACCGCCTGATTGAGAAGACAAACCAG



CAGTTTGAACTGATCGATAATGAGTTTAATGAAGTGGAGAAGCAGATTGGCAACGTTATC



AACTGGACACGGGACTCCATCACCGAAGTGTGGAGCTACAACGCTGAGCTGCTGGTAGCC



ATGGAAAATCAGCACACAATCGATCTGGCTGACTCAGAAATGGACAAGCTCTATGAGAGG



GTCAAAAGGCAACTAAGAGAAAATGCCGAGGAAGATGGGACCGGCTGTTTCGAGATATTT



CACAAATGCGACGATGACTGCATGGCTAGCATTAGGAATAATACCTACGATCATAGCAAA



TATCGGGAAGAAGCTATGCAGAACCGCATCCAAATAGATCCCGTCAAGTTGAGCTCTGGG



TACAAGGATGTGATTCTGTGGTTCTCTTTCGGCGCCTCTTGCTTTATTCTGCTGGCAATC



GTGATGGGTCTGGTGTTTATTTGTGTCAAAAACGGTAACATGCGCTGCACTATCTGCATA





598
ATGAATACACAGATTCTAGTGTTTGCCTTGATAGCTATAATCCCAACCAACGCGGACAAG



ATCTGTCTCGGACACCATGCCGTGTCAAATGGTACTAAGGTGAATACACTGACCGAAAGA



GGAGTGGAGGTCGTGAATGCGACAGAAACGGTTGAGCGAACCAACATTCCTAGGATCTGT



AGTAAGGGAAAGCGAACTGTCGATCTGGGCCAGTGTGGACTCCTCGGGACCATTACAGGG



CCTCCTCAGTGTGATCAGTTTTTGGAATTTTCCGCAGACTTGATAATCGAGAGGCGGGAA



GGGTCTGACGTGTGCTACCCAGGCAAATTTGTAAATGAAGAGGCCCTAAGGCAGATCCTG



AGGGAGAGTGGTGGAATCGATAAAGAAGCCATGGGATTTACATATTCAGGCATCAGGACC



AACGGCGCAACATCAGCCTGCCGAAGATCGGGATCTTCATTCTACGCCGAGATGAAATGG



TTGCTATCCAACACTGACAATGCCGCATTCCCCCAGATGACTAAAAGCTACAAAAACACC



CGGAAGTCCCCAGCTCTCATCGTCTGGGGGATCCATCACAGTGTGTCCACCGCCGAGCAG



ACCAAGCTGTATGGATCCGGCAGTAAACTGGTTACTGTGGGGTCATCTAATTACCAACAG



AGTTTTGTGCCATCGCCTGGCGCCAGACCTCAAGTGAATGGACTGTCCGGTAGAATTGAT



TTTCACTGGCTCATGCTGAACCCTAATGACACGGTTACCTTTTCTTTCAACGGAGCATTT



ATAGCTCCGGATCGCGCCAGTTTTCTACGGGGGAAAAGCATGGGAATCCAGTCGGGTGTG



CAGGTAGATGCTAACTGCGAAGGTGATTGCTACCACTCCGGTGGTACAATCATCAGCAAT



CTGCCGTTCCAGAACATAGATAGTCGTGCAGTGGGTAAGTGCCCTAGGTACGTGAAACAA



AGATCTCTGCTGCTTGCAACCGGTATGAAGAACGTGCCTGAGATTCCGAAAGGGCGCGGC



TTATTCGGAGCTATAGCTGGATTCATCGAGAATGGATGGGAGGGCCTGATTGATGGTTGG



TACGGGTTTCGACATCAGAACGCCCAGGGAGAGGGTACCGCTGCTGACTACAAGAGCACC



CAATCCGCTATCGACCAGATAACTGGCAAGCTGAATAGACTGATTGAAAAGACAAATCAG



CAATTTGAATTGATCGACAACGAATTCAACGAAGTGGAAAAGCAGATTGGTAACGTGATC



AACTGGACCAGAGACTCTATCACAGAGGTATGGTCTTACAATGCCGAGCTCCTGGTTGCC



ATGGAAAACCAACATACCATTGACTTGGCCGACAGCGAAATGGATAAACTATACGAGCGG



GTCAAACGACAGCTGCGCGAGAATGCCGAGGAGGATGGAACTGGCTGCTTCGAAATCTTC



CACAAGTGTGACGACGATTGTATGGCCAGCATCCGGAACAATACATATGATCATTCAAAA



TATCGCGAGGAGGCTATGCAGAATAGAATTCAGATTGACCCCGTGAAGCTGAGCAGCGGG



TACAAGGACGTCATTCTGTGGTTCAGTTTCGGAGCCTCTTGTTTTATCCTCCTCGCGATC



GTGATGGGATTAGTGTTTATTTGTGTGAAGAACGGCAATATGAGGTGTACGATTTGTATC





599
ATGAACACGCAGATCTTGGTGTTCGCACTAATCGCGATAATCCCCACTAATGCAGACAAA



ATTTGTTTAGGCCATCATGCTGTATCCAATGGCACAAAAGTCAACACCCTGACGGAAAGA



GGTGTGGAAGTCGTCAACGCTACCGAGACTGTGGAACGGACGAATATCCCAAGGATCTGT



TCAAAGGGGAAGCGAACGGTCGACCTGGGACAGTGCGGCCTGCTGGGGACCATCACAGGA



CCGCCACAGTGCGACCAGTTTCTGGAGTTTTCTGCGGACTTGATTATCGAAAGACGGGAG



GGAAGTGACGTATGCTATCCCGGCAAATTCGTGAATGAAGAGGCCTTGCGCCAGATATTA



CGCGAGTCCGGAGGGATCGACAAGGAAGCTATGGGGTTCACATACTCCGGCATCAGAACC



AACGGCGCCACATCCGCATGCCGGCGCAGTGGATCCAGCTTCTACGCAGAAATGAAATGG



CTCCTCAGCAATACGGATAACGCCGCCTTCCCACAAATGACCAAGTCATACAAAAATACC



AGAAAGAGCCCAGCCTTGATAGTGTGGGGAATCCACCACTCTGTGTCTACCGCCGAACAG



ACTAAGCTGTATGGATCTGGCTCGAAATTAGTCACCGTCGGCTCCTCCAACTATCAGCAA



TCATTCGTGCCAAGCCCCGGAGCCCGCCCACAGGTTAATGGACTGTCAGGAAGGATTGAC



TTCCACTGGCTGATGCTGAATCCTAATGATACTGTGACTTTCTCATTTAATGGCGCTTTT



ATTGCCCCTGACAGAGCCAGCTTCCTTCGAGGGAAGTCCATGGGAATCCAGTCTGGCGTG



CAAGTAGACGCAAACTGTGAAGGGGATTGCTATCATAGTGGTGGGACAATCATTTCAAAT



CTGCCCTTCCAGAATATCGATAGTAGAGCAGTAGGAAAATGTCCCAGGTACGTGAAACAG



AGATCACTGTTATTGGCTACAGGAATGAAAAATGTCCCAGAAATCCCGAAGGGGAGAGGC



CTCTTTGGGGCCATAGCAGGCTTTATTGAGAATGGGTGGGAAGGCCTAATCGATGGATGG



TACGGGTTCCGCCATCAGAATGCGCAGGGCGAGGGGACTGCAGCCGACTACAAAAGCACG



CAATCCGCTATCGACCAGATTACTGGAAAGCTCAACCGATTAATTGAAAAGACTAATCAG



CAGTTCGAACTGATCGATAACGAGTTCAACGAGGTCGAAAAGCAGATCGGGAATGTGATC



AACTGGACCAGGGATTCCATAACCGAGGTTTGGAGCTATAATGCAGAGTTGCTTGTAGCA



ATGGAGAACCAACATACCATAGACCTGGCCGATTCGGAAATGGACAAGCTGTATGAGCGA



GTGAAACGGCAGCTGCGGGAGAATGCAGAAGAAGACGGCACAGGTTGTTTTGAAATTTTT



CACAAATGCGATGACGATTGCATGGCATCGATCAGAAATAACACCTATGATCATTCAAAG



TATCGCGAGGAGGCCATGCAGAATAGGATCCAAATCGACCCTGTCAAACTCTCTAGTGGC



TACAAGGATGTCATCCTCTGGTTCTCCTTTGGTGCCTCTTGCTTCATTTTGCTCGCCATT



GTAATGGGATTGGTGTTCATTTGTGTTAAATCCAGAAATATGCGTTGTACCATTTGTATC





600
ATGAACACCCAGATTCTGGTCTTCGCTCTGATCGCCATTATACCAACAAATGCGGATAAA



ATTTGCCTGGGACACCATGCTGTAAGCAACGGCACGAAGGTGAACACACTCACCGAAAGG



GGAGTCGAAGTAGTCAATGCCACAGAGACCGTTGAACGTACGAACATCCCTAGAATTTGT



AGCAAAGGGAAACGGACTGTCGATTTGGGACAATGTGGACTGCTTGGGACTATCACAGGG



CCCCCTCAGTGCGATCAGTTCCTGGAATTCTCGGCCGATCTGATCATTGAACGGAGAGAA



GGAAGCGACGTGTGCTACCCAGGTAAATTCGTGAACGAAGAGGCACTGCGCCAAATTCTT



CGGGAGTCCGGGGGGATCGACAAGGAGGCAATGGGATTTACGTATTCTGGCATTAGGACC



AACGGGGCTACATCTGCCTGCCGGCGAAGTGGATCCTCCTTCTATGCAGAAATGAAGTGG



CTCCTTTCAAACACAGACAATGCCGCCTTTCCACAGATGACCAAGAGTTATAAGAATACC



AGGAAAAGTCCTGCCTTGATTGTGTGGGGGATTCACCACTCCGTGAGCACTGCCGAGCAG



ACCAAGCTTTACGGGAGCGGCAATAAGCTGGTGACAGTGGGCTCTTCCAATTATCAACAA



TCCTTCGTGCCTAGCCCTGGGGAAAGACCCCAGGTGAATGGACTGTCCGGCCGGATCGAC



TTTCACTGGCTCATGCTGAATCCCAACGACACTGTAACCTTTAGCTTTAACGGCGCCTTC



ATCGCTCCCGATAGGGCGTCTTTCCTACGGGGGAAAAGTATGGGAATTCAATCAGGCGTC



CAGGTAGACGCCAACTGCGAGGGTGACTGTTACCACAGCGGAGGTACAATAATTTCCAAC



CTGCCTTTCCAAAACATAGATTCCCGCGCAGTGGGGAAATGCCCCAGGTACGTGAAGCAG



CGAAGTCTCCTCCTTGCCACAGGAATGAAGAACGTGCCTGAGATTCCAAAAGGGCGGGGG



TTGTTCGGGGCCATCGCTGGATTTATCGAAAACGGGTGGGAAGGCCTTATCGACGGCTGG



TACGGTTTTAGGCACCAGAACGCACAGGGTGAGGGGACTGCGGCCGACTACAAGTCGACA



CAAAGCGCTATAGACCAGATCACCGGGAAACTTAATCGGCTGATCGAAAAGACTAACCAG



CAGTTTGAATTAATCGACAACGAATTTAATGAGGTGGAGAAGCAGATCGGAAACGTGATT



AATTGGACCAGGGATTCCATCACGGAAGTTTGGTCCTATAACGCGGAGTTGCTTGTTGCC



ATGGAAAACCAGCACACCATTGACCTCGCTGACTCTGAGATGGACAAACTATATGAGAGA



GTCAAAAGACAGCTGCGCGAAAATGCAGAGGAGGATGGCACGGGTTGTTTCGAAATCTTT



CACAAATGTGATGACGATTGTATGGCCAGTATACGGAATAACACCTATGACCACTCAAAG



TACCGAGAAGAAGCCATGCAGAATCGCATCCAGATCGATCCTGTTAAGCTGTCCTCAGGA



TATAAAGACGTCATCCTGTGGTTCTCTTTTGGCGCAAGCTGCTTTATCCTTTTAGCGATC



GTGATGGGCCTGGTTTTTATATGTGTCAAGAATGGAAATATGCGGTGTACAATTTGCATC





601
ATGAACACTCAGATCTTAGTGTTTGCACTGATTGCCATAATCCCAACAAACGCCGATAAA



ATCTGCCTGGGCCATCACGCGGTGTCGAATGGCACAAAGGTCAACACACTGACCGAAAGA



GGCGTAGAGGTCGTGAACGCGACGGAGACCGTGGAGCGCACTAACATTCCTCGCATCTGT



TCAAAAGGTAAGAAAACAGTGGATTTGGGACAGTGTGGCCTTCTCGGTACCATTACCGGC



CCTCCCCAGTGCGACCAGTTCCTCGAATTTTCTGCTGATTTAATTATTGAACGGCGGGAG



GGGTCAGACGTGTGTTATCCCGGCAAGTTTGTGAACGAAGAAGCTCTTAGACAGATCCTC



CGGGAGAGCGGGGGGATTGACAAGGAAGCAATGGGCTTTACATACTCAGGTATTCGAACA



AATGGAGCCACTAGCGCCTGCCGACGATCCGGGTCATCTTTCTACGCAGAGATGAAATGG



CTGCTCAGCAACACTGATAATGCTGCCTTTCCACAGATGACAAAATCCTATAAAAACACC



AGAAAATCCCCTGCGTTAATTGTCTGGGGCATCCACCATTCGGTTTCTACAGCAGAGCAG



ACCAAGCTGTACGGCAGCGGAAATAAACTCGTGACTGTAGGATCGAGTAATTATCAGCAA



AGCTTTGTTCCATCACCAGGGGCCCGTCCACAGGTCAATGGACAGAGTGGAAGGATCGAT



TTCCATTGGCTAATGCTGAACCCAAACGATACTGTGACCTTTTCTTTCAACGGGGCCTTC



ATTGCTCCTGATCGGGCATCATTTTTGCGTGGGAAGTCAATGGGTATACAATCAGGGGTG



CAAGTGGACGCTAATTGCGAAGGTGACTGTTACCATTCTGGAGGCACCATTATCTCTAAC



TTGCCTTTCCAAAACATTGACAGCAGAGCCGTGGGTAAGTGCCCTCGATACGTGAAGCAG



CGGTCGCTTCTCCTTGCCACGGGCATGAAGAACGTGCCTGAAATCCCTAAAGGTCGTGGT



CTATTCGGAGCAATTGCCGGTTTCATCGAGAATGGGTGGGAAGGCCTTATCGATGGTTGG



TACGGGTTTCGGCACCAGAATGCCCAGGGCGAGGGCACAGCTGCTGACTACAAGTCGACC



CAGAGCGCTATCGACCAGATCACAGGCAAGCTCAACAGGCTGATCGAAAAGACTAACCAG



CAATTCGAATTGATCGATAACGAGTTTAATGAGGTGGAAAAGCAGATTGGGAATGTTATC



AACTGGACCCGCGATTCCATTACTGAGGTATGGTCCTACAACGCTGAGCTCTTAGTCGCT



ATGGAGAACCAGCACACCATAGATCTGGCTGATTCAGAGATGGATAAGCTCTATGAACGG



GTTAAAAGGCAGCTTCGGGAGAACGCCGAGGAAGACGGAACTGGTTGCTTCGAGATCTTT



CACAAATGTGACGATGACTGCATGGCTTCCATTAGAAATAACACGTATGACCATAGCAAG



TATAGAGAGGAAGCAATGCAAAACCGGATCCAGATCGACCCAGTCAAATTGAGCTCGGGA



TACAAGGACGTTATCCTGTGGTTCTCATTTGGCGCCTCCTGTTTCATATTGTTGGCTATT



GTGATGGGTCTGGTGTTCATCTGTGTCAAGAATGGGAACATGAGGTGCACCATTTGTATA





602
ATGAACACACAGATTCTCGTGTTTGCGCTAATTGCAATCATACCCACTAATGCAGACAAA



ATCTGTCTGGGACACCACGCGGTTAGCAATGGCACGAAGGTGAATACCCTGACAGAGAGA



GGAGTGGAGGTTGTTAACGCGACCGAAACTGTTGAAAGGACTAATATCCCTCGTATCTGT



TCAAAGGGAAAAAAGACCGTAGACCTGGGCCAGTGTGGACTGCTCGGCACGATCACAGGG



CCACCTCAGTGTGACCAATTTCTGGAGTTCAGTGCTGACCTGATTATCGAAAGAAGAGAG



GGATCAGACGTATGTTATCCCGGAAAGTTCGTGAATGAGGAAGCCCTTCGACAGATCTTA



AGAGAATCAGGCGGGATCGATAAGGAAGCAATGGGCTTCACCTACTCTGGCATTCGGACC



AATGGCGCAACTTCTGCATGCCGCAGATCCGGCTCTAGTTTTTACGCGGAGATGAAGTGG



CTCCTCTCCAATACAGACAATGCAGCATTCCCACAAATGACCAAGTCTTATAAAAACACC



CGCAAGTCCCCCGCTCTCATCGTTTGGGGTATCCACCATAGTGTGTCCACAGCCGAGCAA



ACAAAGCTATACGGAAGTGGCAACAAGCTGGTCACAGTGGGCAGTAGTAATTATCAGCAG



AGCTTCGTGCCTAGCCCCGGGGCCAGGCCACAGGTTAACGGCCAGTCAGGGCGCATCGAC



TTTCACTGGCTTATGCTGAACCCGAACGACACTGTCACATTCTCATTCAACGGCGCCTTC



ATAGCACCCGATAGGGCCTCATTTTTAAGGGGGAAGTCTATGGGAATTCAGTCCGGAGTG



CAGGTCGACGCCAACTGTGAGGGCGACTGCTACCATAGTGGAGGAACCATCATAAGTAAT



CTGCCATTTCAAAACATCGATTCACGCGCGGTGGGAAAATGCCCCAGGTATGTCAAGCAG



CGGAGCCTTTTGCTTGCTACCGGGATGAAGAATGTGCCCGAGATTCCCAAGGGGAGAGGT



TTATTCGGGGCTATAGCCGGGTTTATTGAAAACGGTTGGGAGGGGCTAATAGACGGATGG



TACGGCTTCAGGCACCAGAATGCTCAAGGGGAAGGGACTGCCGCTGATTATAAGAGCACG



CAGTCAGCTATCGACCAGATCACTGGGAAATTGAATCGTTTAATCGAGAAAACCAATCAG



CAGTTCGAACTGATTGATAACGAGTTCAACGAGGTCGAGAAACAAATAGGAAACGTTATA



AACTGGACACGAGATTCCATAACCGAGGTGTGGTCCTATAATGCTGAACTACTCGTAGCC



ATGGAGAACCAGCATACCATTGATCTGGCCGACTCTGAGATGGACAAGCTATATGAACGG



GTGAAAAGACAGTTGCGCGAAAACGCGGAAGAAGACGGGACAGGTTGCTTTGAAATTTTT



CACAAATGCGATGACGACTGCATGGCTAGTATACGGAACAACACATACGATCACTCTAAG



TATCGCGAGGAGGCAATGCAGAATCGCATCCAGATCGATCCCGTCAAACTGTCTTCCGGA



TATAAAGATGTCATACTGTGGTTCTCTTTCGGCGCAAGCTGTTTCATTCTCCTAGCCATC



GTCATGGGTCTGGTTTTCATATGTGTGAAGAACGGGAACATGCGGTGCACCATATGTATA





603
ATGAATACGCAGATCCTGGTGTTTGCTTTAATAGCCATCATCCCTACTAACGCAGACAAA



ATTTGTCTCGGGCACCACGCCGTGTCTAATGGAACAAAGGTCAACACTCTGACAGAACGC



GGAGTTGAAGTAGTGAATGCCACTGAAACTGTGGAGAGGACCAATATCCCTCGCATTTGT



TCTAAGGGAAAGAAGACCGTCGACCTCGGTCAGTGCGGCCTATTGGGAACCATCACTGGC



CCTCCTCAGTGTGACCAGTTTCTGGAGTTTAGTGCCGATTTGATCATCGAAAGAAGAGAG



GGAAGCGACGTTTGTTATCCCGGAAAGTTTGTCAACGAGGAGGCTCTCCGCCAAATTCTC



AGGGAATCTGGAGGTATCGACAAGGAAGCAATGGGCTTCACTTATTCAGGCATTCGCACA



AACGGGGCCACCTCTGCATGCCGCCGCAGCGGCTCTAGCTTTTACGCCGAAATGAAATGG



CTGCTCTCCAATACTGACAACGCTGCCTTTCCCCAAATGACCAAGTCCTATAAAAACACG



CGCAAAAGTCCGGCCCTCATTGTGTGGGGGATTCACCACTCCGTCTCCACAGCCGAGCAG



ACTAAGCTGTACGGTAGTGGTAATAAGTTGGTCACCGTGGGGTCAAGTAATTATCAGCAA



AGCTTCGTCCCTAGCCCCGGGGCCAGACCCCAGGTGAACGGACAAAGCGGAAGGATCGAT



TTTCACTGGCTGATGCTTAACCCTAATGACACCGTTACATTCAGTTTTAATGGTGCGTTT



ATCGCCCCCGATCGGGCCTCCTTTCTTAGAGGCAAAAGTATGGGTATCCAGAGTGGAGTA



CAGGTCGATGCCAATTGCGAAGGCGACTGCTATCACTCTGGGGGAACAATTATCTCCAAT



TTACCGTTCCAGAACATCGACTCTAGGGCAGTCGGCAAATGCCCTAGATATGTAAAGCAG



AGGTCTCTGCTGCTCGCCACGGGAATGAAAAACGTCCCAGAGATCCCAAAAGGCAGAGGA



CTGTTCGGAGCCATAGCTGGCTTTATCGAGAACGGCTGGGAGGGACTGATCGATGGATGG



TATGGTTTCCGGCACCAGAATGCACAAGGTGAGGGAACTGCCGCAGATTATAAGTCCACC



CAAAGTGCCATCGATCAGATTACAGGCAAGTTAAACAGACTTATTGAAAAAACAAATCAA



CAGTTTGAGCTTATTGACAACGAGTTCAATGAAGTTGAGAAGCAAATCGGTAACGTTATC



AATTGGACTCGCGACTCCATCACCGAGGTGTGGTCTTACAACGCGGAACTACTTGTAGCG



ATGGAAAATCAGCATACCATCGACTTGGCCGACTCGGAGATGGATAAGTTGTACGAGAGA



GTGAAACGGCAGCTCAGGGAAAACGCGGAGGAGGACGGAACAGGTTGTTTCGAAATATTT



CACAAGTGCGATGATGACTGTATGGCTAGCATTCGGAACAACACTTACGATCACTCCAAG



TACCGTGAAGAGGCTATGCAGAACAGGATTCAGATCGATCCGGTGAAACTCTCAAGCGGA



TACAAGGACGTTATACTTTGGTTCAGCTTCGGAGCTTCTTGCTTTATTCTTTTGGCTATC



GTTATGGGACTAGTGTTTATATGTGTGAAAAACGGCAACATGCGCTGTACGATATGCATA





604
ATGAACACACAGATCCTTGTGTTTGCACTGATTGCCATCATTCCCACCAATGCCGACAAA



ATCTGCTTAGGTCACCACGCTGTTAGCAACGGAACGAAGGTCAACACCCTGACCGAACGA



GGCGTCGAAGTAGTTAATGCTACCGAAACTGTGGAGAGGACCAACATACCCAGGATCTGC



AGTAAGGGTAAGAAGACAGTCGATCTAGGCCAGTGCGGACTACTCGGCACAATTACCGGA



CCTCCCCAGTGCGACCAGTTTCTTGAGTTCAGTGCTGATCTTATTATAGAACGACGAGAA



GGGAGTGATGTGTGCTATCCCGGCAAGTTTGTGAACGAAGAGGCGCTGCGACAAATCTTG



AGGGAGTCAGGCGGGATTGACAAGGAAGCAATGGGGTTTACATATTCAGGTATTCGTACT



AATGGAGCAACATCTGCCTGCCGGCGCAGTGGCTCCAGCTTTTACGCGGAAATGAAATGG



CTGTTAAGTAACACCGACAATGCAGCATTTCCCCAAATGACAAAGAGTTATAAGAATACA



CGAAAGTCACCCGCACTGATTGTATGGGGCATCCACCATTCGGTGTCGACCGCTGAACAG



ACAAAATTGTACGGCTCAGGCAACAAACTGGTGACTGTTGGTTCTTCTAACTACCAGCAG



AGCTTTGTCCCGTCACCCGGAGCCCGACCACAGGTGAATGGACAGTCCGGACGGATTGAC



TTTCACTGGCTTATGCTCAATCCCAATGATACTGTGACATTTAGTTTCAACGGGGCCTTT



ATAGCTCCCGATCGGGCTTCTTTTCTTCGAGGAAAATCAATGGGCATTCAATCCGGAGTT



CAGGTGGACGCCAATTGTGAAGGAGACTGTTACCATTCCGGAGGTACAATTATTTCCAAC



CTGCCTTTCCAAAATATCGATAGTCGAGCCGTGGGAAAGTGTCCCAGATATGTAAAACAG



AGAAGTCTATTGCTGGCTACAGGGATGAAAAATGTGCCCGAAATACCCAAGGGACGGGGA



TTGTTTGGTGCCATAGCTGGGTTTATCGAGAATGGGTGGGAAGGCCTTATCGACGGCTGG



TATGGCTTTCGGCACCAAAACGCGCAGGGTGAGGGGACCGCGGCAGACTACAAGTCTACT



CAGAGCGCAATTGATCAGATTACCGGCAAACTGAACCGACTAATAGAAAAAACAAACCAG



CAGTTTGAGCTCATTGATAATGAATTCAACGAAGTGGAGAAGCAGATTGGGAACGTGATC



AATTGGACGCGCGATTCCATCACTGAGGTGTGGAGTTACAATGCCGAACTCCTGGTGGCC



ATGGAAAACCAGCACACAATTGACCTCGCTGACTCTGAGATGGACAAGTTGTATGAGCGC



GTGAAGCGGCAGCTTAGAGAGAACGCCGAGGAAGACGGGACAGGGTGTTTTGAGATCTTC



CATAAGTGCGATGACGACTGCATGGCATCCATCCGTAACAACACATATGATCACTCAAAG



TATAGGGAGGAAGCCATGCAGAACAGGATTCAGATCGACCCTGTGAAACTCTCATCAGGG



TACAAAGATGTAATCTTGTGGTTTTCGTTTGGAGCTTCGTGCTTCATTCTGCTAGCGATT



GTCATGGGCCTTGTGTTTATCTGCGTCAAGAACGGCAACATGAGGTGTACTATCTGTATA





605
ATGAATACCCAGATTCTGGTGTTTGCGCTGATTGCCATAATCCCCACTAACGCTGATAAG



ATCTGCCTGGGGCACCATGCAGTGTCTAATGGCACTAAGGTCAATACGCTCACGGAGAGA



GGCGTGGAAGTGGTTAATGCTACCGAAACTGTGGAACGGACTAACATTCCAAGAATCTGT



TCAAAGGGTAAGAAAACTGTGGACCTCGGCCAATGTGGCTTGCTGGGCACCATCACTGGG



CCACCACAGTGTGATCAGTTTCTCGAGTTCTCTGCCGATTTAATCATCGAGCGCCGGGAA



GGATCAGATGTGTGCTACCCGGGTAAATTCGTGAATGAGGAAGCACTGAGACAGATTCTG



CGTGAATCAGGAGGGATTGATAAGGAGGCTATGGGGTTTACATACTCTGGCATCAGAACA



AATGGGGCCACCAGCGCGTGCCGGCGCTCTGGGAGTTCTTTCTACGCTGAAATGAAATGG



CTGCTTTCTAACACGGACAATGCCGCTTTCCCCCAGATGACAAAAAGCTACAAGAACACT



CGCAAGAGCCCTGCACTCATAGTGTGGGGCATCCACCACTCCGTCTCTACTGCAGAGCAG



ACCAAGCTGTACGGCAGCGGGAACAAGCTTGTAACCGTTGGATCTTCAAACTACCAACAA



TCATTCGTTCCCTCTCCTGGAGCCCGGCCCCAAGTTAATGGGCAGTCCGGGAGAATCGAC



TTCCATTGGCTGATGCTAAATCCCAATGATACAGTTACCTTTAGCTTTAACGGCGCCTTC



ATCGCTCCGGATAGAGCGAGCTTCCTTCGCGGTAAGTCTATGGGAATCCAGTCCGGGGTG



CAAGTCGACGCAAACTGCGAGGGAGACTGTTACCATTCCGGGGGTACTATCATTTCAAAT



TTACCCTTTCAGAACATTGATAGCCGCGCCGTAGGCAAATGTCCTAGGTATGTGAAACAG



AGAAGCCTGCTCCTGGCAACCGGAATGAAGAACGTGCCTGAGATCCCTAAGGGTAGAGGA



CTTTTCGGAGCTATCGCCGGGTTCATCGAGAACGGTTGGGAGGGACTCATTGATGGGTGG



TATGGTTTCCGCCACCAGAACGCCCAAGGGGAAGGCACTGCTGCTGACTATAAATCAACG



CAGTCCGCCATAGACCAGATTACAGGTAAATTAAATAGACTGATTGAGAAAACAAACCAG



CAATTCGAGCTAATCGACAATGAGTTTAATGAGGTCGAGAAGCAGATCGGTAACGTCATA



AATTGGACACGGGATAGTATCACCGAAGTGTGGAGCTACAATGCTGAGCTCCTAGTTGCC



ATGGAGAATCAACATACGATCGACCTGGCGGATTCTGAAATGGACAAGTTATACGAAAGA



GTGAAGCGACAGCTAAGAGAGAATGCAGAGGAAGACGGCACTGGCTGCTTCGAAATATTT



CACAAGTGTGATGATGACTGTATGGCAAGCATCAGGAATAACACCTACGACCACAGTAAG



TATAGAGAGGAGGCAATGCAGAACAGGATACAGATCGATCCCGTCAAACTTTCCAGTGGC



TATAAGGACGTTATCCTTTGGTTCTCGTTTGGGGCGAGCTGCTTCATCTTGCTGGCGATC



GTGATGGGCCTCGTGTTTATTTGCGTGAAAAACGGAAACATGAGGTGTACAATTTGTATT





606
ATGAATACACAAATTCTGGTCTTCGCACTGATCGCCATAATCCCCACTAACGCAGACAAG



ATCTGTCTCGGTCACCACGCCGTTTCGAATGGTACTAAGGTAAATACGCTGACAGAGAGG



GGGGTGGAAGTCGTGAACGCCACTGAGACCGTCGAAAGGACAAACATTCCCCGCATCTGT



TCGAAGGGAAAGAAGACCGTCGATCTTGGGCAGTGCGGTCTCTTGGGTACGATCACAGGG



CCTCCTCAGTGCGATCAATTCCTGGAGTTTTCAGCCGACCTGATAATCGAAAGAAGGGAG



GGAAGCGATGTGTGTTACCCCGGGAAGTTCGTGAATGAGGAAGCCCTGCGACAGATCCTA



AGGGAGAGCGGGGGAATCGATAAAGAGGCAATGGGGTTCACCTATAGTGGAATCAGAACT



AACGGCGCCACTTCCGCCTGCCGGAGATCGGGTAGCTCTTTCTATGCTGAAATGAAATGG



CTGCTCAGTAATACAGACAACGCGGCGTTCCCACAGATGACCAAGTCCTATAAGAATACC



CGGAAATCTCCTGCGCTTATTGTGTGGGGCATCCACCACTCTGTGTCCACCGCTGAGCAG



ACAAAACTTTACGGATCAGGAAATAAGCTCGTCACCGTGGGAAGCTCCAATTATCAGCAA



TCCTTCGTGCCATCCCCCGGAGCAAGACCACAGGTGAATGGACAGTCCGGGAGGATCGAT



TTCCACTGGTTGATGCTGAACCCCAATGATACTGTCACGTTCAGCTTCAACGGTGCTTTT



ATTGCTCCCGATAGGGCCAGCTTTCTGAGAGGCAAGTCCATGGGCATCCAGAGCGGGGTC



CAAGTGGACGCTAATTGCGAGGGTGATTGCTACCACTCTGGAGGCACCATCATCAGCAAC



CTGCCTTTCCAGAATATAGATTCCCGGGCGGTGGGGAAGTGCCCAAGATACGTCAAGCAA



CGGAGCCTCCTCCTTGCGACTGGAATGAAAAACGTGCCAGAGATTCCAAAGGGGAGGGGC



CTGTTTGGAGCGATTGCCGGATTCATCGAGAATGGCTGGGAAGGGCTCATTGACGGATGG



TATGGCTTTCGCCATCAGAACGCCCAGGGAGAGGGGACCGCGGCCGACTACAAGTCCACC



CAAAGCGCCATTGACCAAATCACAGGAAAGCTGAATCGCCTAATCGAAAAGACTAATCAG



CAGTTCGAGCTGATAGATAATGAGTTCAACGAGGTCGAGAAACAAATCGGAAATGTCATC



AATTGGACCCGCGACTCTATAACAGAAGTTTGGTCCTATAACGCGGAGCTGCTAGTCGCC



ATGGAAAACCAGCACACTATTGACCTTGCCGATAGCGAAATGGACAAGCTGTATGAAAGG



GTGAAAAGACAGCTGCGCGAGAATGCAGAAGAGGACGGTACCGGCTGTTTCGAGATTTTC



CATAAGTGTGACGACGACTGCATGGCATCGATTCGAAACAACACATACGACCACTCTAAG



TATAGAGAGGAGGCCATGCAGAACAGAATCCAGATCGATCCTGTGAAGCTGTCATCCGGG



TACAAGGATGTCATTCTTTGGTTCTCATTCGGTGCGTCTTGTTTCATCCEGCTCGCCATA



GTCATGGGGCTGGTCTTCATTTGCGTGAAAAACGGGAACATGCGGTGTACAATTTGCATC





607
ATGAATACCCAGATACTCGTGTTTGCCCTTATCGCTATAATCCCCACGAATGCAGACAAA



ATCTGCCTTGGGCATCACGCCGTGAGTAATGGCACCAAAGTGAACACATTGACCGAGCGG



GGGGTGGAGGTAGTCAATGCCACCGAAACAGTGGAACGCACCAACATTCCTCGGATCTGT



AGCAAAGGAAAGAAAACAGTCGATCTGGGCCAGTGTGGCCTGTTAGGAACCATCACTGGA



CCGCCTCAATGCGATCAGTTTCTCGAATTCAGCGCGGATCTCATTATTGAAAGAAGAGAG



GGTTCTGACGTGTGTTACCCCGGCAAGTTTGTGAACGAAGAAGCACTCCGCCAGATACTT



AGGGAGTCCGGCGGGATCGACAAAGAGGCTATGGGGTTTACTTATAGTGGAATCCGCACG



AACGGGGCCACGTCCGCCTGCAGACGGAGCGGCTCCTCATTTTACGCGGAGATGAAGTGG



CTGCTCAGCAACACAGACAATGCCGCCTTTCCCCAGATGACAAAGTCTTACAAGAACACC



AGAAAGTCGCCAGCCCTCATAGTCTGGGGGATACATCACAGCGTTTCCACCGCCGAGCAG



ACTAAGCTGTATGGCAGCGGAAATAAACTGGTGACTGTGGGCTCCAGCAATTACCAGCAA



AGCTTTGTACCCAGCCCCGGAGCAAGGCCCCAAGTGAATGGCCAGTCTGGTAGAATCGAT



TTCCATTGGCTTATGTTGAACCCTAACGACACGGTTACATTCAGTTTCAATGGGGCATTT



ATCGCCCCCGACCGTGCCTCTTTCTTGAGGGGTAAATCTATGGGCATCCAGTCAGGTGTG



CAGGTGGATGCTAATTGCGAAGGCGACTGCTATCACAGTGGCGGTACTATCATATCCAAT



CTGCCTTTTCAAAACATCGATTCCCGTGCGGTGGGGAAGTGTCCTCGATACGTGAAACAG



CGCTCATTGCTGTTGGCCACCGGAATGAAAAACGTGCCAGAGATCCCAAAGGGCAGAGGT



CTGTTCGGAGCTATTGCTGGCTTTATCGAAAACGGCTGGGAAGGGCTGATTGACGGCTGG



TATGGATTTAGGCACCAAAATGCTCAAGGCGAGGGCACAGCCGCCGACTATAAAAGCACT



CAAAGTGCGATAGACCAGATCACAGGCAAGCTGAACCGCCTGATTGAGAAAACAAACCAG



CAGTTCGAACTCATTGACAACGAATTCAACGAAGTGGAGAAACAGATCGGAAATGTTATC



AATTGGACAAGAGACAGTATTACAGAGGTGTGGTCCTATAACGCCGAGCTCCTGGTCGCT



ATGGAGAATCAGCATACCATCGACCTGGGGGATTCAGAGATGGACAAACTTTATGAGAGA



GTTAAAAGACAACTGCGTGAGAATGCTGAAGAAGATGGAACTGGATGCTTCGAAATTTTT



CATAAGTGTGATGATGACTGTATGGCGTCAATCCGGAATAACACCTACGATCACTCCAAA



TATAGAGAAGAGGCAATGCAGAATCGTATTCAGATAGACCCTGTGAAATTGTCCAGTGGA



TACAAGGACGTAATTTTGTGGTTCAGCTTCGGGGCTTCCTGTTTCATCCTCCTCGCCATC



GTGATGGGTCTCGTTTTCATATGCGTGAAGAACGGGAATATGAGGTGCACGATATGTATC





608
ATGAACACCCAGATTCTGGTGTTCGCTCTCATCGCAATCATACCCACCAATGCTGACAAA



ATCTGTTTGGGGCATCATGCCGTCAGCAACGGCACTAAGGTCAATACTCTTACAGAACGC



GGGGTTGAGGTTGTCAATGCAACTGAAACCGTGGAAAGAACGAATATCCCACGTATTTGC



AGTAAGGGCAAGAAAACCGTGGACCTCGGGCAATGCGGGCTGCTTGGAACGATTACCGGC



CCACCCCAATGCGATCAGTTCCTCGAGTTTTCTGCAGATTTGATTATTGAGCGAAGGGAG



GGCTCCGACGTCTGTTATCCTGGAAAGTTTGTGAATGAGGAGGCACTGCGCCAGATACTC



CGTGAAAGCGGCGGGATTGATAAGGAGGCCATGGGCTTTACTTACTCGGGAATACGCACA



AATGGAGCCACTAGCGCCTGCCGGAGGTCTGGATCAAGCTTCTACGCAGAAATGAAGTGG



TTACTAAGCAACACAGATAACGCAGCTTTCCCACAGATGACAAAAAGCTATAAGAATACT



CGCAAGTCCCCTGCCCTGATAGTATGGGGCATCCACCACTCTGTCTCTACCGCCGAACAG



ACTAAGCTGTATGGAAGCGGGAATAAACTGGTTACAGTGGGAAGCAGTAACTATCAGCAG



AGTTTTGTCCCATCCCCAGGCGCTAGGCCACAAGTCAACGGACAGAGGGGGAGAATAGAT



TTTCATTGGCTCATGTTAAATCCTAACGACACAGTGACTTTCTCGTTTAATGGCGCTTTT



ATCGCCCCTGATAGGGCCTCTTTTTTAAGAGGCAAGAGCATGGGAATCCAGTCTGGAGTG



CAGGTCGATGCTAATTGCGAAGGCGACTGCTACCACAGCGGAGGAACAATCATCTCTAAT



TTGCCCTTCCAGAATATTGATAGTCGCGCAGTGGGCAAATGCCCCCGGTACGTAAAGCAG



CGCTCACTCCTGCTGGCAACAGGGATGAAAAATGTCCCTGAGATCCCAAAGGGCAGAGGA



CTGTTTGGTGCCATTGCCGGATTCATCGAGAACGGATGGGAGGGGCTGATCGACGGATGG



TATGGATTCCGGCATCAGAACGCCCAGGGCGAAGGGACAGCCGCTGATTATAAGTCCACC



CAATCAGCCATTGATCAGATTACCGGCAAACTAAATCGCTTGATTGAGAAAACAAATCAG



CAATTCGAATTGATTGACAATGAGTTTAATGAGGTTGAGAAACAGATCGGAAACGTGATT



AATTGGACACGGGATTCTATAACCGAGGTCTGGTCATACAATGCTGAACTTCTGGTCGCG



ATGGAGAACCAGCACACAATTGACCTGGCCGATAGTGAAATGGATAAGTTATACGAACGG



GTCAAACGGCAGCTGAGGGAGAACGCCGAAGAAGACGGTACCGGTTGTTTCGAAATCTTC



CATAAGTGTGATGACGACTGCATGGCCTCAATTCGGAACAACACCTACGATCACAGCAAG



TATAGAGAAGAGGCTATGCAAAACCGCATACAGATCGACCCAGTAAAATTAAGTAGTGGC



TACAAAGATGTGATTCTTTGGTTCTCCTTTGGAGCCAGCTGCTTTATTCTGCTGGCAATA



GTTATGGGCCTCGTCTTTATCTGTGTCAAGAATGGAAACATGAGGTGTACTATTTGCATA





609
ATGAACACGCAGATCCTTGTATTTGCGCTCATAGCAATAATCCCTACGAATGCAGATAAG



ATTTGCCTGGGACACCATGCTGTCTCTAACGGAACCAAGGTCAATACACTGACTGAACGT



GGCGTTGAGGTGGTGAATGCAACTGAGACCGTTGAGCGAACCAACATCCCCCGCATTTGC



TCTAAGGGAAAGAAGACAGTCGATCTCGGACAGTGTGGCCTGCTCGGCACAATTACGGGG



CCCCCTCAGTGCGATCAGTTCTTGGAATTCTCTGCCGACCTCATCATCGAGCGCCGGGAA



GGCTCTGACGTTTGTTATCCTGGCAAATTCGTGAACGAGGAGGCATTGAGGCAAATCTTG



AGAGAATCTGGAGGTATAGATAAGGAAGCCATGGGCTTTACGTACTCTGGGATTAGGACC



AATGGTGCAACTTCTGCGTGCCGTAGGAGCGGAAGTTCTTTCTACGCTGAGATGAAATGG



CTGCTGTCGAATACTGATAATGCCGCTTTTCCCCAGATGACCAAGTCTTACAAGAATACC



AGGAAGTCTCCTGCCCTGATTGTGTGGGGTATCCACCACAGCGTGTCCACAGCCGAACAA



ACCAAACTTTATGGCTCAGGTAATAAGCTCGTCACTGTCGGTAGCTCTAATTATCAGCAG



TCTTTTGTCCCTAGCCCCGGGGCTAGGCCACAGGTCAACGGCCAGAGCGGACGGATTGAC



TTCCACTGGCTGATGCTGAACCCGAACGACACAGTAACGTTTAGCTTCAATGGCGCCTTT



ATTGCCCCGGACCGAGCTTCATTCCTGCGGGGTAAGAGTATGGGGATCCAATCAGGTGTT



CAGGTGGACGCCAATTGCGAAGGCGATTGCTATCATTCCGGGGGTACCATTATCTCCAAC



CTCCCATTTCAAAATATTGATAGCAGGGCCGTGGGCAAATGTCCCAGGTATGTTAAGCAG



CGTTCTCTGTTACTGGCCACTGGCATGAAGAATGTCCCTGAAATCCCAAAGGGCAGAGGA



CTGTTCGGCGCGATCGCGGGATTTATCGAAAACGGATGGGAGGGCTTGATCGATGGCTGG



TATGGGTTTCGACATCAGAACGCCCAAGGGGAGGGAACCGCCGCTGATTATAAAAGCACC



CAGAGTGCCATTGATCAGATCACGGGCAAACTGAACCGGCTCATTGAGAAAACAAACCAG



CAGTTCGAACTCATCGATAACGAGTTTAATGAGGTGGAGAAACAAATCGGCAACGTTATT



AACTGGACTAGGGATTCTATCACGGAGGTCTGGTCCTACAACGCAGAACTGCTGGTGGCA



ATGGAAAATCAACATACTATTGATCTGGCCGATTCCGAAATGGACAAGCTTTACGAGAGG



GTCAAGAGACAGCTGAGAGAGAACGCTGAAGAGGATGGGACCGGATGCTTCGAAATCTTT



CATAAGTGTGATGATGATTGCATGGCCAGTATCCGTAATAATACATATGATCATTCTAAA



TACCGCGAAGAGGCGATGCAGAATCGAATCCAAATTGACCCAGTTAAACTGTCTAGTGGC



TACAAAGACGTCATCCTGTGGTTTTCGTTCGGAGCTTCTTGCTTCATTCTGTTGGCAATA



GTGATGGGCCTCGTATTTATATGTGTGAAAAACGGGAATATGAGATGCACAATTTGTATT





610
ATGAATACCCAGATCCTGGTGTTCGCCCTTATTGCCATCATTCCGACCAACGCTGACAAA



ATCTGTCTCGGACACCACGCTGTCTCCAATGGGACAAAGGTGAATACCTTGACCGAGCGA



GGGGTCGAGGTCGTCAACGCGACAGAAACAGTGGAGAGGACCAACATTCCCCGGATATGC



TCAAAGGGCAAAAGAACGGTGGATCTGGGGCAATGCGGGCTGCTGGGCACTATAACCGGA



CCCCCCCAATGTGACCAGTTTCTTGAATTTTCTGCCGATCTGATAATCGAACGCCGGGAA



GGATCCGACGTGTGCTATCCTGGAAAGTTTGTGAATGAGGAAGCCCTCCGGCAGATTCTG



AGGGAATCCGGAGGGATAGATAAGGAAGCAATGGGGTTCACTTATAGCGGTATCCGCACA



AATGGGGCGACTAGTGCATGTCGTCGAAGTGGAAGCAGTTTCTATGCCGAGATGAAATGG



CTGCTAAGCAATACAGACAACGCCGCATTCCCACAGATGACCAAGTCCTATAAAAATACA



AGAAAGAGTCCCGCGCTTATCGTGTGGGGCATACATCACTCCGTCAGCACCGCCGAACAG



ACCAAGCTCTATGGCTCAGGCAACAAGTTGGTGACAGTCGGCAGTAGCAATTACCAGCAG



TCCTTCGTGCCTAGCCCAGGCGAAAGGCCTCAGGTGAATGGTTTGAGCGGCCGAATAGAC



TTCCATTGGTTAATGCTCAATCCTAACGATACAGTCACGTTCAGTTTCAATGGTGCCTTT



ATAGCGCCTGATCGCGCATCATTCCTGCGTGGAAAATCTATGGGCATTCAGAGCGGAGTC



CAGGTCGACGCCAACTGCGAAGGCGACTGTTATCACTCCGGGGGCACCATTATTTCCAAT



TTGCCCTTCCAGAACATTGATAGCAGAGCAGTTGGCAAGTGCCCGCGCTACGTAAAACAA



AGGTCTCTGCTTTTGGCTACAGGTATGAAAAATGTCCCAGAAATTCCCAAGGGCCGCGGA



TTGTTCGGGGCGATCGCTGGTTTTATTGAGAACGGTTGGGAAGGCCTCATCGATGGGTGG



TATGGTTTTCGGCATCAGAACGCCCAGGGCGAAGGCACTGCCGCGGATTATAAGTCCACC



CAGTCAGCGATCGATCAGATCACAGGAAAGCTGAACCGACTTATCGAAAAAACAAACCAG



CAGTTTGAACTAATTGACAATGAATTCAACGAGGTGGAGAAACAGATTGGCAATGTGATT



AACTGGACCCGTGATAGCATCACAGAGGTCTGGAGCTATAATGCAGAACTGTTGGTTGCT



ATGGAGAATCAGCACACCATCGACCTGGCCGACTCTGAAATGGACAAACTGTACGAGCGA



GTGAAACGGCAGCTGCGTGAGAACGCTGAGGAAGACGGCACCGGTTGTTTCGAAATCTTC



CATAAATGCGACGACGACTGTATGGCTTCTATTAGAAACAATACCTACGATCACTCCAAG



TACCGGGAGGAAGCAATGCAGAATCGAATCCAGATCGACCCAGTTAAGTTGTCCAGCGGA



TACAAGGACGTGATTCTATGGTTTAGTTTTGGAGCCTCCTGCTTCATTCTTCTGGCCATT



GTGATGGGTTTGGTTTTTATCTGTGTAAAAAATGGAAATATGCGCTGTACTATTTGTATT





611
ATGAACACTCAGATTCTTGTGTTCGCTCTGATCGCAATTATACCCACAAACGCGGATAAA



ATCTGCCTTGGACATCACGCAGTGTCGAACGGAACTAAGGTGAACACTCTCACCGAGCGG



GGCGTCGAAGTAGTCAATGCTACAGAGACCGTCGAACGCACTAATATTCCACGTATCTGC



TCCAAGGGGAAAAGGACCGTCGACCTGGGACAATGTGGCTTGCTAGGGACTATTACCGGC



CCACCGCAGTGTGATCAATTCCTCGAGTTCTCAGCCGACCTGATCATCGAGCGACGCGAG



GGCAGCGATGTCTGTTACCCCGGGAAATTTGTTAATGAGGAAGCATTAAGGCAGATCCTG



CGCGAGTCTGGCGGGATCGACAAGGAGGCCATGGGCTTTACATATTCCGGGATCCGGACA



AACGGCGCCACAAGTGCCTGTCGACGGTCAGGATCATCATTCTATGCCGAGATGAAATGG



CTTCTCAGCAATACCGATAACGCTGCATTTCCACAGATGACAAAGTCGTATAAAAACACA



AGAAAGTCACCCGCTCTGATTGTTTGGGGAATTCACCACAGTGTCTCAACCGCAGAACAG



ACCAAGTTGTACGGGAGTGGAAACAAGTTGGTAACCGTGGGATCTTCAAACTATCAGCAG



AGCTTCGTGCCAAGCCCCGGGGAACGCCCCCAAGTGAATGGACTGTCTGGACGGATTGAC



TTCCACTGGCTGATGCTGAACCCCAACGACACAGTGACATTCAGTTTTAATGGAGCATTT



ATCGCCCCGGACAGAGCAAGCTTTCTCAGGGGTAAGAGTATGGGAATTCAGAGTGGTGTA



CAGGTTGACGCTAACTGCGAAGGTGACTGTTATCATTCTGGTGGGACTATCATCTCCAAC



CTGCCTTTCCAGAACATTGACTCCAGAGCAGTCGGCAAGTGCCCCAGGTACGTGAAGCAA



AGGTCTTTGCTGCTCGCAACCGGCATGAAGAACGTGCCTGAAATACCTAAGGGCCGTGGC



TTGTTTGGCGCAATCGCGGGATTTATCGAAAATGGGTGGGAGGGGTTGATTGACGGTTGG



TACGGCTTCCGTCATCAGAATGCCCAAGGGGAGGGCACCGCCGCAGACTATAAAAGCACC



CAAAGTGCAATCGATCAGATCACCGGCAAATTGAACCGGCTGATTGAGAAAACGAATCAG



CAGTTCGAACTGATCGACAACGAATTTAACGAGGTCGAAAAGCAGATTGGAAATGTGATC



AACTGGACCCGGGATTCCATCACCGAAGTCTGGTCATATAACGCGGAACTGCTTGTAGCA



ATGGAGAATCAACACACTATCGATCTGGCGGACAGTGAGATGGATAAGCTCTACGAGAGG



GTTAAGAGACAACTGCGCGAGAATGCTGAGGAAGATGGTACCGGGTGTTTCGAGATTTTT



CACAAATGTGATGATGACTGCATGGCTAGTATTCGCAACAACACATATGATCACTCCAAA



TACCGCGAAGAGGCTATGCAGAACCGCATCCAAATAGATCCCGTAAAGCTTAGCTCGGGT



TACAAAGATGTAATCTTATGGTTTAGTTTCGGAGCGAGCTGTTTTATTCTACTCGCCATT



GTGATGGGGCTTGTCTTCATATGTGTGAAGAATGGAAATATGCGCTGCACAATCTGTATA





612
ATGAATACCCAGATTCTTGTCTTCGCACTCATAGCTATTATTCCTACGAACGCGGACAAG



ATTTGTCTGGGGCATCACGCCGTCTCCAATGGGACAAAAGTGAACACCCTGACTGAACGA



GGGGTTGAAGTGGTCAATGCAACTGAAACAGTGGAACGGACAAACATTCCAAGAATCTGT



TCCAAAGGAAAGCGAACAGTGGACCTGGGACAGTGCGGCCTGCTGGGTACCATTACTGGC



CCCCCACAGTGCGACCAGTTCCTGGAATTTAGCGCAGATCTTATCATCGAGCGGGGGGAA



GGAAGTGACGTGTGTTATCCCGGGAAGTTTGTAAACGAGGAGGCCCTCCGGCAGATCCTT



CGTGAGAGCGGCGGGATTGATAAAGAGGCTATGGGCTTTACCTATTCCGGAATAAGAACC



AACGGGGCCACTTCTGCGTGTCGTAGGAGCGGCAGCAGCTTCTACGCCGAAATGAAGTGG



CTGTTGTCTAACACCGATAATGCCGCCTTCCCTCAGATGACCAAGTCCTATAAGAACACC



CGGAAATCCCCTGCCCTGATTGTTTGGGGGATTCACCATTCCGTATCTACCGCCGAACAG



ACCAAGTTGTACGGTTCCGGAAACAAGCTCGTCACAGTTGGCTCCTCCAATTACCAGCAG



AGTTTCGTACCTTCTCCCGGCGCAAGACCACAGGTCAACGGACTAAGCGGGCGGATTGAC



TTTCACTGGCTCATGTTGAATCCAAATGACACTGTAACCTTTAGTTTCAACGGTGCCTTT



ATAGCACCAGATCGGGCCAGCTTTCTGCGTGGAAAGTCTATGGGCATTCAAAGTGGTGTG



CAAGTGGATGCTAACTGTGAGGGAGATTGCTACCATTCAGGTGGGACAATCATTAGCAAT



CTTCCGTTTCAGAATATTGATTCACGGGCTGTGGGCAAGTGCCCCCGTTACGTGAAGCAG



AGAAGCCTGCTTCTTGCCACGGGAATGAAGAATGTTCCCGAAATACCAAAGGGTAGGGGT



CTCTTCGGAGCAATAGCCGGATTTATCGAGAATGGCTGGGAGGGGCTTATCGATGGTTGG



TACGGCTTTCGCCATCAGAACGCTCAGGGAGAGGGGACCGCAGCAGACTACAAATCCACC



CAGTCTGCTATCGACCAGATCACTGGCAAGCTGAATCGGATAATCGAGAAGACTAACCAG



CAGTTTGAGCTGATCGACAATGAGTTTAACGAAGTGGAGAAACAGATTGGCAATGTGATC



AATTGGACAAGAGATTCCATTACGGAAGTTTGGTCATATAATGCCGAGCTCCTGGTTGCA



ATGGAGAACCAACATACAATCGACCTGGCGGACAGTGAGATGGACAAGCTGTACGAGCGT



GTGAAGCGCCAACTCCGGGAAAATGCTGAGGAAGACGGCACGGGCTGCTTTGAAATCTTC



CACAAGTGTGACGACGACTGCATGGCAAGCATAAGGAACAACACCTATGATCATTCTAAG



TACAGAGAGGAGGCGATGCAGAATCGCATCCAGATTGACCCAGTTAAGCTTTCCAGGGGG



TACAAAGACGTCATCTTGTGGTTTTCCTTTGGTGCCTCTTGTTTCATTTTGCTCGCTATC



GTAATGGGACTGGTATTCATCTGCGTGAAAAATGGAAATATGAGATGCACCATCTGCATT





613
ATGAACACACAAATTCTGGTGTTCGCTCTCATCGCAATAATTCCTACCAACGCCGATAAG



ATTTGCCTGGGGCACCATGCGGTCAGTAACGGAACCAAAGTCAATACACTCACAGAAAGA



GGCGTTGAGGTGGTGAATGCCACAGAAACTGTTGAACGTACAAATATTCCGCGAATCTGT



TCTAAAGGCAAGAAAACCGTTGATCTGGGTCAATGCGGCCTTCTGGGAACCATTACAGGG



CCACCTCAGTGCGACCAGTTTCTCGAATTTTCTGCTGATCTCATTATCGAGAGGCGGGAA



GGCAGTGACGTTTGCTACCCTGGTAAGTTCGTAAATGAGGAGGCCCTCAGGCAGATCCTG



AGGAAGTCCGGCGGTATTGATAAGGAAGCCATGGGCTTCACTTATTCTGGGATCAGGACC



AACGGGGCCACTTCAACATGTAGAAGGTCCGGAAGCTCTTTCTATGCAGAGATGAAATGG



CTCCTGAGCAACACAGACAACGCCGCCTTTCCACAGATGACCAAGAGCTATAAGAATACT



CGCAAATCTCCAGCCATCATAGTGTGGGGTATCCACCACAGCGTGTCCACGGCCGAGCAG



ACAAAGCTGTATGGGAGCGGCAACAAGCTGGTGACTGTCGGTAGCTCGAATTACCAGCAG



TCTTTCGTGCCTAGCCCCGGGGCCCGGCCGCAGGTCAATGGGCTTTCCGGGCGAATCGAC



TTTCACTGGTTGATGTTAAACCCAAACGACACGGTGACATTCAGCTTTAACGGCGCCTTT



ATTGCACCTGACCGCGCATGTTTCCTGAGGGGCAAGTCTATGGGTATCCAGTCTGGTGTA



CAAGTCGACGCCGACTGTGAAGGAGACTGCTACCATTCCGGGGGGACAATAATCTCAAAC



CTACCCTTCCAGAACATCGACAGTAGGGCGGTGGGCAAGTGTCCTAGGTACGTGAAACAG



CGGAGCCTGCTGTTGGCCACAGGCATGAAGAATGTCCCCGAAATTCCAAAGGGGGGGGGT



CTCTTTGGAGCAATTGCAGGATTCATTGAGAATGGTTGGGAAGGTCTCATCGATGGATGG



TACGGGTTCCGCCATCAGAACGCCCAGGGTGAGGGGACCGCAGCCGACTATAAGAGTACC



CAGTCAGCGATCGACCAAATCACCGGCAAGCTAAATCGGCTGATTGAGAAGACAAACCAA



CAGTTTGAATTAATTGACAACGAGTTTAATGAGGTGGAAAGACAGATCGGCAACGTGATC



AACTGGACACGCGATTCCATCACAGAAGTCTGGTCTTATAATGCAGAGCTGCTAGTGGCC



ATGGAGAATCAGCACACCATTGATCTAGCCGACTCTGAAATGGACAAGTTGTATGAACGG



GTAAAACGTCAGTTACGAGAAAATGCCGAGGAAGATGGCACAGGGTGTTTCGAGATTTTT



CACAAATGTGACGACGATTGTATGGCAAGTATTCGTAACAACACATACGACCACAGCAAA



TACAGAGAGGAGGCCATGCAGAACCGCATCCAGATAGACCCAGTTAAACTGAGCTCCGGG



TACAAGGATGTGATCCTCTGGTTTAGTTTCGGCGCAAGTTGTTTCATCCTACTCGCGATA



GTTATGGGCCTGGTATTCATTTGCGTCAAGAACGGGAACATGAGGTGTACCATCTGCATT





614
ATGAATACCCAGATTCTCGTGTTTGCTTTGATTGCTATCATCCCCACGAATGCTGATAAA



ATTTGCCTAGGCCATCATGCTGTGTCTAACGGGACCAAGGTGAACACCCTCACTGAGAGA



GGCGTGGAGGTCGTGAACGCGACCGAGACTGTTGAGCGCACAAACATTCCCAGGATTTGT



AGCAAAGGAAAAAGAACCGTTGATCTCGGCCAATGCGGCCTCCTGGGTACCATCACGGGG



CCTCCACAGTGTGACCAGTTCTTGGAATTCAGTGCAGACCTTATCATCGAGCGCAGGGAG



GGCTCTGATGTATGCTACCCTGGAAAATTCGTGAACGAGGAGGCTTTGAGACAAATCCTG



AGGGAGTCTGGAGGCATCGATAAGGAGGCCATGGGCTTTACATACAGCGGCATTCGCACT



AACGGAGCCACTTCCGCATGCAGGCGGTCCGGCAGCTCATTCTACGCTGAAATGAAGTGG



CTCCTGAGTAATACGGATAACGCCGCCTTTCCGCAGATGACCAAAAGTTATAAGAATACA



AGGAAATCACCTGCTCTCATTGTCTGGGGTATCCACCACTCGGTGAGCACCGCTGAGCAG



ACCAAACTGTACGGGTCAGGCAATAAACTTGTGACCGTGGGCTCAAGCAATTACCAGCAG



TCCTTTGTGCCTTCACCCGGCGAAAGACCTCAAGTCAACGGACTGTCTGGTCGGATCGAC



TTTCACTGGCTGATGTTAAACCCAAATGATACAGTGACATTCTCCTTCAACGGAGCATTC



ATAGCCCCCGATAGGGCCAGCTTCCTCCGGGGGAAATCCATGGGAATTCAGTCAGGCGTC



CAGGTTGACGCTAACTGCGAGGGTGACTGTTATCATTCCGGAGGTACTATAATAAGCAAT



CTTCCATTCCAGAATATAGATTCACGAGCGGTCGGCAAGTGTCCGCGGTACGTTAAACAG



CGTAGCTTACTGCTCGCAACCGGGATGAAAAACGTTCCAGAAATTCCTAAGGGCAGAGGG



CTGTTTGGGGCCATCGCCGGCTTCATCGAGAACGGTTGGGAAGGGCTCATCGATGGCTGG



TACGGTTTTAGACACCAGAATGCCCAGGGCGAGGGGACCGCAGCAGATTACAAGAGCACA



CAGTCAGCCATAGATCAAATTACTGGGAAGCTCAATCGGTTGATAGAAAAGACTAACCAG



CAGTTCGAATTGATCGATAATGAATTTAACGAGGTCGAGAAACAAATCGGCAATGTTATT



AATTGGACTAGAGACTCCATCACAGAAGTGTGGTCCTACAATGCCGAACTGCTGGTGGCT



ATGGAGAACCAGCACACAATCGACCTTGCAGACAGTGAGATGGATAAACTGTATGAGAGA



GTGAAAAGGCAGCTCCGCGAGAACGCTGAGGAAGATGGAACCGGCTGTTTTGAAATTTTC



CATAAGTGCGACGATGATTGCATGGCTTCTATCCGGAATAATACTTACGACCACAGTAAG



TACCGAGAAGAAGCCATGCAGAATCGAATTCAGATAGACCCCGTCAAGCTGAGCTCCGGC



TATAAAGATGTGATTCTGTGGTTCAGCTTTGGGGCCTCTTGTTTCATTCTTTTGGCCATC



GTGATGGGCCTTGTGTTCATTTGTGTAAAAAATGGCAATATGAGGTGCACAATATGTATT





615
ATGAATACCCAGATACTGGTGTTCGCCCTGATTGCAATCATCCCAACTAACGCTGATAAG



ATTTGTCTCGGTCACCACGCTGTGAGTAACGGAACTAAAGTTAACACACTGACAGAGAGG



GGAGTGGAGGTTGTTAACGCGACAGAGACAGTGGAGCGCACTAATATACCACGGATATGT



AGTAAGGGAAAAAGAACTGTGGACTTGGGTCAATGCGGACTGTTGGGGACGATAACTGGC



CCCCCTCAGTGTGATCAGTTTCTGGAGTTCTCAGCCGATCTGATCATCGAGAGGCGAGAG



GGGAGTGATGTGTGTTATCCTGGTAAGTTTGTGAATGAGGAGGCTCTCAGGCAAATCCTC



AGGGAATCTGGAGGGATCGATAAGGAGGCTATGGGCTTCACTTACTCTGGAATAAGAACT



AACGGCGCCACTAGCGCCTGTAGGCGATCCGGAAGTTCGTTCTACGCTGAAATGAAGTGG



TTGCTCAGCAACACTGACAACGCAGCATTTCCCCAAATGACCAAAAGCTATAAGAATACT



CGCAAGTCTCCCGCCCTGATAGTGTGGGGGATTCACCATAGTGTCTCTACAGCCGAGCAG



ACTAAATTATACGGCAGTGGCAACAAGCTGGTGACGGTGGGGAGTTCAAATTACCAGCAG



AGCTTCGTGCCCAGTCCGGGAGCTCGCCCTCAAGTTAATGGTCTTTCCGGCAGAATTGAT



TTTCACTGGCTGATGCTTAACCCTAACGACACCGTGACCTTTTCCTTCAACGGCGCTTTC



ATTGCCCCGGACCGAGCTAGTTTCCTTAGGGGGAAGTCTATGGGCATACAGTCTGGTGTG



CAAGTTGATGCGAATTGCGAGGGGGATTGTTACCACTCTGGAGGTACAATCATCAGTAAT



TTACCCTTCCAGAACATTGATAGTAGAGCCGTTGGGAAGTGTCCACGGTATGTTAAACAG



CGCAGCCTGCTTCTGGCCACAGGGATGAAGAATGTCCCCGAAATCCCCAAAGGCAGAGGA



TTGTTCGGCGCAATCGCGGGGTTTATTGAAAACGGTTGGGAAGGCCTCATTGACGGCTGG



TACGGGTTCCGGCACCAGAATGCTCAAGGAGAGGGCACCGCCGCCGATTATAAGTCTACC



CAGAGCGCCATCGACCAGATCACAGGCAAATTGAACCGAATTATCGAGAAGACCAACCAA



CAGTTCGAGCTTATCGACAACGAATTTAATGAAGTAGAAAAGCAGATCGGAAACGTTATT



AACTGGACTCGGGACAGTATTACTGAAGTGTGGTCCTATAATGCTGAGCTGTTGGTGGCA



ATGGAGAACCAGCACACCATTGACCTGGCCGACAGCGAGATGGACAAGCTTTACGAAAGA



GTGAAGCGACAGCTTCGGGAAAACGCCGAGGAAGATGGAACCGGCTGTTTTGAAATCTTC



CATAAGTGCGATGATGACTGTATGGCCAGTATACGCAACAACACTTATGACCATTCAAAA



TACCGCGAAGAAGCCATGCAGAATCGGATCCAGATCGACCCTGTGAAGCTGTCGAGCGGG



TATAAGGACGTGATACTGTGGTTCAGCTTCGGAGCCAGCTGCTTCATTCTGCTGGCTATT



GTCATGGGCCTGGTGTTCATTTGCGTCAAAAATGGTAATATGAGGTGTACGATCTGCATC





616
ATGAACACTCAGATCCTCGTGTTTGCCTTGATCGCAATAATCCCCACCAATGCCGATAAG



ATATGTCTCGGACACCACGCTGTGTCCAACGGGACCAAGGTTAATACTCTGACAGAGCGG



GGCGTTGAAGTGGTGAATGCCACCGAAACCGTGGAACGGACAAATATTCCACGAATTTGC



AGCAAGGGAAAGAAGACCGTGGACCTTGGTCAGTGTGGGCTGCTGGGGACTATCACCGGG



CCTCCCCAATGCGACCAGTTCCTCGAGTTCTCTGCAGATCTGATTATTGAGCGGCGCGAG



GGTAGTGATGTGTGCTACCCTGGCAAATTCGTGAATGAGGAGGCACTGAGACAGATCCTG



AGAGAGAGTGGCGGAATCGATAAAGAAGCAATGGGGTTTACCTATTCCGGGATACGGACT



AACGGGGCAACATCGGCTTGCAGGCGAAGTGGCTCATCTTTCTACGCCGAAATGAAGTGG



CTCCTGAGCAACACCGATAATGCCGCTTTCCCACAGATGACTAAGTCCTATAAGAACACC



CGGAAGAGCCCGGCCTTGATTGTCTGGGGGATCCACCATTCTGTCAGTACAGCTGAACAA



ACTAAGTTGTACGGTTCCGGAAACAAGCTGGTGACCGTGGGATCTAGCAATTATCAGCAG



TCATTCGTGCCTTCACCTGGCGCACGACCACAGGTCAATGGACAGAGTGGTAGAATCGAC



TTTCACTGGCTGATGCTTAATCCGAATGACACCGTGACCTTCTCCTTCAACGGAGCCTTT



ATTGCCCCTGACCGAGCTAGCTTTCTCAGGGGAAAGTCTATGGGCATACAGAGCGGCGTG



CAGGTCGACGCAAATTGTGAAGGGGACTGTTACCACTCAGGCGGGACCATTATAAGTAAT



CTGCCTTTTCAGAACATTGACAGCAGAGCGGTGGGCAAATGTCCGCGTTACGTGAAGCAG



AGATCACTGCTCTTGGCCACCGGCATGAAGAATGTCCCTGAGATCCCGAAAGGCAGGGGT



CTGTTTGGGGCTATTGCGGGCTTCATTGAAAACGGCTGGGAAGGTCTCATCGATGGTTGG



TACGGATTCCGGCACCAGAATGCTCAGGGGGAGGGCACCGCCGCCGATTATAAGAGTACC



CAGTCTGCCATCGACCAAATCACCGGCAAGCTTAACCGTCTTATCGAGAAAACAAATCAG



CAGTTCGAGCTGATCGATAACGAATTTAATGAGGTAGAGAAACAGATTGGTAATGTGATT



AACTGGACACGCGACTCCATTACCGAGGTGTGGTCGTATAATGCAGAATTACTGGTGGCC



ATGGAGAATCAACACACCATTGATCTGGCCGATAGCGAGATGGACAAGCTGTATGAGAGA



GTGAAGAGACAACTGAGGGAAAACGCGGAGGAGGATGGAACAGGATGTTTCGAGATCTTC



CACAAGTGTGACGACGATTGCATGGCGAGTATCCGGAACAACACCTACGATCATTCAAAA



TATCGAGAGGAAGCTATGCAAAACCGAATTCAGATCGATCCAGTAAAATTATCTTCAGGG



TATAAGGATGTCATACTATGGTTCAGCTTCGGGGCGTCGTGCTTCATCTTGCTGGCTATC



GTCATGGGGCTCGTCTTTATTTGTGTGAAAAATGGAAATATGCGGTGCACGATCTGCATT





617
ATGAACACGCAAATCCTGGTATTTGCGCTGATCGCTATCATTCCCACTAATGCTGACAAA



ATCTGTCTGGGCCATCACGCTGTGTCAAACGGAACCAAGGTGAATACGCTGACCGAACGC



GGCGTCGAGGTGGTCAATGCCACGGAAACAGTCGAAAGAACAAACATTCCCAGAATCTGC



TCAAAGGGTAAAAAGACGGTAGATCTCGGGCAGTGTGGGCTTCTTGGAACAATCACTGGC



CCACCACAATGCGATCAATTTCTCGAATTCAGCGCCGACCTGATCATCGAGAGGAGGGAA



GGTAGTGATGTGTGCTACCCCGGGAAGTTTGTGAATGAGGAGGCATTGCGCCAAATACTG



AGAGAGAGCGGAGGGATTGACAAGGAGGCCATGGGATTCACCTACAGCGGGATCAGAACT



AATGGAGCCACGAGCGCTTGCAGGAGGAGTGGAAGCAGCTTTTATGCTGAAATGAAGTGG



CTACTGTCCAATACGGATAACGCTGCGTTCCCACAAATGACAAAGTCGTACAAGAATACG



CGAAAGAGCCCAGCCCTCATTGTCTGGGGTATCCATCACAGCGTGAGTACCGCAGAACAA



ACCAAACTTTACGGGTCAGGTAACAAACTGGTAACCGTTGGAAGCTCCAATTATCAGCAA



TCGTTCGTTCCTTCACCTGGGGCTCGCCCACAAGTCAATGGACAGAGCGGCAGAATTGAC



TTCCATTGGCTCATGCTCAATCCAAACGATACAGTCACCTTTTCATTTAACGGAGCTTTC



ATCGCTCCTGATCGGGCTAGCTTTCTAAGGGGCAAGTCTATGGGTATTCAGTCCGGCGTA



CAAGTCGACGCCAACTGTGAGGGGGACTGCTACCATAGCGGAGGCACTATCATATCAAAT



CTCCCCTTCCAGAATATCGACTCCAGGGCTGTTGGTAAGTGCCCAAGATACGTGAAGCAG



AGATCCCTCCTTCTGGCTACAGGCATGAAAAATGTGCCAGAAATTCCAAAGGGACGGGGC



CTATTTGGAGCTATTGCAGGCTTCATCGAGAACGGATGGGAAGGACTGATCGATGGGTGG



TACGGATTTAGGCACCAGAACGCCCAGGGAGAGGGAACAGCTGCTGACTACAAATCTACC



CAGTCTGCAATTGATCAGATCACCGGTAAACTGAATAGACTGATTGAGAAAACTAACCAG



CAGTTCGAGCTAATTGATAATGAGTTCAATGAAGTGGAGAAGCAGATCGGCAACGTGATT



AACTGGACCAGAGATTCAATCACGGAGGTCTGGTCTTACAACGCCGAGTTGCTGGTGGCT



ATGGAAAACCAGCACACCATAGACCTGGCCGACTCTGAAATGGACAAATTGTACGAGAGG



GTAAAAAGGCAGCTCCGAGAAAACGCCGAGGAGGACGGTACTGGCTGCTTTGAGATATTT



CACAAGTGCGACGATGATTGCATGGCCTCCATTCGAAACAACACGTACGACCACAGTAAA



TACAGGGAGGAAGCCATGCAGAACCGCATCCAGATTGACCCTGTCAAGCTGAGTAGTGGC



TACAAGGACGTTATCCTCTGGTTTAGTTTTGGAGCATCATGTTTTATACTGTTGGCAATA



GTCATGGGGCTTGTCTTCATCTGCGTGAAAAATGGCAACATGCGTTGTACAATCTGCATT





618
ATGAATACCCAAATTCTGGTGTTCGCTCTAATTGCCATCATACCAACAAACGCAGACAAG



ATTTGTCTGGGCCACCACGCCGTGTCAAACGGAACGAAAGTGAACACTCTGACTGAGCGT



GGCGTGGAGGTAGTGAACGCTACCGAAACTGTGGAGCGGACTAATATCCCAAGGATCTGT



AGCAAGGGAAAAAAGACAGTGGACCTGGGTCAGTGCGGATTGCTAGGAACCATAACCGGT



CCACCTCAGTGCGATCAGTTTTTGGAGTTTAGCGCCGATCTCATCATCGAAAGAAGGGAG



GGTTCTGATGTTTGTTACCCAGGAAAATTTGTTAACGAAGAAGCCCTTCGCCAGATCCTT



AGAGAATCAGGCGGCATCGATAAAGAGGCAATGGGGTTCACCTATTCAGGAATACGCACA



AATGGCGCCACGAGCGCGTGCAGGCGCAGCGGGAGTTCATTTTATGCTGAAATGAAATGG



CTCCTCTCAAACACTGATAACGCTGCATTTCCACAAATGACGAAAAGTTATAAGAATACG



AGAAAGTCTCCAGCCCTCATTGTCTGGGGCATTCATCACTCAGTGTCGACTGCCGAGCAA



ACCAAGCTGTACGGCAGCGGTAACAAATTGGTAACTGTCGGCAGTAGTAACTACCAGCAA



AGTTTTGTGCCTAGCCCCGGCGCTCGGCCACAAGTGAACGGACAGAGCGGGCGCATCGAT



TTTCACTGGCTGATGCTAAATCCAAATGACACAGTCACCTTTTCGTTTAACGGGGCCTTC



ATCGCCCCTGACCGGGCTTCTTTCCTGAGAGGAAAAAGCATGGGAATCCAGTCCGGAGTC



CAGGTTGACGCCAACTGCGAAGGAGACTGTTATCATTCCGGGGGCACTATTATAAGCAAT



CTGCCTTTTCAGAACATAGATAGTCGCGCCGTAGGCAAGTGTCCCCGCTACGTCAAACAG



AGAAGCCTTCTGCTGGCTACCGGTATGAAGAACGTCCCCGAAATCCCTAAAGGCCGAGGA



CTATTCGGCGCTATCGCCGGCTTCATTGAAAATGGCTGGGAGGGCTTGATAGATGGGTGG



TATGGCTTTCGCCATCAGAATGCACAGGGTGAAGGGACTGCAGCCGATTATAAATCTACT



CAGTCCGCCATCGATCAGATTACCGGGAAGCTCAATAGACTCATTGAGAAGACAAATCAA



CAGTTCGAACTGATCGATAACGAGTTCAACGAGGTAGAGAAACAGATCGGGAATGTCATT



AACTGGACCCGAGATTCTATCACAGAAGTTTGGTCTTACAACGCGGAGCTGCTGGTCGCA



ATGGAAAATCAGCATACCATCGATCTGGCCGATTCAGAAATGGACAAGCTTTATGAGAGA



GTGAAGCGCCAGTTGCGCGAGAATGCGGAAGAGGACGGCACCGGATGCTTCGAGATTTTT



CACAAATGTGATGATGATTGTATGGCTTCGATTCGGAATAACACCTACGATCACTCCAAA



TATCGCGAAGAGGCTATGCAGAACAGAATACAAATCGATCCCGTCAAACTTAGCAGCGGC



TACAAAGACGTCATTCTGTGGTTTTCCTTCGGGGCATCCTGTTTTATACTGCTGGCCATA



GTGATGGGTCTGGTGTTTATATGTGTAAAGAACGGCAACATGCGCTGTACCATTTGCATC





619
ATGAACACCCAGATCCTCGTGTTCGCCTTAATCGCTATCATTCCAACCAATGCAGACAAG



ATATGTCTGGGTCATCATGCCGTTAGCAATGGCACCAAGGTCAACACCCTGACCGAGCGC



GGAGTCGAGGTTGTTAATGCAACCGAAACTGTGGAGCGGACAAATATTCCCCGGATCTGC



AGCAAGGGGAAGAGGACAGTCGATCTGGGCCAATGCGGACTGCTGGGCACAATCACCGGA



CCCCCTCAGTGCGATCAATTTCTGGAGTTCAGCGCCGACCTGATCATCGAGAGAAGGGAG



GGGAGTGACGTATGTTACCCAGGGAAGTTTGTGAACGAGGAGGCCCTGAGACAGATTCTG



AGAGAAAGCGGCGGCATCGATAAAGAGGCCATGGGATTTACCTATAGCGGCATTCGCACC



AATGGAGCCACTTCAGCTTGTAGGAGATCCGGGAGTAGCTTTTACGCTGAGATGAAATGG



CTGCTTTCCAATACTGATAATGCCGCTTTCCCACAGATGACTAAGTCTTATAAGAATACT



CGCAAGAGTCCTGCCCTGATAGTCTGGGGCATCCATCATTCCGTCTCAACCGCTGAACAG



ACCAAACTCTACGGGTCTGGGAACAAGTTGGTGACCGTGGGCTCCTCGAATTATCAACAA



TCATTCGTGCCGTCCCCCGGCGCTCGGCCGCAGGTTAACGGTCTTTCAGGCCGCATCGAC



TTCCACTGGCTAATGTTGAACCCAAACGATACTGTTACTTTTAGCTTTAACGGCGCATTT



ATTGCCCCCGACCGGGCCTCCTTCCTGCGAGGCAAGTCCATGGGTATCCAGTCTGGAGTC



CAAGTGGATGCTAACTGTGAAGGCGACTGTTACCATAGTGGAGGGACAATTATTAGTAAC



CTGCCCTTCCAGAACATTGACAGTAGGGCCGTGGGCAAATGCCCACGGTACGTGAAGCAG



CGGTCCCTGCTGCTGGCAACTGGAATGAAGAACGTGCCAGAGATCCCTAAAGGGGGGGGC



CTCTTCGGCGCTATCGCCGGGTTTATAGAGAATGGTTGGGAAGGGCTGATCGATGGATGG



TATGGGTTCCGCCACCAGAATGCTCAGGGTGAGGGGACAGCTGCTGACTACAAGTCTACA



CAGAGTGCTATTGACCAGATCACCGGAAAACTTAACAGGATCATCGAGAAAACGAATCAG



CAATTTGAGCTCATTGATAACGAGTTCAATGAAGTCGAGAAGCAAATCGGGAACGTGATA



AATTGGACACGCGACTCCATCACTGAGGTCTGGAGCTATAACGCCGAGCTTCTGGTGGCA



ATGGAGAATCAGCATACTATCGATCTCGCGGATTCCGAAATGGATAAGCTCTACGAGAGA



GTTAAGAGGCAGCTCCGCGAGAATGCCGAGGAAGATGGGACCGGATGCTTCGAGATATTC



CATAAGTGCGACGACGACTGCATGGCGTCAATAAGGAATAATACTTATGATCATTCTAAG



TACAGGGAGGAGGCCATGCAGAATCGCATTCAGATTGATCCTGTTAAACTAAGCTCAGGC



TATAAGGACGTAATATTATGGTTTTCTTTTGGCGCTTCCTGTTTTATCCTCCTGGCTATA



GTTATGGGGCTGGTGTTTATTTGTGTTAAAAATGGAAATATGAGATGCACAATTTGCATC





620
ATGAATACCCAAATTCTGGTCTTCGCTCTGATAGCTATAATCCCAACGAATGCCGATAAG



ATATGTCTGGGTCATCACGCTGTCTCCAATGGGACCAAAGTGAACACATTGACTGAACGC



GGCGTGGAGGTGGTTAACGCCACTGAGACCGTAGAGCGGACTAATATACCCCGGATCTGC



AGTAAGGGAAAAAAGACAGTCGACTTGGGTCAGTGCGGCCTGCTAGGGACCATCACAGGG



CCTCCTCAATGTGACCAGTTCCTGGAGTTCAGCGCAGACCTTATAATCGAAAGAAGAGAG



GGGTCGGACGTCTGTTACCCCGGCAAGTTTGTGAACGAGGAAGCACTGAGGCAGATCCTG



AGAGAATCCGGCGGAATTGATAAGGAAGCCATGGGTTTCACCTACAGTGGCATACGCACC



AATGGAGCAACATCCGCTTGTAGACGGAGCGGTTCTTCCTTTTACGCCGAGATGAAGTGG



CTGCTGTCCAACACGGATAATGCAGCCTTCCCTCAAATGACTAAGAGTTATAAGAATACG



AGAAAGTCCCCCGCCTTGATTGTGTGGGGGATCCACCATAGCGTTAGCACAGCCGAACAG



ACTAAGCTTTACGGTTCAGGCAACAAGCTCGTAACCGTGGGATCCTCCAATTATCAGCAA



TCCTTCGTGCCTTCTCCTGGCGCCCGCCCTCAGGTTAACGGTCAAAGCGGTCGCATAGAT



TTTCATTGGCTCATGCTGAACCCGAATGATACAGTCACGTTTTCTTTCAATGGGGCATTT



ATCGCACCAGACCGGGCCTCCTTTCTTCGCGGGAAGTCTATGGGAATACAATCCGGCGTA



CAGGTTGATGCTAACTGCGAGGGCGACTGTTATCATTCAGGGGGTACCATAATCTCCAAC



TTGCCTTTCCAAAATATTGATTCCCGGGCTGTCGGAAAGTGCCCGAGATATGTGAAGCAA



CGCAGTTTACTCCTGGCCACGGGAATGAAAAACGTTCCCGAAATCCCTAAGGGAAGGGGA



CTATTTGGTGCTATTGCAGGGTTTATTGAGAATGGCTGGGAGGGCTTAATCGACGGCTGG



TATGGCTTCCGCCACCAAAACGCACAGGGGGAGGGGACAGCAGCAGACTATAAAAGCACG



CAGAGCGCAATCGACCAAATTACCGGCAAGTTGAATAGGCTCATTGAAAAAACAAACCAG



CAATTTGAGCTCATCGACAACGAGTTCAATGAAGTTGAGAAACAGATAGGAAATGTGATC



AATTGGACTCGCGACAGCATTACCGAGGTATGGTCATACAACGCAGAGCTCTTAGTGGCG



ATGGAGAACCAGCACACCATCGATCTAGCCGACAGTGAGATGGACAAGCTGTACGAACGA



GTCAAGAGACAGTTACGAGAGAATGCCGAGGAGGACGGAACCGGCTGCTTTGAGATTTTC



CACAAGTGTGACGATGACTGTATGGCTAGCATTCGCAATAATACCTATGACCACAGTAAA



TACCGGGAGGAGGCTATGCAGAATCGTATTCAGATCGATCCTGTGAAGCTGTCTAGTGGA



TACAAGGACGTAATCCTGTGGTTTTCTTTCGGTGCTTCTTGTTTCATCCTGTTAGCAATA



GTAATGGGTCTGGTATTTATCTGCGTTAAGAACGGAAATATGCGGTGTACTATTTGCATC





621
ATGAACACACAGATACTGGTCTTTGCTCTTATCGCTATCATTCCCACCAATGCCGATAAA



ATCTGCTTGGGGCACCACGCCGTGTCCAACGGGACGAAAGTTAATACACTCACTGAGCGA



GGCGTGGAGGTCGTCAACGCCACAGAGACGGTGGAGCGCACCAACATCCCGAGGATCTGC



AGCAAGGGCAAACGAACCGTCGATCTTGGGCAGTGCGGGCTGTTGGGCACCATTACGGGA



CCTCCCCAGTGTGATCAGTTCTTGGAGTTTTCTGCTGACCTCATCATTGAGAGAAGGGAA



GGCAGCGACGTGTGCTATCCCGGCAAGTTCGTGAAAGAAGAGGCCCTGCGGCAGATACTG



CGGGAGTCAGGCGGTATTGATAAAGAAGCGATGGGCTTCACGTACAGCGGTATCAGGACT



AACGGCGCTACCAGCGCTTGCCGACGGAGCGGTAGCTCTTTCTACGCCGAGATGAAATGG



TTACTTTCTAACACCGATAACGCTGCGTTTCCACAGATGACGAAATCCTACAAGAATACT



AGAAAAAGTCCAGCCCTGATCGTTTGGGGAATTCACCACTCTGTCTCCACAGCTGAACAG



ACCAAGTTGTATGGCTCCGGCAACAAGCTGGTTACAGTAGGCTCCAGCAATTACCAGCAG



TCTTTTGTCCCCTCCCCTGGAGCTCGTCCACAGGTCAATGGACTGTCAGGCCGAATCGAC



TTCCACTGGCTGATGTTGAATCCAAACGATACAGTGACTTTCTCATTTAATGGCGCTTTT



ATTGCCCCAGATCGGGCCAGTTTCCTCAGAGGTAAGTCCATGGGAATCCAGTCGGGGGTC



CAAGTCGATGCCAACTGCGAAGGCGACTGTTACCACAGCGGCGGTACCATTATCTCCAAC



CTGCCCTTCCAAAACATCGACTCTCGGGCAGTTGGAAAATGTCCAAGGTACGTCAAGCAG



AGATCCCTGCTGCTGGCCACAGGCATGAAGAACGTGCCCGAGATTCCCAAAGGACGGGGC



CTATTCGGAGCGATCGCAGGATTCATTGAGAACGGATGGGAGGGCTTGATTGATGGCTGG



TACGGCTTTAGACACCAAAATGCTCAGGGGGAGGGCACTGCCGCCGACTACAAATCTACT



CAGTCGGCGATTGACCAGATTACTGGAAAGTTGAACCGGCTCATTGAAAAAACCAACCAG



CAGTTCGAATTGATTGATAATGAGTTCAATGAAGTGGAAAAACAGATCGGGAATGTGATT



AACTGGACCAGAGACTCCATCACAGAGGTTTGGAGCTACAACGCGGAATTACTAGTTGCC



ATGGAAAATCAGCACACCATTGACCTCGCTGACAGTGAGATGGATAAACTGTACGAGCGC



GTGAAAAGACAGCTACGCGAGAATGCGGAAGAAGACGGCACAGGATGCTTTGAGATCTTT



CACAAGTGCGACGATGATTGCATGGCTTCGATTCGGAATAATACCTACGATCACTCCAAA



TATAGAGAGGAGGCTATGCAAAATCGAATTCAGATCGACCCCGTCAAGTTGTCCTCCGGC



TACAAGGACGTTATCTTGTGGTTCTCCTTTGGCGCATCATGCTTCATTTTGCTGGCCATA



GTCATGGGCCTGGTATTCATTTGTGTCAAGAATGGAAATATGAGGTGCACCATATGCATC





622
ATGAATACCCAGATTCTTGTGTTCGCTCTGATCGCGATTATTCCTACCAACGCTGATAAA



ATCTGCCTCGGACATCACGCTGTTAGCAACGGAACCAAGGTGAACACACTGACAGAGCGC



GGGGTCGAAGTTGTCAACGCTACTGAGACGGTGGAACGGACCAACATACCACGGATCTGC



TCTAAGGGCAAGCGAACTGTGGATCTCGGGCAGTGTGGCTTGCTGGGAACGATTACGGGC



CCTCCTCAGTGTGATCAGTTTCTCGAGTTCTCTGCAGATCTGATAATCGAGAGAAGGGAA



GGATCAGATGTCTGCTACCCTGGGAAATTCGTGAAAGAAGAAGCACTGAGACAAATCTTA



CGCGAGTCAGGGGGCATAGATAAGGAAGCCATGGGCTTCACATACTCTGGGATCCGTACC



AACGGCGCCACGTCAGCTTGTCGTAGGTCTGGCTCTTCTTTCTATGCCGAGATGAAATGG



CTCCTGTCGAATACTGACAATGCTGCGTTCCCCCAGATGACTAAGAGCTACAAAAATACA



AGAAAGTCTCCCGCGCTGATAGTTTGGGGGATTCACCACTCTGTCTCCACTGCCGAACAG



ACAAAGTTATACGGCAGCGGTAACAAGCTAGTGACAGTTGGGAGCTCAAACTATCAACAA



TCATTTGTACCATCCCCCGGTGCCAGGCCACAGGTAAACGGCCTTTCCGGACGTATCGAC



TTTCACTGGCTGATGCTGAATCCCAATGATACCGTAACTTTTTCCTTCAACGGGGCTTTT



ATTGCCCCAGATAGGGCATCCTTTCTGCGAGGTAAGAGTATGGGCATACAGAGCGGCGTG



CAAGTGGACGCTAATTGTGAGGGGGACTGCTACCATTCCGGGGGAACCATCATCTCGAAT



TTACCGTTTCAGAACATCGATTCACGCGCTGTTGGGAAGTGTCCTAGGTATGTAAAACAG



CGATCCCTTCTTCTGGCCACAGGCATGAAGAACGTACCAGAGATACCTAAAGGACGGGGA



CTGTTCGGGGCCATTGCAGGGTTCATCGAAAACGGCTGGGAAGGCCTGATCGACGGCTGG



TATGGCTTTCGGCATCAGAACGCCCAGGGAGAGGGTACTGCAGCCGATTATAAGAGTACA



CAGTCTGCAATCGACCAAATTACAGGAAAGCTGAATAGACTCATAGAGAAGACAAATCAG



CAGTTTGAACTCATTGACAATGAGTTCAATGAAGTGGAAAAGCAAATCGGGAACGTGATT



AATTGGACCAGGGATAGCATAACAGAAGTCTGGTCCTATAACGCTGAACTACTTGTTGCA



ATGGAGAACCAGCACACTATCGATCTGGCAGACTCTGAAATGGACAAACTGTATGAGAGG



GTTAAACGCCAACTGAGAGAGAATGCTGAGGAAGACGGTACTGGCTGTTTTGAGATTTTC



CACAAATGTGACGACGATTGTATGGCGTCCATCAGGAACAACACCTATGACCATTCTAAA



TATAGAGAGGAAGCCATGCAGAATCGGATACAGATTGATCCTGTGAAACTTAGCTCTGGA



TATAAGGACGTGATCCTGTGGTTTTCATTTGGAGCGTCATGCTTTATCCTGCTGGCCATC



GTGATGGGATTGGTCTTCATATGTGTCAAGAATGGCAATATGCGGTGTACCATATGTATT





623
ATGAATACACAGATACTCGTGTTTGCCCTCATTGCCATCATCCCTACCAATGCAGATAAG



ATCTGCCTCGGCCACCATGCTGTTAGCAACGGAACCAAGGTTAACACCCTCACTGAACGA



GGAGTGGAGGTCGTTAACGCCACAGAAACCGTGGAACGGACGAACATCCCCCGCATCTGC



AGCAAAGGCAAGCGCACCGTGGATCTGGGGCAGTGCGGCCTGCTGGGCACGATTACAGGG



CCCCCCCAATGCGACCAGTTTTTGGAGTTCAGCGCAGACCTGATCATTGAAAGGCGTGAG



GGGAGTGACGTGTGTTATCCCGGTAAATTTGTGAACGAAGAGGCCCTCAGACAGATCCTG



CGGGAGTCTGGTGGGATCGATAAAGAGGCAATGGGCTTCACTTATTCTGGAATCCGGACC



AACGGGGCCACCTCTGCGTGCAGGCGTTCCGGCAGCTCATTCTATGCAGAGATGAAATGG



CTACTTAGTAACACGGACAACGCAGCTTTCCCCCAGATGACTAAAAGTTACAAGAACACT



CGAAAGAGTCCAGCACTCATTGTGTGGGGGATTCATCATTCCGTGTCTACCGCCGAGCAG



ACTAAACTATACGGTAGTGGGAATAAACTAGTAACCGTCGGCTCTTCTAACTACCAGCAG



TCTTTTGTGCCCTCTCCAGGTGAACGCCCCCAGGTCAACGGGCTGTCTGGTCGCATCGAC



TTTCATTGGCTGATGCTCAACCCTAATGACACAGTCACGTTCAGTTTCAATGGTGCTTTC



ATTGCACCCGATAGGGCCTCATTTCTTCGGGGCAAGTCCATGGGCATCCAAAGTGGAGTT



CAGGTGGACGCCAATTGCGAAGGTGACTGCTATCACAGTGGGGGCACAATCATTTCTAAC



CTGCCGTTTCAGAATATTGACTCCCGTGCTGTAGGGAAGTGTCCCCGATACGTGAAGCAG



CGGTCCTTGCTTCTGGCAACCGGTATGAAGAATGTCCCTGAGATTCCTAAAGGCCGGGGG



CTGTTCGGAGCTATTGCAGGGTTCATCGAAAACGGCTGGGAGGGGCTCATCGATGGTTGG



TACGGATTCAGACATCAAAATGCACAAGGGGAAGGAACCGCAGCCGACTATAAGAGCACA



CAAAGCGCTATCGATCAGATCACCGGGAAATTAAACCGCCTGATTGAGAAAACCAATCAG



CAGTTCGAGCTTATTGACAACGAATTCAATGAGGTGGAAAAACAGATAGGGAATGTGATC



AACTGGACCAGAGATTCTATCACCGAGGTTTGGTCTTATAACGCGGAACTGCTGGTTGCT



ATGGAGAATCAGCATACCATCGACCTGGCTGACAGCGAGATGGATAAGTTATACGAGCGT



GTCAAACGACAGCTGAGGGAGAATGCGGAGGAGGATGGAACCGGGTGTTTCGAGATCTTC



CATAAATGTGACGATGACTGCATGGCCAGTATTCGGAACAATACATATGACCATTCCAAA



TACCGCGAAGAGGCAATGCAGAATCGAATACAGATAGATCCTGTGAAACTGAGCAGCGGG



TATAAAGACGTCATCTTGTGGTTTAGTTTTGGGGCATCCTGCTTTATTCTGCTCGCCATA



GTGATGGGGTTAGTGTTTATATGTGTTAAAAACGGAAATATGCGGTGTACAATTTGTATC





624
ATGAATACCCAGATTCTTGTGTTTGCCCTGATCGCTATAATACCTACTAATGCAGATAAG



ATCTGTTTAGGACATCACGCCGTCTCCAATGGAACTAAGGTAAACACGCTGACCGAGCGG



GGCGTCGAGGTGGTGAACGCAACCGAAACTGTTGAGCGCACCAATATTCCCCGGATATGC



TCAAAGGGGAAGCGAACCGTTGACCTAGGCCAATGCGGCTTGCTGGGGACAATTACCGGA



CCACCCCAATGTGACCAGTTTCTGGAATTTTCAGCCGACCTAATCATCGAGCGACGCGAG



GGCAGCGACGTGTGTTATCCCGGTAAGTTTGTCAATGAGGAAGCCCTGAGGCAGATACTT



AGAGAATCGGGCGGGATCGACAAGGAGGCCATGGGGTTCACATATAGTGGTATCCGCACT



AATGGAGCTACATCCGCCTGTCGGAGGAGCGGGAGCTCCTTCTACGCTGAAATGAAGTGG



CTCCTCAGTAACACGGATAACGCTGCTTTCCCCCAGATGACTAAAAGCTATAAAAACACT



AGAAAGAGCCCAGCACTCATTGTGTGGGGTATTCACCACTCAGTGTCTACGGCCGAACAA



ACAAAATTATATGGATCCGGGAACAAGCTGGTAACCGTCGGAAGTAGCAATTATCAGCAG



TCCTTTGTGCCAAGCCCGGGAGCCCGGCCCCAGGTGAACGGCCTATCTGGGGGGATCGAT



TTTCATTGGCTTATGCTCAACCCTAACGACACCGTTACCTTTAGCTTCAACGGGGCTTTC



ATTGCACCCGACCGTGCATCATTCCTGCGTGGGAAGAGCATGGGGATACAGAGCGGCGTA



CAGGTGGACGCGAACTGCGAAGGCGACTGTTACCATTCAGGCGGCACCATTATTTCCAAT



TTGCCGTTTCAGAACATCGACTCACGCGCCGTAGGAAAATGTCCCCGGTACGTCAAACAG



CGCAGCCTCCTACTAGCCACCGGGATGAAAAACGTGCCCGAGATCCCCAAGGGACGGGGA



CTATTCGGAGCGATAGCCGGGTTCATTGAGAATGGATGGGAGGGTCTGATCGATGGCTGG



TACGGGTTCCGGCATCAAAACGCACAGGGCGAGGGGACTGCAGCCGATTACAAATCTACC



CAATCGGCAATCGACCAGATTACAGGCAAACTGAATAGGATCATAGAGAAAACCAATCAG



CAGTTCGAACTGATTGACAATGAGTTTAATGAAGTAGAGAAGCAGATTGGGAATGTGATA



AATTGGACTCGAGACAGCATTACCGAAGTCTGGTCTTACAATGCCGAGTTACTCGTCGCT



ATGGAGAACCAGCACACCATTGACCTGGCCGACTCAGAGATGGACAAACTCTATGAGCGC



GTAAAGAGACAATTGAGGGAAAACGCGGAGGAAGACGGAACAGGCTGTTTCGAAATATTT



CACAAGTGCGACGACGACTGTATGGCATCCATCCGGAATAATACCTATGATCACAGCAAG



TACAGGGAGGAGGCTATGCAAAATCGGATCCAGATTGATCCTGTAAAACTGAGCTCGGGA



TACAAGGATGTTATCCTGTGGTTTAGTTTCGGCGCCAGCTGCTTTATTCTCCTTGCCATC



GTCATGGGCCTGGTCTTCATCTGCGTCAAAAATGGAAATATGAGATGCACAATTTGCATT





625
ATGAACACTCAAATTCTCGTGTTTGCTCTAATTGCCATCATCCCGACAAATGCAGATAAG



ATTTGCCTGGGTCACCATGCGGTGTCTAATGGAACAAAGGTTAATACCCTGACCGAAAGG



GGCGTGGAGGTCGTGAATGCCACCGAGACGGTGGAAAGAACCAACATTCCAAGAATTTGC



TCCAAAGGAAAGAAAACCGTCGACCTGGGTCAGTGCGGATTGCTGGGAACAATCACCGGG



CCACCCCAGTGCGACCAGTTCCTGGAATTCAGCGCCGACCTCATTATTGAGCGCAGAGAA



GGTTCTGACGTGTGTTATCCAGGGAAGTTCGTGAACGAGGAGGCACTGCGGCAAATCCTG



CGTGAAAGCGGCGGCATTGACAAGGAGGCGATGGGCTTTACATACTCCGGGATCCGTACA



AACGGGGCCACTAGTGCGTGCAGAAGATCTGGAAGCAGCTTTTATGCTGAAATGAAATGG



TTGCTCTCCAACACGGACAACGCTGCCTTCCCCCAGATGACAAAGAGCTACAAAAATACT



CGAAAAAGCCCCGCCCTAATAGTGTGGGGCATCCACCATTCTGTGAGCACCGCCGAACAG



ACCAAGCTGTATGGCAGCGGTAACAAATTGGTTACCGTAGGCTCTTCTAACTATCAGCAG



AGCTTCGTCCCATCGCCTGGTGCCAGGCCCCAGGTCAACGGCCAAAGCGGTCGGATTGAT



TTTCACTGGTTAATGCTTAATCCAAATGATACAGTGACCTTTAGTTTTAACGGAGCTTTC



ATCGCCCCCGATCGGGCGAGCTTTCTCCGGGGGAAATCCATGGGAATCCAGTCTGGGGTG



CAGGTGGACGCTAATTGCGAGGGCGACTGCTACCACTCCGGGGGGACCATCATAAGTAAC



CTCCCTTTCCAAAACATCGATTCACGAGCTGTGGGAAAATGCCCCCGTTACGTAAAACAG



CGTTCTCTCTTATTGGCCACAGGTATGAAAAATGTGCCAGAAATTCCTAAGGGCCGGGGG



CTCTTCGGCGCCATAGCCGGATTCATTGAGAATGGGTGGGAAGGTCTGATCGACGGGTGG



TACGGTTTCCGACACCAGAACGCACAGGGAGAGGGTACGGCTGCAGATTACAAGTCTACT



CAGTCAGCTATTGACCAGATCACCGGCAAGCTGAATAGGCTTATCGAGAAAACAAACCAA



CAGTTTGAACTGATCGACAATGAGTTTAACGAGGTCGAGAAGCAGATCGGCAACGTTATT



AACTGGACTAGAGACTCCATCACCGAAGTGTGGAGCTACAATGCCGAGCTGCTAGTGGCT



ATGGAGAATCAACATACCATTGATCTGGCCGATAGTGAGATGGACAAGCTGTATGAACGA



GTCAAGCGACAACTACGCGAAAATGCGGAAGAAGATGGGACAGGATGTTTTGAGATTTTC



CACAAATGCGATGACGATTGTATGGCCAGCATCCGGAACAACACATACGATCATAGCAAA



TACAGAGAGGAGGCCATGCAAAATCGCATTCAAATAGACCCTGTCAAGCTTAGCTCCGGG



TATAAAGACGTGATTCTATGGTTCTCGTTTGGGGCCTCATGTTTCATTCTGCTGGCCATC



GTCATGGGCCTCGTGTTTATTTGCGTAAAGAATGGCAACATGCGCTGTACCATCTGTATT





626
ATGAACACTCAGATTCTGGTGTTTGCTCTGATCGCGATTATCCCCACTAATGCCGACAAG



ATATGTCTCGGTCATCATGCGGTTTCTAACGGGACGAAGGTGAACACATTGACAGAGCGA



GGGGTGGAGGTGGTTAATGCGACTGAGACTGTAGAAAGGACCAATATTCCGCGTATTTGT



AGCAAGGGTAAGAAAACTGTTGACTTGGGACAATGTGGTCTGCTCGGAACCATTACTGGC



CCCCCTCAGTGTGATCAATTCCTGGAGTTCAGCGCCGATCTGATTATAGAGCGAAGAGAG



GGTAGCGATGTTTGCTATCCCGGGAAATTTGTAAACGAGGAGGCCCTCCGCCAAATCCTA



CGAGAGTCAGGTGGGATTGACAAGGAGGCTATGGGGTTCACCTATAGTGGAATCCGGACC



AATGGGGCAACTTCTGCCTGTCGGAGATCTGGCTCGAGCTTCTACGCGGAGATGAAGTGG



TTGCTGAGTAACACTGATAACGCTGCGTTTCCCCAAATGACCAAGTCGTATAAAAATACA



AGAAAGAGTCCTGCTCTGATCGTGTGGGGAATCCATCACTCTGTAAGCACGGCCGAGCAA



ACTAAACTTTATGGATCGGGCAATAAACTTGTCACAGTGGGCAGCAGCAACTACCAGCAA



TCATTTGTGCCTTCTCCGGGCGCGAGACCACAGGTCAATGGCCAGTCTGGGAGGATCGAT



TTTCACTGGCTCATGCTAAATCCCAACGACACAGTGACCTTTAGCTTTAATGGCGCATTT



ATTGCACCTGATAGAGCGTCATTCCTTAGGGGAAAAAGCATGGGGATACAATCAGGGGTC



CAGGTCGACGCTAATTGCGAGGGCGACTGCTACCACTCAGGGGGTACCATCATATCTAAT



CTTCCATTCCAGAACATCGACTCGCGAGCCGTTGGAAAGTGCCCCAGGTACGTGAAGCAG



CGGAGTCTGCTCCTGGCAACTGGCATGAAGAACGTGCCTGAGATCCCCAAAGGCCGTGGC



TTATTTGGAGCTATCGCAGGGTTTATCGAGAATGGCTGGGAGGGATTGATCGATGGTTGG



TATGGCTTTCGGCACCAAAATGCCCAGGGAGAGGGAACCGCCGCCGATTATAAGTCAACT



CAGAGTGCGATAGATCAGATTACAGGTAAGCTAAATAGACTGATTGAGAAGACTAACCAA



CAGTTCGAGCTTATCGACAACGAATTTAATGAAGTGGAAAAGCAAATAGGAAACGTTATC



AACTGGACACGCGATAGCATCACAGAAGTTTGGTCTTACAACGCCGAGCTCTTGGTGGCT



ATGGAGAATCAACATACAATCGACCTGGCAGATAGCGAAATGGATAAGTTATACGAACGG



GTCAAGCGACAGCTGAGGGAGAACGCTGAAGAGGATGGAACTGGCTGTTTTGAGATCTTC



CACAAGTGCGATGATGACTGTATGGCAAGCATACGAAACAACACTTACGATCATTCAAAG



TACCGGGAGGAGGCCATGCAAAACAGGATTCAGATTGATCCAGTGAAGTTGTCCTCTGGC



TACAAGGATGTGATACTGTGGTTTTCCTTCGGAGCAAGCTGCTTTATCTTACTGGCAATT



GTGATGGGACTCGTGTTTATATGCGTGAAAAATGGAAATATGCGCTGTACAATCTGCATC





627
ATGAACACGCAGATACTTGTGTTTGCCCTTATTGCCATTATTCCCACTAACGCGGACAAA



ATATGCCTGGGCCATCACGCTGTCTCCAATGGGACGAAAGTGAACACATTGACCGAGCGA



GGCGTGGAAGTGGTAAATGCGACCGAAACCGTAGAGAGAACCAACATTCCTAGAATTTGC



TCCAAGGGCAAACGGACAGTAGATCTGGGGCAGTGCGGACTGTTGGGTACAATTACAGGA



CCTCCCCAGTGCGATCAGTTCCTGGAGTTTTCCGCTGATCTGATTATAGAAAGGCGAGAG



GGTTCCGACGTGTGCTACCCTGGTAAGTTTGTTAAAGAGGAAGCTCTCCGTCAGATTCTC



CGAGAGTCTGGCGGGATCGATAAAGAGGCGATGGGGTTTACCTACTCTGGAATAAGGACC



AACGGAGCAACCTCCGCCTGCAGGAGATCAGGGTCGTCCTTCTATGCTGAAATGAAATGG



TTGCTGTCTAATACCGACAATGCAGCCTTCCCCCAGATGACCAAAAGCTACAAGAATACA



CGCAAATCTCCCGCCCTGATTGTGTGGGGCATACACCATAGTGTGAGTACTGCAGAACAG



ACCAAGCTTTACGGATCCGGCAATAAGCTGGTGACTGTAGGCTCTAGCAACTACCAACAG



AGCTTTGTACCATCCCCCGGTGCACGCCCTCAGGTGAACGGACTCTCGGGGCGGATAGAT



TTCCACTGGTTGATGTTGAATCCCAACGACACCGTGACGTTCAGTTTCAACGGTGCTTTC



ATCGCGCCTGATAGGGCCTCTTTCTTAAGAGGGAAATCAATGGGCATCCAGAGCGGGGTT



CAGGTAGACGCTAACTGTGAGGGTGACTGCTATCATAGCGGCGGCACTATTATATCTAAC



CTGCCCTTCCAGAATATCGACTCCCGGGCCGTGGGAAAATGCCCAAGGTATGTGAAACAG



AGGTCACTGCTACTGGCGACCGGGATGAAGAACGTTCCAGAAATACCTAAAGGTCGTGGG



CTGTTCGGCGCAATTGCCGGTTTCATTGAAAACGGCTGGGAGGGCCTGATCGACGGATGG



TATGGGTTCAGACACCAGAACGCCCAGGGAGAGGGCACAGCTGCCGACTATAAGTCCACA



CAAAGCGCCATTGATCAGATCACAGGCAAGCTTAACAGACTGATCGAGAAGACAAACCAG



CAATTTGAGTTGATAGACAACGAGTTCAACGAAGTGGAGAAGCAAATCGGGAACGTCATT



AATTGGACCCGGGATTCTATCACCGAAGTATGGTCATACAACGCCGAGCTGCTCGTGGCT



ATGGAGAATCAGCATACCATTGATCTTGCCGATTCCGAGATGGACAAGCTGTATGAAAGA



GTCAAACGACAGTTGCGAGAAAACGCTGAAGAGGACGGAACAGGATGCTTTGAAATCTTT



CACAAATGTGACGACGACTGTATGGCAAGCATTCGGAACAATACCTATGATCACTCAAAG



TACCGAGAGGAGGCCATGCAGAATAGGATTCAGATCGACCCAGTCAAGCTCTCCTCCGGG



TACAAAGATGTAATCCTGTGGTTTTCGTTCGGCGCCAGTTGTTTCATCTTACTGGCCATA



GTCATGGGCCTGGTCTTTATCTGCGTTAAGAACGGCAACATGCGCTGCACTATTTGCATC





628
ATGAACACCCAGATACTTGTTTTTGCCCTGATTGCCATCATCCCAACCAACGCCGACAAG



ATCTGCTTGGGGCACCATGCTGTTAGCAACGGAACAAAAGTGAACACCCTGACCGAAAGA



GGCGTCGAGGTAGTAAACGCCACTGAAACGGTCGAGCGAACCAATATACCTAGGATATGT



TCAAAGGGAAAAAGGACGGTTGATTTAGGTCAGTGTGGACTTCTGGGGACAATCACCGGA



CCACCCCAATGTGACCAGTTCCTTGAGTTCAGCGCGGACCTGATTATTGAGAGACGTGAA



GGATCTGACGTCTGCTACCCAGGAAAGTTTGTGAATGAGGAAGCACTCCGCCAGATTCTC



AGGGAATCCGGCGGCATTGATAAAGAGGCAATGGGATTTACCTACTCCGGCATTCGGACT



AACGGTGCTACATCTGCATGTAGACGGTCCGGCTCTTCATTCTATGCAGAGATGAAATGG



CTGCTTTCAAATACTGATAACGCCGCCTTTCCTCAGATGACCAAATCCTACAAGAACACC



CGGAAATCCCCCGCCCTCATTGTTTGGGGGATCCACCACTCAGTGTCAACCGCCGAGCAG



ACCAAGCTCTACGGAAGTGGAAATAAGTTGGTAACTGTGGGAAGCTCTAACTACCAGCAA



AGCTTTGTGCCAAGTCCTGGAGAGAGGCCCCAGGTGAACGGACTTAGCGGTAGGATCGAT



TTTCATTGGCTTATGCTCAACCCCAACGATACGGTCACCTTTTCATTCAATGGGGCCTTT



ATTGCACCGGATAGAGCCAGCTTTCTGAGAGGGAAGTCTATGGGCATCCAGTCGGGCGTA



CAGGTGGATGCAAACTGTGAGGGGGATTGCTATCATAGTGGAGGCACCATCATAAGTAAT



CTGCCCTTCCAGAATATCGATAGCCGGGCCGTGGGCAAATGTCCAAGGTATGTGAAACAG



AGGTCACTGCTGCTCGCTACAGGCATGAAAAACGTGCCTGAAATACCCAAAGGACGGGGG



CTTTTCGGCGCCATCGCCGGCTTCATTGAGAACGGATGGGAAGGTTTGATCGATGGATGG



TATGGATTTAGGCACCAAAACGCCCAGGGGGAAGGCACCGCCGCGGACTACAAGAGTACT



CAGTCTGCAATCGACCAAATCACTGGCAAACTGAATCGGCTGATTGAGAAGACCAATCAG



CAATTCGAACTCATTGACAACGAGTTTAATGAAGTGGAGAAACAGATCGGTAACGTGATA



AATTGGACCAGAGACTCGATCACGGAAGTATGGAGCTACAATGCTGAACTGTTGGTCGCT



ATGGAGAATCAACACACTATCGACCTGGCCGACAGCGAGATGGATAAACTCTATGAAAGA



GTGAAACGGCAGCTCAGAGAGAACGCAGAGGAGGACGGAACCGGCTGCTTTGAAATATTC



CATAAATGCGACGACGATTGCATGGCCAGCATCAGGAACAATACCTATGATCATAGCAAG



TACCGGGAGGAAGCCATGCAGAATAGAATTCAGATCGACCCAGTGAAACTGTCTAGCGGA



TATAAGGACGTGATTCTGTGGTTCTCATTCGGCGCCTCATGCTTCATTCTATTGGCGATT



GTGATGGGACTTGTGTTCATCTGCGTCAAAAATGGCAATATGCGGTGCACGATATGTATC





629
ATGAACACCCAAATTCTGGTCTTTGCTCTGATCGCAATTATCCCAACCAATGCTGACAAA



ATTTGCCTCGGACATCATGCGGTATCCAACGGCACAAAGGTAAACACTCTCACTGAACGC



GGAGTTGAGGTGGTAAATGCCACGGAAACAGTTGAGAGGACTAATATACCTAGAATTTGT



AGCAAAGGAAAAAAAACGGTGGACCTCGGGCAGTGTGGCCTGCTTGGAACAATTACAGGC



CCGCCCCAGTGCGACCAGTTCCTAGAATTCTCCGCCGATCTGATCATCGAACGCCGCGAA



GGAAGCGATGTGTGTTATCCAGGCAAGTTTGTGAATGAGGAGGCCCTGAGACAAATCCTG



CGGGAGAGCGGCGGAATTGATAAAGAGGCAATGGGATTCACTTACAGTGGGATCCGGACA



AACGGGGCCACGTCGGCCTGCAGACGTAGCGGGAGTTCCTTCTATGCCGAAATGAAGTGG



CTGCTGTCCAACACTGACAACGCGGCCTTTCCACAAATGACTAAATCTTATAAAAACACA



CGGAAGTCACCAGCTCTCATCGTGTGGGGTATCCACCATTCGGTCTCTACAGCTGAGCAA



ACTAAGCTTTACGGAAGTGGCAACAAACTGGTGACAGTGGGCAGCTCTAACTACCAGCAG



TCATTTGTCCCGTCTCCCGGGGCCAGACCACAGGTTAATGGGCAGTCAGGCCGGATCGAT



TTTCATTGGTTGATGTTAAACCCAAACGACACAGTCACATTTAGTTTTAATGGGGCATTT



ATAGCCCCTGATAGAGCTAGTTTCTTGAGGGGAAAGAGTATGGGGATCCAGTCAGGTGTA



CAGGTCGACGCCAACTGCGAGGGTGACTGTTACCATTCCGGGGGTACCATCATTAGTAAC



CTGCCTTTCCAGAACATCGACAGTAGAGCAGTGGGTAAATGCCCAAGGTACGTGAAACAA



CGCAGCTTACTGCTGGCTACAGGAATGAAAAACGTGCCCGAGATTCCAAAAGGGAGGGGT



TTGTTCGGTGCTATTGCCGGTTTTATTGAAAACGGATGGGAGGGTCTCATCGATGGATGG



TATGGGTTTAGGCACCAGAATGCACAAGGGGAAGGAACTGCCGCCGATTATAAATCCACC



CAGTCCGCTATTGACCAGATTACCGGTAAACTGAATCGTTTGATTGAGAAAACAAACCAG



CAGTTTGAACTAATCGACAACGAATTCAATGAAGTGGAGAAGCAGATTGGTAACGTCATT



AACTGGACCCGTGACAGTATCACTGAAGTTTGGTCTTATAATGCCGAACTCCTAGTAGCG



ATGGAGAACCAGCACACCATAGACCTCGCCGATAGTGAAATGGACAAACTGTATGAGAGA



GTGAAGCGGCAGTTACGCGAAAACGCTGAGGAGGACGGGACTGGCTGCTTCGAGATTTTT



CACAAGTGCGACGACGACTGCATGGCATCAATCCGCAACAATACATACGATCATTCCAAG



TATCGTGAAGAAGCCATGCAGAACCGGATCCAAATAGACCCTGTCAAACTTAGCAGCGGG



TATAAAGATGTTATTCTGTGGTTTAGCTTTGGAGCCAGTTGTTTCATACTGCTGGCCATT



GTTATGGGCCTCGTCTTCATCTGCGTGAAAAACGGGAACATGCGATGTACGATCTGCATT





630
ATGAACACTCAAATTTTAGTCTTCGCCCTCATTGCGATAATCCCTACTAACGCAGACAAG



ATCTGTCTGGGACACCACGCCGTGTCTAATGGCACCAAAGTGAACACATTGACGGAGAGA



GGAGTAGAGGTGGTGAACGCCACCGAGACCGTCGAGAGAACCAATATACCTAGGATCTGC



AGCAAGGGAAAGAAGACTGTCGATCTGGGCCAATGCGGGTTGCTCGGGACTATTACTGGA



CCTCCGCAATGTGACCAGTTCCTTGAATTCTCTGCTGACCTGATAATCGAACGACGAGAG



GGATCCGATGTTTGCTATCCAGGGAAGTTTGTGAATGAGGAGGCTCTCAGACAAATCCTG



CGGGAGTCCGGCGGCATCGACAAAGAAGCCATGGGTTTCACCTATAGTGGAATTCGGACC



AATGGCGCAACCAGCGCATGCCGGCGTAGTGGAAGCTCCTTTTATGCCGAGATGAAGTGG



TTACTTTCCAATACCGATAACGCAGCATTCCCTCAGATGACCAAAAGTTACAAGAACACT



CGTAAATCTCCTGCTCTTATTGTATGGGGGATACACCACAGTGTGAGCACCGCCGAGCAA



ACTAAGCTTTACGGATCAGGGAATAAGCTTGTAACAGTGGGAAGCTCTAACTACCAACAG



TCCTTTGTTCCATCTCCCGGGGCGAGACCTCAAGTAAACGGGCAATCTGGTAGGATAGAC



TTTCATTGGCTGATGCTGAATCCGAATGATACAGTTACCTTCTCCTTTAATGGAGCCTTT



ATCGCCCCCGACAGAGCGAGTTTTCTGAGGGGGAAGTCTATGGGGATCCAGTCCGGCGTT



CAGGTAGACGCGAATTGCGAAGGGGATTGCTATCACAGCGGGGGTACAATTATCTCTAAC



CTCCCTTTCCAGAATATCGACTCCCGAGCCGTTGGGAAGTGCCCTCGGTATGTTAAGCAA



CGGAGCCTGCTGCTGGCTACCGGGATGAAAAACGTGCCTGAGATTCCTAAAGGCCGGGGC



CTATTTGGGGCCATCGCTGGTTTTATAGAGAACGGCTGGGAAGGTCTGATCGATGGCTGG



TATGGTTTTAGACATCAGAATGCCCAGGGTGAAGGGACCGCCGCCGACTACAAGAGTACC



CAATCTGCCATCGACCAGATCACCGGGAAGCTGAACCGTCTCATCGAGAAGACGAACCAG



CAGTTCGAACTGATTGATAATGAGTTCAATGAAGTGGAGAAGCAGATCGGTAACGTTATC



AACTGGACGCGCGACAGCATAACCGAGGTGTGGAGTTATAACGCTGAACTCTTGGTTGCC



ATGGAGAACCAGCATACCATCGATCTCGCCGATAGTGAGATGGATAAGCTGTATGAACGG



GTGAAAAGGCAACTGCGCGAGAACGCCGAGGAAGACGGCACCGGCTGCTTTGAAATCTTT



CACAAATGCGATGATGATTGTATGGCATCTATCAGGAACAATACCTACGATCACAGCAAA



TACCGCGAGGAAGCCATGCAGAATAGAATCCAGATAGATCCCGTGAAGCTGTCCAGCGGG



TATAAGGACGTCATCTTGTGGTTCAGTTTTGGGGCTTCGTGTTTTATTCTGTTGGCTATC



GTCATGGGCCTCGTGTTCATCTGCGTCAAGAACGGGAACATGCGCTGCACCATCTGCATA





631
ATGAACACTCAAATTTTAGTCTTTGCATTAATTGCCATTATCCCAACCAACGCAGACAAA



ATCTGCCTGGGACATCACGCCGTGTCAAACGGCACCAAAGTGAACACGCTGACCGAACGT



GGGGTCGAAGTGGTGAATGCCACAGAGACTGTCGAGCGCACAAATATCCCGCGCATTTGT



TCCAAGGGTAAGCGGACGGTGGACTTAGGTCAGTGTGGACTTCTAGGTACTATTACCGGA



CCTCCACAGTGTGACCAGTTCCTGGAGTTCTCTGCCGATCTCATCATTGAGCGTCGCGAA



GGAAGTGATGTCTGTTACCCAGGAAAATTCGTGAATGAAGAAGCCCTCCGGCAAATTCTG



CGCGAGTCCGGGGGCATCGACAAGGAGGCGATGGGCTTCACCTATAGTGGCATCCGAACA



AACGGCGCCACCTCCGCATGCCGGAGGAGTGGCAGCTCCTTCTACGCCGAGATGAAGTGG



CTCTTATCCAACACAGACAATGCCGCTTTCCCGCAGATGACAAAGAGTTACAAAAACACG



CGGAAAAGTCCCGCTTTGATTGTGTGGGGTATCCACCACTCTGTCTCTACAGCGGAGCAG



ACAAAGTTATACGGGTCTGGCAGTAAACTGGTTACAGTGGGCTCAAGCAACTACCAACAG



TCTTTCGTCCCCTCCCCTGGCGCAAGACCCCAGGTAAATGGCCTCTCTGGAAGGATTGAC



TTCCACTGGCTGATGCTCAACCCAAATGATACCGTGACATTTAGCTTCAACGGTGCATTT



ATCGCCCCAGACAGAGCTAGTTTCCTTCGGGGCAAATCAATGGGGATTCAGAGCGGAGTG



CAGGTGGATGCTAATTGTGAAGGCGATTGCTACCACTCCGGCGGTACTATTATCTCAAAC



CTGCCTTTTCAGAATATCGATAGTAGAGCCGTGGGCAAGTGCCCGCGTTATGTGAAACAG



CGCTCTCTTTTGCTCGCTACAGGAATGAAAAACGTACCAGAGATCCCCAAGGGGCGTGGC



CTATTTGGAGCTATCGCTGGTTTTATTGAAAACGGGTGGGAGGGCCTGATAGACGGTTGG



TATGGCTTCAGACACCAGAATGCTCAGGGAGAGGGCACCGCCGCCGACTATAAATCAACA



CAGAGTGCGATCGACCAGATTACCGGAAAACTGAATCGCCTCATAGAGAAGACAAACCAA



CAGTTCGAGCTCATCGACAACGAATTTAACGAGGTAGAAAAACAGATCGGTAACGTTATC



AACTGGACACGGGACAGCATCACGGAGGTGTGGTCTTACAATGCCGAGCTTTTGGTGGCT



ATGGAGAACCAGCACACAATCGACCTCGCCGATAGTGAAATGGATAAACTTTATGAGAGG



GTAAAGCGTCAGCTGCGAGAGAATGCTGAAGAAGATGGGACAGGTTGCTTTGAGATCTTC



CACAAGTGCGATGACGATTGCATGGCCTCTATTAGAAATAACACTTACGATCATAGCAAA



TATAGAGAGGAAGCTATGCAGAATAGGATCCAGATAGATCCCGTAAAGCTGTCCTCTGGA



TATAAGGACGTGATCCTCTGGTTCAGTTTTGGGGCATCATGTTTTATTCTGCTCGCAATC



GTTATGGGTTTAGTTTTCATTTGTGTCAAATCACGGAATATGAGATGTACAATCTGTATT





632
ATGAATACACAGATCCTGGTGTTCGCACTGATCGCTATCATCCCCACAAACGCTGACAAA



ATCTGTCTGGGGCACCACGCGGTGAGTAACGGCACTAAGGTGAATACACTGACCGAACGC



GGGGTAGAGGTGGTGAATGCTACAGAGACCGTTGAGCGCACTAACATCCCCAGAATATGT



AGTAAAGGTAAGAAAACCGTCGACCTGGGCCAGTGTGGCCTGCTGGGCACAATTACCGGT



CCACCCCAATGCGATCAGTTCTTAGAGTTCTCAGCAGATCTAATTATCGAGCGCCGCGAG



GGGAGCGACGTCTGCTACCCTGGGAAATTTGTCAACGAAGAGGCCCTTCGGCAAATCCTT



CGAGAGAGTGGCGGCATTGACAAGGAGGCAATGGGGTTTACTTATAGCGGAATCCGGACC



AATGGAGCAACCTCTGCATGCAGGAGAAGCGGCAGTTCCTTCTATGCCGAAATGAAATGG



CTGCTGAGCAATACAGATAACGCTGCCTTCCCACAGATGACCAAGAGTTACAAGAATACT



AGGAAGTCCCCAGCCCTGATTGTTTGGGGAATTCACCACTCCGTTAGTACCGCCGAGCAA



ACTAAACTGTACGGATCTGGAAACAAATTAGTTACAGTCGGAAGTTCTAACTACCAACAG



TCATTTGTTCCATCTCCTGGTGCTAGGCCGCAGGTCAATGGCCAATCCGGCCGAATAGAC



TTTCACTGGCTTATGCTTAATCCGAACGACACAGTGACCTTTAGCTTCAATGGCGCCTTC



ATTGCCCCTGACAGAGCAAGCTTCCTGAGAGGCAAGAGCATGGGGATTCAGAGCGGTGTC



CAGGTGGACGCTAACTGTGAGGGTGACTGCTATCACTCCGGTGGCACTATAATCTCTAAC



CTACCCTTTCAGAATATCGACAGTCGGGCTGTGGGCAAGTGCCCCCGGTATGTTAAACAG



CGTAGCCTTTTGCTGGCTACTGGGATGAAAAACGTGCCCGAGATACCCAAGGGGCGCGGA



CTCTTCGGGGCCATCGCGGGCTTCATCGAGAATGGTTGGGAAGGTCTCATCGATGGCTGG



TACGGATTCAGGCATCAGAACGCACAGGGTGAGGGGACAGCGGCTGACTACAAGTCGACC



CAGAGTGCTATCGATCAGATAACTGGCAAGCTCAACCGGCTCATAGAGAAAACGAACCAG



CAATTCGAGCTGATTGACAACGAATTCAACGAGGTTGAGAAGCAGATTGGCAATGTGATC



AACTGGACGAGAGACAGCATTACCGAGGTGTGGAGTTACAACGCCGAGCTACTGGTAGCA



ATGGAGAATCAACATACCATTGATTTGGCGGATTCTGAGATGGACAAGTTGTACGAGAGG



GTCAAGCGGCAGCTGCGCGAAAACGCAGAAGAGGACGGCACTGGCTGCTTCGAGATTTTT



CACAAATGTGATGACGATTGCATGGCGTCTATCAGGAATAACACATATGACCACAGCAAA



TACCGGGAGGAAGCGATGCAGAACCGGATCCAAATTGATCCAGTCAAGCTGTCAAGGGGC



TACAAGGATGTGATCTTATGGTTCAGTTTCGGAGCAAGTTGCTTTATTCTCCTTGCTATC



GTTATGGGACTTGTCTTCATCTGTGTTAAAAACGGTAATATGCGGTGTACCATTTGTATT





633
ATGAACACCCAGATCCTGGTATTTGCTCTGATTGCCATCATTCCTACCAATGCCGACAAA



ATCTGTCTGGGCCACCACGCAGTTTCGAATGGCACTAAAGTGAATACCCTGACCGAGCGC



GGCGTCGAGGTCGTGAATGCCACAGAGACCGTCGAACGCACAAATATACCTCGGATTTGC



AGCAAGGGAAAGCGGACAGTGGACCTCGGGCAGTGCGGACTGCTCGGGACTATAACTGGA



CCGCCTCAGTGCGATCAATTTTTGGAGTTTTCCGCTGATTTGATCATCGAGAGAAGAGAA



GGAAGCGACGTCTGCTATCCAGGAAAGTTCGTGAACGAGGAGGCCCTGAGGCAAATCTTG



AGGGAGAGTGGTGGCATCGACAAAGAGGCTATGGGTTTCACCTACTCAGGTATACGCACC



AACGGCGCAACAAGTGCTTGTCGGCGGTCAGGATCTTCCTTCTACGCCGAGATGAAATGG



TTGCTAAGTAATACAGACAATGCTGCGTTCCCTCAGATGACAAAGTCCTATAAGAATACA



CGGAAGTCACCTGCCCTGATCGTGTGGGGCATTCACCACAGCGTTAGCACAGCTGAGCAG



ACCAAGTTATATGGCAGTGGTAACAAACTCGTAACGGTGGGGAGTTCCAATTACCAACAG



AGCTTCGTGCCGTCTCCTGGAGCTCGTCCACAGGTCAACGGACTGAGTGGGCGCATTGAC



TTCCATTGGCTTATGTTAAACCCTAATGACACCGTGACGTTTAGCTTCAACGGCGCTTTT



ATCGCCCCTGACCGGGCCTCATTTCTGAGGGGAAAGAGCATGGGGATCCAGTCCGGAGTG



CAGGTGGATGCTAATTGCGAAGGGGACTGCTATCACAGCGGAGGCACCATCATTTCGAAT



CTCCCATTCCAGAACATCGACTCTAGGGCTGTGGGCAAGTGCCCTCGATATGTGAAACAG



CGGAGCTTGCTGCTTGCTACCGGGATGAAGAACGTGCCGGAGATCCCCAAGGGCCGTGGC



TTATTTGGCGCTATCGCGGGTTTCATCGAAAATGGTTGGGAGGGCCTAATAAACGGCTGG



TACGGTTTCCGCCACCAGAACGCGCAGGGCGAGGGGACCGCCGCCGATTACAAATCCACA



CAGAGCGCAATCGATCAAATAACTGGAAAGCTGAATCGCTTGATCGAAAAGACCAATCAG



CAGTTTGAGCTAATCGATAACGAATTTAATGAAGTGGAAAAGCAAATCGGAAACGTGATC



AATTGGACCAGAGACTCGATAACAGAGGTGTGGAGTTACAATGCAGAGCTGCTGGTAGCC



ATGGAAAATCAGCACACGATTGACCTGGCAGATTCAGAGATGGATAAGCTGTACGAGAGG



GTGAAGAGGCAGCTCCGTGAGAATGCTGAAGAGGATGGAACCGGGTGTTTCGAGATTTTT



CACAAATGCGACGACGATTGTATGGCCTCCATCAGGAATAACACATACGACCATAGCAAA



TACAGAGAGGAGGCAATGCAAAATCGGATTCAAATTGATCCCGTGAAACTTTCTAGCGGG



TACAAGGATGTTATCTTGTGGTTCAGTTTCGGCGCCTCCTGTTTTATTCTGCTGGCAATT



GTGATGGGTCTGGTGTTTATTTGTGTAAAGAACGGGAATATGAGGTGCACAATTTGCATC





634
ATGAACACTCAGATACTGGTTTTCGCTTTGATCGCTATCATACCCACAAATGCCGACAAG



ATATGCTTGGGTCATCACGCCGTGTCCAACGGCACTAAAGTGAACACATTGACCGAGAGA



GGAGTAGAAGTGGTCAATGCTACAGAGACCGTGGAACGCACTAATATCCCGCGGATATGT



AGTAAGGGCAAAAAAACCGTGGACCTCGGCCAGTGTGGCCTGCTGGGCACCATTACCGGC



CCGCCACAATGTGATCAGTTCTTGGAATTCTCTGCAGACCTTATCATAGAGCGCCGGGAA



GGATCTGACGTGTGTTATCCAGGCAAGTTCGTTAACGAGGAGGCCCTTAGGCAGATTTTG



CGTGAGAGCGGAGGCATCGATAAAGAAGCTATGGGGTTTACATATAGCGGTATTCGAACA



AACGGAGCCACCTCTGCATGCAGGCGGTCCGGGTCATCATTCTACGCGGAGATGAAGTGG



CTGCTCTCAAATACGGACAATGCGGCATTTCCCCAGATGACAAAAAGTTACAAAAACACA



AGGAAATCCCCAGCCCTGATCGTGTGGGGAATTCACCACAGTGTTAGCACCGCTGAGCAG



ACCAAACTCTATGGCTCTGGCAACAAATTAGTTACCGTCGGATCAAGTAATTACCAGCAG



TCTTTTGTCCCGAGCCCAGGGGCTAGACCTCAGGTGAATGGACAGTCCGGAAGGATCGAC



TTCCACTGGCTGATGCTTAATCCAAACGATACAGTTACTTTCTCATTCAATGGCGCCTTC



ATCGCTCCCGATAGAGCTTCTTTCTTGCGAGGCAAATCAATGGGCATCCAGAGCGGGGTG



CAGGTCGATGCAAATTGTGAGGGTGATTGCTATCATTCAGGCGGTACCATCATATCCAAT



CTCCCTTTCCAAAACATTGATTCCCGGGCAGTGGGAAAATGTCCCCGCTATGTGAAACAG



AGGTCACTTCTATTAGCCACAGGGATGAAAAATGTGCCAGAGATTCCCAAAGGAAGGGGC



CTCTTTGGCGCAATCGCAGGTTTCATCGAGAATGGTTGGGAGGGTCTGATCGACGGCTGG



TACGGCTTCAGGCACCAGAACGCTCAGGGGGAGGGCACCGCAGCCGATTATAAAAGCACC



CAAAGTGCTATTGATCAGATCACAGGCAAACTGAACCGGCTTATAGAGAAGACAAATCAG



CAGTTTGAGTTAATAGACAACGAATTCAACGAGGTGGAGAAACAGATTGGAAACGTTATA



AACTGGACTCGGGACTCTATTACCGAGGTTTGGTCTTACAACGCCGAACTCCTAGTGGCC



ATGGAGAATCAGCATACCATCGATCTCGCTGATTCTGAAATGGACAAGCTGTACGAGAGG



GTTAAACGGCAGCTGCGAGAGAATGCAGAGGAAGACGGAACAGGCTGCTTCGAGATCTTC



CACAAATGCGATGACGATTGTATGGCTTCCATCCGCAATAACACCTACGACCACAGCAAG



TATCGGGAAGAAGCCATGCAGAACCGCATTCAAATTGACCCGGTAAAACTTTCCAGCGGA



TACAAGGACGTCATCCTGTGGTTTAGTTTCGGTGCGAGCTGCTTCATCTTACTAGCTATC



GTGATGGGCCTCGTGTTCATCTGCGTTAAAAACGGCAACATGCGTTGTACCATATGTATT





635
ATGAACACACAGATCCTCGTTTTCGCTCTGATAGCAATTATCCCAACAAACGCAGACAAA



ATCTGTCTGGGGCACCATGCCGTGAGTAACGGCACTAAGGTCAATACACTGACAGAGCGC



GGCGTGGAGGTTGTCAATGCTACAGAAACTGTTGAGAGAACGAACATACCTCGGATTTGC



AGCAAGGGCAAAAAGACCGTCGACCTGGGCCAGTGTGGCTTGCTCGGAACCATCACCGGC



CCACCCCAATGCGACCAGTTCCTTGAATTCAGTGCGGACCTCATCATCGAAAGGAGAGAA



GGAAGTGATGTGTGCTATCCCGGGAAGTTCGTGAACGAAGAGGCCCTGAGGCAGATTCTT



CGGGAGTCTGGTGGTATCGAAAAGGAGGCCATGGGATTCACCTACAGCGGCATTCGCGCC



AACGGTGCAACTTCTGCATGTCGCCGCTCTGGGTCTTCTTTTTACGCCGAAATGAAGTGG



CTGCTTTCTAATACAGATAATGCGGCATTCCCACAAATGACCAAGTCATATAAAAACACG



AGAAAGAGTCCCGCCCTTATAGTGTGGGGGATTCACCACTCCGTCTCCACAGCTGAACAG



ACAAAATTATACGGCAGTGGGAATAAGCTTGTTACTGTCGGCTCCAGCAATTATCAGCAA



AGCTTCGTGCCATCCCCAGGGGCCAGACCACAGGTAAACGGGCTCAGCGGACGCATCGAT



TTTCATTGGTTGATGCTAAACCCAAACGACACCGTAACATTTAGTTTCAACGGTGCCTTC



ATAGCGCCCGATCGGGCATCGTTCCTGCGGGGAAAATCCATGGGCATTCAAAGCGGCGTG



CAGGTGGACGCGAATTGCGAAGGTGACTGTTATCATAGCGGCGGGACCATTATAAGCAAT



CTGCCTTTTCAGAACATCGACTCACGGGCCGTGGGCAAATGCCCTCGTTACGTGAAACAA



CGAAGCCTGCTGCTGGCGACCGGAATGAAAAATGTCCCGGAAATACCTAAAGGAAGGGGG



CTCTTCGGGGCTATAGCCGGTTTTATCGAGAACGGCTGGGAGGGCCTGATCGATGGATGG



TACGGGTTCAGGCACCAGAACGCCCAAGGGGAAGGCACGGCCGCGGACTATAAGTCAACT



CAGTCTGCCATTGACCAGATTACTGGGAAGCTCAATCGCCTGATCGAAAAGACCAACCAG



CAATTTGAGTTGATCGACAATGAGTTTAATGAAGTGGAAAAACAGATCGGGAATGTGATC



AACTGGACCAGGGACTCTATTACCGAGGTTTGGTCCTACAACGCAGAGTTACTCGTAGCC



ATGGAAAACCAACACACCATTGACCTCGCCGATAGTGAGATGGATAAACTGTATGAACGC



GTCAAGCGGCAGTTGCGAGAAAATGCAGAAGAGGATGGCACAGGGTGTTTTGAGATTTTC



CATAAGTGCGACGATGACTGTATGGCCTCCATCCGCAATAACACCTACGATCACTCAAAG



TACCGGGAAGAGGCCATGCAGAATCGAATTCAGATTGACCCAGTTAAACTATCTTCAGGG



TACAAAGATGTGATTCTATGGTTTAGTTTTGGTGCATCGTGCTTTATCCTCCTGGCTATC



GTTATGGGCCTCGTCTTTATCTGTGTCAAGAACGGGAATATGAGATGTACTATTTGCATC





636
ATGAACACCCAGATTCTAGTATTCGCCCTGATTGCAATAATCCCAACAAATGCAGATAAA



ATCTGTCTGGGACACCACGCGGTCTCAAACGGGACTAAGGTTAATACCCTCACGGAAAGA



GGAGTGGAGGTGGTGAACGCTACGGAGACCGTCGAGCGTACAAACATACCCCGGATCTGC



TCAAAAGGCAAGAGGACCGTGGATTTAGGACAGTGCGGATTGTTGGGAACAATCACCGGC



CCTCCTCAGTGTGACCAATTTCTCGAGTTTAGTGCCGATCTGATTATCGAACGGCGCGAG



GGATCAGACGTGTGCTACCCGGGGAAATTCGTAAACGAGGAGGCTCTGCGCCAGATTCTC



CGGGAGTCCGGGGGGATTGATAAGGAGGCCATGGGGTTCACATATTCTGGCATTCGGACC



AATGGCGCCACTTCTGCCTGCAGACGCTCCGGCTCGAGCTTTTATGCCGAAATGAAATGG



CTCCTTAGCAACACCGATAATGCCGCATTCCCCCAAATGACCAAAAGTTACAAGAATACA



CGTAAGTCGCCTGCACTTATCGTGTGGGGCATACACCACTCAGTGAGCACAGCTGAGCAA



ACCAAGTTATATGGTTCGGGGAGTAAGCTGGTGACCGTAGGGTCTTCAAATTATCAGCAG



AGTTTCGTCCCTAGTCCAGGCGCCAGGCCTCAGGTTAACGGTCTGTCTGGACGCATCGAT



TTTCATTGGTTGATGCTTAATCCGAACGATACAGTGACTTTCTCTTTTAATGGCGCCTTC



ATCGCCCCCGATCGCGCTAGCTTCCTCCGGGGTAAAAGCATGGGTATCCAGAGCGGCGTG



CAGGTTGACGCCAACTGCGAGGGAGACTGCTATCACAGCGGGGGTACCATCATCTCCAAC



CTTCCCTTTCAGAACATAGACTCTCGGGCTGTCGGAAAATGTCCTCGATACGTGAAGCAG



AGATCACTGCTGCTTGCTACTGGAATGAAGAACGTCCCCGAGATACCGAAAGGGAGAGGT



CTCTTTGGTGCTATAGCAGGGTTTATTGAAAACGGGTGGGAAGGCTTGATCGACGGTTGG



TATGGCTTCAGACATCAGAATGCTCAGGGCGAGGGCACAGCAGCAGATTATAAGTCGACA



CAGAGTGCAATCGATCAGATTACTGGCAAACTGAATAGGCTTATTGAGAAGACCAATCAG



CAATTTGAGCTTATCGACAACGAGTTTAACGAAGTTGAAAAGCAAATTGGGAACGTCATC



AACTGGACCCGGGACTCAATCACCGAAGTATGGAGCTATAATGCCGAGTTGCTGGTTGCA



ATGGAGAACCAGCACACTATCGATCTTGCGGATTCCGAAATGGATAAACTTTACGAAAGA



GTGAAGAGACAGCTCAGAGAAAACGCCGAGGAGGACGGTACGGGTTGTTTTGAGATATTC



CACAAGTGCGATGATGATTGCATGGCTAGCATCAGGAACAACACCTATGATCACAGCAAA



TACCGTGAGGAGGCAATGCAGAACAGGATTCAGATTGACCCTGTGAAACTGTCTAGCGGC



TACAAGGACGTGATCTTGTGGTTTTCTTTCGGTGCCAGTTGTTTTATCTTACTCGCCATT



GTCATGGGGCTCGTTTTCATTTGTGTAAAAAATGGAAACATGAGGTGTACGATTTGTATA





637
ATGAACACACAAATTCTCGTGTTTGCCCTAATCGCCATTATCCCGACAAACGCAGATAAG



ATCTGTCTGGGGCACCACGCAGTCAGCAATGGCACCAAAGTGAATACTCTTACCGAGAGA



GGAGTGGAAGTCGTGAATGCCACGGAGACCGTCGAGAGGACTAATATCCCAAGGATTTGT



AGCAAAGGTAAGAAAACGGTTGACCTGGGCCAATGCGGCCTGCTGGGCACAATCACAGGT



CCGCCCCAGTGCGATCAGTTCCTGGAGTTCTCAGCGGATCTGATAATTGAGCGGCGAGAG



GGGTCAGATGTATGTTACCCAGGTAAATTCGTCAACGAGGAGGCACTGCGGCAGATCCTG



CGAGAAAGTGGAGGGATAGAAAAGGAAGCAATGGGTTTTACCTACTCCGGAATCCGAGCC



AATGGGGCCACTTCCGCGTGTAGGAGAAGCGGAAGTTCTTTCTACGCTGAAATGAAGTGG



CTCCTGAGTAACACAGATAACGCGGCTTTCCCTCAAATGACCAAGTCATACAAGAATACG



CGCAAGTCACCAGCCCTCATTGTGTGGGGAATCCATCATTCCGTCTCGACTGCGGAACAG



ACAAAACTCTACGGATCCGGAAACAAACTGGTGACCGTAGGTTCCAGTAATTACCAGCAA



AGTTTTGTGCCCTCACCCGGAGCCAGGCCTCAGGTCAATGGGTTAAGTGGGCGCATTGAC



TTCCACTGGTTGATGCTGAATCCCAACGACACAGTGACTTTCTCTTTCAACGGGGCTTTC



ATAGCTCCCGATCGGGCCTCTTTCCTGCGGGGTAAGTCTATGGGTATTCAAAGCGGCGTC



CAGGTGGATGCTAATTGTGAAGGGGACTGTTACCACTCGGGAGGCACAATCATTAGTAAC



CTGCCTTTCCAGAATATTGACTCGAGGGCAGTAGGCAAGTGTCCCCGCTATGTGAAGCAA



AGGTCACTCCTTTTGGCAACCGGGATGAAGAATGTGCCCGAGATACCAAAGGGTAGAGGG



CTATTTGGCGCAATTGCAGGATTTATCGAGAATGGTTGGGAGGGCCTGATTGACGGCTGG



TACGGGTTTCGGCATCAGAATGCCCAGGGGGAAGGGACTGCCGCAGACTACAAAAGCACA



CAGTCGGCTATTGATCAGATAACGGGAAAACTGAACAGGTTGATTGAGAAGACCAACCAA



CAATTCGAACTTATAGACAACGAGTTCAACGAGGTCGAGAAGCAAATCGGCAACGTGATC



AATTGGACCCGGGACTCGATCACCGAGGTGTGGTCATATAACGCTGAGCTGTTAGTAGCT



ATGGAGAATCAGCACACGATCGACCTTGCAGATAGCGAGATGGATAAACTGTATGAACGG



GTCAAGCGGCAGCTGAGAGAAAATGCCGAAGAGGACGGTACGGGCTGCTTTGAAATTTTT



CATAAGTGCGACGATGACTGCATGGCCAGTATTAGAAACAACACCTACGACCATTCCAAA



TATCGGGAAGAAGCGATGCAGAACAGAATTCAGATAGATCCAGTTAAGCTGTCCTCTGGA



TATAAGGATGTGATACTGTGGTTTTCTTTTGGCGCCAGTTGCTTTATATTGCTCGCAATT



GTGATGGGGCTGGTGTTCATTTGCGTCAAAAACGGGAACATGAGGTGCACCATTTGCATT





638
ATGAATACACAGATTCTGGTATTTGCTCTGATCGCGATTATTCCGACGAATGCAGATAAG



ATCTGTTTAGGCCACCACGCTGTTAGCAATGGGACGAAAGTGAATACTCTAACAGAACGT



GGGGTGGAAGTCGTCAATGCTACGGAGACTGTCGAGCGCACCAATATTCCAAGGATCTGT



TCCAAGGGTAAGAAGACTGTGGACCTCGGGCAATGCGGTCTCCTAGGCACCATTACCGGT



CCTCCTCAGTGCGATCAGTTTCTGGAATTCTCTGCAGATCTTATTATAGAGCGGCGCGAG



GGCAGTGATGTGTGCTACCCAGGTAAGTTCGTCAATGAAGAGGCTCTGCGTCAAATTTTG



AGAGAGTCAGGCGGCATTGATAAGGAGGCCATGGGCTTTACCTACAGCGGAATCCGCACC



AACGGAGCAACCAGCGCCTGTCGGAGAAGCGGTAGCAGTTTCTACGCCGAAATGAAATGG



CTACTTTCTAATACCGATAATGCTGCGTTTCCACAGATGACAAAGAGTTACAAGAACACC



CGTAAGAGTCCTGCCCTCATCGTGTGGGGGATCCATCACAGTGTGTCAACCGCAGAGCAA



ACCAAATTGTATGGTTCCGGAAACAAACTGGTTACCGTGGGCTCTAGCAATTACCAGCAG



AGTTTCGTTCCGTCCCCCGGCGCTAGACCCCAAGTCAATGGTCAGAGCGGAAGAATCGAT



TTCCACTGGCTGATGCTGAATCCCAATGACACTGTGACTTTCTCCTTTAATGGGGCCTTC



ATTGCTCCCGACCGCGCTTCATTCTTGCGCGGCAAATCCATGGGAATACAGAGCGGTGTG



CAGGTGGATGCCAATTGCGAAGGTGATTGTTATCACAGTGGAGGAACTATTATCTCTAAT



CTGCCGTTTCAGAACATTGACAGCAGAGCCGTTGGCAAGTGTCCACGATACGTCAAACAG



CGGTCCCTCCTGTTGGCCACAGGCATGAAGAACGTGCCTGAGATCCCTAAGGGGCGCGGA



CTGTTTGGAGCCATCGCGGGATTTATTGAGAACGGATGGGAAGGCTTGATAGATGGCTGG



TATGGCTTTAGGCACCAGAATGCACAGGGGGAGGGCACCGCCGCTGATTACAAGAGCACG



CAGTCTGCGATCGACCAAATAACCGGTAAGTTAAATCGCCTGATCGAGAAAACCAATCAG



CAGTTCGAGCTGATCGACAACGAGTTTAATGAAGTCGAAAAACAGATCGGCAACGTGATC



AATTGGACCAGGGACAGTATCACAGAGGTATGGAGCTACAATGCCGAGCTGCTGGTGGCC



ATGGAGAATCAGCATACAATTGACCTAGCTGATAGTGAGATGGACAAACTGTATGAGAGG



GTCAAGAGACAATTGCGGGAAAACGCGGAGGAAGATGGGACAGGCTGCTTCGAGATCTTC



CATAAGTGCGACGACGACTGTATGGCCAGTATCAGAAATAACACGTACGACCACTCGAAG



TATAGGGAGGAGGCAATGCAGAACAGAATTCAGATCGACCCTGTGAAGCTTAGTAGTGGA



TACAAGGACGTGATTCTCTGGTTCTCTTTCGGGGCCTCATGTTTCATTTTGCTCGCTATA



GTTATGGGCCTAGTGTTCATCTGCGTGAAGAATGGGAATATGCGGTGCACGATTTGCATC





639
ATGAATACTCAGATCTTAGTGTTCGCATTGATCGCCATCATCCCAACCAACGCCGATAAA



ATTTGCCTTGGACATCATGCTGTGAGCAACGGCACAAAGGTCAATACACTTACAGAAAGA



GGGGTGGAAGTGGTGAACGCCACAGAAACCGTGGAACGGACGAACATTCCCCGAATTTGT



TCTAAGGGAAAGAGAACAGTAGACCTCGGACAGTGTGGCCTCCTGGGCACCATAACCGGC



CCTCCACAGTGTGACCAGTTTCTGGAATTCAGCGCGGATCTGATTATTGAGAGGCGGGAG



GGCTCCGATGTCTGCTACCCTGGCAAGTTTGTGAACGAGGAGGCCCTGAGGCAGATCCTA



CGGGAGTCCGGAGGGATCGATAAAGAGGCAATGGGTTTTACCTACAGCGGCATCCGGACC



AATGGAGCCACTTCTGCATGCCGGCGCTCCGGGAGTTCATTTTATGCTGAGATGAAATGG



TTACTTTCTAACACCGATAACGCAGCCTTCCCACAGATCACCAAGAGCTATAAAAATACG



CGAAAATCTCCAGCCCTCATAGTCTGGGGTATCCATCACTCTGTTAGCACAGCGGAGCAG



ACCAAGTTATACGGGTCAGGAAATAAACTTGTGACAGTGGGCTCCTCTAACTATCAGCAG



TCTTTTGTGCCCAGCCCTGGGGCCAGGCCCCAAGTCAATGGCCTTTCTGGTAGGATTGAT



TTCCACTGGTTGATGTTGAACCCCAATGATACCGTCACATTCAGCTTTAATGGTGCTTTT



ATCGCCCCTGACCGAGCTAGTTTCCTAAGAGGAAAATCTATGGGTATCCAGTCTGGCGTT



CAGGTGGACGCCAATTGTGAGGGCGACTGTTATCATTCCGGGGGAACCATCATCTCTAAC



CTTCCCTTCCAAAATATCGACTCCAGGGCAGTTGGCAAATGTCCACGGTATGTGAAGCAG



AGATCACTCCTGTTAGCGACTGGGATGAAAAACGTGCCAGAAATCCCTAAAGGTCGTGGA



TTGTTCGGAGCGATCGCGGGATTTATCGAAAACGGGTGGGAGGGTCTTATAGACGGCTGG



TATGGGTTTAGACACCAGAACGCACAGGGTGAGGGCACCGCGGCAGACTACAAATCTACA



CAATCTGCAATAGATCAGATCACCGGCAAGCTGAACCGACTTATTGAAAAGACCAATCAG



CAGTTTGAGTTAATCGATAACGAATTCAACGAGGTGGAGAAGCAAATAGGGAATGTTATT



AACTGGACACGGGACTCAATCACAGAAGTATGGTCGTATAATGCAGAGCTGCTAGTCGCA



ATGGAGAATCAGCATACGATTGACCTCGCCGACAGTGAGATGGACAAGTTGTATGAAAGG



GTCAAAAGACAGCTCCGGGAAAATGCCGAGGAAGACGGCACAGGCTGTTTTGAAATATTC



CATAAGTGCGACGATGACTGCATGGCAAGTATTAGGAACAACACGTATGACCATTCAAAG



TACAGGGAGGAGGCCATGCAGAACCGCATCCAGATTGATCCAGTTAAGCTTAGCAGTGGC



TATAAGGATGTCATCCTGTGGTTTAGTTTTGGCGCCTCCTGTTTTATCCTGCTGGCCATC



GTTATGGGGCTTGTGTTCATATGCGTGAAGAATGGCAATATGCGCTGCACCATTTGTATT





640
ATGAATACACAAATTCTGGTATTCGCCCTCATAGCTATAATTCCCACCAACGCCGATAAG



ATTTGTTTAGGTCACCACGCCGTGTCAAACGGGACAAAGGTTAATACACTTACAGAGCGG



GGCGTGGAAGTCGTGAACGCTACTGAGACAGTCGAAAGGACTAACATCCCCAGAATTTGT



AGCAAAGGAAAAAAGACCGTGGATTTGGGGCAGTGTGGCTTACTAGGGACAATCACCGGT



CCACCCCAGTGTGACCAGTTCCTCGAGTTCTCAGCGGACCTAATTATCGAGCGTCGAGAG



GGCAGCGATGTGTGCTATCCCGGGAAATTCGTGAATGAGGAGGCCTTACGGCAGATCTTG



CGTGAAAGTGGGGGCATAGATAAAGAGGCGATGGGGTTCACGTATTCTGGCATTCGCACC



AACGGAGCTACCTCAGCCTGTCGTCGTTCAGGATCCAGCTTCTACGCAGAAATGAAGTGG



TTACTCTCTAACACAGATAACGCAGCCTTCCCGCAAATGACGAAGAGCTACAAAAACACT



CGCAAATCCCCCGCCCTCATCGTCTGGGGTATTCACCACAGCGTTAGCACCGCTGAACAG



ACTAAATTATACGGCAGCGGAAATAAGCTTGTCACCGTCGGGAGCTCCAACTATCAGCAG



AGCTTTGTCCCATCTCCTGGGGCCCGGCCCCAGGTGAACGGACAGTCCGGGCGCATTGAT



TTCCACTGGTTGATGCTGAACCCAAACGACACTGTTACGTTCAGCTTTAACGGCGCCTTC



ATTGCACCTGACCGAGCTAGCTTTTTGCGGGGCAAATCGATGGGAATACAGTCAGGGGTC



CAGGTAGACGCCAACTGCGAAGGCGATTGCTACCATTCCGGCGGGACAATCATCTCCAAC



CTGCCCTTCCAGAACATTGACAGCCGGGCAGTCGGGAAGTGTCCCAGATATGTGAAACAA



CGCTCTCTGCTGCTTGCGACCGGCATGAAAAACGTTCCAGAAATCCCGAAGGGGCGAGGT



TTGTTTGGCGCTATAGCTGGGTTCATTGAGAACGGCTGGGAAGGCCTCATCGACGGCTGG



TATGGATTTAGGCATCAAAATGCACAGGGCGAAGGTACCGCTGCCGACTATAAGTCAACT



CAGAGCGCAATAGACCAAATTACCGGAAAGCTCAATCGCCTGATTGAGAAAACCAATCAG



CAGTTTGAACTGATAGACAACGAATTTAATGAAGTGGAGAAGCAGATCGGGAATGTGATC



AACTGGACTCGTGACAGTATTACTGAGGTATGGAGTTATAACGCTGAACTTCTGGTGGCT



ATGGAGAACCAACACACTATTGATCTCGCCGACTCCGAGATGGATAAACTCTACGAAAGA



GTTAAAAGACAGCTTAGGGAAAACGCCGAGGAGGATGGTACTGGATGTTTCGAGATCTTT



CATAAATGCGATGACGACTGCATGGCTAGCATCCGGAATAACACCTACGATCATTCTAAG



TATCGTGAAGAAGCCATGCAAAATCGTATTCAGATTGATCCGGTAAAATTGAGCTCAGGC



TATAAGGACGTCATACTGTGGTTCTCCTTCGGCGCTTCCTGCTTTATCTTATTAGCAATT



GTGATGGGATTAGTTTTCATCTGCGTGAAAAACGGAAACATGCGCTGTACCATTTGCATA





641
ATGAACACTCAAATTTTAGTGTTCGCCTTGATAGCAATCATCCCCACAAATGCGGATAAA



ATCTGTCTCGGCCATCATGCCGTGTCTAATGGTACCAAAGTAAATACCCTTACCGAGCGT



GGGGTTGAGGTCGTTAATGCCACCGAGACTGTGGAGAGAACCAATATCCCCCGCATCTGT



TCCAAGGGAAAAAAGACCGTTGACCTCGGTCAGTGTGGTCTGCTTGGTACAATAACCGGA



CCGCCCCAGTGCGACCAATTCCTGGAATTCAGTGCGGATCTCATAATCGAAAGGCGAGAA



GGCTCCGATGTTTGTTACCCCGGAAAGTTCGTCAACGAGGAGGCCCTGCGACAGATATTG



CGGGAAAGCGGAGGCATCGATAAGGAGGCTATGGGCTTCACATATAGTGGAATCCGCACG



AATGGGGCCACCTCAGCCTGTCGGCGCAGCGGGTCTAGTTTTTATGCTGAAATGAAGTGG



CTTCTTTCGAATACTGACAATGCTGCCTTCCCCCAGATGACCAAGAGTTATAAAAATACC



AGAAAGAGCCCTGCCCTGATAGTCTGGGGAATCCATCACAGCGTAAGCACTGCCGAACAG



ACTAAGCTCTATGGCAGCGGGAATAAGCTCGTGACCGTGGGCAGTTCCAATTACCAGCAG



AGCTTTGTGCCATCCCCGGGGGCCCGTCCACAGGTTAACGGGCAATCTGGCCGAATTGAT



TTTCATTGGCTGATGCTGAATCCAAACGATACTGTGACTTTCTCTTTTAACGGAGCCTTC



ATTGCACCCGATCGGGCAAGCTTCCTGCGGGGAAAATCTATGGGAATTCAGAGTGGGGTG



CAGGTGGACGCAAACTGTGAAGGCGATTGCTACCACTCTGGCGGGACAATCATTAGCAAT



CTGCCTTTCCAGAACATAGACAGCCGCGCAGTTGGAAAATGCCCGCGTTATGTCAAGCAA



AGGAGTTTACTGCTCGCTACAGGCATGAAGAATGTTCCGGAGATCCCGAAGGGAAGAGGT



TTGTTCGGCGCCATAGCAGGATTCATTGAAAATGGCTGGGAAGGGTTAATCGACGGGTGG



TATGGTTTTCGACACCAGAACGCACAAGGGGAGGGGACAGCAGCAGATTACAAGAGCACA



CAGTCAGCAATTGACCAGATTACTGGAAAGCTAAACCGGCTCATCGAGAAGACCAACCAG



CAGTTCGAATTGATTGACAACGAATTTAATGAGGTGGAAAAACAGATCGGTAACGTCATA



AACTGGACTAGAGATTCCATTACTGAGGTCTGGTCATATAATGCCGAACTGCTCGTGGCG



ATGGAGAATCAGCATACCATAGATCTCGCCGACTCCGAGATGGACAAACTTTATGAACGG



GTGAAGCGCCAGCTGCGGGAAAATGCCGAAGAGGACGGTACAGGGTGTTTCGAGATTTTC



CATAAATGTGATGACGACTGCATGGCAAGCATACGCAATAACACATATGATCACTCTAAG



TATAGGGAAGAGGCCATGCAGAACCGAATTCAAATCGACCCAGTAAAGCTTTCTAGCGGC



TATAAAGATGTGATTCTGTGGTTTAGCTTCGGGGCCTCTTGTTTTATCCTGTTAGCCATC



GTCATGGGGCTAGTTTTCATCTGCGTGAAAAATGGCAACATGCGTTGCACTATATGCATC





642
ATGAATACGCAGATCCTCGTGTTCGCACTGATAGCGATCATCCCGACAAATGCTGACAAA



ATCTGTTTGGGCCATCATGCCGTTAGCAATGGTACCAAAGTGAACACTCTCACTGAGCGC



GGCGTGGAAGTGGTGAACGCCACTGAAACAGTAGAAAGAACAAACATTCCCAGAATCTGC



AGTAAGGGTAAGAAAACTGTCGACTTGGGCCAGTGTGGCCTATTAGGAACAATCACCGGA



CCTCCCCAATGCGATCAGTTCCTAGAATTTAGCGCTGATCTGATAATTGAAAGAAGAGAA



GGTTCGGATGTCTGTTACCCGGGTAAATTCGTGAACGAAGAAGCCTTAAGACAGATTCTC



AGAGAAAGTGGCGGAATTGATAAAGAAGCCATGGGGTTCACTTATTCTGGCATACGGACA



AATGGGGCCACTAGCGCATGTAGACGATCAGGCAGCTCTTTCTACGCCGAGATGAAGTGG



CTGTTATCCAACACAGACAATGCAGCCTTTCCTCAGATGACCAAATCCTACAAAAATACA



AGGAAGAGCCCCGCACTAATCGTATGGGGCATCCATCACTCTGTGTCGACGGCAGAACAA



ACCAAGCTCTATGGTAGTGGGAACAAGTTGGTGACGGTGGGGTCCTCTAATTACCAGCAG



TCGTTCGTGCCCTCTCCAGGTGCCCGGCCCCAGGTGAATGGTCAGTCCGGCCGAATCGAC



TTTCACTGGCTTATGCTGAATCCCAATGATACCGTAACATTTAGCTTTAATGGAGCTTTC



ATTGCTCCTGACCGTGCCAGCTTCTTGAGAGGAAAATCTATGGGCATACAGTCTGGTGTC



CAGGTGGATGCTAACTGCGAAGGTGACTGTTACCACTCAGGAGGTACTATAATTAGCAAT



CTCCCCTTCCAGAACATCGACAGCCGCGCTGTAGGAAAGTGCCCTCGCTACGTGAAGCAA



CGATCATTACTGCTGGCCACTGGCATGAAGAACGTACCCGAGATCCCAAAGGGAAGGGGT



TTGTTTGGCGCCATTGCGGGCTTTATTGAGAACGGATGGGAGGGTCTGATCGATGGATGG



TATGGATTCCGTCATCAGAATGCCCAGGGCGAGGGGACCGCTGCTGATTACAAATCCACA



CAATCTGCAATAGATCAAATCACAGGAAAACTGAACCGGCTTATTGAAAAAACCAATCAG



CAGTTCGAGTTGATCGACAATGAGTTCAATGAAGTGGAAAAGCAGATCGGCAACGTCATC



AACTGGACTCGGGACTCTATCACAGAGGTCTGGTCCTACAATGCAGAGTTACTAGTTGCC



ATGGAGAACCAGCACACGATTGATTTGGCCGATAGCGAGATGGATAAACTCTACGAGCGT



GTGAAGAGGCAGCTGCGCGAAAATGCCGAAGAGGATGGAACAGGTTGCTTCGAGATCTTC



CACAAATGCGATGACGACTGCATGGCCTCCATCAGGAATAATACTTATGATCACAGCAAG



TACCGGGAGGAAGCCATGCAAAACAGAATTCAGATTGATCCCGTAAAGTTAAGCTCCGGC



TACAAAGATGTGATTCTGTGGTTCTCTTTCGGAGCTTCATGCTTCATCCTCCTCGCTATA



GTGATGGGTCTCGTATTCATTTGCGTTAAGAACGGCAATATGAGATGCACAATCTGTATT





643
ATGAATACTCAAATCCTGGTGTTCGCACTCATTGCCATCATACCAACCAACGCAGACAAG



ATATGCTTGGGCCATCACGCCGTGTCTAATGGTACGAAAGTGAATACTCTGACTGAGCGC



GGGGTCGAAGTAGTAAACGCGACTGAAACAGTGGAACGAACTAATATTCCCAGAATTTGC



AGTAAAGGGAAAAAGACCGTCGATCTCGGCCAATGCGGACTGCTGGGGACAATCACAGGG



CCACCGCAATGCGATCAGTTCCTGGAGTTTAGCGCGGATCTCATCATCGAGCGAAGAGAA



GGGTCCGACGTCTGTTACCCGGGTAAATTTGTGAATGAAGAGGCCCTGCGTCAGATTCTG



CGGGAAAGCGGCGGAATTGACAAGGAGGCAATGGGGTTCACGTACAGTGGTATCAGAACC



AACGGAGCTACAAGCGCATGCAGACGGTCCGGGTCCTCGTTTTACGCGGAGATGAAGTGG



CTGTTATCCAACACTGACAACGCTGCTTTCCCACAGATGACCAAAAGCTATAAGAACACA



AGAAAAAGTCCAGCCCTGATTGTGTGGGGGATCCACCATTCGGTATCAACTGCTGAGCAA



ACAAAGTTATATGGAAGTGGAAACAAGCTTGTCACCGTAGGTTCATCCAACTATCAACAG



AGTTTCGTGCCCTCCCCCGGAGCCCGCCCCCAGGTGAATGGACAGTCGGGAAGAATAGAC



TTTCATTGGTTGATGCTGAATCCCAATGACACCGTGACCTTCAGCTTTAATGGGGCCTTC



ATTGCCCCGGACAGGGCTAGCTTTCTCCGAGGAAAGAGCATGGGCATTCAATCTGGAGTT



CAAGTGGATGCCAACTGTGAGGGCGATTGCTACCATAGCGGAGGGACAATCATCAGCAAC



CTCCCCTTCCAAAACATTGATAGTCGTGCTGTAGGAAAATGCCCTCGGTACGTTAAACAA



AGATCGCTGCTACTGGCTACAGGAATGAAGAACGTGCCCGAGATCCCAAAAGGACGAGGC



CTATTTGGGGCCATCGCGGGTTTTATCGAAAATGGATGGGAGGGCCTCATCGACGGGTGG



TATGGCTTTCGTCATCAGAATGCTCAAGGCGAAGGAACAGCCGCTGATTACAAATCAACC



CAATCTGCCATCGACCAGATCACCGGAAAGCTCAACCGCCTGATTGAAAAGACTAATCAG



CAGTTCGAGCTGATCGACAATGAGTTCAATGAAGTGGAAAAGCAGATTGGTAACGTGATT



AACTGGACTAGAGATTCCATTACCGAAGTGTGGTCTTATAACGCCGAGCTACTGGTCGCC



ATGGAGAACCAGCATACCATTGATTTAGCTGATTCTGAGATGGACAAGCTGTACGAAAGG



GTGAAACGGCAGCTCCGAGAAAATGCCGAAGAAGACGGAACCGGGTGTTTCGAGATCTTC



CACAAGTGCGACGACGATTGCATGGCTAGCATTAGAAACAACACTTATGACCACAGCAAG



TATCGCGAAGAGGCGATGCAGAATCGAATCCAGATCGATCCTGTCAAGCTGAGCAGGGGG



TACAAGGACGTGATCTTATGGTTTTCCTTCGGGGCTAGCTGTTTTATCCTGCTGGCTATC



GTGATGGGTCTGGTTTTTATATGTGTTAAAAACGGCAACATGCGGTGCACAATCTGCATT





644
ATGAATACCCAGATTTTAGTGTTTGCACTTATCGCTATCATACCAACTAATGCTGACAAG



ATCTGCCTGGGCCACCATGCAGTGAGCAACGGGACCAAAGTGAACACCCTAACCGAGCGG



GGCGTGGAGGTGGTAAATGCCACTGAAACCGTCGAAAGGACGAACATTCCGCGGATTTGC



AGTAAAGGCAAACGAACCGTGGACCTGGGCCAGTGTGGCCTCCTGGGGACCATCACGGGA



CCACCCCAATGTGACCAGTTCCTGGAGTTCTCCGCTGACCTTATCATCGAAAGGCGAGAA



GGGTCTGATGTCTGTTACCCTGGAAAATTCGTAAACGAGGAGGCTCTCCGACAAATTCTG



CGGGAATCCGGCGGCATCGACAAGGAGGCGATGGGTTTTACCTATTCCGGGATACGCACT



AACGGAGCTACATCAGCATGTAGGCGCTCTGGGTCTAGTTTCTATGCCGAAATGAAATGG



TTGCTGTCAAACACTGACAACGCTGCTTTCCCTCAGATGACTAAGTCCTATAAGAATACC



CGGAAGTCCCCAGCACTAATAGTCTGGGGGATTCACCACTCCGTATCTACTGCGGAGCAG



ACGAAACTTTACGGGAGCGGGAACAAACTGGTCACTGTTGGGTCATCAAATTATCAGCAA



TCATTCGTACCCTCTCCCGGCGCTCGGCCCCAGGTCAATGGCCTGTCCGGCAGAATTGAC



TTCCACTGGCTTATGCTAAATCCTAACGACACCGTGACCTTCTCCTTCAACGGCGCCTTC



ATCGCGCCTGACCGAGCTAGCTTTCTGCGTGGGAAAAGTATGGGAATTCAGAGCGGTGTG



CAGGTGGATGCAAATTGTGAAGGCGACTGCTATCATAGCGGGGGTACCATTATCTCTAAT



CTGCCTTTCCAGAACATCGACAGTAGAGCCGTGGGCAAATGCCCCAGATATGTGAAACAA



CGTAGCCTTCTGCTGGCAACAGGAATGAAAAATGTGCCCGAGATTCCCAAAGGGCGTGGG



CTGTTTGGGGCCATCGCCGGCTTCATCGAAAACGGTTGGGAGGGATTAATCGACGGGTGG



TATGGCTTCAGGCACCAAAACGCTCAAGGGGAGGGCACGGCGGCGGATTACAAATCTACC



CAGTCCGCCATTGATCAAATTACTGGCAAATTAAACAGAATCATCGAAAAGACTAACCAG



CAGTTCGAACTGATTGATAATGAGTTCAACGAGGTTGAGAAGCAAATCGGTAACGTTATC



AACTGGACGCGTGACAGTATCACCGAGGTCTGGTCATATAATGCTGAGCTGCTCGTGGCT



ATGGAAAACCAGCACACTATCGATCTGGCGGACTCCGAGATGGACAAGTTGTATGAACGG



GTGAAAAGACAGCTTCGGGAGAACGCCGAGGAGGACGGGACCGGATGCTTCGAGATCTTT



CACAAGTGCGATGATGATTGCATGGCTTCAATTCGCAATAATACATATGACCATTCTAAG



TACAGGGAGGAGGCTATGCAGAACCGGATCCAGATAGATCCCGTCAAACTTAGTAGCGGG



TACAAGGATGTCATCCTGTGGTTTTCCTTCGGGGCCTCATGCTTTATTCTTCTGGCCATC



GTGATGGGACTCGTGTTCATCTGCGTTAAGAATGGCAACATGCGATGTACAATCTGCATC





645
ATGAACACCCAGATTCTCGTGTTCGCTTTGATCGCGATTATACCTACTAACGCAGATAAA



ATATGTCTGGGTCATCACGCTGTCAGTAACGGGACAAAGGTGAACACGTTGACCGAGAGG



GGCGTCGAGGTGGTTAACGCCACTGAAACAGTGGAACGGACCAATATACCAAGGATCTGT



AGCAAGGGTAAGAAGACTGTCGACCTCGGTCAGTGTGGGTTGCTTGGGACCATCACCGGG



CCTCCACAGTGTGATCAGTTTCTGGAGTTCTCGGCTGACCTGATAATCGAGAGACGGGAG



GGCAGTGACGTGTGCTACCCAGGGAAGTTTGTGAACGAAGAAGCATTGCGACAGATTCTT



CGGGAATCAGGTGGAATCGACAAGGAGGCCATGGGATTTACATACTCTGGGATCAGGACC



AACGGTGCTACCTCCGCTTGTAGGAGAAGTGGATCAAGCTTTTATGCTGAAATGAAATGG



CTTCTGTCCAATACGGACAACGCAGCTTTCCCTCAGATGACAAAGTCCTACAAAAACACA



AGAAAGTCACCCGCTCTGATTGTTTGGGGAATCCACCACTCAGTGTCCACGGCGGAGCAG



ACGAAACTCTATGGCTCTGGGAATAAGCTGGTGACAGTCGGGAGCTCAAATTATCAGCAA



TCCTTCGTTCCATCCCCCGGCGCCCGACCTCAGGTCAACGGCCAATCGGGCAGGATTGAC



TTCCATTGGCTAATGCTCAATCCCAATGACACCGTCACATTCTCTTTTAATGGTGCCTTC



ATCGCCCCAGATCGAGCCTCTTTTCTCAGAGGTAAGTCGATGGGAATACAGTCAGGGGTT



CAGGTGGACGCTAATTGCGAAGGGGACTGCTATCATTCTGGGGGCACAATTATTTCAAAT



CTGCCATTCCAGAACATTGACTCTCGAGCCGTCGGAAAATGCCCTCGATATGTAAAGCAG



CGAAGTCTGCTGCTGGCAACCGGCATGAAAAACGTACCCGAGATCCCAAAGGGCAGAGGG



CTTTTCGGTGCGATCGCCGGGTTTATCGAAAATGGCTGGGAGGGCCTGATCGATGGGTGG



TACGGTTTTCGGCACCAGAACGCTCAGGGTGAGGGCACTGCAGCGGATTATAAGAGTACC



CAGTCAGCCATTGACCAGATCACAGGTAAGTTGAACCGCCTCATTGAAAAGACCAACCAG



CAGTTTGAGCTGATCGATAATGAGTTTAATGAGGTGGAGAAGCAGATCGGGAATGTTATT



AATTGGACGCGCGATTCAATCACAGAGGTATGGTCATACAACGCTGAGCTGCTGGTGGCA



ATGGAGAATCAACACACGATCGACCTCGCTGACTCAGAAATGGATAAACTGTACGAAAGG



GTCAAAAGGCAGCTGCGCGAGAACGCCGAAGAAGACGGAACTGGTTGTTTCGAAATTTTC



CACAAGTGTGACGACGACTGTATGGCATCCATCAGAAACAACACATACGACCATAGCAAA



TACCGGGAGGAGGCAATGCAGAATCGAATCCAGATTGATCCCGTGAAGTTGTCTAGCGGA



TACAAAGATGTGATCTTATGGTTTTCATTCGGGGCTAGCTGTTTCATCCTCCTGGCCATA



GTTATGGGGCTCGTTTTCATCTGCGTAAAGAATGGGAATATGAGATGTACTATCTGCATT





646
ATGAATACGCAGATTCTGGTGTTCGCTCTCATCGCTATTATTCCTACCAATGCCGATAAG



ATCTGTCTGGGGCACCACGCCGTCAGCAACGGCACTAAAGTGAACACCTTGACAGAAAGG



GGGGTGGAAGTGGTGAACGCAACGGAAACAGTGGAGAGGACAAACATACCGCGGATTTGC



TCGAAAGGAAAACGGACTGTAGACCTGGGCCAATGCGGCCTGCTCGGAACCATCACCGGG



CCACCCCAATGTGACCAGTTCCTAGAATTTTCCGCCGACCTTATAATTGAGCGGAGGGAG



GGATCCGATGTGTGTTATCCTGGCAAGTTCGTGAACGAGGAGGCCCTGCGGCAGATATTG



CGTGAATCTGGGGGCATCGACAAGGAGGCGATGGGATTCACATACTCCGGCATCCGCACC



AACGGCGCGACCAGCGCATGCCGTCGCTCCGGGTCCTCATTCTACGCTGAAATGAAATGG



CTCCTCTCAAATACTGATAATGCTGCTTTTCCTCAAATGACCAAAAGTTACAAAAACACC



AGGAAAAGCCCAGCTCTGATTGTCTGGGGCATTCACCATTCCGTATCTACGGCAGAACAG



ACTAAACTATATGGCAGTGGCAGCAAGCTCGTGACCGTCGGCTCCTCCAACTATCAGCAA



TCTTTCGTTCCATCACCAGGCGCCCGGCCCCAGGTCAATGGGCTCTCCGGCCGTATCGAT



TTCCACTGGCTGATGCTCAATCCTAACGACACCGTTACCTTTTCTTTTAACGGCGCCTTT



ATTGCTCCAGACAGAGCGTCTTTCCTGCGGGGTAAAAGCATGGGCATTCAGTCTGGTGTC



CAAGTGGACGCAAACTGTGAAGGGGATTGCTATCATAGTGGCGGCACTATCATTAGTAAC



CTGCCTTTCCAGAACATTGATTCGCGGGCAGTTGGCAAATGCCCCAGGTATGTCAAACAG



AGATCACTCTTGTTAGCTACCGGAATGAAGAACGTACCGGAGATTCCTAAGGGTAGGGGA



CTGTTCGGGGCTATTGCCGGGTTCATCGAGAATGGGTGGGAAGGTCTCATCGACGGGTGG



TATGGCTTTCGTCATCAGAACGCCCAGGGCGAAGGTACAGCAGCCGATTATAAGTCTACC



CAGTCCGCTATCGACCAAATAACCGGGAAGTTGAACCGGTTAATCGAGAAAACCAACCAA



CAGTTCGAATTGATCGACAATGAATTTAATGAGGTGGAAAAACAAATAGGGAACGTGATA



AACTGGACAAGGGACTCCATTACAGAAGTCTGGAGCTATAACGCCGAACTGCTGGTAGCT



ATGGAGAATCAGCATACCATTGACCTGGCAGACAGTGAGATGGACAAACTTTACGAACGG



GTTAAAAGACAGTTGCGAGAGAATGCCGAAGAAGATGGAACTGGCTGCTTTGAGATTTTT



CACAAATGCGATGATGACTGTATGGCCAGCATTAGAAACAACACATACGACCACAGTAAG



TACAGGGAAGAAGCCATGCAAAACCGGATCCAGATTGACCCCGTCAAGCTGAGCTCGGGT



TATAAGGATGTAATCTTATGGTTCAGTTTTGGCGCCTCCTGCTTCATTCTTCTAGCAATC



GTGATGGGATTGGTCTTCATTTGCGTGAAAAATGGCAATATGAGGTGCACCATCTGCATT





647
ATGAATACACAGATCCTAGTCTTCGCCTTAATTGCAATAATACCTACCAACGCAGACAAA



ATTTGTCTTGGGCACCACGCCGTGTCCAACGGGACCAAAGTTAATACCCTCACCGAACGT



GGGGTGGAGGTGGTAAACGCTACGGAGACAGTAGAAAGGACCAACATACCTCGCATCTGT



TCCAAAGGGAAAAGAACCGTCGACCTGGGGCAGTGCGGGCTGCTAGGAACTATTACTGGC



CCACCACAGTGCGATCAGTTTCTGGAATTTAGTGCTGATCTGATCATCGAAAGGCGTGAG



GGTAGCGATGTCTGTTATCCCGGGAAGTTCGTGAATGAAGAGGCGCTGAGACAAATTCTG



AGAGAAAGCGGGGGGATCGATAAGGAAGCAATGGGGTTTACTTATTCTGGCATTAGAACC



AATGGGGCCACATCCGCCTGCCGCAGGTCTGGAAGCTCCTTTTATGCTGAAATGAAATGG



CTGCTGAGTAATACTGACAACGCCGCTTTTCCTCAGATGACAAAATCTTATAAAAACACG



AGAAAATCTCCTGCCCTGATTGTGTGGGGCATTCACCATTCGGTTTCAACAGCGGAGCAA



ACTAAACTATATGGAAGCGGCAGCAAGCTGGTCACAGTGGGAAGCTCTAACTACCAACAG



TCTTTTGTTCCCAGTCCCGGCGCCCGACCTCAGGTCAACGGACTGAGTGGCAGAATTGAT



TTCCACTGGCTGATGCTTAATCCGAACGATACCGTCACCTTTTCTTTCAATGGTGCTTTT



ATTGCCCCTGACAGGGCAAGCTTCTTGCGCGGGAAGTCTATGGGAATCCAATCCGGCGTA



CAAGTGGACGCAAACTGTGAAGGGGACTGTTATCACTCCGGAGGCACAATTATTAGTAAC



TTGCCTTTCCAGAATATCGATTCCAGAGCCGTGGGTAAATGCCCTCGATACGTAAAACAG



CGCTCTCTGCTTCTGGCTACCGGAATGAAGAATGTGCCTGAGATCCCTAAGGGCAGAGGC



CTGTTCGGGGCCATCGCTGGTTTTATTGAGAATGGGTGGGAAGGCTTAATAGACGGGTGG



TACGGTTTTCGTCACCAAAATGCACAGGGCGAAGGCACAGCAGCCGACTACAAAAGTACG



CAAAGCGCCATAGATCAGATAACAGGAAAACTTAATCGCCTGATCGAAAAAACGAACCAA



CAGTTCGAACTGATTGACAATGAATTTAACGAAGTCGAAAAGCAGATAGGCAATGTCATC



AATTGGACGAGAGACAGTATTACAGAAGTTTGGAGCTATAATGCAGAGCTGTTAGTGGCG



ATGGAAAATCAGCACACCATTGATTTGGCGGACAGCGAAATGGACAAGCTGTACGAACGA



GTGAAGCGACAGCTACGCGAGAATGCAGAAGAAGATGGGACTGGCTGCTTCGAAATCTTT



CACAAGTGCGACGACGATTGCATGGCCAGCATTCGCAATAACACATACGATCACTCCAAG



TATCGAGAGGAGGCGATGCAAAACCGAATCCAAATTGACCCTGTGAAATTATCTAGTGGG



TATAAAGACGTGATACTGTGGTTTTCATTCGGAGCTTCATGTTTCATTCTGTTGGCAATT



GTCATGGGACTGGTGTTTATATGTGTAAAAAGCAGAAATATGCGATGCACCATTTGCATC





648
ATGAATACCCAGATCCTGGTATTCGCATTAATTGCTATCATTCCTACAAATGCTGACAAA



ATCTGTCTCGGCCATCACGCCGTGAGTAATGGAACTAAAGTGAATACTCTCACTGAGCGC



GGGGTAGAGGTAGTGAATGCCACTGAGACCGTCGAGCGAACTAACATCCCCCGCATCTGT



AGCAAAGGCAAGAAGACGGTGGACTTAGGACAGTGTGGCCTCCTGGGGACCATCACAGGA



CCTCCTCAGTGCGACCAGTTTCTGGAATTTAGTGCTGACCTTATCATTGAACGGCGCGAG



GGCAGCGATGTCTGCTACCCTGGCAAGTTTGTCAATGAGGAAGCCTTACGACAGATCCTC



AGAGAATCAGGGGGGATTGACAAGGAGGCAATGGGGTTCACCTATAGCGGAATCCGGACT



AATGGCGCAACAAGTGCATGTAGACGGAGTGGGAGTAGTTTTTACGCCGAAATGAAGTGG



CTGTTAAGCAACACGGACAACGCTGCTTTTCCACAGATGACTAAGTCTTACAAAAACACC



AGGAAGTCACCTGCTCTGATCGTGTGGGGAATTCACCATAGCGTGAGCACAGCTGAGCAG



ACCAAGCTTTACGGAAGTGGCAACAAACTCGTGACAGTGGGCAGCTCCAACTACCAGCAG



TCTTTCGTGCCCTCCCCCGGCGCAAGACCTCAGGTCAACGGGCAGTCGGGGCGTATTGAC



TTCCACTGGCTCATGCTGAACCCCAATGATACTGTGACCTTTTCGTTCAATGGGGCGTTT



ATCGCCCCTGATCGGGCAAGCTTCCTGAGGGGTAAATCAATGGGAATACAGTCCGGCGTC



CAGGTGGATGCCAACTGTGAAGGCGACTGCTATCATTCCGGGGGTACCATTATCAGCAAC



CTTCCCTTTCAGAACATTGATTCTCGGGCTGTGGGAAAATGTCCCAGGTACGTCAAGCAG



CGGTCACTCCTGCTGGCAACTGGGATGAAGAACGTCCCTGAAATCCCGAAAGGGCGTGGG



CTGTTTGGTGCTATCGCTGGATTCATCGAAAACGGCTGGGAAGGGCTTATTGATGGTTGG



TACGGGTTTCGCCACCAGAACGCGCAGGGCGAGGGCACCGCTGCAGACTATAAATCTACT



CAGTCTGCAATTGACCAGATCACCGGCAAACTGAACCGCCTGATTGAGAAGACCAACCAA



CAGTTTGAGCTCATAGATAACGAATTTAACGAGGTGGAAAAGCAAATCGGAAACGTTATC



AACTGGACTAGGGACTCTATCACTGAAGTGTGGTCCTACAATGCAGAGCTGCTCGTTGCC



ATGGAAAACCAGCACACCATTGACCTAGCTGACTCCGAGATGGATAAACTGTATGAGCGG



GTAAAACGGCAGCTGAGAGAGAACGCCGAAGAGGACGGGACAGGATGTTTTGAGATATTT



CACAAATGCGACGACGACTGTATGGCAAGCATCCGGAACAACACCTACGATCATTCTAAA



TATCGGGAGGAAGCCATGCAGAATCGCATTCAGATTGATCCCGTCAAACTGAGTTCTGGC



TATAAGGACGTAATTCTGTGGTTCTCCTTCGGAGCTAGTTGCTTCATTCTGCTTGCAATA



GTAATGGGACTCGTTTTTATTTGTGTCAAGAACGGCAACATGAGGTGTACCATTTGCATA





649
ATGAATACACAGATTCTGGTCTTTGCTCTCATCGCTATAATCCCGACCAACGCTGACAAA



ATCTGTCTGGGTCACCACGCCGTATCTAATGGAACTAAGGTGAATACATTGACCGAGCGC



GGCGTTGAGGTCGTTAATGCTACAGAAACTGTTGAGCGGACAAATATCCCCCGGATATGC



TCAAAGGGAAAAAAGACTGTCGACTTAGGACAATGCGGGTTACTAGGCACAATAACAGGG



CCGCCCCAGTGCGACCAGTTTCTCGAGTTCAGTGCCGATCTGATTATCGAACGCCGGGAG



GGAAGCGACGTCTGTTATCCCGGCAAATTCGTGAATGAAGAGGCCCTCCGCCAGATCCTG



AGAGAATCCGGAGGCATCGACAAGGAGGCCATGGGATTCACTTACTCTGGAATCAGGACC



AACGGGGCTACCTCCGCGTGCCGACGGTCCGGGTCCTCTTTCTACGCAGAGATGAAGTGG



CTACTATCTAATACCGATAACGCAGCTTTCCCCCAAATGACAAAATCATATAAGAATACA



AGGAAATCTCCGGCATTGATCGTCTGGGGCATTCATCACTCTGTCAGTACCGCTGAACAA



ACAAAGCTGTATGGCAGCGGGAACAAGCTGGTTACAGTGGGGTCTAGTAACTATCAACAG



TCCTTCGTGCCATCTCCGGGAGCGCGGCCACAGGTGAATGGGCAGTCTGGCCGGATTGAC



TTTCACTGGTTAATGTTAAATCCAAACGACACGGTGACTTTTTCATTTAACGGTGCCTTT



ATTGCTCCTGACAGAGCCTCATTTCTCAGAGGCAAATCAATGGGTATCCAATCAGGCGTG



CAGGTGGACGCTAACTGCGAGGGCGATTGCTACCACTCTGGGGGCACAATCATATCCAAC



CTGCCCTTCCAGAATATTGACTCAAGAGCCGTCGGGAAATGTCCACGGTACGTGAAACAG



AGGAGTCTACTGCTAGCTACAGGAATGAAGAATGTGCCCGAGATTCCGAAAGGGAGAGGG



TTGTTTGGAGCCATCGCAGGATTCATTGAAAATGGATGGGAAGGTCTCATAGATGGTTGG



TATGGCTTTCGACACCAAAACGCGCAGGGCGAGGGGACTGCAGCTGACTACAAAAGTACG



CAATCTGCCATTGATCAGATTACAGGAAAGCTCAACCGACTGATCGAAAAAACAAATCAG



CAGTTTGAGCTCATAGACAATGAGTTCAATGAAGTGGAAAAGCAGATCGGCAACGTTATC



AACTGGACGCGCGACTCAATCACAGAAGTGTGGTCTTACAATGCAGAATTGCTTGTCGCC



ATGGAGAATCAGCACACTATCGACCTGGCCGACAGCGAAATGGATAAGCTCTACGAGAGG



GTCAAGCGCCAACTTCGAGAGAATGCTGAGGAGGACGGAACCGGTTGCTTTGAGATATTT



CACAAGTGTGATGACGATTGCATGGCATCAATCAGAAATAATACTTACGACCATTCGAAA



TACAGGGAAGAGGCAATGCAGAACAGAATTCAGATCGACCCTGTGAAGCTTTCTAGTGGG



TATAAAGACGTGATCCTCTGGTTCAGTTTTGGAGCATCTTGTTTCATTCTGCTAGCCATT



GTTATGGGACTTGTCTTCATTTGCGTGAAGAACGGGAATATGCGTTGTACGATCTGCATT





650
ATGAACACTCAGATACTCGTCTTCGCCCTCATAGCCATCATTCCCACGAATGCCGACAAA



ATCTGTCTGGGTCACCACGCGGTAAGTAACGGGACTAAGGTCAACACACTGACAGAAAGA



GGCGTCGAAGTCGTGAACGCCACAGAGACGGTGGAGAGGACAAACATACCCAGAATTTGC



TCGAAGGGCAAGAAGACCGTAGATCTGGGCCAGTGCGGGCTGTTGGGCACCATCACAGGC



CCCCCCCAGTGCGATCAGTTCCTGGAATTCTCTGCCGACCTTATCATTGAAAGGAGAGAG



GGGAGCGATGTTTGTTACCCCGGGAAGTTCGTTAACGAGGAGGCCCTTAGACAGATCCTT



CGGGAATCCGGTGGGATTGACAAGGAAGCCATGGGATTCACCTACTCTGGTATACGGACT



AACGGAGCCACCTCAGCCTGCAGAAGAAGCGGTAGTTCTTTTTATGCCGAAATGAAATGG



CTGTTGTCAAACACCGACAATGCTGCCTTCCCACAGATGACCAAATCATACAAGAATACC



CGCAAGTCTCCCGCCCTGATTGTGTGGGGCATCCATCACTCGGTGTCCACCGCCGAACAG



ACTAAGCTCTACGGCTCAGGGAATAAGCTGGTGACTGTTGGCAGCTCAAACTACCAGCAG



TCCTTCGTGCCTAGCCCTGGTGCCCGTCCCCAGGTGAACGGCCAGAGCGGTCGGATTGAC



TTCCATTGGCTTATGTTGAACCCAAACGATACCGTGACCTTCTCCTTCAATGGTGCCTTT



ATAGCACCCGATCGGGCGTCCTTTCTGCGCGGTAAATCTATGGGGATTCAAAGCGGCGTC



CAGGTGGATGCTAATTGTGAAGGAGATTGCTATCACAGCGGGGGAACTATAATTTCTAAC



CTGCCATTTCAAAATATTGATAGCCGGGCAGTGGGAAAGTGTCCTCGCTATGTTAAACAA



AGATCTCTTTTGCTGGCTACCGGAATGAAGAACGTGCCAGAGATCCCCAAAGGAAGGGGA



CTGTTCGGAGCAATCGCCGGGTTTATTGAAAATGGATGGGAGGGCCTCATTGACGGTTGG



TACGGGTTCCGCCACCAGAACGCTCAAGGAGAGGGGACGGCAGCGGATTATAAGAGCACT



CAGTCCGCAATCGACCAGATCACAGGAAAGCTGAATCGCCTCATTGAGAAAACAAACCAG



CAGTTCGAGTTGATTGATAACGAATTCAACGAGGTGGAAAAACAGATCGGCAATGTGATA



AACTGGACCCGCGACTCCATTACTGAGGTCTGGTCTTACAACGCAGAACTGCTTGTCGCA



ATGGAGAATCAACACACCATAGATCTCGCTGATTCTGAAATGGATAAGCTGTACGAAAGG



GTGAAAAGACAGCTGAGAGAGAATGCTGAAGAAGATGGCACCGGTTGCTTCGAGATCTTT



CACAAATGTGACGATGACTGCATGGCCTCCATTAGGAATAACACATATGATCATTCCAAG



TACAGGGAAGAGGCCATGCAGAACCGGATTCAGATTGATCCGGTTAAGCTGAGTTCCGGG



TACAAAGATGTGATACTATGGTTTTCTTTCGGCGCGAGTTGCTTCATTTTGCTTGCCATA



GTGATGGGTTTAGTTTTCATCTGCGTGAAGAACGGAAACATGCGCTGCACTATTTGCATA





651
ATGAATACCCAGATTCTTGTTTTTGCTCTTATAGCCATAATACCCACGAACGCAGACAAA



ATCTGCTTGGGCCACCACGCAGTATCTAACGGCACCAAGGTGAATACTCTCACCGAACGT



GGGGTGGAGGTCGTGAATGCTACAGAAACAGTGGAGCGCACAAACATTCCTCGTATTTGT



TCAAAAGGGAAGAAGACAGTGGATCTGGGCCAGTGCGGCCTATTAGGAACAATCACAGGG



CCCCCTCAATGTGACCAGTTTCTGGAGTTTTCCGCGGACCTCATTATCGAGCGACGGGAA



GGGAGCGACGTATGCTACCCGGGAAAATTCGTCAATGAGGAGGCCCTGCGTCAGATTCTT



AGGGAGTCAGGCGGCATCGACAAGGAAGCTATGGGATTTACATATTCTGGAATTCGCACT



AACGGCGCCACCTCCGCTTGTCGACGGAGCGGATCGTCCTTCTATGCCGAAATGAAGTGG



CTGCTGTCGAATACGGACAACGCTGCTTTTCCACAAATGACTAAGAGCTATAAGAATACC



AGAAAGTCTCCTGCGTTAATTGTATGGGGAATACATCATAGTGTGTCTACCGCCGAGCAG



ACAAAACTGTACGGTTCCGGCAATAAGCTAGTCACTGTGGGCTCTTCCAATTACCAGCAG



TCGTTTGTCCCCTCGCCAGGGGCCCGCCCGCAAGTAAATGGACAATCTGGGCGTATCGAT



TTCCATTGGCTTATGCTGAACCCTAATGACACCGTGACATTTTCATTCAATGGGGCTTTC



ATTGCCCCCGACAGGGCTAGCTTCCTTCGCGGCAAGAGCATGGGGATACAATCCGGGGTT



CAAGTGGATGCCAACTGCGAGGGCGACTGTTACCACTCAGGCGGAACCATCATTTCAAAT



CTGCCCTTTCAGAACATTGACAGCCGCGCCGTGGGCAAGTGTCCACGATATGTGAAGCAG



AGATCACTGCTCCTTGCAACCGGTATGAAAAATGTTCCTGAGATACCGAAGGGCCGGGGG



CTCTTCGGTGCTATCGCTGGATTCATTGAAAACGGGTGGGAAGGACTGATCGACGGTTGG



TATGGATTTAGGCACCAGAACGCACAGGGCGAAGGGACCGCCGCTGATTATAAAAGCACG



CAGAGCGCTATAGATCAGATCACCGGAAAGCTGAACCGCCTGATCGAGAAAACGAACCAA



CAGTTCGAACTGATTGATAACGAGTTTAACGAAGTGGAAAAACAGATTGGTAACGTGATC



AACTGGACTAGAGACTCCATCACCGAAGTGTGGTCATATAACGCAGAGTTACTCGTCGCG



ATGGAAAACCAACACACCATCGACCTGGCAGACAGTGAGATGGATAAACTCTACGAACGG



GTCAAGAGACAACTACGTGAGAATGCCGAGGAAGATGGCACAGGTTGTTTTGAAATTTTT



CACAAGTGTGACGACGACTGCATGGCATCAATAAGAAACAATACTTACGACCATAGTAAG



TACCGGGAGGAAGCTATGCAGAATAGAATCCAAATAGATCCAGTGAAATTGAGTAGCGGA



TATAAGGATGTGATTCTATGGTTTAGCTTCGGCGCTAGTTGTTTTATCCTTTTGGCTATA



GTGATGGGGCTCGTTTTTATCTGCGTGAAGAACGGAAACATGAGATGTACGATCTGCATT





652
ATGAATACCCAAATTCTCGTTTTTGCCCTCATCGCCATTATCCCTACTAACGCCGATAAG



ATCTGTCTGGGGCATCATGCCGTCTCCAACGGGACCAAGGTAAACACTCTGACCGAGCGC



GGTGTCGAAGTAGTCAATGCTACAGAGACAGTTGAACGCACTAATATTCCCAGGATCTGT



AGTAAAGGAAAGCGTACCGTGGACCTAGGACAATGTGGCTTGCTCGGCACTATCACCGGC



CCTCCACAGTGCGACCAATTTCTGGAATTCTCCGCTGATCTGATTATCGAGAGAAGAGAA



GGCAGTGACGTGTGCTACCCGGGAAAGTTTGTCAACGAAGAGGCCTTAAGGCAGATCCTG



CGCGAGAGCGGGGGTATAGATAAAGAAGCCATGGGCTTCACTTACAGTGGAATTAGGACA



AACGGCGCCACGTCGGCCTGCAGAAGGTCTGGGTCCTCATTCTACGCCGAGATGAAGTGG



CTTCTGTCGAATACCGACAATGCAGCATTTCCACAAATGACTAAATCCTATAAGAACACC



CGGAAGTCACCAGCCCTCATAGTGTGGGGGATCCATCACTCCGTGAGCACTGCAGAGCAA



ACAAAGCTGTATGGGTCCGGGAATAAACTGGTAACCGTTGGCAGTAGCAATTATCAGCAG



TCATTTGTTCCCTCCCCAGGTGCCCGGCCTCAGGTGAATGGTCTGTCTGGTCGCATCGAC



TTTCACTGGCTGATGCTGAATCCAAATGATACAGTCACATTTTCGTTTAATGGAGCCTTC



ATCGCGCCCGACAGGGCTAGCTTCCTACGCGGCAAGAGCATGGGCATTCAGAGCGGCGTC



CAGGTTGACGCCAATTGCGAGGGAGATTGTTATCATAGCGGAGGCACAATCATCTCAAAC



CTCCCCTTTCAGAATATAGACTCCAGAGCCGTTGGGAAGTGCCCTAGATACGTGAAACAG



CGATCCCTGCTCCTAGCTACAGGAATGAAGAATGTGCCAGAAATCCCCAAGGGTCGGGGG



CTCTTTGGAGCCATCGCCGGTTTTATCGAAAATGGTTGGGAAGGCCTCATTAATGGCTGG



TACGGCTTTCGACACCAGAATGCCCAGGGTGAAGGAACAGCGGCAGACTATAAGTCCACA



CAGAGTGCTATAGACCAGATCACCGGCAAGCTTAACAGACTGATTGAAAAGACCAATCAG



CAGTTCGAGTTGATCGACAACGAATTCAACGAGGTTGAGAAACAAATAGGAAACGTGATA



AATTGGACCCGCGATTCTATAACAGAAGTGTGGTCATATAATGCGGAACTGCTCGTGGCA



ATGGAGAACCAACATACAATAGACCTTGCAGACTCCGAAATGGATAAGCTGTACGAGCGC



GTCAAGCGACAGCTCAGAGAAAATGCAGAGGAGGATGGAACAGGCTGTTTTGAAATTTTC



CACAAGTGTGACGACGATTGCATGGCCTCCATCAGAAATAACACATATGACCATTCAAAG



TATCGCGAAGAAGCTATGCAGAATCGAATCCAAATAGATCCTGTGAAGTTGTCGTCCGGC



TACAAAGATGTTATCCTGTGGTTCAGTTTCGGGGCCTCATGCTTCATCCTGCTGGCCATA



GTGATGGGTCTCGTGTTCATCTGCGTGAAGAACGGCAACATGCGCTGCACTATCTGCATT





653
ATGAATACCCAGATTTTGGTGTTCGCACTTATCGCAATAATCCCGACTAACGCTGATAAA



ATTTGTTTAGGACATCATGCCGTTTCTAACGGAACTAAGGTGAACACACTTACCGAGAGA



GGTGTGGAAGTGGTGAACGCTACCGAAACTGTGGAGCGGACTAACATCCCCCGGATATGC



TCAAAGGGCAAGAGAACTGTGGATTTAGGTCAATGTGGTCTACTGGGCACAATTACCGGC



CCACCCCAATGCGACCAGTTCCTGGAGTTTAGCGCCGACCTGATTATTGAGAGACGTGAG



GGCTCAGACGTATGTTATCCTGGGAAATTTGTCAACGAAGAAGCCTTGCGGCAGATCCTA



CGTGAGAGCGGGGGCATTGACAAAGAGGCCATGGGGTTTACATACTCAGGCATCCGAACT



AACGGGGCAACAAGTGCATGTAGACGATCTGGGTCTAGCTTCTATGCCGAGATGAAATGG



CTCCTCTCGAACACCGATAACGCCGCTTTTCCGCAGATGACTAAATCTTATAAGAATACA



AGGAAGTCCCCCGCTTTAATTGTCTGGGGCATCCACCACTCTGTGAGCACCGCCGAACAG



ACAAAATTGTACGGCTCGGGGTCCAAGCTTGTCACTGTGGGCTCATCCAATTACCAGCAA



AGCTTTGTGCCCTCCCCCGGGGCAAGACCTCAGGTGAACGGGTTGAGCGGAAGGATTGAT



TTCCATTGGCTGATGTTGAACCCTAACGACACAGTCACCTTCTCGTTTAACGGGGCCTTC



ATTGCCCCAGATAGGGCCTCTTTTCTGCGCGGAAAGTCGATGGGGATCCAGTCAGGGGTG



CAGGTGGACGCCAACTGTGAAGGCGACTGTTATCACAGCGGAGGAACGATAATTTCCAAT



CTACCCTTTCAGAATATAGATTCAAGAGCCGTTGGGAAATGTCCCAGGTACGTCAAGCAG



AGGTCGCTCCTCTTGGCTACCGGCATGAAGAATGTTCCTGAAATCCCGAAGGGCAGAGGA



CTCTTTGGCGCCATAGCCGGCTTTATTGAAAATGGATGGGAAGGATTAATTGACGGCTGG



TACGGCTTCCGGCATCAGAATGCACAGGGCGAGGGCACGGCGGCTGACTACAAGTCTACT



CAGAGTGCCATAGACCAGATTACCGGGAAGTTAAATCGTCTGATCGAGAAGACCAACCAA



CAGTTTGAACTCATTGACAATGAGTTCAACGAAGTGGAGAAACAGATCGGCAACGTAATC



AATTGGACTCGCGATTCCATTACCGAGGTGTGGTCTTATAACGCAGAACTCTTGGTGGCC



ATGGAAAACCAACACACGATTGATCTCGCAGACAGCGAGATGGACAAGTTGTATGAGAGA



GTTAAGCGCCAGCTCAGGGAGAATGCCGAAGAGGACGGAACCGGTTGCTTTGAGATCTTT



CACAAATGTGATGATGACTGCATGGCGAGCATTCGTAATAATACTTATGACCATAGTAAA



TACCGGGAGGAAGCCATGCAGAATCGCATCCAAATTGACCCCGTAAAGCTAAGTTCAGGT



TATAAGGATGTTATTCTTTGGTTTTCATTCGGAGCTTCATGCTTCATCCTTCTTGCAATT



GTAATGGGACTGGTTTTCATTTGTGTAAAGAACGGAAATATGCGATGTACGATTTGTATT





654
ATGAATACTCAAATCCTTGTCTTTGCGCTGATCGCTATCATTCCAACAAATGCAGATAAA



ATCTGTCTAGGACATCATGCTGTGTCAAACGGTACTAAAGTGAATACACTGACGGAGAGG



GGAGTCGAGGTGGTGAACGCAACAGAGACAGTGGAACGCACAAATATCCCCCGCATCTGT



TCTAAGGGGAAAAAAACCGTGGACTTGGGGCAGTGCGGTTTACTGGGGACCATTACTGGT



CCGCCCCAGTGCGACCAGTTCCTAGAGTTTTCCGCAGACCTGATTATAGAGAGACGCGAA



GGAAGCGACGTATGTTACCCCGGGAAGTTTGTCAATGAAGAAGCCCTCAGACAGATTCTT



CGGGAGTCCGGAGGCATCGATAAAGAGGCTATGGGCTTCACCTACTCCGGCATTCGTACA



AATGGTGCTACGTCTGCCTGTCGACGCAGTGGGTCATCCTTTTACGCCGAAATGAAGTGG



CTATTGAGCAATACCGACAACGCAGCTTTCCCTCAGATGACTAAGAGCTATAAAAACACC



CGCAAGAGCCCAGCTCTGATCGTATGGGGAATTCACCACTCAGTTTCGACTGCAGAGCAG



ACTAAACTGTATGGCTCCGGGAATAAGCTGGTTACCGTGGGTAGCTCTAACTACCAGCAG



TCATTCGTTCCTTCACCCGGCGCACGCCCCCAAGTGAATGGGCAATCTGGGCGCATAGAC



TTCCACTGGCTTATGCTAAACCCAAACGACACTGTGACCTTTTCATTCAACGGCGCATTC



ATTGCACCTGACCGCGCGTCATTTCTCCGGGGCAAGAGCATGGGGATCCAGAGCGGCGTA



CAGGTGGACGCGAATTGCGAGGGGGATTGCTACCATTCAGGAGGAACCATTATTTCTAAC



CTCCCGTTCCAAAATATAGACTCTCGTGCTGTGGGAAAGTGCCCGAGATACGTCAAACAG



CGTTCTCTACTCCTGGCTACGGGGATGAAGAACGTGCCCGAGATTCCGAAAGGGCGCGGA



CTGTTTGGCGCCATCGCGGGATTTATTGAGAACGGCTGGGAGGGGCTTATTGATGGTTGG



TATGGCTTCCGGCACCAGAACGCTCAGGGGGAGGGGACTGCAGCTGATTACAAGTCAACA



CAATCAGCAATCGATCAGATTACCGGAAAGCTGAACAGACTCATCGAGAAGACGAATCAA



CAGTTTGAATTGATCGATAACGAATTCAACGAAGTCGAGAAACAAATCGGAAACGTCATT



AACTGGACTAGAGATTCCATCACCGAGGTGTGGTCTTATAACGCCGAGCTCCTGGTGGCG



ATGGAGAACCAGCACACAATTGATCTCGCTGACAGCGAGATGGACAAGTTGTACGAGAGG



GTAAAACGACAGCTCCGGGAAAATGCCGAGGAAGATGGGACAGGGTGCTTCGAGATCTTT



CACAAGTGTGACGACGACTGTATGGCCTCAATTCGAAATAACACCTATGATCACTCGAAA



TACCGCGAGGAAGCTATGCAGAACAGAATCCAGATTGACCCTGTGAAGCTGAGCAGTGGG



TATAAAGACGTCATCTTATGGTTCAGCTTCGGGGCTTCTTGCTTCATACTGCTTGCCATC



GTTATGGGCCTGGTGTTTATCTGTGTCAAGAATGGTAACATGAGGTGCACTATCTGTATA





655
ATGAACACCCAAATTCTTGTATTTGCTCTGATCGCCATTATTCCAACCAATGCCGACAAG



ATCTGTTTGGGGCACCATGCCGTTTCTAATGGCACAAAAGTCAATACATTAACTGAGCGC



GGCGTAGAAGTCGTGAACGCTACCGAAACAGTTGAGAGAACCAACATCCCTCGAATATGT



TCCAAGGGGAAGAAAACAGTGGATCTCGGGCAGTGCGGCTTGCTGGGAACAATAACTGGC



CCGCCTCAGTGTGATCAGTTCCTGGAATTTAGTGCTGACCTGATAATCGAGCGAAGAGAG



GGGAGCGATGTGTGTTATCCCGGGAAATTTGTAAACGAGGAGGCCCTGCGGCAGATACTT



AGAGAGAGTGGGGGAATCGACAAAGAAGCGATGGGGTTTACCTACTCTGGAATCAGAACT



AACGGGGCTACAAGCGCCTGCCGGCGCAGCGGATCGTCCTTCTACGCAGAGATGAAGTGG



CTGCTCAGCAACACTGACAATGCCGCTTTTCCTCAAATGACCAAGTCTTACAAGAACACC



CGTAAAAGTCCCGCGCTCATAGTATGGGGTATCCACCATTCTGTCTCAACAGCAGAACAG



ACCAAACTGTACGGCAGCGGCAACAAACTGGTGACAGTGGGATCTAGCAATTACCAGCAG



AGTTTTGTCCCATCCCCTGGCGCGCGGCCCCAGGTGAATGGGCAAAGTGGACGGATAGAC



TTCCACTGGTTGATGCTGAACCCAAATGATACCGTGACATTTTCTTTCAACGGTGCATTT



ATAGCCCCTGACCGTGCAAGCTTCTTGAGAGGTAAGAGCATGGGAATTCAGTCAGGTGTT



CAGGTGGATGCCAATTGCGAGGGCGATTGCTACCACAGCGGCGGCACTATTATTTCTAAT



CTTCCTTTCCAGAATATAGACTCCCGTGCTGTGGGTAAATGCCCTAGGTACGTAAAGCAA



AGGAGCTTACTGTTGGCAACAGGCATGAAGAATGTGCCAGAAATTCCCAAGGGGGGGGGC



CTGTTTGGCGCCATTGCAGGCTTTATTGAGAATGGCTGGGAGGGCCTAATTGATGGTTGG



TACGGCTTCAGGCACCAGAACGCACAGGGGGAAGGCACAGCTGCGGATTACAAAAGTACC



CAGAGCGCCATAGATCAAATAACCGGCAAGTTAAACCGATTGATTGAGAAAACAAACCAG



CAATTTGAGCTGATAGACAATGAATTCAACGAAGTCGAAAAGCAGATTGGCAACGTGATC



AATTGGACCCGGGATAGCATTACTGAGGTATGGAGCTATAATGCAGAGTTGCTGGTGGCC



ATGGAAAACCAGCATACCATCGATCTGGCCGACTCAGAAATGGATAAGCTCTACGAGCGG



GTGAAGAGGCAGCTGAGAGAAAATGCCGAAGAAGACGGAACCGGCTGCTTTGAGATTTTT



CACAAGTGCGACGATGATTGCATGGCCAGTATTAGAAACAACACCTATGATCACTCCAAG



TACCGCGAAGAAGCCATGCAGAACCGCATCCAAATCGATCCGGTCAAACTCTCCTCTGGC



TATAAGGATGTAATCCTGTGGTTCTCTTTTGGAGCGTCCTGCTTCATATTATTGGCTATT



GTGATGGGCTTGGTGTTTATCTGTGTTAAGAACGGAAACATGCGGTGTACAATCTGCATT





656
ATGAATACACAGATACTCGTGTTCGCCCTTATTGCTATCATCCCTACAAATGCTGACAAG



ATATGTCTGGGCCACCACGCCGTGAGCAATGGCACCAAGGTTAATACCCTAACCGAACGG



GGAGTTGAGGTGGTTAACGCTACCGAGACCGTAGAGCGCACTAATATTCCACGCATTTGC



TCGAAAGGCAAGAAAACAGTGGACTTAGGCCAATGTGGACTCCTCGGAACAATAACCGGC



CCACCACAGTGCGATCAGTTCCTCGAGTTTTCAGCCGACCTAATTATTGAGCGACGGGAA



GGTAGCGATGTGTGTTATCCAGGGAAGTTCGTCAATGAAGAGGCCTTGCGGCAGATACTG



CGCGAAAGTGGGGGCATAGACAAGGAGGCTATGGGGTTTACATACAGTGGAATTCGCACC



AATGGGGCCACTAGCGCCTGTAGGAGATCAGGCTCCTCTTTCTACGCTGAGATGAAATGG



TTACTGTCAAATACTGATAACGCCGCCTTTCCTCAGATGACAAAATCCTATAAGAACACT



AGGAAGTCACCTGCTCTAATCGTTTGGGGAATCCATCACTCCGTGAGCACCGCTGAGCAG



ACCAAGCTTTATGGCTCAGGAAACAAGCTCGTGACGGTGGGCTCCAGTAACTATCAACAA



AGCTTCGTGCCTTCTCCAGGAGCAAGGCCCCAGGTGAATGGACAGTCCGGGAGAATCGAC



TTTCACTGGCTCATGCTGAATCCAAACGATACCGTTACCTTTTCATTCAATGGGGCCTTC



ATCGCCCCAGACAGGGCCAGCTTCCTCCGCGGCAAAAGCATGGGCATACAAAGCGGCGTG



CAGGTGGATGCTAATTGCGAGGGTGACTGCTATCATTCAGGCGGCACCATAATCAGTAAC



CTGCCCTTTCAAAATATAGATTCGCGGGCAGTAGGTAAATGCCCTCGTTATGTGAAACAG



CGGTCCTTGCTGCTTGCGACTGGAATGAAAAACGTGCCCGAGATTCCCAAGGGCCGTGGA



TTATTTGGCGCTATCGCCGGGTTCATCGAGAACGGCTGGGAGGGTCTCATTGATGGATGG



TACGGTTTCAGACACCAGAACGCCCAGGGGGAGGGGACCGCAGCCGACTACAAATCAACC



CAGTCCGCCATTGATCAGATCACAGGGAAGCTAAATCGCCTGATTGAGAAGACAAATCAG



CAGTTCGAGCTGATCGACAACGAATTCAATGAGGTAGAGAAACAGATTGGGAACGTTATT



AATTGGACCAGAGATTCCATAACAGAGGTATGGTCTTATAACGCAGAACTGCTCGTTGCG



ATGGAGAACCAGCATACAATCGACCTGGCAGACAGTGAAATGGACAAGCTCTATGAGAGG



GTCAAGAGGCAATTGAGAGAGAATGCCGAAGAAGACGGGACCGGTTGCTTCGAGATCTTC



CACAAATGTGATGATGACTGCATGGCAAGCATTAGAAACAACACCTACGATCACTCCAAA



TACCGAGAGGAGGCTATGCAAAATCGGATACAGATCGATCCTGTCAAGCTGTCTTCTGGT



TACAAAGATGTTATTCTGTGGTTCAGTTTTGGGGCCTCATGTTTCATCTTACTGGCAATC



GTGATGGGACTCGTTTTCATCTGTGTTAAAAATGGCAACATGAGGTGTACCATTTGTATC





657
ATGAACACACAAATTTTAGTGTTTGCTCTGATTGCCATTATCCCCACCAACGCTGATAAG



ATTTGTCTGGGGCACCACGCAGTGTCTAATGGCACCAAAGTCAACACACTTACAGAGAGA



GGAGTGGAGGTGGTTAACGCCACTGAAACCGTCGAGAGAACCAATATTCCTCGGATCTGC



TCCAAGGGCAAGAAAACAGTTGATCTAGGACAGTGTGGGTTGCTAGGGACAATCACCGGA



CCACCTCAGTGTGATCAGTTCTTAGAGTTCTCCGCTGATCTAATTATTGAGCGAAGAGAA



GGGTCCGATGTGTGCTACCCCGGTAAATTTGTCAATGAAGAAGCCTTGAGGCAGATTCTG



AGAGAAAGCGGCGGCATCGATAAGGAGGCAATGGGTTTCACTTACTCTGGAATCCGGACC



AACGGAGCCACTAGCGCTTGTCGAAGGAGTGGATCGTCCTTCTACGCCGAGATGAAATGG



CTCTTGTCAAATACAGATAATGCCGCATTTCCCCAGATGACTAAGAGCTACAAGAATACA



CGTAAGAGCCCGGCTCTGATCGTCTGGGGTATTCATCATAGTGTGTCTACTGCAGAGCAG



ACCAAACTATACGGTAGTGGCAACAAACTTGTCACCGTCGGCAGTTCTAATTACCAGCAA



TCCTTTGTCCCTTCCCCCGGCGCTCGGCCTCAGGTGAATGGACAGAGCGGCAGGATTGAC



TTCCACTGGCTTATGCTGAACCCTAATGATACTGTTACCTTCTCGTTTAATGGGGCGTTT



ATTGCTCCCGATAGGGCCAGTTTTCTTCGGGGCAAGTCCATGGGGATCCAGTCAGGTGTG



CAGGTCGATGCTAATTGTGAGGGCGACTGCTATCATTCTGGCGGCACGATCATCTCAAAC



TTGCCCTTCCAAAATATAGATAGCCGAGCAGTGGGAAAATGCCCTCGTTACGTCAAGCAG



AGGAGCCTCCTGTTAGCCACCGGGATGAAAAATGTTCCAGAAATACCCAAGGGGAGGGGC



TTATTTGGCGCTATTGCAGGATTTATCGAGAACGGTTGGGAGGGACTCATTGACGGATGG



TATGGCTTCCGCCACCAGAACGCCCAGGGGGAGGGTACCGCAGCTGATTACAAGTCCACA



CAGAGTGCCATAGATCAAATCACCGGTAAGCTGAATAGGCTGATCGAAAAAACCAATCAG



CAGTTTGAGCTCATCGATAATGAGTTCAACGAGGTGGAGAAACAGATTGGTAATGTCATC



AACTGGACAAGGGACTCGATTACCGAAGTGTGGAGCTATAACGCAGAGCTCTTGGTTGCC



ATGGAGAATCAGCACACCATCGATTTAGCAGATAGCGAAATGGACAAACTATACGAAAGG



GTGAAACGGCAACTTAGGGAGAACGCCGAAGAGGATGGGACCGGGTGCTTCGAAATTTTT



CACAAGTGTGATGACGACTGCATGGCCTCTATCCGGAATAATACCTACGATCACAGCAAA



TACAGGGAGGAAGCCATGCAGAACCGCATCCAGATCGATCCAGTCAAGCTGTCTTCTGGC



TATAAGGACGTGATCCTGTGGTTCTCTTTCGGCGCTAGTTGTTTTATCCTGCTGGCCATC



GTGATGGGCCTTGTTTTCATCTGTGTGAAAAACGGGAATATGAGGTGCACAATCTGCATT





658
ATGAACACACAGATCCTCGTCTTTGCACTCATCGCAATCATCCCCACCAACGCTGATAAA



ATTTGTCTCGGACATCATGCCGTGAGCAATGGGACCAAAGTTAACACCCTAACGGAGAGA



GGTGTCGAGGTGGTGAACGCGACAGAAACCGTAGAACGAACCAATATTCCAAGGATCTGC



AGTAAGGGAAAAAGGACCGTGGATTTGGGGCAGTGTGGATTGCTGGGGACTATCACAGGA



CCACCACAGTGCGACCAATTCCTTGAATTTTCCGCGGATCTGATTATTGAGAGGAGGGAG



GGATCTGACGTCTGTTACCCAGGCAAGTTCGTTAATGAGGAAGCGCTGAGACAGATTCTG



CGAGAGAGCGGAGGCATAGACAAAGAGGCTATGGGTTTTACCTATTCTGGGATACGCACA



AACGGAGCTACAAGCGCATGCCGGAGAAGTGGAAGCTCATTTTATGCGGAAATGAAATGG



CTCCTCTCCAACACCGACAATGCAGCATTCCCTCAGATGACCAAATCATATAAAAACACC



AGAAAAAGTCCGGCTCTCATAGTGTGGGGTATACATCATTCCGTCTCGACCGCAGAGCAA



ACTAAGCTCTACGGCTCTGGAAACAAACTCGTGACTGTCGGCAGTTCTAATTACCAGCAG



TCTTTTGTACCTAGCCCCGGGGCTAGGCCACAGGTGAATGGCTTATCTGGGCGCATAGAC



TTCCACTGGCTTATGCTGAACCCAAACGATACAGTGACCTTCTCCTTTAACGGCGCCTTC



ATTGCCCCCGACAGAGCTAGTTTCCTGCGCGGAAAATCAATGGGAATCCAGAGTGGGGTG



CAGGTGGATGCAAACTGCGAAGGCGACTGCTATCACTCAGGCGGCACAATAATTAGTAAC



CTACCATTCCAGAACATTGATTCACGCGCCGTCGGGAAGTGTCCGAGATACGTGAAACAG



CGGTCTCTCCTGTTAGCAACAGGCATGAAGAATGTGCCTGAGATTCCCAAAGGCCGGGGG



CTCTTCGGAGCCATTGCTGGTTTCATCGAGAACGGGTGGGAGGGTCTGATCGATGGCTGG



TATGGTTTCCGGCATCAGAACGCGCAGGGGGAGGGCACAGCCGCAGATTACAAGAGTACT



CAGAGTGCCATCGATCAGATTACAGGGAAGCTGAATAGAATAATCGAAAAAACTAATCAG



CAGTTTGAACTGATAGACAACGAATTCAACGAGGTCGAGAAGCAGATCGGGAATGTGATC



AACTGGACCCGCGACTCAATCACAGAGGTTTGGAGTTATAATGCCGAGCTCCTCGTTGCC



ATGGAGAATCAACATACAATTGACCTTGCTGACTCTGAGATGGATAAACTGTATGAACGA



GTTAAGCGACAGTTGAGGGAGAATGCGGAAGAAGACGGGACCGGCTGCTTCGAAATATTC



CATAAGTGCGACGATGACTGTATGGCATCAATCAGGAACAACACCTATGACCACTCCAAG



TATCGAGAGGAAGCGATGCAGAACAGGATCCAGATCGATCCAGTCAAGTTGTCCTCTGGC



TATAAGGACGTGATTCTGTGGTTTTCTTTCGGCGCAAGCTGTTTCATTTTATTAGCTATC



GTCATGGGTCTAGTGTTCATCTGTGTTAAAAATGGCAATATGCGATGTACAATCTGTATT





659
ATGAACACCCAAATCCTTGTTTTCGCTCTGATTGCAATTATCCCAACGAATGCTGACAAA



ATTTGCCTGGGCCACCACGCTGTGTCCAACGGAACTAAGGTAAATACTCTGACTGAACGC



GGCGTGGAGGTGGTGAACGCCACCGAAACAGTGGAGAGAACTAATATTCCCCGCATCTGT



TCTAAGGGCAAAAAGACAGTGGATCTCGGTCAGTGCGGGCTGTTGGGAACAATTACCGGA



CCTCCCCAATGCGATCAGTTCCTAGAGTTTTCCGCCGACCTGATAATCGAAAGACGTGAA



GGCTCTGACGTGTGTTACCCCGGAAAGTTTGTGAATGAAGAAGCACTGCGGCAGATCTTA



CGCGAGAGTGGCGGCATTGACAAGGAGGCAATGGGATTTACCTACTCCGGAATCAGGACA



AATGGCGCAACCAGTGCTTGTAGGCGCTCCGGAAGCTCCTTTTATGCCGAGATGAAATGG



CTTCTGTCCAACACGGACAACGCCGCTTTCCCTCAAATGACCAAATCCTACAAAAATACC



CGTAAGTCACCGGCGCTGATTGTATGGGGGATACACCACAGTGTTTCTACCGCCGAACAA



ACCAAGCTGTACGGCAGCGGAAATAAACTGGTAACTGTCGGATCATCCAATTACCAGCAG



TCCTTCGTCCCTAGCCCTGGGGCGCGCCCGCAGGTCAATGGGCAGTCTGGAAGAATTGAC



TTTCATTGGCTGATGTTAAATCCAAACGACACAGTTACATTCAGTTTCAACGGGGCCTTT



ATTGCACCCGATAGAGCATCCTTTCTGCGAGGCAAAAGTATGGGGATTCAATCTGGGGTG



CAGGTTGATGCGAATTGCGAGGGAGATTGCTATCACTCTGGCGGAACCATCATCAGCAAC



CTCCCATTCCAAAATATTGACTCACGCGCTGTGGGAAAGTGCCCTAGGTATGTGAAGCAG



CGGTCCTTGCTTTTAGCTACCGGAATGAAAAACGTGCCAGAAATCCCTAAGGGGCGCGGA



TTATTCGGCGCCATTGCTGGCTTCATTGAGAATGGATGGGAGGGCCTAATCGACGGTTGG



TATGGTTTTCGTCATCAGAACGCACAAGGGGAAGGGACTGCTGCCGACTACAAGTCTACC



CAGTCCGCTATAGACCAGATTACCGGTAAGCTAAATCGGCTTATAGAGAAGACTAACCAA



CAGTTCGAGCTGATCGACAACGAATTTAACGAAGTGGAGAAGCAGATTGGGAACGTCATC



AACTGGACGCGAGACTCTATTACTGAAGTCTGGTCTTACAATGCTGAGTTGCTCGTGGCT



ATGGAAAACCAGCATACTATAGACCTGGCCGACTCAGAGATGGATAAGTTATATGAACGC



GTGAAGCGGCAGCTCCGAGAAAATGCCGAAGAGGACGGAACAGGGTGTTTTGAGATCTTC



CACAAATGTGACGATGACTGCATGGCATCTATACGGAACAATACCTATGACCATTCCAAG



TACCGTGAGGAAGCCATGCAAAATAGAATACAAATCGATCCAGTCAAACTCTCTAGCGGC



TACAAGGACGTTATCTTGTGGTTCTCCTTCGGAGCGAGCTGTTTTATTTTGCTCGCGATT



GTGATGGGATTGGTGTTTATTTGCGTTAAAAACGGAAACATGCGGTGCACCATCTGTATC





660
ATGAATACCCAGATCCTGGTCTTCGCTCTGATCGCAATCATTCCTACCAACGCTGACAAA



ATTTGCCTGGGCCACCACGCAGTTAGTAATGGAACAAAAGTGAATACTCTTACAGAGCGG



GGTGTCGAGGTAGTAAACGCTACGGAAACCGTAGAGCGCACAAATATCCCCAGAATGTGT



AGCAAAGGTAAAAGGACAGTAGACTTGGGCCAGTGTGGACTGCTCGGAACAATTACAGGC



CCCCCTCAGTGTGATCAGTTCCTGGAATTCTCAGCCGACCTTATCATCGAACGAAGGGAG



GGGAGCGATGTCTGCTACCCAGGCAAGTTTGTGAATGAAGAGGCCCTTCGTCAAATACTC



CGAGAATCGGGGGGAATCGATAAAGAAGCAATGGGATTTACCTATAGCGGAATCAGAACT



AACGGCGCAACTTCCGCCTGCAGGCGGTCTGGCAGCTCCTTTTATGCCGAGATGAAGTGG



CTATTGAGCAATACTGACAACGCAGCCTTCCCTCAAATGACCAAGTCATACAAAAATACA



CGCAAGTCTCCAGCTCTGATCGTGTGGGGCATTCACCATAGCGTCAGCACAGCCGAGCAA



ACAAAGCTCTACGGCAGCGGCAACAAACTCGTGACCGTCGGCAGTTCTAACTACCAGCAG



TCCTTTGTGCCCAGCCCAGGGGCCCGTCCACAGGTTAACGGACTGTCTGGCCGGATCGAT



TTCCACTGGCTGATGTTAAATCCCAACGACACAGTCACGTTTAGCTTTAACGGAGCCTTT



ATCGCCCCCGACAGGGCTAGCTTTCTTAGGGGCAAGAGCATGGGAATTCAATCAGGGGTT



CAAGTGGACGCAAACTGCGAGGGCGATTGCTATCACTCCGGTGGAACTATTATAAGTAAT



CTACCATTCCAAAACATCGATTCAAGGGCGGTGGGTAAGTGTCCTCGCTACGTTAAGCAG



CGCAGCCTGCTACTCGCGACGGGAATGAAAAATGTCCCGGAGATACCTAAAGGCAGAGGC



CTCTTCGGCGCCATCGCAGGTTTCATCGAAAACGGCTGGGAAGGTCTGATCGACGGTTGG



TATGGATTCCGTCACCAAAACGCACAGGGAGAGGGTACAGCCGCAGACTATAAGTCTACC



CAGTCAGCTATCGACCAAATTACTGGAAAACTGAATCGTATCATTGAAAAGACCAATCAA



CAATTCGAGCTGATCGACAACGAGTTTAATGAAGTTGAGAAACAGATCGGAAATGTGATT



AACTGGACACGTGACAGCATTACTGAGGTCTGGAGCTACAACGCGGAACTTCTCGTAGCG



ATGGAGAACCAGCACACTATTGACCTGGCTGATAGTGAAATGGATAAACTATATGAAAGG



GTCAAAAGACAACTGCGGGAAAATGCCGAGGAAGATGGTACTGGATGTTTTGAAATCTTT



CACAAGTGCGATGACGACTGTATGGCTAGCATCAGGAACAATACATACGACCATTCGAAG



TATCGCGAAGAGGCCATGCAGAACCGAATACAGATTGATCCGGTTAAGCTGTCTTCTGGA



TATAAAGACGTCATCCTGTGGTTTAGTTTCGGGGCGAGTTGTTTCATTCTACTGGCTATT



GTCATGGGCCTGGTTTTTATCTGCGTGAAAAATGGCAACATGCGGTGCACGATCTGCATC





661
ATGAACACACAGATCTTGGTGTTCGCCCTCATCGCGATAATACCCACTAATGCCGACAAA



ATTTGTTTGGGTCATCACGCCGTGAGCAATGGCACTAAGGTGAACACGCTTACAGAACGG



GGCGTAGAAGTTGTGAACGCCACAGAGACAGTGGAGAGGACAAATATCCCGCGGATCTGC



TCAAAGGGGAAAAAAACCGTTGACCTGGGACAGTGCGGCCTGCTGGGGACAATAACAGGC



CCCCCCCAGTGTGACCAATTTCTGGAGTTCTCTGCCGACCTGATTATCGAAAGACGGGAG



GGCAGTGATGTCTGCTACCCCGGCAAGTTCGTAAATGAAGAGGCTCTGCGGCAGATCCTA



CGGGAGTCCGGAGGAATCGATAAGGAGGCAATGGGGTTTACGTATAGCGGCATTAGAACC



AACGGAGCAACCAGTGCTTGCAGGAGGAGCGGCAGCTCATTCTACGCGGAAATGAAGTGG



CTGCTGTCAAATACAGATAACGCCGCTTTCCCACAGATGACTAAATCCTATAAGAACACC



CGCAAGAGTCCTGCTCTCATCGTTTGGGGTATCCACCACTCTGTGTCAACTGCCGAGCAG



ACCAAACTTTACGGATCTGGGAATAAGCTTGTGACAGTTGGGAGCAGCAACTATCAGCAG



TCATTTGTGCCCTCTCCGGGTGCCAGGCCACAGGTTAATGGACAGTCGGGGCGTATCGAC



TTCCATTGGCTTATGCTCAATCCTAATGACACTGTTACCTTTTCTTTCAACGGCGCGTTC



ATTGCCCCCGACAGAGCGAGCTTTCTTAGGGGGAAATCGATGGGTATTCAGAGCGGGGTC



CAGGTCGATGCGAACTGCGAGGGCGATTGCTACCACTCAGGGGGAACAATTATCTCTAAT



TTACCCTTTCAGAACATCGACTCAAGGGCAGTGGGGAAGTGTCCGCGATACGTTAAACAA



CGGAGTTTGCTCCTGGCCACAGGCATGAAAAACGTCCCAGAAATCCCCAAAGGCAGAGGG



TTGTTTGGGGCGATCGCCGGCTTTATCGAGAACGGATGGGAAGGCTTAATTGACGGCTGG



TACGGCTTCCGCCACCAGAACGCTCAGGGGGAAGGTACCGCCGCTGATTATAAAAGTACG



CAAAGCGCTATTGATCAGATTACGGGCAAATTGAATCGGCTGATTGAGAAAACAAATCAG



CAGTTTGAACTGATCGACAACGAGTTTAATGAGGTGGAGAAGCAGATAGGAAATGTAATT



AACTGGACTCGGGATTCGATCACGGAGGTTTGGTCCTATAACGCAGAGCTACTGGTCGCC



ATGGAGAATCAGCACACTATTGACCTGGCAGATTCTGAGATGGACAAGCTGTACGAGAGG



GTAAAAAGACAACTGCGGGAGAACGCTGAAGAGGATGGAACAGGGTGTTTTGAGATCTTT



CACAAGTGCGACGATGATTGCATGGCATCTATCCGCAACAATACTTACGACCACTCTAAG



TACAGAGAAGAGGCGATGCAGAATCGAATTCAGATTGACCCGGTGAAGCTGAGCAGTGGA



TATAAAGATGTAATCCTCTGGTTTAGCTTCGGAGCCTCATGTTTTATCCTCCTTGCTATC



GTTATGGGCCTCGTCTTTATATGTGTCAAAAACGGCAATATGCGCTGCACAATCTGCATT





662
ATGAATACCCAAATTTTGGTTTTTGCTCTGATTGCCATTATTCCCACTAATGCCGACAAG



ATCTGCCTCGGCCATCATGCCGTGTCTAATGGCACAAAGGTGAATACCTTGACAGAAAGG



GGTGTGGAAGTAGTGAATGCCACAGAAACTGTAGAGCGGACCAATATTCCCAGGATTTGC



TCTAAGGGAAAGAAGACCGTTGATCTGGGCCAATGCGGCTTGCTGGGCACCATCACTGGG



CCACCACAGTGCGACCAGTTCCTGGAATTTAGCGCCGATCTGATAATAGAGAGACGGGAA



GGTAGCGACGTCTGCTATCCTGGGAAATTCGTCAACGAGGAAGCTCTGCGGCAGATCCTA



CGGGAGAGTGGCGGGATAGACAAGGAGGCAATGGGCTTTACGTACTCAGGAATTCGAACC



AATGGGGCGACGTCCGCCTGCCGGAGATCGGGCTCTTCTTTTTACGCAGAAATGAAGTGG



CTGCTGTCGAATACAGATAATGCGGCTTTCCCCCAGATGACCAAGTCATATAAAAATACG



AGAAAATCGCCCGCACTTATTGTGTGGGGCATCCACCACTCCGTGTCAACTGCCGAGCAA



ACCAAGCTATATGGCAGCGGCAATAAGCTGGTGACAGTAGGAAGTTCTAATTACCAGCAG



TCTTTCGTGCCGAGCCCTGGAGCCAGACCACAGGTGAATGGCCAGTCGGGCAGGATAGAT



TTCCACTGGTTAATGCTTAACCCAAACGACACGGTGACCTTCAGTTTCAACGGTGCCTTC



ATCGCCCCCGATCGCGCCTCCTTTTTGCGCGGCAAGTCTATGGGTATTCAGAGTGGAGTG



CAGGTGGACGCAAACTGCGAAGGGGATTGTTATCACAGGGGGGGGACCATAATCAGCAAT



CTCCCGTTTCAAAATATCGATTCTCGGGCAGTCGGTAAATGTCCCAGGTACGTTAAGCAA



CGGAGCCTGCTGCTCGCTACAGGCATGAAGAATGTGCCCGAGATCCCCAAGGGAAGAGGC



CTGTTCGGGGCCATCGCTGGTTTCATCGAGAACGGATGGGAGGGATTAATCGACGGGTGG



TACGGTTTCCGACACCAGAACGCACAGGGTGAGGGCACTGCCGCTGATTACAAATCAACC



CAGTCTGCAATCGACCAGATCACTGGGAAATTGAACCGATTGATCGAAAAGACGAACCAG



CAGTTCGAACTCATTGACAACGAGTTTAATGAAGTCGAGAAGCAGATTGGAAATGTGATC



AACTGGACAAGGGATTCTATCACAGAGGTCTGGTCATACAACGCTGAACTCCTTGTGGCC



ATGGAGAACCAGCACACCATCGATCTGGCTGATTCAGAAATGGATAAACTATATGAAAGG



GTGAAGCGGCAACTTAGGGAAAATGCTGAGGAGGACGGCACGGGATGCTTTGAAATCTTC



CACAAGTGTGATGATGACTGTATGGCGTCCATCCGGAACAATACATATGACCATTCAAAA



TATAGAGAAGAGGCAATGCAGAACAGGATACAGATTGACCCTGTCAAGTTGAGTTCTGGC



TACAAGGACGTGATTCTGTGGTTCAGCTTCGGAGCCAGTTGTTTCATCCTCCTGGCCATC



GTGATGGGCCTAGTGTTCATCTGCGTGAAAAATGGCAATATGCGCTGCACAATATGTATA





663
ATGAATACCCAAATCCTCGTTTTCGCACTGATTGCTATTATACCCACCAACGCTGACAAG



ATTTGTCTGGGTCACCACGCAGTTTCTAACGGCACAAAGGTGAATACTCTCACAGAGCGC



GGGGTTGAGGTCGTCAACGCTACTGAGACCGTCGAACGAACCAATATCCCCAGGATCTGT



AGCAAGGGAAAGAAAACAGTCGATTTAGGCCAGTGTGGCCTCTTAGGCACCATCACAGGC



CCACCCCAATGCGACCAGTTCCTGGAGTTCTCCGCAGATTTAATCATTGAGCGGCGAGAG



GGGAGTGATGTTTGCTACCCAGGTAAGTTCGTCAATGAAGAAGCCTTGCGCCAGATCCTG



CGGGAAAGCGGCGGCATTGACAAAGAGGCTATGGGATTTACTTATTCTGGCATACGAACT



AACGGGGCAACGTCTGCTTGTCGACGCTCAGGCTCATCCTTCTACGCAGAAATGAAATGG



TTGCTCAGTAATACAGATAATGCCGCATTTCCCCAAATGACCAAGAGCTACAAGAATACA



CGGAAGAGCCCAGCCCTGATTGTGTGGGGTATCCACCATTCTGTAAGTACAGCAGAGCAG



ACAAAACTGTATGGGTCTGGCAACAAACTGGTGACGGTGGGCAGTAGCAACTACCAACAG



AGTTTCGTGCCGTCACCTGGGGCAAGACCCCAGGTTAACGGGCAGTCCGGCCGCATAGAC



TTTCACTGGCTCATGCTGAATCCGAACGATACAGTGACTTTTTCATTCAATGGTGCATTT



ATCGCCCCCGATCGCGCTTCGTTCCTCCGCGGCAAATCTATGGGAATTCAATCCGGGGTA



CAGGTCGACGCCAACTGCGAGGGCGACTGTTACCATTCCGGCGGGACTATTATAAGTAAT



CTACCTTTTCAGAACATAGATTCCAGAGCCGTGGGAAAATGCCCTCGCTACGTGAAACAG



AGGTCCCTGCTTCTGGCTACTGGAATGAAGAATGTTCCAGAGATACCTAAGGGACGGGGC



CTTTTCGGGGCAATCGCCGGATTCATCGAAAATGGGTGGGAAGGGCTGATCGATGGCTGG



TACGGCTTTCGCCATCAGAACGCACAGGGAGAGGGTACAGCGGCTGATTACAAATCGACT



CAAAGTGCTATAGATCAGATTACCGGCAAACTGAACAGGCTGATCGAGAAAACGAATCAA



CAGTTCGAACTGATTGATAACGAGTTTAACGAGGTGGAAAAACAAATCGGAAACGTTATC



AATTGGACGAGGGACAGCATTACCGAAGTGTGGTCGTATAATGCAGAGCTGTTAGTCGCC



ATGGAGAATCAACACACCATCGATCTTGCCGACAGCGAGATGGACAAGCTTTATGAGCGC



GTGAAGAGACAACTGCGAGAAAATGCCGAGGAAGATGGAACCGGATGTTTTGAGATATTC



CACAAGTGCGACGATGATTGTATGGCGAGCATCCGCAACAATACCTATGATCACTCCAAA



TACAGGGAAGAGGCTATGCAAAATAGAATCCAAATTGATCCCGTCAAACTGTCAAGTGGG



TACAAGGATGTGATATTATGGTTTTCCTTTGGCGCCTCATGCTTTATACTGCTGGCTATC



GTGATGGGCTTGGTCTTTATTTGCGTGAAGAATGGCAACATGCGGTGTACAATATGTATT





664
ATGAATACACAAATTCTGGTGTTCGCACTCATTGCTATCATACCCACTAATGCCGATAAG



ATCTGTCTGGGCCACCACGCTGTTAGCAACGGGACCAAAGTTAACACCCTTACCGAGAGG



GGCGTGGAGGTGGTCAACGCAACCGAAACCGTCGAACGGACAAACATCCCGAGGATCTGC



AGTAAAGGAAAGAGAACAGTCGACCTCGGGCAATGTGGACTGCTGGGGACTATTACAGGG



CCCCCCCAATGTGATCAGTTCCTGGAGTTTTCTGCGGATTTAATCATTGAGAGGGGGGAG



GGGAGTGATGTTTGTTACCCAGGTAAGTTTGTTAATGAAGAAGCGCTGCGCCAGATACTT



AGAGAGAGTGGGGGAATCGACAAGGAGGCTATGGGTTTTACCTACAGCGGCATCAGAACA



AATGGCGCCACCAGCGCATGCCGCAGGAGCGGTTCCTCATTCTACGCCGAAATGAAGTGG



CTCCTATCCAATACAGATAACGCCGCCTTCCCCCAGATGACAAAGTCCTACAAAAACACC



CGGAAGAGCCCTGCCCTAATTGTGTGGGGTATCCACCACTCCGTGTCTACGGCCGAGCAG



ACCAAGCTGTACGGAAGCGGCAACAAACTAGTGACCGTAGGATCTAGTAACTATCAGCAG



AGTTTCGTACCTTCACCAGGAGCGCGGCCTCAGGTTAATGGTCTGAGCGGGAGGATCGAT



TTCCATTGGCTTATGCTGAACCCCAATGACACTGTTACGTTTTCTTTCAACGGAGCATTC



ATCGCTCCAGACCGCGCGAGCTTTCTCCGAGGAAAATCAATGGGGATACAGTCTGGGGTC



CAAGTGGACGCTAACTGTGAGGGGGACTGTTATCACTCAGGTGGAACCATTATTTCTAAC



TTGCCATTCCAGAACATAGATTCGCGAGCCGTGGGCAAATGTCCCCGTTACGTGAAACAG



CGTTCCCTCCTGCTAGCCACCGGGATGAAGAACGTACCCGAAATTCCTAAAGGGAGAGGC



CTCTTTGGCGCTATTGCGGGGTTTATTGAAAACGGATGGGAGGGCCTAATTGACGGCTGG



TATGGGTTCAGACATCAGAATGCACAGGGTGAGGGGACAGCTGCTGACTACAAGTCCACG



CAGTCTGCAATAGATCAAATAACCGGCAAACTCAACCGCTTAATCGAGAAAACGAACCAG



CAGTTCGAGCTTATAGACAATGAGTTCAATGAGGTTGAAAAACAGATCGGCAACGTGATT



AATTGGACTCGGGACTCTATCACCGAGGTCTGGAGCTATAACGCAGAGTTGCTGGTCGCC



ATGGAGAATCAGCACACAATAGATCTTGCTGACTCGGAAATGGACAAACTTTACGAAAGG



GTCAAGCGGCAGCTGAGGGAGAACGCTGAAGAAGATGGGACGGGGTGCTTCGAAATTTTT



CATAAGTGCGATGATGATTGTATGGCGTCCATTAGAAATAACACCTACGACCATAGTAAA



TACCGGGAGGAAGCCATGCAGAACAGGATCCAGATCGACCCAGTAAAACTGTCAAGTGGG



TATAAGGATGTTATATTGTGGTTCTCGTTCGGCGCCAGTTGCTTCATCCTCCTCGCTATT



GTCATGGGCCTTGTGTTTATTTGCGTGAAGAATGGAAATATGCGCTGCACCATTTGCATT





665
ATGAATACCCAGATACTGGTGTTTGCCTTAATAGCAATTATCCCAACAAATGCCGACAAG



ATCTGCCTTGGACACCACGCCGTGTCCAATGGTACTAAAGTGAACACCTTGACCGAGCGG



GGGGTGGAGGTGGTAAATGCCACGGAGACTGTCGAACGTACAAATATCCCCCGCATCTGT



TCTAAAGGCAAAAAAACTGTCGACTTGGGCCAGTGCGGACTACTGGGGACGATTACTGGT



CCGCCTCAGTGCGACCAATTCCTCGAATTTAGTGCAGATCTCATTATTGAAAGACGAGAG



GGGAGTGACGTTTGCTATCCAGGCAAGTTCGTTAACGAGGAAGCCCTTAGGCAAATTTTG



AGGGAGTCGGGGGGAATTGATAAAGAAGCAATGGGATTTACTTACAGCGGCATTCGGACC



AACGGTGCTACCTCAGCATGCAGGCGCTCTGGCTCCTCCTTCTACGCTGAGATGAAATGG



CTACTGTCCAACACCGACAATGCAGCATTTCCTCAAATGACTAAGAGCTATAAGAACACA



AGAAAATCCCCCGCCCTCATAGTCTGGGGGATCCACCACTCAGTGTCCACCGCAGAGCAG



ACGAAATTATATGGATCCGGAAATAAACTGGTGACAGTGGGGAGTAGTAACTACCAACAG



AGTTTTGTTCCCAGCCCAGGCGCCAGACCTCAGGTAAATGGACAGTCCGGAAGGATCGAT



TTTCATTGGCTCATGCTAAACCCCAACGATACCGTCACATTCTCATTCAACGGAGCATTT



ATAGCTCCCGACCGGGCTTCATTCCTTCGGGGTAAATCAATGGGCATTCAGTCTGGGGTA



CAAGTGGACGCCAATTGTGAGGGCGACTGCTATCACTCTGGCGGAACAATCATATCTAAT



CTCCCATTCCAGAACATCGATTCCCGCGCAGTCGGCAAGTGTCCAAGGTACGTGAAACAG



CGCTCCCTGTTGTTGGCAACTGGAATGAAAAATGTACCAGAGATTCCTAAGGGACGTGGA



CTGTTCGGAGCTATTGCAGGGTTCATCGAAAATGGGTGGGAGGGCCTAATCGACGGTTGG



TATGGGTTCAGACATCAGAACGCCCAGGGGGAGGGTACTGCCGCCGATTACAAGTCCACC



CAGTCCGCAATTGACCAGATCACGGGTAAATTAAACAGACTCATTGAAAAAACTAATCAG



CAGTTCGAGCTTATTGATAATGAATTTAATGAAGTGGAAAAGCAGATAGGGAATGTGATT



AACTGGACCCGCGACTCTATCACAGAAGTCTGGTCATACAATGCTGAACTGCTTGTCGCC



ATGGAAAATCAGCATACCATAGACCTTGCAGATTCAGAAATGGACAAGCTGTACGAAAGA



GTCAAAAGACAGCTGAGGGAGAATGCCGAGGAGGATGGTACAGGGTGCTTCGAAATCTTC



CACAAGTGCGACGATGACTGTATGGCGAGCATCCGCAATAATACGTATGACCATTCTAAA



TACAGAGAAGAGGCGATGCAGAATCGGATCCAAATCGACCCGGTAAAGCTCAGTTCGGGC



TACAAAGACGTAATACTATGGTTCTCCTTTGGAGCTTCGTGCTTCATTCTCCTAGCTATC



GTCATGGGGTTAGTCTTCATCTGCGTGAAGAATGGTAATATGCGCTGTACAATTTGTATA





666
ATGAACACACAGATCCTAGTGTTTGCCCTCATCGCCATTATTCCAACAAACGCTGATAAG



ATTTGCCTAGGACATCACGCAGTGTCCAACGGAACTAAGGTGAACACCTTAACTGAGAGG



GGAGTAGAGGTGGTGAATGCCACAGAGACTGTTGAAAGAACCAATATTCCCCGTATCTGC



TCAAAGGGGAAGAGAACGGTAGACCTGGGGCAGTGTGGCTTGCTGGGCACCATCACCGGC



CCACCCCAGTGCGATCAGTTTTTGGAATTCTCTGCCGATTTAATAATAGAACGCAGAGAA



GGTTCCGACGTGTGCTACCCTGGAAAATTCGTCAATGAGGAAGCACTGAGGCAGATCTTA



CGCGAGTCCGGAGGCATCGACAAAGAGGCAATGGGATTCACTTACTCCGGAATCCGGACT



AACGGGGCGACGAGCGCCTGCAGGCGTAGCGGCTCCTCTTTTTACGCGGAAATGAAGTGG



CTTCTATCCAACACTGACAATGCCGCTTTTCCACAAATGACCAAGTCTTATAAAAACACA



CGCAAGTCGCCCGCCTTAATAGTGTGGGGCATTCATCATTCCGTGTCAACAGCAGAGCAG



ACTAAGTTGTATGGCAGTGGTTCTAAGTTGGTGACAGTAGGATCCTCCAACTACCAGCAA



AGTTTCGTGCCTAGCCCAGGCGCACGTCCCCAGGTGAACGGCCTTTCAGGGAGGATCGAT



TTCCATTGGCTGATGCTCAACCCCAACGACACTGTTACTTTCTCCTTCAACGGAGCATTT



ATCGCACCAGATCGGGCCTCCTTCTTGCGGGGAAAATCTATGGGAATCCAGAGCGGAGTG



CAGGTGGATGCCAATTGTGAAGGGGATTGCTACCACTCTGGGGGAACAATTATCTCCAAT



TTGCCCTTCCAGAATATCGATTCCCGAGCTGTCGGAAAATGTCCGAGGTATGTCAAGCAG



CGTAGTCTGCTCCTTGCCACGGGCATGAAGAACGTCCCAGAGATTCCCAAGGGCCGGGGC



TTATTCGGGGCTATCGCCGGGTTCATCGAGAACGGATGGGAGGGGCTAATAGACGGCTGG



TATGGCTTCAGGCATCAGAATGCACAAGGTGAAGGAACGGCGGCTGATTATAAATCCACC



CAGAGTGCCATCGATCAGATTACAGGTAAGCTTAACCGGCTAATCGAAAAGACGAATCAG



CAGTTTGAACTCATCGATAACGAGTTCAATGAGGTGGAGAAGCAGATCGGAAATGTCATC



AACTGGACTCGAGACTCGATCACTGAGGTGTGGTCCTACAATGCTGAGCTTCTGGTCGCT



ATGGAAAATCAACACACCATCGATCTGGCAGACTCAGAAATGGACAAGTTGTACGAGCGG



GTGAAGAGACAACTAAGGGAAAACGCCGAGGAAGATGGCACTGGATGCTTTGAAATCTTT



CACAAGTGCGACGATGACTGCATGGCTTCAATCAGAAATAACACCTACGATCACAGCAAG



TACAGAGAAGAAGCAATGCAGAACCGTATTCAAATCGACCCCGTCAAGCTGTCCAGCGGA



TACAAGGATGTGATCCTGTGGTTCTCCTTCGGGGCAAGCTGTTTCATCCTGCTGGCTATA



GTGATGGGCCTGGTCTTCATTTGTGTCAAGTCCAGGAATATGCGGTGTACTATCTGTATT





667
ATGAACACCCAGATACTGGTCTTTGCTCTCATAGCGATCATACCAACCAACGCTGACAAA



ATCTGTCTGGGGCACCACGCGGTGTCTAACGGCACTAAGGTAAACACCCTCACTGAACGC



GGTGTGGAGGTGGTGAACGCCACCGAGACCGTTGAGCGTACAAATATACCCAGGATCTGT



TCCAAGGGTAAAAGGACCGTCGACCTTGGCCAGTGTGGCCTGCTGGGCACCATTACGGGC



CCTCCCCAATGCGATCAATTTCTTGAGTTCAGCGCCGATTTGATCATAGAGCGACGTGAG



GGGTCAGACGTGTGTTACCCTGGGAAATTTGTGAAGGAAGAAGCACTGCGACAGATCCTT



CGAGAGTCTGGAGGGATTGATAAGGAAGCTATGGGCTTCACCTATAGCGGAATCAGGACT



AACGGCGCTACTAGTGCGTGCAGACGATCTGGAAGCAGTTTTTACGCCGAAATGAAGTGG



CTGCTGTCTAATACTGATAATGCCGCCTTCCCACAAATGACCAAGTCCTACAAGAACACA



CGGAAGTCCCCAGCTCTGATCGTGTGGGGCATCCATCACTCGGTCTCCACAGCCGAGCAA



ACAAAGCTTTACGGGTCAGGAAACAAATTGGTAACCGTGGGCTCTAGTAACTATCAACAG



AGCTTCGTCCCGTCCCCCGGTGCACGCCCACAGGTGAACGGTTTAAGTGGGCGCATCGAC



TTCCATTGGCTCATGCTGAACCCTAATGACACAGTGACCTTTTCCTTTAACGGGGCATTC



ATCGCCCCTGATAGGGCATCCTTCCTCCGGGGCAAGAGTATGGGGATACAATCGGGGGTG



CAAGTCGACGCAAATTGCGAGGGTGATTGTTACCACTCTGGGGGTACCATCATTTCCAAC



CTGCCCTTTCAGAACATAGATTCGAGGGCTGTCGGGAAGTGCCCTCGATATGTGAAGCAG



CGGAGTCTCCTGCTGGCAACAGGCATGAAGAACGTCCCCGAGATCCCCAAAGGACGAGGA



CTCTTCGGCGCAATCGCCGGTTTTATAGAGAACGGATGGGAAGGCCTGATCGACGGTTGG



TATGGCTTTCGTCACCAGAACGCGCAGGGTGAGGGCACTGCCGCCGACTATAAGAGCACA



CAGTCCGCCATCGACCAAATTACTGGAAAGCTTAATAGACTAATCGAAAAAACAAACCAA



CAGTTTGAGCTGATTGACAATGAGTTTAATGAGGTGGAGAAGCAGATAGGTAATGTGATA



AATTGGACCCGGGATTCTATTACCGAAGTGTGGTCATACAATGCGGAACTGCTGGTAGCA



ATGGAAAATCAGCACACAATCGATCTGGCCGATAGTGAGATGGACAAGTTGTACGAGAGG



GTTAAGAGGCAGCTTCGGGAAAATGCAGAAGAGGATGGTACCGGGTGTTTTGAAATCTTC



CACAAGTGCGATGACGACTGCATGGCTTCTATCAGAAACAATACATACGACCACAGCAAA



TATCGGGAGGAAGCCATGCAGAACCGAATCCAGATCGATCCCGTCAAGCTTAGCTCGGGC



TATAAAGATGTCATTCTGTGGTTTTCCTTTGGAGCCTCCTGTTTCATCCTCCTAGCCATT



GTGATGGGTCTTGTGTTTATCTGCGTGAAGAACGGCAATATGAGGTGCACTATCTGCATT





668
ATGAATACCCAAATTCTTGTGTTCGCCCTGATCGCTATTATCCCGACGAACGCCGATAAG



ATCTGCCTAGGACACCACGCTGTGAGTAATGGAACCAAGGTGAACACACTGACTGAGAGG



GGCGTGGAGGTGGTGAACGCGACAGAGACCGTGGAACGAACAAATATTCCGAGGATCTGT



TCAAAGGGGAAGAGAACCGTGGATCTGGGCCAGTGCGGACTGCTAGGCACTATTACCGGC



CCACCACAGTGTGACCAGTTCCTGGAGTTTAGTGCCGACCTGATTATTGAAAGGCGCGAG



GGAAGTGACGTTTGTTACCCCGGGAAATTCGTAAATGAGGAGGCCCTCAGACAAATACTA



AGAGAGTCCGGCGGAATTGACAAAGAGGCGATGGGCTTTACATACAGCGGTATAAGAACG



AACGGGGCGACCTCCGCATGTAGGCGTAGTGGCTCAAGTTTCTATGCCGAGATGAAGTGG



CTGCTGAGCAATACAGACAATGCCGCCTTTCCCCAGATGACCAAGTCTTACAAGAATACG



AGAAAAAGTCCAGCACTCATTGTGTGGGGTATCCATCATTCTGTGAGCACAGCAGAACAA



ACAAAGCTGTACGGCTCAGGAAACAAGCTCGTGACTGTGGGCAGCTCTAACTACCAGCAA



TCATTCGTCCCCTCCCCGGGAGCCAGACCACAGGTTAACGGACTGAGTGGGCGAATTGAT



TTCCACTGGCTTATGTTAAACCCCAATGATACTGTGACATTTTCTTTCAACGGCGCGTTT



ATCGCTCCAGATCGTGCCAGTTTTCTGAGGGGGAAGTCCATGGGCATCCAGTCCGGAGTG



CAGGTTGACGCCAATTGTGAAGGGGACTGTTACCATTCTGGTGGGACTATTATTTCGAAC



CTACCCTTCCAGAATATTGACAGCCGGGCCGTTGGTAAATGCCCTCGGTACGTTAAACAA



AGAAGCCTCCTGCTGGCGACCGGAATGAAGAATGTGCCTGAAATTCCGAAAGGACGCGGA



CTGTTCGGCGCTATCGCAGGGTTTATAGAAAACGGTTGGGAGGGCTTAATTAACGGTTGG



TATGGCTTTCGGCACCAGAACGCCCAGGGCGAGGGGACCGCCGCCGACTATAAAAGCACA



CAGTCTGCGATTGATCAGATTACCGGGAAGCTCAACAGGCTCATAGAGAAAACAAACCAA



CAGTTTGAACTGATTGACAATGAATTTAACGAGGTAGAAAAACAGATTGGCAATGTTATC



AACTGGACCAGGGATTCAATTACAGAGGTGTGGTCTTATAATGCCGAGCTATTGGTGGCC



ATGGAAAACCAACATACAATCGACCTCGCCGATTCAGAGATGGACAAGCTGTATGAGAGG



GTCAAAAGACAGTTGCGCGAGAATGCCGAGGAGGACGGGACTGGCTGCTTCGAGATCTTT



CACAAATGCGATGACGACTGTATGGCTAGTATCCGCAACAACACGTATGATCACTCTAAG



TACCGCGAGGAAGCCATGCAGAATCGGATCCAAATTGATCCAGTTAAACTGTCTAGCGGC



TACAAGGATGTGATTCTGTGGTTTTCTTTCGGAGCATCCTGCTTCATCTTGTTAGCCATT



GTGATGGGCCTGGTTTTTATCTGCGTGAAGAACGGCAATATGCGGTGTACTATCTGCATC





669
ATGAATACGCAGATTCTGGTGTTTGCCTTAATAGCTATTATCCCCACTAATGCCGACAAG



ATCTGTTTAGGGCACCACGCTGTATCAAATGGCACCAAAGTCAATACGCTCACCGAACGG



GGGGTGGAAGTTGTGAACGCGACTGAAACTGTCGAAAGAACCAATATTCCGCGAATTTGC



AGTAAGGGAAAGAAGACTGTGGACCTGGGCCAATGTGGCTTGTTGGGCACCATTACCGGT



CCACCGCAGTGCGATCAATTTCTTGAATTCTCTGCAGACCTGATAATCGAACGCCGCGAG



GGCTCTGACGTGTGTTATCCTGGGAAATTTGTTAATGAGGAAGCCCTCAGGCAGATACTC



AGGGAATCTGGCGGTATTGATAAGGAGGCCATGGGGTTCACGTACTCTGGTATACGCACC



AATGGTGCCACATCCGCATGCAGGAGAAGCGGCTCCTCGTTCTATGCAGAAATGAAGTGG



TTGCTGTCGAACACAGACAACGCCGCCTTTCCACAGATGACAAAGAGTTACAAGAACACA



AGGAAGTCACCTGCCCTGATCGTTTGGGGTATTCATCATTCTGTCTCCACAGCTGAGCAG



ACCAAACTGTACGGGTCAGGAAACAAGCTGGTGACTGTGGGTTCCTCGAATTATCAGCAG



AGCTTTGTTCCGTCCCCAGGTGCGAGGCCCCAGGTGAACGGCCAATCCGGGCGCATCGAC



TTTCACTGGCTGATGCTTAACCCAAACGATACTGTGACCTTCTCCTTTAACGGAGCGTTT



ATCGCTCCAGACAGGGCCTCGTTTCTGAGAGGGAAAAGCATGGGAATCCAGTCAGGGGTG



CAGGTGGATGCTAATTGTGAAGGTGACTGTTACCACTCAGGAGGCACAATCATTAGCAAC



CTGCCCTTTCAGAACATTGACTCCAGGGCAGTGGGCAAATGTCCACGGTATGTGAAGCAG



AGAAGCCTCCTCCTGGCCACAGGCATGAAGAACGTGCCAGAGATTCCCAAGGGTAGGGGC



CTGTTCGGTGCTATAGCCGGATTTATTGAGAATGGATGGGAAGGGCTGATCGACGGTTGG



TACGGCTTTAGACACCAGAACGCTCAGGGAGAGGGAACTGCCGCAGACTATAAAAGTACT



CAAAGCGCGATCGACCAGATAACAGGTAAGCTCAACCGTCTCATTGAGAAAACAAACCAG



CAGTTCGAACTCATCGATAACGAGTTTAACGAAGTCGAGAAACAAATTGGAAACGTCATT



AACTGGACTAGAGATTCAATCACTGAGGTGTGGAGCTACAACGCTGAGCTGCTTGTGGCT



ATGGAGAATCAGCATACCATAGATCTGGCTGACTCTGAAATGGATAAACTCTATGAACGA



GTCAAGAGACAGCTCAGGGAGAATGCTGAAGAGGATGGCACAGGATGTTTCGAAATCTTC



CACAAGTGTGACGACGACTGCATGGCAAGCATTAGGAATAACACATATGATCATTCTAAA



TATAGGGAAGAGGCAATGCAGAATCGGATCCAAATTGATCCAGTCAAGTTATCTTCCGGG



TATAAAGACGTGATCCTTTGGTTCAGCTTTGGCGCTTCATGTTTCATCTTGCTTGCCATC



GTCATGGGACTCGTCTTTATCTGCGTCAAAAATGGTAACATGAGATGCACAATTTGTATC





670
ATGAATACCCAGATTTTAGTGTTTGCCCTGATTGCCATAATCCCAACTAACGCCGATAAG



ATTTGCTTGGGCCACCACGCTGTGAGCAACGGCACCAAAGTCAACACCCTGACCGAACGC



GGCGTGGAGGTCGTCAATGCCACCGAAACCGTGGAGCGAACCAACATTCCACGCATCTGT



TCCAAGGGAAAAAGAACGGTTGATCTCGGCCAGTGTGGCCTGCTCGGGACAATCACCGGG



CCGCCGCAGTGCGACCAGTTCCTGGAGTTTAGCGCCGACCTAATCATCGAACGCCGGGAG



GGTTCTGATGTGTGCTACCCTGGCAAATTTGTGAATGAGGAGGCGCTTAGGCAGATTCTC



AGGGAGTCCGGTGGAATTGACAAGGAAGCCATGGGTTTCACATACAGCGGTATTAGGACT



AATGGCGCAACATCAGCTTGTCGAAGATCTGGTTCTAGCTTTTACGCAGAGATGAAATGG



CTTCTATCCAATACTGATAATGCAGCTTTTCCCCAAATTACAAAGTCATATAAAAACACC



CGCAAATCGCCCGCTCTCATAGTGTGGGGAATTCACCATTCCGTTAGTACCGCTGAACAG



ACCAAATTGTATGGGAGCGGTAACAAGCTGGTCACCGTTGGGTCCTCCAATTATCAGCAG



TCGTTCGTGCCGAGTCCTGGAGCCCGCCCCCAGGTCAACGGCCTTTCTGGCCGGATTGAC



TTTCATTGGCTGATGTTGAACCCTAACGACACAGTTACATTCTCATTTAATGGAGCCTTC



ATCGCTCCGGATCGAGCCAGCTTCCTCCGTGGTAAGAGTATGGGGATCCAAAGCGGTGTT



CAGGTCGATGCCAACTGCGAGGGCGATTGTTATCATTCAGGGGGTACTATAATCAGCAAC



CTGCCCTTTCAAAACATAGACAGCAGGGCAGTCGGAAAATGTCCTCGATATGTCAAACAA



CGGTCTCTGTTGCTGGCTACAGGGATGAAGAACGTGCCGGAGATCCCCAAAGGACGTGGA



TTATTTGGGGCCATAGCCGGGTTTATTGAGAATGGATGGGAGGGCCTGATTGATGGATGG



TACGGTTTTCGCCATCAGAATGCACAGGGAGAAGGAACAGCTGCCGACTACAAGTCAACG



CAGAGTGCTATTGACCAGATAACTGGCAAGTTAAACCGGCTGATCGAAAAGACTAATCAA



CAATTTGAGTTGATCGACAATGAGTTTAATGAAGTTGAGAAACAGATCGGCAACGTCATC



AACTGGACGCGCGATAGCATTACAGAAGTCTGGTCTTATAACGCCGAGTTGCTTGTAGCA



ATGGAGAACCAGCATACCATTGATCTCGCGGACAGTGAAATGGACAAGCTCTACGAGCGC



GTAAAGCGACAGCTAAGAGAAAATGCAGAAGAAGATGGGACGGGATGTTTCGAAATCTTC



CACAAATGCGATGACGATTGCATGGCCAGCATACGGAATAATACCTACGATCATTCCAAG



TATCGGGAAGAGGCCATGCAGAACCGCATTCAGATTGATCCCGTGAAACTTTCAAGTGGC



TACAAGGACGTCATCCTGTGGTTCTCTTTCGGGGCAAGTTGTTTTATTCTGCTCGCTATT



GTCATGGGTCTGGTCTTTATCTGTGTCAAAAATGGCAACATGCGGTGCACAATCTGTATT





671
ATGAACACACAGATTCTAGTGTTTGCACTGATTGCTATCATTCCTACAAATGCAGACAAG



ATTTGTCTGGGCCATCACGCCGTCTCGAATGGTACAAAAGTGAATACCCTGACTGAAAGA



GGGGTCGAAGTGGTTAACGCAACAGAGACCGTAGAGAGAACGAATATTCCAAGAATCTGC



TCTAAGGGCAAAAAAACAGTGGATCTGGGTCAGTGTGGACTGTTAGGGACAATCACAGGT



CCACCACAATGCGACCAGTTCCTTGAATTCTCGGCGGATCTTATCATCGAGCGCCGAGAA



GGTTCCGACGTGTGTTACCCAGGAAAATTCGTCAATGAGGAGGCTTTGAGACAGATCTTG



CGCGAAAGCGGTGGCATCGACAAAGAGGCTATGGGATTCACTTACTCTGGAATACGAACT



AACGGTGCCACGTCCGCTTGCCGCAGGAGTGGATCTAGCTTCTATGCAGAGATGAAGTGG



CTATTGAGCAACACTGATAATGCTGCCTTCCCTCAGATGACAAAGAGCTATAAAAACACT



AGAAAGAGCCCAGCATTGATCGTTTGGGGCATTCACCACAGTGTATCCACAGCAGAGCAG



ACCAAACTGTATGGGAGTGGAAACAAGCTTGTTACTGTAGGGTCCAGCAACTATCAACAG



AGCTTTGTTCCGTCACCAGGTGCTCGGCCCCAGGTTAATGGGCAAAGTGGGGGGATCGAC



TTCCACTGGCTGATGCTCAATCCTAATGACACGGTCACATTTTCCTTTAACGGGGCCTTC



ATTGCTCCGGATCGCGCCAGCTTTCTGCGTGGAAAGAGTATGGGTATTCAAAGTGGCGTT



CAGGTCGACGCCAACTGCGAGGGCGACTGCTATCATAGCGGTGGAACAATCATCTCTAAC



CTGCCTTTCCAGAACATCGATAGCAGAGCCGTTGGCAAGTGTCCCAGGTACGTGAAGCAG



CGATCACTGTTGTTGGCTACGGGCATGAAAAACGTCCCAGAGATTCCAAAAGGGAGGGGA



CTATTCGGCGCCATTGCTGGGTTCATTGAAAATGGCTGGGAGGGTCTGATTGATGGATGG



TACGGGTTTAGGCACCAAAACGCCCAAGGCGAAGGGACAGCAGCTGACTATAAATCCACT



CAATCTGCTATCGACCAGATCACTGGAAAACTCAACAGACTTATTGAGAAGACTAATCAG



CAGTTTGAGCTCATCGACAACGAGTTTAATGAAGTGGAGAAGCAGATTGGGAACGTTATC



AACTGGACGAGGGACTCAATCACGGAAGTATGGTCCTACAATGCCGAATTGCTGGTGGCC



ATGGAGAACCAGCACACCATTGACCTGGCGGACTCCGAAATGGATAAACTCTACGAACGA



GTGAAGAGGCAACTCCGAGAAAATGCTGAGGAAGATGGGACCGGTTGTTTCGAGATCTTT



CATAAGTGTGACGATGACTGCATGGCTTCTATTAGAAACAATACTTACGATCACTCAAAA



TATAGAGAAGAGGCAATGCAGAACCGCATTCAGATCGACCCGGTGAAGCTGAGCAGTGGT



TATAAGGATGTCATTTTATGGTTTAGTTTTGGAGCATCTTGTTTTATTTTGCTCGCTATC



GTAATGGGCCTCGTGTTTATCTGCGTGAAAAATGGTAACATGCGGTGCACGATATGCATT





672
ATGAATACGCAGATTTTGGTTTTCGCCTTGATTGCCATTATTCCTACAAACGCCGACAAG



ATCTGCCTGGGACATCACGCCGTGAGTAATGGAACCAAGGTGAATACACTGACCGAGAGG



GGCGTAGAAGTTGTAAATGCTACTGAGACAGTGGAGCGAACAAATATTCCCAGAATTTGC



TCCAAGGGCAAGAAGACTGTCGACCTTGGCCAATGTGGGCTGCTCGGCACGATCACGGGG



CCACCCCAATGTGATCAGTTTCTGGAGTTTTCTGCCGACCTCATTATAGAACGCCGGGAG



GGGAGCGACGTATGCTACCCCGGTAAGTTCGTAAACGAAGAAGCCCTCAGACAGATTTTG



AGGGAGTCCGGAGGCATCGATAAGGAGGCAATGGGCTTCACCTACAGCGGCATCAGAACA



AACGGTGCCACAAGTGCATGTAGGCGCTCTGGCTCATCATTCTATGCAGAGATGAAGTGG



CTGCTTTCCAATACTGATAATGCGGCCTTTCCTCAGATGACTAAATCATATAAGAACACC



AGAAAATCTCCCGCCTTGATCGTCTGGGGGATCCATCACAGCGTCTCTACCGCTGAGCAG



ACCAAACTCTACGGTTCAGGGAACAAATTAGTGACCGTTGGCAGCTCCAACTACCAGCAA



TCATTTGTGCCTTCCCCAGGTGCCAGGCCGCAAGTAAACGGTCAGTCAGGACGAATTGAT



TTCCACTGGCTAATGCTGAACCCGAATGACACAGTCACCTTCAGCTTTAACGGGGCTTTC



ATCGCACCCGACCGCGCCAGTTTCTTACGGGGAAAATCAATGGGAATACAATCCGGCGTT



CAAGTGGACGCGAATTGCGAGGGAGATTGTTACCATAGTGGTGGTACAATTATCTCCAAT



CTTCCCTTTCAGAATATCGACAGTAGGGCAGTGGGAAAATGTCCCCGATACGTCAAACAG



CGGAGCCTGCTCCTCGCCACCGGGATGAAGAACGTCCCCGAGATTCCAAAAGGTAGGGGT



TTGTTCGGAGCTATCGCAGGGTTCATCGAAAACGGCTGGGAAGGCCTGATAGACGGTTGG



TATGGATTCCGACACCAAAACGCTCAAGGCGAGGGCACTGCAGCAGATTACAAATCTACA



CAAAGCGCTATCGACCAGATTACCGGAAAACTTAACCGTCTAATCGAAAAGACCAATCAG



CAGTTCGAGCTCATCGATAACGAATTCAATGAGGTGGAGAAACAGATCGGAAACGTAATC



AATTGGACACGAGATTCCATCACTGAGGTTTGGTCTTATAACGCCGAACTCTTAGTGGCT



ATGGAGAATCAGCACACCATCGACCTGGCTGATTCCGAGATGGACAAGCTGTACGAAAGA



GTGAAGAGACAGCTTCGCGAAAACGCAGAGGAGGATGGGACCGGATGTTTCGAAATCTTC



CACAAATGTGATGATGATTGCATGGCCAGCATCCGGAACAACACATATGATCATTCGAAA



TATCGCGAGGAGGCTATGCAAAATCGGATCCAGATCGATCCCGTCAAGCTAAGCTCTGGG



TACAAGGACGTGATTTTATGGTTTTCCTTCGGCGCTTCATGTTTCATCCTTCTGGCCATC



GTGATGGGCCTAGTGTTTATCTGCGTCAAGAATGGAAACATGAGATGTACGATCTGCATC





673
ATGAACACTCAGATTCTGGTATTTGCGCTAATCGCAATCATTCCCACCAACGCAGACAAG



ATTTGTCTGGGACATCATGCCGTGAGCAACGGCACAAAAGTGAACACTCTGACTGAAAGG



GGAGTGGAGGTTGTAAATGCGACCGAAACTGTGGAAAGAACCAATATACCCCGAATCTGT



AGCAAGGGTAAAAAGACCGTAGACTTAGGACAGTGTGGTCTCTTGGGGACAATCACAGGC



CCCCCTCAATGTGACCAGTTCTTAGAGTTTAGCGCAGATTTGATTATCGAGCGAAGGGAG



GGAAGTGACGTTTGTTACCCTGGGAAGTTCGTGAATGAAGAAGCTCTCCGTCAGATCTTG



AGGGAGTCCGGAGGCATAGACAAAGAGGCCATGGGGTTCACTTACTCCGGGATTCGCACA



AATGGAGCTACAAGTGCCTGTAGAAGGTCAGGCAGTTCTTTCTATGCTGAGATGAAATGG



CTCTTATCAAACACAGACAACGCTGCCTTCCCACAGATGACAAAATCCTACAAAAACACT



CGCAAATCCCCAGCCCTTATCGTGTGGGGGATCCATCACTCCGTGTCCACTGCGGAACAG



ACTAAGCTGTATGGATCCGGGAACAAACTGGTAACTGTAGGGAGTAGCAACTACCAGCAG



TCCTTCGTCCCATCTCCTGGGGCACGCCCCCAGGTAAACGGACAGTCTGGAAGAATTGAT



TTCCACTGGTTGATGCTGAACCCAAATGATACTGTGACCTTCTCTTTCAATGGCGCTTTC



ATCGCGCCCGATCGCGCTAGCTTCCTAAGGGGAAAATCCATGGGGATTCAGTCTGGCGTC



CAGGTCGATGCAAATTGCGAAGGCGACTGTTACCATTCTGGAGGGACCATTATCAGTAAC



CTGCCATTCCAGAATATTGACTCGAGGGCAGTGGGTAAGTGCCCCAGGTACGTGAAACAA



AGATCACTGCTTCTGGCTACAGGAATGAAGAACGTACCTGAGATCCCTAAAGGGGGGGGA



TTATTCGGAGCCATCGCAGGCTTCATAGAGAACGGGTGGGAGGGCCTGATTGATGGGTGG



TACGGATTCAGGCACCAAAATGCCCAGGGAGAAGGGACCGCTGCGGATTACAAGAGTACC



CAGTCCGCTATAGACCAGATCACAGGCAAACTTAATAGGCTGATTGAAAAGACCAATCAG



CAGTTTGAACTCATCGATAACGAATTTAACGAGGTGGAAAAGCAGATTGGGAACGTGATT



AACTGGACAAGGGATTCTATTACCGAGGTGTGGAGCTACAATGCCGAGCTGTTGGTTGCG



ATGGAGAATCAGCACACTATCGATCTAGCAGACTCCGAAATGGACAAGTTGTATGAAAGA



GTGAAGCGCCAATTAAGGGAAAACGCAGAGGAGGATGGGACCGGATGTTTTGAGATCTTC



CATAAATGCGATGACGACTGCATGGCCAGCATTAGAAATAATACCTACGACCATAGTAAG



TATAGGGAGGAGGCGATGCAAAACAGAATTCAAATAGACCCAGTGAAACTGAGTTCTGGG



TACAAAGACGTTATTCTCTGGTTTTCATTCGGCGCCAGCTGCTTTATACTGCTGGCTATC



GTCATGGGCTTGGTCTTCATCTGCGTGAAAAACGGGAATATGCGATGCACAATTTGTATT





674
ATGAATACCCAGATCCTGGTGTTCGCTCTCATCGCCATCATACCAACAAACGCTGACAAG



ATCTGCCTAGGTCACCACGCTGTGTCTAATGGAACCAAAGTGAATACACTGACCGAGCGC



GGTGTGGAGGTGGTGAACGCTACAGAGACCGTGGAACGCACTAATATCCCTCGAATATGT



TCTAAGGGCAAGAAAACTGTAGATCTGGGGCAGTGCGGCCTTCTGGGAACTATCACGGGC



CCTCCACAGTGCGATCAATTTTTGGAGTTTTCTGCCGACCTCATCATCGAACGCCGTGAG



GGATCGGACGTGTGTTATCCAGGAAAGTTTGTGAATGAGGAAGCGCTCCGGCAGATCTTA



AGAGAAAGCGGTGGTATTGACAAAGAAGCAATGGGCTTCACCTATTCAGGAATTAGGACC



AACGGAGCAACCAGTGCGTGTAGACGAAGCGGGTCTTCATTCTACGCCGAAATGAAGTGG



CTGCTTTCTAACACCGATAACGCAGCATTCCCACAAATGACCAAGAGCTACAAGAATACA



AGAAAATCCCCTGCATTAATTGTATGGGGAATCCATCACTCCGTCTCAACAGCAGAACAG



ACAAAACTTTATGGCAGTGGCAACAAACTCGTCACCGTTGGTAGCTCCAACTACCAGCAG



TCTTTCGTGCCAAGTCCCGGGGCCCGACCGCAAGTGAACGGGCAGTCTGGCAGAATCGAC



TTTCACTGGCTCATGCTGAATCCAAACGACACAGTTACCTTCAGCTTCAATGGGGCATTC



ATTGCCCCAGACAGAGCCAGCTTTCTTCGAGGCAAGAGCATGGGCATCCAGAGCGGGGTA



CAGGTCGACGCAAACTGTGAAGGAGATTGCTACCACTCCGGGGGGACGATCATTTCGAAT



CTGCCATTCCAGAATATCGACTCTAGGGCTGTGGGGAAATGTCCTAGGTATGTGAAACAG



CGGAGCCTCCTTCTGGCAACAGGAATGAAAAACGTACCTGAGATCCCTAAGGGGCGAGGA



TTGTTTGGTGCCATCGCGGGATTCATTGAAAATGGCTGGGAGGGATTGATTGACGGCTGG



TACGGATTCCGGCATCAAAACGCGCAAGGGGAGGGTACGGCGGCAGATTACAAAAGCACT



CAGTCCGCGATCGACCAGATCACCGGCAAACTCAATAGACTTATCGAGAAGACTAACCAA



CAGTTCGAGCTCATCGACAATGAGTTTAATGAAGTAGAGAAACAGATCGGCAATGTCATA



AACTGGACCAGGGACAGCATCACCGAAGTGTGGTCCTATAACGCCGAGCTCCTGGTGGCC



ATGGAGAATCAGCACACTATAGACTTAGCTGACTCTGAGATGGACAAGCTCTATGAGAGA



GTTAAACGGCAGCTCAGAGAAAACGCAGAAGAAGATGGCACCGGGTGCTTCGAGATCTTT



CATAAATGTGATGACGACTGCATGGCCTCGATACGTAACAATACATATGATCATAGTAAG



TATCGGGAGGAAGCAATGCAGAACAGGATTCAGATCGACCCCGTTAAATTGTCCAGCGGC



TATAAGGACGTAATTCTGTGGTTCTCGTTTGGCGCCTCCTGTTTCATTTTGTTGGCCATT



GTGATGGGTCTCGTCTTCATTTGCGTAAAAAATGGCAATATGCGGTGCACTATTTGTATC





675
ATGAATACTCAGATCCTAGTTTTTGCTCTGATTGCCATAATTCCGACGAATGCGGACAAG



ATTTGCCTGGGACACCACGCTGTCAGTAACGGTACCAAAGTAAATACCCTGACGGAGCGA



GGTGTCGAGGTGGTGAATGCCACCGAAACTGTGGAGAGAACCAACATCCCTCGGATCTGT



AGCAAGGGCAAGAAAACTGTGGACCTCGGTCAGTGTGGGTTGCTCGGGACCATTACAGGC



CCCCCACAGTGCGATCAATTTCTGGAGTTCTCTGCCGACTTAATTATTGAAAGACGGGAG



GGTAGCGACGTTTGTTATCCCGGCAAATTCGTAAATGAGGAGGCCTTGCGCCAGATTTTG



CGCGAGTCCGGCGGCATTGATAAAGAGGCTATGGGATTCACTTATTCTGGCATTAGGACA



AACGGCGCGACCAGTGCATGTCGCCGATCCGGCTCCTCCTTTTACGCTGAGATGAAATGG



CTGTTGTCGAACACTGACAACGCTGCATTTCCACAGATGACAAAGTCCTATAAGAACACC



AGGAAGAGTCCGGCCCTGATCGTGTGGGGAATACATCACTCTGTGTCCACCGCCGAACAG



ACCAAGCTGTACGGAAGTGGCAATAAGCTGGTTACTGTCGGGAGCAGCAATTACCAGCAG



AGTTTTGTGCCGTCACCCGGGGCCCGGCCTCAGGTGAATGGTCAGTCCGGTAGAATAGAC



TTCCACTGGCTTATGCTAAACCCAAATGACACCGTTACCTTCTCATTTAACGGTGCCTTT



ATTGCCCCCGACCGGGCTTCATTCCTGCGCGGGAAATCCATGGGCATCCAATCTGGGGTG



CAGGTTGACGCTAATTGTGAGGGAGACTGTTATCATAGCGGAGGCACCATAATCTCCAAT



CTGCCCTTCCAGAACATTGACAGCAGAGCAGTAGGCAAATGCCCCAGGTATGTCAAGCAA



CGAAGCCTTCTTCTCGCTACCGGTATGAAGAATGTGCCCGAAATACCAAAGGGACGGGGG



CTCTTTGGCGCGATAGCCGGGTTCATCGAGAATGGATGGGAGGGACTCATTGACGGTTGG



TATGGGTTCCGCCATCAGAACGCGCAGGGGGAAGGCACAGCAGCCGACTATAAGTCCACA



CAGAGTGCAATTGACCAAATTACCGGCAAATTAAACAGACTCATTGAGAAGACTAACCAG



CAGTTTGAGTTAATTGATAATGAGTTTAACGAAGTGGAGAAACAAATTGGAAACGTGATC



AACTGGACACGAGATAGCATTACGGAGGTATGGTCATATAACGCCGAGCTGCTCGTTGCG



ATGGAGAATCAACACACAATTGATTTAGCAGACTCCGAAATGGACAAACTTTACGAACGG



GTGAAACGCCAGCTGCGCGAAAACGCTGAAGAAGATGGGACAGGTTGCTTTGAAATTTTT



CACAAGTGCGATGATGACTGCATGGCCTCAATCCGTAATAATACATACGATCACAGCAAG



TATAGGGAAGAAGCCATGCAGAATAGGATTCAAATAGACCCGGTGAAATTATCTTCTGGC



TATAAAGATGTTATTCTGTGGTTCTCCTTCGGCGCGTCATGTTTCATTTTATTGGCCATT



GTGATGGGCCTGGTTTTCATATGCGTGAAGAACGGAAATATGAGATGCACCATCTGTATT





676
ATGAACACACAAATCCTGGTGTTTGCCTTAATAGCTATTATCCCAACCAACGCAGACAAG



ATCTGTCTTGGACACCATGCTGTAAGCAATGGAACCAAAGTGAACACATTGACCGAGCGT



GGGGTCGAAGTGGTTAACGCCACCGAGACAGTGGAGAGGACTAATATCCCCAGAATTTGT



AGTAAAGGGAAGAGGACAGTTGACTTAGGACAATGCGGACTGTTGGGTACCATTACAGGT



CCACCCCAGTGTGATCAGTTTCTGGAATTCAGCGCTGATTTGATCATCGAGCGGAGAGAA



GGCAGTGATGTCTGTTACCCTGGGAAATTCGTCAACGAAGAGGCATTGCGCCAGATTTTG



AGGGAATCCGGCGGAATCGACAAAGAAGCCATGGGGTTCACATACTCAGGGATCCGGACG



AATGGCGCAACGAGCGCTTGTAGGAGGTCCGGGAGTTCTTTCTATGCGGAGATGAAATGG



CTATTGAGCAACACAGATAATGCCGCTTTCCCTCAAATGACCAAGTCATACAAAAATACA



AGGAAGAGCCCAGCCCTTATCGTGTGGGGTATCCATCACAGTGTGTCTACCGCAGAACAG



ACAAAACTCTACGGCAGCGGGAACAAACTTGTGACCGTCGGCTCTTCAAACTATCAACAG



AGTTTCGTTCCGTCTCCAGGCGCAAGGCCACAGGTGAATGGATTAAGTGGGCGGATCGAT



TTTCATTGGCTTATGCTCAACCCTAATGATACAGTCACATTCTCTTTTAATGGAGCTTTC



ATTGCCCCAGACAGGGCGTCCTTCCTGCGAGGCAAATCTATGGGTATACAAAGCGGCGTC



CAGGTAGACGCAAATTGTGAGGGTGATTGCTACCACAGCGGGGGAACCATTATCAGCAAC



TTGCCATTCCAAAACATCGATTCCCGTGCTGTGGGCAAGTGTCCAAGATATGTGAAACAG



AGGAGTCTGTTGTTGGCGACGGGAATGAAAAACGTTCCCGAGATTCCAAAGGGCCGGGGA



CTTTTTGGGGCCATCGCCGGATTCATAGAGAACGGCTGGGAAGGACTCATTAATGGATGG



TATGGGTTCCGGCATCAGAACGCTCAGGGGGAGGGCACCGCTGCTGACTACAAGAGTACC



CAGTCTGCCATCGATCAGATTACCGGTAAGTTGAATAGGCTGATCGAGAAAACTAACCAG



CAGTTTGAGCTCATTGATAATGAATTCAACGAGGTAGAAAAACAGATAGGCAACGTGATT



AACTGGACCCGTGACTCCATAACGGAGGTATGGAGTTATAATGCAGAACTCCTCGTGGCT



ATGGAAAATCAGCACACAATTGATTTAGCTGACTCAGAAATGGATAAGCTGTACGAGCGG



GTCAAACGCCAACTGCGCGAGAATGCAGAAGAAGACGGGACCGGGTGTTTCGAAATCTTT



CATAAATGCGACGATGACTGTATGGCCAGCATCCGTAACAACACTTACGACCACAGCAAG



TATCGGGAGGAAGCTATGCAAAATAGGATCCAGATCGACCCTGTCAAATTATCCAGTGGG



TACAAAGATGTCATCCTGTGGTTTTCCTTTGGCGCGTCATGCTTTATTTTGTTGGCTATC



GTGATGGGCCTCGTTTTTATCTGTGTGAAGAATGGAAACATGCGATGCACCATCTGTATT





677
ATGAACACTCAGATTCTGGTGTTCGCACTAATCGCAATCATACCTACTAATGCCGACAAA



ATTTGCCTCGGCCACCATGCCGTGTCAAATGGCACAAAAGTGAATACCCTGACGGAGCGC



GGCGTCGAGGTTGTCAATGCCACAGAGACAGTGGAACGGACCAACATTCCACGTATTTGT



TCAAAAGGCAAGCGTACCGTTGACCTGGGTCAGTGCGGACTTCTCGGGACAATCACTGGA



CCACCACAGTGCGATCAGTTCTTGGAGTTTTCAGCAGACCTTATCATCGAGAGGGGGGAA



GGTAGCGACGTTTGCTACCCCGGCAAATTTGTTAATGAAGAAGCCTTAAGGCAGATCCTA



CGAGAATCAGGGGGCATTGACAAAGAAGCGATGGGATTCACTTACAGTGGAATTAGAACA



AACGGTGCCACGTCTGCTTGCAGACGCTCGGGCTCTAGCTTTTATGCTGAAATGAAATGG



TTGCTGAGCAATACCGATAATGCTGCCTTCCCACAGATGACAAAAAGTTACAAGAATACT



AGAAAGTCACCCGCACTGATCGTCTGGGGGATTCACCATTCAGTCAGCACCGCCGAGCAG



ACCAAACTTTATGGTAGCGGTAACAAGTTAGTGACAGTTGGAAGCTCCAATTATCAACAG



TCATTTGTGCCATCTCCCGGGGCTCGACCCCAAGTGAACGGGTTAAGTGGTCGGATCGAC



TTCCACTGGTTGATGCTCAACCCTAACGACACAGTCACATTCTCCTTCAACGGCGCATTC



ATAGCCCCCGACCGGGCAAGCTTCCTAAGGGGAAAGAGTATGGGAATCCAGTCTGGGGTG



CAAGTTGATGCCAACTGCGAAGGGGATTGCTATCATTCCGGCGGGACAATTATAAGCAAC



CTGCCATTCCAGAACATCGATTCACGGGCAGTCGGGAAGTGCCCCAGGTATGTGAAGCAG



CGGTCACTGCTGTTGGCTACTGGCATGAAAAACGTGCCGGAGATCCCAAAAGGCCGTGGG



CTCTTCGGGGCTATCGCCGGGTTTATCGAGAACGGCTGGGAGGGCCTGATTAATGGGTGG



TATGGCTTTAGGCATCAGAACGCGCAAGGAGAGGGAACCGCGGCCGACTATAAGAGCACA



CAGTCTGCGATCGATCAAATAACCGGTAAGCTCAATCGGCTGATTGAAAAAACCAACCAG



CAGTTTGAGCTAATCGACAATGAATTCAACGAGGTGGAAAAGCAGATTGGTAACGTCATT



AATTGGACAAGAGACAGTATTACTGAGGTGTGGAGTTATAACGCTGAACTGCTGGTTGCC



ATGGAGAATCAGCACACTATTGACCTGGCAGATTCTGAGATGGATAAGCTCTATGAGAGA



GTGAAACGGCAGCTGAGAGAGAATGCTGAAGAGGATGGAACCGGGTGCTTCGAAATTTTT



CATAAGTGTGATGACGATTGTATGGCCTCGATTAGAAATAATACATACGATCACTCCAAG



TACCGAGAGGAGGCCATGCAGAACAGGATCCAAATTGACCCGGTTAAGCTGAGTAGTGGC



TACAAGGATGTTATATTATGGTTTAGCTTCGGAGCCTCCTGCTTCATACTGCTGGCTATT



GTGATGGGGTTAGTCTTTATCTGCGTGAAAAATGGGAACATGAGATGTACAATCTGTATA





678
ATGAACACGCAGATCCTAGTCTTTGCCCTTATTGCCATAATCCCTACCAACGCCGATAAG



ATCTGCCTCGGTCACCACGCCGTTTCCAATGGCACAAAGGTGAATACTTTGACAGAACGG



GGGGTTGAGGTGGTCAATGCTACCGAAACCGTAGAGCGAACAAATATCCCGAGAATATGT



TCCAAAGGCAAGAAGACCGTGGACCTCGGACAGTGTGGATTACTCGGGACAATCACAGGT



CCCCCACAGTGCGATCAGTTCTTGGAATTCTCTGCCGACCTCATTATCGAACGGAGAGAA



GGATCGGATGTGTGTTATCCTGGCAAGTTCGTCAATGAGGAAGCTCTTAGACAGATCTTA



CGCGAGAGTGGTGGCATCGACAAGGAAGCAATGGGTTTCACATATAGCGGAATTCGGACT



AATGGAGCAACTTCAGCTTGTAGGAGAAGCGGCTCATCTTTTTATGCCGAAATGAAGTGG



CTGTTATCTAACACCGATAACGCTGCCTTCCCACAGATGACGAAATCATACAAGAACACT



AGGAAGAGCCCAGCTCTGATTGTGTGGGGTATTCATCATAGTGTCTCCACGGCGGAACAG



ACTAAGCTGTATGGGTCCGGCAATAAACTTGTCACCGTAGGCAGCAGCAACTACCAGCAG



AGCTTCGTGCCTAGCCCAGGAGCTAGGCCCCAGGTGAATGGACAGTCTGGGCGAATAGAC



TTCCACTGGCTTATGCTCAATCCGAATGACACAGTGACATTCAGCTTCAATGGGGCTTTT



ATTGCTCCAGACAGAGCCAGCTTCCTGAGAGGCAAATCAATGGGGATCCAAAGCGGAGTA



CAGGTTGACGCCAACTGTGAAGGCGATTGCTACCACTCAGGGGGCACAATTATCTCTAAC



CTGCCATTCCAGAATATTGATTCGAGAGCTGTGGGGAAGTGTCCTAGGTATGTAAAACAG



CGGAGCCTGCTCCTCGCTACAGGGATGAAGAATGTCCCGGAAATCCCAAAAGGACGGGGC



CTGTTTGGCGCAATTGCCGGCTTCATAGAGAATGGGTGGGAGGGACTGATCGATGGATGG



TACGGGTTTCGCCACCAGAACGCCCAGGGAGAAGGGACAGCCGCTGATTACAAATCCACA



CAAAGCGCAATCGACCAGATCACAGGTAAACTGAATAGGCTCATCGAGAAGACCAATCAG



CAATTCGAACTTATCGACAATGAGTTTAATGAGGTGGAGAAACAAATCGGAAATGTGATC



AATTGGACGCGAGATTCTATTACTGAGGTGTGGTCATACAATGCCGAACTCCTTGTGGCT



ATGGAAAATCAGCACACCATAGACCTGGCCGACTCCGAGATGGATAAGCTATACGAGCGC



GTCAAGCGCCAGCTGAGGGAAAATGCTGAGGAAGACGGAACGGGTTGCTTCGAAATTTTT



CACAAGTGCGACGATGACTGCATGGCCTCTATTAGAAATAATACATACGACCACTCTAAG



TATAGGGAAGAGGCCATGCAGAATCGCATACAGATCGATCCTGTGAAACTCTCCAGCGGG



TATAAGGATGTCATTCTGTGGTTCAGTTTCGGCGCTAGCTGTTTTATACTTTTGGCTATT



GTTATGGGTCTAGTGTTTATTTGCGTGAAAAACGGCAATATGCGGTGCACAATATGCATT





679
ATGAATACCCAGATCCTTGTCTTCGCATTAATAGCAATCATTCCAACCAATGCTGACAAG



ATCTGTCTGGGTCACCATGCAGTTTCCAATGGCACAAAAGTTAATACACTGACAGAACGC



GGGGTGGAAGTAGTCAACGCCACCGAAACCGTAGAGAGGACCAATATCCCCAGGATCTGC



TCAAAGGGAAAGCGTACAGTGGACCTGGGACAGTGTGGGCTGCTCGGCACAATTACAGGA



CCACCACAGTGTGACCAGTTCCTGGAGTTTAGCGCTGACTTAATAATCGAGAGAAGAGAG



GGAAGCGACGTCTGTTATCCTGGCAAGTTTGTCAAGGAGGAGGCTCTTAGGCAGATCTTG



AGAGAGTCGGGCGGCATAGATAAAGAGGCAATGGGATTCACCTATTCAGGGATTAGGACC



AATGGTGCCACAAGTGCCTGCAGAAGATCAGGCTCTAGTTTTTACGCTGAGATGAAGTGG



CTTCTGTCGAACACAGATAACGCCGCGTTCCCTCAGATGACTAAGTCATACAAAAATACA



CGCAAAAGTCCTGCCTTAATCGTGTGGGGGATACATCATAGTGTATCCACCGCCGAGCAG



ACTAAGCTCTACGGTAGCGGTAATAAGCTGGTCACTGTGGGCAGTTCCAACTACCAGCAG



AGTTTTGTTCCCAGCCCCGGTGCTCGTCCCCAAGTGAACGGACTTAGCGGTAGGATTGAC



TTTCATTGGCTGATGTTGAATCCTAATGACACGGTCACTTTTAGTTTCAACGGCGCTTTC



ATCGCTCCCGATAGAGCTTCCTTCTTGCGCGGAAAGAGTATGGGGATACAGTCAGGCGTG



CAGGTCGACGCGAATTGTGAAGGGGATTGCTACCATAGTGGAGGCACTATTATCTCAAAC



CTCCCTTTCCAGAACATCGACAGTAGGGCCGTGGGAAAATGCCCTAGGTACGTTAAGCAG



AGATCCCTATTGCTGGCCACGGGTATGAAGAATGTCCCCGAAATTCCAAAAGGAAGAGGA



CTGTTCGGCGCCATCGCTGGCTTTATCGAGAACGGGTGGGAGGGGCTCATCGACGGGTGG



TACGGGTTCAGACACCAGAATGCCCAAGGGGAGGGCACCGCCGCTGACTACAAATCTACG



CAAAGTGCCATTGACCAGATTACCGGAAAGCTCAACCGGCTGATTGAGAAGACCAACCAG



CAATTTGAGCTAATTGACAATGAATTTAACGAGGTCGAGAAGCAAATTGGGAACGTCATA



AACTGGACTAGGGATTCAATTACCGAAGTCTGGAGCTATAACGCAGAACTATTGGTCGCT



ATGGAGAACCAGCACACAATCGATCTCGCTGATTCTGAGATGGATAAGCTGTATGAGAGG



GTGAAGAGACAGTTGAGGGAGAATGCTGAGGAGGATGGTACCGGCTGTTTTGAAATCTTT



CATAAGTGTGACGATGACTGTATGGCTTCAATCCGGAACAATACGTACGATCACAGTAAA



TATAGGGAAGAAGCTATGCAGAACAGAATTCAGATTGATCCTGTGAAACTAAGCAGTGGT



TATAAAGATGTGATCCTCTGGTTCAGTTTCGGCGCCAGCTGTTTCATCCTGCTCGCCATC



GTAATGGGACTGGTCTTCATATGCGTGAAGAATGGAAACATGCGTTGCACCATCTGTATT





680
ATGAATACACAGATTCTGGTGTTCGCTTTGATAGCGATCATTCCAACAAATGCAGACAAG



ATCTGCCTCGGTCATCACGCGGTTTCAAATGGCACCAAAGTGAACACTCTCACCGAACGG



GGGGTCGAGGTAGTTAACGCGACCGAGACTGTGGAGCGTACTAATATCCCCAGGATCTGT



TCAAAGGGAAAGAGAACTGTGGACCTTGGGCAGTGTGGTCTGCTGGGCACCATCACTGGC



CCCCCCCAGTGTGACCAGTTCCTGGAGTTCTCAGCCGACCTTATAATTGAGCGACGCGAA



GGATCTGATGTATGCTACCCAGGCAAGTTTGTGAAAGAGGAGGCGTTACGCCAGATTCTG



AGAGAGTCTGGTGGGATCGACAAAGAAGCGATGGGTTTCACATACAGCGGGATCCGGACC



AACGGTGCCACCTCGGCATGTCGTCGTAGCGGCTCATCCTTCTACGCCGAGATGAAATGG



CTGCTGTCAAACACCGACAACGCCGCTTTCCCGCAGATGACTAAGAGCTACAAAAACACC



AGAAAGTCACCCGCCCTGATTGTGTGGGGAATTCATCACTCTGTGTCTACCGCCGAACAG



ACCAAATTGTATGGTTCGGGGAATAAGCTGGTTACGGTAGGATCGTCAAATTACCAACAA



AGCTTTGTGCCCTCTCCAGGAGCCAGACCTCAGGTAAACGGCCTCTCAGGAAGGATTGAC



TTCCACTGGCTGATGCTGAATCCCAATGATACCGTAACATTCTCATTTAATGGCGCGTTC



ATCGCACCGGATAGGGCATCCTTCTTAAGGGGGAAGAGTATGGGCATCCAGTCCGGGGTT



CAAGTGGATGCCAATTGCGAAGGCGATTGTTACCACTCCGGAGGAACGATTATTAGCAAT



CTGCCCTTCCAAAACATCGACTCTAGGGCCGTGGGCAAATGCCCTAGATATGTGAAGCAG



AGGTCCCTGCTCCTAGCGACTGGCATGAAGAATGTGCCCGAGATACCAAAAGGGAGAGGA



CTATTCGGTGCCATCGCCGGGTTCATTGAAAACGGATGGGAAGGCCTCATCGATGGGTGG



TACGGATTTCGGCACCAGAATGCGCAAGGGGAAGGTACTGCTGCTGATTATAAGAGCACT



CAGAGCGCTATTGATCAGATTACCGGTAAATTGAACCGTCTCATTGAAAAGACGAACCAG



CAGTTCGAGCTGATCGATAATGAGTTTAATGAAGTGGAAAAGCAAATCGGGAACGTGATC



AACTGGACAAGAGACTCAATCACTGAAGTCTGGTCCTACAATGCCGAGCTTTTGGTTGCC



ATGGAGAACCAGCATACGATCGACCTTGCCGATAGCGAGATGGACAAACTATACGAGCGA



GTCAAGAGGCAACTCAGAGAAAATGCAGAAGAGGATGGAACCGGCTGTTTCGAGATCTTT



CATAAGTGCGACGACGATTGCATGGCTTCCATTAGAAATAACACCTACGACCACTCTAAG



TATAGAGAGGAGGCTATGCAAAATCGCATCCAGATTGATCCGGTGAAACTCTCCTCGGGG



TACAAAGATGTGATCCTGTGGTTCTCCTTTGGCGCAAGCTGTTTCATTTTATTAGCTATT



GTGATGGGGCTCGTCTTTATCTGCGTGAAGAATGGCAACATGCGGTGTACCATCTGTATA





681
ATGAACACTCAGATACTCGTCTTTGCGCTCATCGCTATTATTCCTACCAACGCGGATAAA



ATTTGCCTCGGGCACCACGCAGTGTCCAACGGAACTAAAGTGAACACGCTGACTGAACGT



GGTGTGGAAGTGGTGAACGCAACAGAAACAGTGGAAAGGACTAATATTCCGCGTATATGC



AGTAAGGGTAAGAAGACGGTCGACCTGGGGCAGTGCGGGCTTCTCGGTACCATCACGGGT



CCTCCTCAGTGTGATCAGTTCCTTGAGTTTTCAGCCGACCTCATCATTGAACGTCGTGAG



GGAAGTGATGTTTGTTATCCCGGGAAGTTCGTGAACGAAGAGGCATTGAGACAGATTCTG



CGGGAGTCTGGGGGAATCGATAAGGAGGCCATGGGTTTCACATACTCCGGTATCAGGACT



AACGGCGCAACCTCCGCCTGCCGGCGAAGCGGCAGCTCTTTCTACGCTGAAATGAAGTGG



CTGTTGTCTAACACCGATAACGCCGCTTTCCCTCAGATGACCAAATCCTATAAGAATACG



AGAAAGTCTCCTGCTCTCATCGTATGGGGGATCCACCATAGTGTGTCTACCGCCGAGCAG



ACCAAACTGTACGGCTCAGGCAACAAATTGGTGACTGTAGGGAGCAGTAATTATCAGCAA



AGCTTCGTTCCTTCCCCTGGAGCCAGACCTCAGGTGAATGGACAGTCAGGGCGGATCGAT



TTCCATTGGCTGATGCTGAACCCAAACGATACAGTGACATTCTCATTCAATGGCGCGTTC



ATAGCCCCAGATCGCGCCTCTTTCCTGCGCGGGAAATCAATGGGCATTCAATCTGGGGTA



CAGGTGGACGCTAACTGTGAGGGGGACTGCTATCATTCCGGGGGCACAATTATTAGTAAC



CTCCCTTTCCAGAACATTGATTCCAGAGCCGTGGGTAAGTGCCCGCGGTACGTGAAGCAG



AGGTCACTGCTGCTAGCCACCGGAATGAAAAATGTGCCTGAAATCCCAAAAGGACGGGGC



TTATTCGGCGCTATTGCTGGCTTCATCGAAAATGGGTGGGAGGGGTTGATCGACGGTTGG



TACGGGTTCCGCCACCAGAACGCTCAGGGCGAAGGAACCGCCGCTGACTATAAGTCCACC



CAGTCTGCCATCGACCAGATCACAGGAAAACTGAATAGGCTGATAGAAAAAACCAATCAG



CAGTTCGAACTGATTGACAACGAGTTCAACGAGGTCGAGAAACAGATCGGAAATGTTATT



AATTGGACCCGAGATAGCATCACTGAAGTCTGGTCCTATAACGCTGAGCTTCTAGTAGCG



ATGGAAAATCAGCACACGATCGACCTGGCAGATAGCGAAATGGACAAACTCTACGAGAGA



GTGAAGCGCCAGCTTCGAGAAAACGCCGAAGAAGATGGAACTGGGTGCTTTGAAATTTTC



CACAAGTGTGATGACGATTGCATGGCCTCTATCCGCAATAATACCTACGATCACAGTAAA



TATCGCGAAGAAGCGATGCAAAATCGTATCCAGATCGATCCTGTAAAGCTCAGCTCCGGA



TACAAAGACGTGATTCTCTGGTTCAGTTTTGGCGCCAGCTGTTTTATCCTGCTCGCCATA



GTCATGGGTTTGGTATTTATCTGCGTCAAGAACGGGAACATGCGTTGCACAATCTGCATA





682
ATGAATACTCAAATCCTGGTATTCGCCCTAATTGCAATCATTCCAACCAACGCTGACAAG



ATCTGTTTAGGCCACCACGCCGTTTCGAACGGTACAAAGGTGAATACCCTGACAGAGAGG



GGCGTGGAAGTGGTGAACGCGACAGAGACCGTGGAACGGACCAATATCCCCCGCATTTGC



TCCAAGGGAAAAAAAACTGTAGACCTCGGACAGTGCGGCCTGCTCGGAACGATCACCGGA



CCCCCTCAGTGCGACCAATTTCTGGAATTTAGTGCAGATCTCATTATTGAGAGGCGGGAA



GGAAGTGACGTTTGCTATCCCGGCAAATTTGTGAATGAAGAGGCCCTTCGCCAGATCCTC



AGAGAAAGCGGGGGCATAGACAAAGAGGCCATGGGCTTTACCTATTCTGGCATTCGAACC



AACGGCGCTACCAGTGCTTGCAGACGGAGCGGCTCGTCCTTCTACGCAGAGATGAAGTGG



CTTTTGTCCAATACCGACAACGCTGCTTTCCCTCAGATGACCAAGTCTTACAAGAACACC



CGAAAGTCTCCAGCGCTGATTGTGTGGGGGATTCATCACTCAGTGAGTACAGCAGAGCAG



ACTAAGCTGTATGGATCCGGCAATAAACTCGTGACTGTAGGTTCCTCAAATTATCAACAG



AGCTTTGTCCCCTCTCCAGGAGCCAGGCCCCAGGTGAACGGACAATCTGGGCGTATAGAT



TTTCACTGGCTGATGTTAAATCCAAACGACACCGTAACCTTCTCGTTTAATGGAGCCTTT



ATCGCTCCTGACAGAGCGAGCTTTTTAAGAGGAAAAAGTATGGGAATACAGTCCGGAGTT



CAGGTGGATGCCAACTGTGAGGGTGATTGCTACCACAGTGGCGGTACAATTATCAGTAAT



CTACCCTTCCAAAATATCGATTCTCGGGCAGTGGGCAAGTGTCCCCGCTATGTCAAGCAG



CGGAGCCTTCTCTTGGCAACAGGTATGAAAAACGTGCCTGAAATCCCTAAAGGAAGGGGC



CTGTTCGGTGCCATTGCAGGATTTATCGAGAATGGGTGGGAAGGGCTTATTGACGGGTGG



TATGGATTCCGGCACCAGAATGCCCAGGGGGAAGGCACCGCCGCTGACTACAAATCTACA



CAGAGTGCCATTGATCAGATCACGGGCAAACTCAACAGACTTATCGAGAAGACAAATCAG



CAATTTGAGCTGATAGACAATGAGTTCAATGAAGTGGAAAAACAGATCGGGAATGTGATT



AACTGGACCAGAGATTCCATCACAGAGGTCTGGTCCTATAACGCCGAACTGCTCGTTGCC



ATGGAAAACCAGCATACCATCGATCTTGCCGATTCCGAGATGGACAAGCTCTATGAACGC



GTCAAGCGACAGCTCAGAGAAAATGCAGAGGAGGATGGGACAGGATGTTTTGAAATTTTC



CACAAGTGCGATGACGACTGTATGGCATCCATTCGCAACAACACATACGATCACAGCAAG



TATAGAGAGGAGGCCATGCAGAACAGAATACAGATCGATCCAGTTAAACTGAGTTCTGGC



TATAAGGATGTGATTCTCTGGTTCTCTTTCGGAGCCAGCTGCTTTATCCTGCTGGCTATC



GTCATGGGCCTGGTGTTCATCTGCGTCAAGAATGGAAACATGCGGTGCACGATTTGCATT





683
ATGAATACTCAGATCCTTGTGTTCGCCTTAATCGCCATCATCCCTACTAACGCCGACAAG



ATCTGCCTGGGCCACCACGCTGTTTCCAATGGCACGAAGGTCAACACTCTCACCGAAAGA



GGGGTTGAGGTGGTGAACGCCACCGAAACAGTAGAGAGAACGAACATCCCCCGTATTTGC



TCCAAGGGGAAACGCACTGTGGATTTAGGACAGTGCGGCCTGCTGGGGACAATTACCGGA



CCTCCTCAGTGCGACCAATTCCTGGAATTTTCAGCTGACCTCATCATAGAGCGGCGAGAG



GGGTCCGATGTATGCTACCCTGGAAAGTTTGTGAATGAAGAGGCCCTTCGGCAGATCCTG



CGCGAGAGCGGGGGGATTGATAAGGAAGCCATGGGTTTTACCTATTCCGGAATTAGAACG



AACGGCGCTACATCAGCTTGCCGCCGTTCAGGTTCCAGCTTCTATGCCGAGATGAAGTGG



CTACTTTCCAATACCGACAATGCGGCATTCCCTCAGATGACTAAGTCTTACAAGAATACT



CGGAAGTCACCAGCCCTTATCGTCTGGGGCATTCACCACAGCGTGTCAACCGCGGAGCAA



ACCAAACTATATGGGTCGGGGTCTAAACTCGTAACCGTGGGTTCGAGCAATTACCAGCAG



AGCTTCGTTCCCAGTCCTGGCGCTCGACCTCAGGTGAATGGGCTGAGTGGGAGGATAGAC



TTTCATTGGTTAATGTTAAATCCTAACGATACTGTCACCTTCTCCTTCAATGGTGCTTTC



ATTGCACCAGACCGTGCTAGCTTCCTCCGCGGGAAATCGATGGGCATACAGTCCGGAGTG



CAAGTCGACGCTAACTGTGAAGGCGATTGTTACCATTCAGGCGGCACCATAATCAGCAAT



CTGCCTTTTCAGAACATTGATAGTCGTGCTGTGGGAAAGTGTCCTAGATACGTGAAGCAG



AGGAGTCTTCTTTTGGCCACTGGCATGAAAAACGTACCAGAGATCCCCAAAGGACGGGGC



CTGTTTGGCGCTATCGCGGGCTTTATAGAAAATGGCTGGGAGGGATTAATCGACGGCTGG



TACGGTTTTAGGCACCAGAATGCCCAAGGCGAAGGTACAGCAGCCGATTACAAAAGTACA



CAGTCCGCCATCGATCAGATTACCGGGAAACTCAATCGTCTCATTGAGAAGACAAACCAA



CAGTTTGAGCTTATAGACAACGAATTTAATGAAGTGGAGAAACAGATTGGAAACGTAATC



AACTGGACACGGGACTCCATAACTGAGGTCTGGAGCTACAATGCTGAACTCTTGGTGGCC



ATGGAGAACCAGCATACCATTGACTTGGCAGACTCTGAGATGGATAAGCTGTACGAAAGG



GTGAAACGGCAGCTTCGTGAAAATGCCGAGGAGGATGGCACCGGATGTTTTGAGATATTC



CACAAGTGTGATGACGACTGCATGGCGAGCATTCGTAACAATACTTACGATCACTCAAAG



TACCGGGAGGAAGCCATGCAGAATAGAATCCAGATCGATCCTGTGAAGCTGTCCTCGGGC



TACAAGGACGTCATCCTGTGGTTCTCCTTTGGCGCTAGCTGTTTCATTCTGTTGGCGATC



GTTATGGGTCTCGTCTTTATTTGCGTTAAGAACGGCAACATGCGTTGCACAATTTGCATT





684
ATGAATACTCAAATTCTCGTCTTTGCCCTGATTGCTATCATTCCCACCAATGCAGACAAG



ATTTGCCTCGGTCACCACGCCGTATCAAACGGCACAAAAGTGAACACACTGACCGAAAGA



GGTGTCGAGGTCGTTAATGCCACTGAGACCGTTGAGCGGACTAACATCCCTAGAATCTGC



AGCAAGGGGAAGAAAACTGTGGATCTTGGGCAGTGCGGACTGCTGGGAACAATAACCGGG



CCTCCCCAATGCGACCAATTCCTGGAGTTTTCCGCTGATCTCATTATTGAGCGCAGAGAA



GGGAGCGATGTATGCTACCCCGGAAAGTTTGTCAACGAGGAAGCTTTGCGCCAGATTCTG



AGGGAATCTGGCGGCATCGACAAAGAGGCTATGGGATTCACATACAGTGGTATAAGGACT



AATGGAGCAACCAGCGCTTGTCGGCGGTCGGGGAGCTCCTTTTATGCTGAAATGAAATGG



CTGCTTTCTAACACTGATAACGCTGCCTTCCCCCAGATGACTAAATCGTACAAGAACACA



CGAAAATCGCCGGCACTGATCGTGTGGGGAATACACCATTCAGTGTCCACTGCCGAACAG



ACCAAACTGTATGGCAGCGGCAACAAGCTCGTGACCGTTGGTTCCTCGAACTATCAGCAA



AGCTTCGTGCCTTCGCCAGGTGCTCGCCCTCAGGTCAATGGACAGTCCGGAAGGATTGAC



TTTCACTGGCTTATGTTGAACCCGAACGATACTGTTACATTTAGTTTTAACGGCGCCTTT



ATTGCACCCGACAGGGCCTCATTTTTGCGAGGCAAGTCGATGGGCATACAATCTGGCGTG



CAGGTAGATGCAAACTGTGAAGGCGATTGCTATCACTCCGGAGGCACAATTATTAGTAAT



CTACCCTTCCAGAATATCGACTCTCGGGCGGTCGGCAAATGTCCCCGATACGTAAAGCAA



CGCTCCCTGTTGCTGGCCACTGGTATGAAGAACGTCCCTGAAATCCCCAAAGGCCGGGGA



TTGTTCGGCGCCATAGCAGGATTCATCGAGAACGGCTGGGAAGGTCTCATAGATGGTTGG



TATGGTTTCCGTCACCAGAACGCCCAGGGGGAAGGCACCGCAGCGGATTACAAGTCGACG



CAGTCTGCAATCGACCAGATCACCGGTAAACTGAACCGCCTGATTGAGAAAACAAACCAA



CAATTCGAATTAATTGACAATGAGTTTAATGAGGTAGAGAAACAGATTGGCAACGTGATT



AACTGGACAAGGGATTCAATTACCGAAGTTTGGAGCTACAACGCCGAGTTGCTGGTCGCT



ATGGAAAACCAGCACACAATCGACCTGGCCGACTCCGAGATGGACAAGTTATATGAACGG



GTGAAACGGCAGCTGCGGGAGAATGCCGAGGAGGATGGTACAGGGTGTTTTGAAATCTTT



CACAAATGTGATGATGATTGCATGGCGTCAATACGCAACAACACATATGACCACTCAAAA



TATCGAGAAGAAGCCATGCAGAACAGAATACAGATTGACCCCGTGAAGCTTTCAAGTGGC



TATAAAGATGTCATTCTGTGGTTCTCCTTCGGGGCATCCTGCTTTATCCTGCTCGCCATC



GTTATGGGGCTTGTGTTCATTTGTGTCAAGAATGGAAACATGAGGTGCACCATCTGCATC





685
ATGAATACCCAGATCCTGGTTTTTGCCCTGATCGCTATCATACCAACAAACGCTGACAAG



ATCTGTCTTGGCCACCACGCTGTCTCTAATGGGACCAAAGTCAATACCCTGACCGAAAGG



GGAGTGGAGGTAGTCAACGCTACTGAGACAGTCGAAAGAACTAATATTCCTAGAATTTGC



AGTAAGGGCAAGAAAACCGTGGATCTGGGGCAGTGTGGCCTGCTGGGCACCATAACCGGG



CCTCCTCAGTGCGATCAGTTCCTGGAGTTTTCCGCCGATCTGATCATTGAACGCAGGGAA



GGCAGCGACGTATGCTACCCAGGGAAGTTTGTTAATGAGGAAGCACTCCGCCAGATTCTC



CGAGAGTCTGGGGGTATTGATAAGGAGGCAATGGGTTTTACATACAGCGGCATTAGGACT



AATGGGGCTACTTCAGCTTGCCGAAGGAGCGGATCTTCCTTTTACGCTGAGATGAAATGG



CTCCTGAGCAATACCGACAATGCCGCCTTTCCTCAGATGACGAAATCTTATAAGAACACA



AGAAAGTCCCCAGCACTGATCGTGTGGGGGATTCACCACTCAGTCTCCACAGCCGAGCAG



ACCAAGCTGTACGGCTCAGGCAATAAACTCGTGACGGTTGGCAGCTCCAATTACCAGCAG



TCCTTTGTCCCTAGTCCTGGAGCCCGGCCTCAGGTGAATGGGCAGTCCGGTCGAATAGAC



TTTCACTGGCTCATGTTAAACCCCAATGACACAGTGACCTTCAGCTTCAATGGGGCTTTC



ATCGCCCCCGACCGTGCCAGCTTTCTGCGGGGGAAAAGCATGGGGATACAGTCTGGGGTT



CAGGTGGATGCCAATTGTGAAGGGGACTGTTACCACTCTGGGGGCACCATCATCAGTAAT



TTACCATTCCAGAATATTGACTCGAGAGCCGTAGGAAAGTGCCCCAGGTACGTGAAGCAG



AGATCTCTGCTGCTTGCGACGGGTATGAAAAATGTCCCAGAGATCCCGAAAGGCCGGGGA



CTTTTTGGAGCAATCGCCGGCTTCATCGAGAATGGCTGGGAAGGGCTGATCGACGGCTGG



TACGGCTTTCGCCACCAGAACGCCCAGGGCGAGGGTACAGCGGCAGACTATAAGTCCACT



CAGAGTGCCATCGATCAGATCACAGGTAAGCTCAATCGTCTCATTGAGAAGACCAATCAG



CAGTTCGAGCTCATCGACAACGAATTCAACGAGGTTGAGAAACAGATCGGCAACGTGATC



AACTGGACAAGGGACAGTATCACCGAGGTGTGGAGCTACAACGCTGAGCTGCTGGTGGCT



ATGGAAAACCAGCACACCATCGATCTGGCAGATTCCGAAATGGATAAGCTTTATGAGCGG



GTGAAGCGTCAACTGAGAGAGAACGCCGAGGAGGATGGAACTGGCTGCTTCGAAATCTTT



CATAAATGTGATGACGACTGCATGGCCTCAATCCGGAATAACACTTATGACCACAGCAAA



TACAGAGAAGAGGCGATGCAGAATCGAATCCAGATAGACCCCGTCAAGCTTTCATCGGGT



TATAAGGACGTTATCCTATGGTTTTCTTTTGGCGCCAGCTGCTTTATCCTCCTCGCGATT



GTCATGGGACTTGTGTTCATTTGCGTGAAAAACGGCAATATGCGCTGTACAATTTGTATC





686
ATGAACACACAGATTCTGGTTTTCGCCTTGATTGCCATTATTCCTACTAATGCAGACAAG



ATCTGTTTGGGCCATCACGCCGTAAGTAACGGTACGAAGGTCAACACCTTGACAGAGCGC



GGGGTTGAGGTTGTCAATGCAACAGAAACCGTCGAACGGACAAACATCCCAAGGATCTGC



TCAAAAGGCAAGAAAACCGTCGACCTGGGGCAATGTGGCCTTCTCGGAACTATAACCGGA



CCCCCACAATGCGATCAATTTCTGGAGTTCAGCGCTGACCTAATAATAGAGAGACGGGAG



GGGTCAGATGTGTGTTATCCGGGGAAATTCGTGAACGAAGAAGCCCTTAGGCAGATCTTA



CGGGAAAGCGGTGGCATCGACAAAGAGGCCATGGGATTTACCTACAGCGGGATCCGGACG



AACGGTGCCACTAGTGCATGTCGGAGGTCGGGAAGCTCTTTTTACGCCGAGATGAAGTGG



CTTCTGAGCAATACAGATAATGCTGCTTTCCCGCAGATGACAAAGTCTTACAAGAATACA



AGAAAATCCCCAGCTCTCATAGTCTGGGGTATCCATCATTCTGTATCCACGGCCGAGCAA



ACCAAACTTTACGGCTCTGGGAATAAACTGGTGACAGTGGGATCATCTAATTATCAGCAG



TCTTTCGTGCCATCACCAGGCGCACGACCGCAAGTTAACGGACAGTCTGGTAGAATCGAC



TTTCATTGGCTAATGCTGAACCCGAATGATACTGTGACCTTCAGTTTCAATGGGGCTTTC



ATAGCACCAGACAGGGCATCATTTCTCAGAGGAAAATCAATGGGCATTCAGTCTGGTGTG



CAGGTGGATGCAAATTGCGAGGGAGACTGCTATCACAGTGGCGGCACTATCATCTCGAAT



CTCCCGTTCCAGAATATCGATAGCCGCGCCGTGGGGAAGTGCCCTCGGTACGTTAAACAA



CGATCTCTGCTGTTAGCCACCGGCATGAAGAATGTACCCGAGATCCCTAAGGGTCGAGGC



CTCTTTGGCGCCATTGCTGGCTTTATCGAGAATGGCTGGGAAGGACTCATAGACGGCTGG



TATGGGTTCCGGCATCAGAACGCTCAGGGAGAAGGGACCGCTGCGGACTATAAGTCAACA



CAGTCCGCCATTGACCAAATCACAGGCAAGCTGAACCGGCTGATTGAAAAAACTAATCAA



CAATTCGAGCTGATAGATAACGAGTTCAACGAAGTCGAAAAGCAGATTGGCAATGTCATT



AATTGGACACGCGATAGCATCACTGAAGTGTGGAGCTACAACGCAGAGCTGCTGGTTGCC



ATGGAGAACCAGCACACCATCGATCTGGCTGACTCTGAGATGGACAAGCTGTACGAACGG



GTGAAGCGTCAGCTCCGTGAGAACGCTGAAGAAGATGGGACAGGTTGCTTCGAAATCTTT



CATAAATGCGACGACGATTGTATGGCCTCAATAAGGAACAATACATATGACCACTCTAAG



TATAGAGAGGAGGCCATGCAGAATCGTATCCAGATCGATCCAGTGAAGCTGTCTTCAGGG



TACAAAGATGTGATCCTCTGGTTTTCATTCGGTGCCAGCTGTTTTATCTTACTGGCCATC



GTCATGGGCCTCGTCTTCATTTGTGTGAAAAACGGTAACATGAGATGCACCATTTGTATT





687
ATGAATACGCAGATTTTGGTGTTCGCCCTGATCGCCATAATCCCCACTAACGCCGACAAA



ATCTGTCTGGGGCACCACGCGGTGTCTAATGGGACTAAGGTAAACACACTGACAGAGAGA



GGCGTTGAGGTTGTTAACGCCACGGAGACAGTAGAACGTACAAACATCCCCCGCATCTGC



TCCAAGGGCAAAAAGACTGTGGATCTGGGGCAGTGCGGTTTGCTCGGAACCATTACAGGC



CCCCCTCAGTGTGACCAATTTCTTGAATTCTCCGCCGACCTCATCATCGAGCGCCGGGAA



GGAAGTGATGTTTGCTATCCCGGGAAATTTGTGAATGAGGAAGCCCTGAGGCAAATTCTC



CGGGAGTCAGGGGGTATTGACAAAGAGGCTATGGGGTTTACATACTCCGGTATCCGTACC



AATGGAGCAACCTCGGCTTGCCGTAGGTCCGGCAGCTCCTTTTACGCTGAGATGAAATGG



CTGCTCTCGAACACCGACAATGCCGCATTTCCCCAGATGACTAAGTCTTACAAGAATACC



CGGAAGTCTCCGGCCCTGATTGTGTGGGGAATCCACCATTCCGTGTCCACCGCCGAACAG



ACTAAGCTTTACGGCTCGGGCAACAAACTGGTCACCGTTGGCTCTTCTAACTATCAGCAG



AGCTTTGTGCCTTCACCAGGGGCTCGACCTCAGGTGAACGGGCAGTCCGGCCGGATCGAT



TTCCACTGGCTAATGCTGAACCCAAATGATACTGTTACGTTTTCCTTCAATGGTGCTTTT



ATAGCACCTGATCGCGCTTCCTTTCTGAGGGGGAAAAGCATGGGCATACAATCTGGGGTT



CAGGTTGATGCCAACTGTGAGGGGGATTGCTATCACTCTGGTGGGACCATAATTTCCAAC



CTCCCCTTTCAGAACATCGACTCACGAGCCGTCGGTAAGTGTCCAAGATACGTGAAGCAA



CGCTCATTACTCCTGGCTACCGGAATGAAAAATGTTCCAGAGATCCCGAAGGGGAGGGGT



CTGTTCGGTGCCATTGCGGGATTTATTGAAAACGGATGGGAGGGACTAATCGACGGATGG



TATGGGTTTAGGCATCAGAACGCACAGGGCGAGGGAACCGCCGCGGACTATAAAAGCACT



CAGTCCGCCATTGATCAGATTACAGGGAAACTCAATAGACTCATTGAGAAGACGAATCAG



CAGTTCGAGCTGATCGACAACGAGTTCAATGAGGTCGAAAAACAGATCGGGAATGTGATA



AATTGGACTAGGGATTCAATAACAGAGGTCTGGAGCTACAACGCAGAGTTACTCGTTGCG



ATGGAGAACCAACATACTATTGATCTTGCAGACTCCGAGATGGATAAGCTATACGAGCGG



GTCAAGCGACAGTTAAGGGAGAATGCAGAAGAAGATGGAACTGGGTGCTTCGAAATATTT



CATAAGTGCGACGACGACTGTATGGCCTCAATCCGCAACAACACATACGACCACTCAAAG



TACAGGGAGGAAGCCATGCAGAACCGGATCCAAATTGACCCGGTGAAACTGAGCTCTGGC



TACAAGGACGTGATCCTATGGTTTTCTTTTGGGGCCAGTTGCTTCATCCTACTCGCTATA



GTCATGGGTCTGGTGTTCATTTGTGTCAAGAACGGGAACATGCGTTGTACTATCTGCATT





688
ATGAATACCCAAATCTTGGTGTTCGCGTTGATCGCAATCATCCCCACTAACGCCGACAAA



ATCTGTTTAGGGCATCACGCTGTTTCCAACGGTACGAAAGTGAATACACTGACTGAACGC



GGGGTCGAGGTCGTTAACGCTACAGAGACGGTGGAGAGAACTAATATCCCTAGGATCTGC



TCCAAGGGCAAGCGCACTGTGGACCTGGGGCAATGCGGACTGCTAGGGACAATTACTGGC



CCGCCCCAGTGCGACCAATTTTTGGAGTTTAGCGCAGACCTGATCATAGAGCGACGCGAG



GGTTCAGACGTTTGTTACCCTGGAAAGTTTGTAAATGAGGAAGCCCTTCGCCAGATCCTG



CGGGAGAGCGGCGGTATCGATAAAGAGGCTATGGGGTTTACGTACTCTGGAATCAGAACC



AATGGGGCCACCTCTGCTTGTAGAAGATCTGGATCCTCCTTTTATGCAGAAATGAAGTGG



TTGTTATCAAATACTGATAACGCGGCATTTCCACAGATGACTAAGAGCTACAAGAACACG



CGGAAGTCACCCGCTTTAATAGTCTGGGGCATCCACCACTCAGTTAGTACAGCTGAGCAG



ACTAAGCTGTATGGCAGTGGTAACAAGCTGGTCACCGTGGGTAGCTCTAATTATCAGCAA



TCTTTCGTACCATCACCCGGAGCTAGACCTCAGGTGAACGGTCTGTCAGGCCGGATCGAC



TTCCACTGGTTGATGCTCAATCCCAATGACACTGTTACATTCAGCTTTAATGGCGCCTTC



ATCGCTCCTGACCGAGCCAGCTTTCTGCGCGGCAAGTCTATGGGGATCCAATCTGGCGTG



CAGGTTGATGCGAACTGCGAAGGGGACTGCTACCACAGTGGAGGCACCATCATTTCTAAC



CTGCCATTCCAGAATATCGACAGTCGCGCCGTGGGGAAGTGTCCTCGATACGTGAAGCAG



AGGAGCCTCCTCCTAGCGACTGGAATGAAGAACGTCCCAGAAATCCCTAAGGGCCGGGGG



CTCTTTGGAGCGATTGCCGGATTTATCGAAAACGGCTGGGAAGGGCTTATTAATGGCTGG



TACGGCTTCAGGCATCAGAATGCTCAAGGCGAGGGAACTGCCGCCGACTACAAGTCCACT



CAATCCGCCATTGATCAGATAACCGGGAAACTTAACCGCCTGATCGAGAAGACAAACCAG



CAGTTTGAGCTGATAGATAATGAGTTCAATGAAGTCGAGAAACAGATAGGAAACGTCATT



AATTGGACCCGCGACTCAATTACAGAAGTCTGGAGCTATAACGCAGAGCTGTTGGTAGCG



ATGGAAAACCAACACACAATTGACCTGGCCGATTCCGAAATGGATAAGCTGTACGAGCGC



GTGAAAAGACAGTTAAGGGAAAATGCCGAGGAAGATGGTACCGGCTGTTTCGAGATCTTC



CACAAGTGCGATGATGATTGCATGGCCTCCATCCGAAATAATACTTACGATCACTCCAAG



TACAGAGAGGAGGCAATGCAAAACAGAATTCAGATCGACCCCGTTAAGTTATCAAGCGGA



TACAAGGACGTCATCCTGTGGTTCTCATTTGGCGCATCGTGTTTTATTCTGCTTGCTATT



GTGATGGGTCTCGTTTTCATTTGTGTCAAGAACGGGAATATGAGGTGTACGATCTGCATC





689
ATGAACACCCAGATTTTAGTCTTTGCACTGATTGCAATTATTCCCACTAATGCTGACAAG



ATCTGTCTGGGCCACCACGCTGTGTCAAACGGAACTAAGGTGAACACGCTGACTGAGCGA



GGTGTCGAAGTGGTGAATGCGACGGAAACCGTGGAGAGAACAAATATCCCCAGAATCTGC



AGTAAAGGAAAAAAAACTGTGGATCTGGGCCAATGCGGGCTGCTGGGTACTATCACCGGG



CCACCACAATGCGACCAGTTTCTTGAGTTCTCCGCAGATCTCATCATCGAACGCCGGGAA



GGCTCCGATGTTTGTTACCCAGGGAAGTTCGTAAATGAAGAAGCCTTAAGGCAAATCCTT



AGAGAGAGCGGAGGAATTGAGAAAGAGGCAATGGGCTTTACCTACTCAGGAATTAGAGCC



AACGGCGCTACTTCCGCTTGTCGACGAAGTGGCTCCAGTTTCTATGCCGAAATGAAGTGG



CTGTTGTCTAACACGGATAACGCAGCCTTTCCTCAGATGACTAAGTCGTACAAAAACACC



CGGAAATCTCCAGCTCTGATTGTGTGGGGAATCCACCATAGTGTGTCCACCGCCGAGCAA



ACCAAACTTTATGGGAGCGGAAACAAGTTGGTTACTGTTGGATCCTCGAACTATCAGCAG



AGCTTCGTGCCTAGCCCAGGCGCTCGTCCACAGGTGAACGGACTCTCCGGTAGAATCGAT



TTTCATTGGCTTATGCTCAATCCTAATGACACTGTGACCTTTAGCTTCAACGGCGCGTTT



ATCGCCCCTGATCGAGCCTCTTTCCTGCGCGGAAAGTCAATGGGTATCCAGTCGGGCGTT



CAGGTGGATGCAAATTGCGAGGGGGACTGCTATCACTCTGGTGGCACCATTATCTCAAAC



CTGCCATTTCAGAACATCGACTCCCGTGCGGTCGGTAAATGCCCGAGATACGTTAAGCAG



CGAAGCCTGCTACTGGCAACAGGCATGAAGAACGTGCCTGAGATACCTAAGGGACGTGGT



CTGTTTGGAGCAATTGCCGGGTTCATTGAGAATGGCTGGGAGGGGCTCATCGATGGGTGG



TATGGCTTTAGACATCAAAATGCTCAGGGAGAAGGTACTGCAGCCGATTACAAGAGTACC



CAGAGCGCCATCGATCAGATCACTGGCAAGTTAAACCGCCTTATCGAAAAGACCAACCAG



CAGTTTGAGCTTATCGACAATGAATTTAACGAAGTGGAGAAGCAAATCGGCAACGTCATC



AACTGGACTCGCGATTCTATCACCGAGGTCTGGTCATATAACGCAGAGTTACTCGTTGCG



ATGGAAAACCAGCACACTATTGACTTGGCCGACTCTGAGATGGACAAACTGTACGAAAGA



GTTAAAAGACAGCTGCGGGAAAACGCTGAGGAAGATGGGACTGGCTGTTTCGAGATCTTT



CACAAATGCGATGACGACTGCATGGCTTCGATTCGGAATAATACATACGATCACTCTAAG



TACAGAGAAGAGGCTATGCAGAACAGAATCCAAATCGATCCCGTTAAGCTGTCATCAGGC



TACAAGGACGTGATCCTGTGGTTCTCTTTCGGGGCGAGTTGCTTTATCCTTCTTGCCATC



GTGATGGGCCTTGTGTTTATTTGTGTTAAAAACGGTAACATGCGCTGTACAATCTGTATA





690
ATGAACACACAAATTCTGGTCTTCGCACTGATTGCAATCATCCCAACTAACGCTGACAAA



ATTTGTCTGGGGCACCATGCGGTCAGTAATGGCACCAAGGTCAACACTCTCACTGAACGC



GGAGTGGAAGTGGTGAACGCAACCGAGACAGTGGAGCGGACCAACATCCCCAGAATATGC



TCAAAGGGTAAAAAGACTGTGGATTTGGGACAGTGCGGTCTTCTTGGGACAATCACCGGC



CCTCCCCAGTGTGACCAGTTCCTGGAATTCTCTGCCGACCTGATTATAGAGCGGCGTGAG



GGCTCCGATGTGTGTTACCCCGGCAAGTTCGTGAACGAGGAGGCACTGCGACAGATCTTG



AGAGAAAGCGGGGGGATTGACAAAGAGGCTATGGGCTTCACTTATTCGGGCATCAGGACT



AATGGCGCAACCTCCGCTTGTAGGAGATCAGGATCCTCTTTCTACGCCGAAATGAAGTGG



CTGCTGTCGAATACAGACAATGCCGCTTTCCCCCAAATGACTAAGAGTTATAAAAACACG



CGTAAATCCCCAGCGCTGATTGTCTGGGGAATCCACCACTCGGTGAGCACTGCAGAGCAG



ACTAAACTGTACGGGAGCGGCAATAAACTTGTTACAGTGGGATCCTCGAATTACCAACAG



AGCTTCGTCCCATCACCAGGTGCTCGACCACAGGTGAACGGCCAGTCTGGGCGAATAGAT



TTTCATTGGCTCATGCTTAATCCCAATGACACTGTGACTTTTTCTTTCAATGGGGCCTTC



ATCGCGCCTGATCGGGCCAGTTTCCTGAGAGGCAAGAGTATGGGAATCCAGTCCGGCGTG



CAGGTGGACGCTAATTGTGAGGGGGATTGCTATCACTCAGGTGGCACTATAATTTCAAAT



CTTCCTTTCCAGAACATCGATTCTCGAGCCGTCGGAAAGTGCCCTAGGTACGTGAAACAA



AGGTCACTCCTTTTGGCAACCGGGATGAAGAACGTGCCAGAGATTCCCAAGGGTCGGGGG



CTCTTTGGCGCTATTGCTGGATTTATCGAGAATGGGTGGGAGGGTCTGATAGACGGTTGG



TATGGCTTCAGACACCAGAACGCCCAGGGGGAGGGCACCGCCGCCGACTATAAGAGTACC



CAGAGCGCAATTGACCAGATTACCGGAAAATTGAACCGACTGATTGAGAAGACAAATCAG



CAGTTTGAGTTGATCGACAACGAATTCAATGAGGTTGAAAAACAGATCGGGAACGTTATA



AACTGGACACGAGATAGCATAACAGAGGTCTGGAGTTACAATGCTGAACTGCTGGTTGCT



ATGGAAAACCAGCATACTATTGACCTTGCGGACAGCGAGATGGACAAACTATACGAAAGA



GTGAAGCGCCAGCTGCGTGAGAACGCCGAAGAAGACGGGACTGGATGCTTCGAGATATTC



CACAAGTGTGATGACGATTGTATGGCAAGCATACGGAACAACACATACGATCATAGCAAA



TATAGGGAGGAGGCGATGCAGAACAGAATACAGATAGACCCTGTGAAGTTATCTTCCGGT



TACAAAGACGTTATCCTCTGGTTTAGCTTCGGAGCCAGCTGCTTTATATTATTAGCCATC



GTCATGGGCCTCGTTTTCATCTGCGTGAAGAATGGAAATATGCGCTGCACCATCTGCATC





691
ATGAATACGCAGATCTTGGTATTCGCACTTATAGCCATCATCCCCACCAACGCCGATAAG



ATTTGCTTAGGCCACCATGCTGTTTCTAACGGCACAAAAGTGAACACACTTACCGAGAGA



GGGGTCGAAGTTGTGAACGCCACGGAGACAGTCGAAAGGACAAACATTCCTCGAATCTGC



AGTAAGGGCAAGAAAACAGTGGATCTCGGCCAGTGTGGGCTGCTGGGAACCATCACGGGT



CCTCCGCAGTGTGACCAGTTCCTGGAGTTCTCTGCCGATCTCATCATCGAAAGGCGGGAG



GGATCCGACGTGTGCTACCCAGGCAAATTCGTGAACGAAGAAGCGCTTCGGCAAATTCTG



CGAGAGTCAGGGGGGATAGATAAAGAGGCAATGGGGTTTACTTATTCTGGCATTAGAACC



AATGGGGCCACGAGTGCATGTAGACGGTCCGGAAGTAGCTTTTACGCAGAAATGAAGTGG



CTGTTGTCTAACACTGACAACGCTGCATTTCCACAGATGACCAAGTCTTATAAAAACACG



AGAAAATCCCCAGCCCTCATTGTGTGGGGGATCCACCATTCTGTGAGCACCGCCGAGCAA



ACGAAGCTGTATGGCAGTGGTAACAAGCTAGTCACAGTAGGATCCAGTAATTACCAGCAA



AGCTTCGTGCCCAGTCCCGGAGCTCGGCCTCAGGTCAACGGGCAATCTGGGAGAATCGAC



TTCCACTGGCTGATGCTGAACCCAAACGACACAGTGACATTTTCTTTTAATGGCGCTTTC



ATTGCCCCCGACAGGGCTAGTTTTCTGAGAGGCAAGTCCATGGGGATCCAAAGCGGAGTG



CAGGTGGACGCTAATTGCGAGGGCGATTGTTACCACAGTGGGGGGACCATTATCAGTAAT



CTGCCTTTCCAGAACATCGATAGTAGAGCCGTGGGCAAATGTCCACGTTACGTCAAGCAG



CGGAGCCTGCTCTTAGCCACGGGCATGAAGAACGTGCCTGAGATCCCAAAGGGCAGAGGG



CTGTTTGGCGCTATCGCGGGATTCATTGAAAATGGGTGGGAGGGACTAATCGACGGATGG



TACGGTTTTCGACACCAGAACGCACAGGGGGAAGGGACAGCTGCCGATTATAAGTCTACT



CAATCTGCTATCGACCAGATAACTGGGAAACTTAATCGGCTGATTGAGAAAACAAACCAG



CAGTTTGAGCTGATAGACAACGAATTCAACGAAGTGGAGAAACAGATCGGTAACGTGATA



AACTGGACTAGGGACTCTATCACCGAGGTGTGGTCCTACAACGCGGAACTCCTTGTCGCT



ATGGAGAATCAGCACACTATAGACCTGGCAGACTCTGAAATGGATAAACTGTACGAACGG



GTTAAGCGGCAATTGCGGGAGAACGCTGAGGAGGATGGCACAGGATGTTTTGAAATTTTT



CATAAATGTGACGACGATTGCATGGCTTCCATTCGCAACAATACTTATGATCATTCGAAG



TACCGGGAAGAGGCCATGCAAAACCGTATCCAGATCGATCCCGTCAAACTGTCGTCGGGG



TACAAGGACGTTATACTTTGGTTCAGCTTTGGAGCCTCTTGTTTCATCTTGCTCGCTATA



GTGATGGGCTTGGTGTTTATATGCGTAAAAAATGGCAACATGCGGTGCACAATTTGCATT





692
ATGAACACTCAGATACTCGTCTTTGCTCTCATTGCAATTATTCCTACCAATGCTGATAAG



ATTTGCTTGGGGCACCACGCAGTTTCCAATGGGACAAAGGTGAACACCCTAACTGAGCGG



GGCGTTGAAGTGGTGAACGCAACCGAGACAGTGGAAAGAACAAATATCCCCCGCATTTGC



AGTAAAGGCAAAAAAACCGTCGACTTGGGACAGTGTGGCCTGCTTGGGACTATCACCGGA



CCCCCACAGTGTGACCAATTTTTGGAGTTTTCAGCTGATCTGATTATCGAAAGACGCGAG



GGAAGCGATGTTTGCTATCCAGGAAAATTTGTGAATGAAGAAGCACTCCGACAGATCCTG



CGGGAGTCCGGCGGAATAGATAAGGAAGCAATGGGGTTCACTTACTCGGGCATCCGGACT



AACGGAGCCACTTCCGCCTGCAGAAGGTCAGGCTCGTCGTTCTATGCCGAGATGAAGTGG



CTGCTTTCAAACACTGATAATGCCGCATTCCCACAGATGACAAAGTCATACAAAAACACC



AGGAAATCACCCGCATTGATAGTGTGGGGCATCCATCATTCTGTGTCCACTGCCGAGCAG



ACTAAACTGTACGGGAGCGGGAATAAGCTTGTTACCGTCGGGTCAAGCAACTATCAGCAA



AGTTTTGTACCAAGCCCGGGCGCACGGCCCCAGGTTAATGGTCAGTCCGGTCGCATTGAT



TTCCATTGGCTAATGCTAAATCCAAATGACACTGTAACGTTCTCATTCAACGGAGCGTTC



ATCGCTCCAGACCGTGCCTCTTTTCTGCGCGGGAAAAGCATGGGGATACAGTCCGGGGTG



CAGGTAGATGCTAACTGTGAGGGAGACTGTTATCACTCTGGCGGCACGATCATCTCCAAC



CTTCCCTTTCAGAACATTGACAGCAGAGCCGTCGGGAAATGCCCCCGATATGTTAAGCAG



AGGTCACTTCTTCTCGCTACGGGTATGAAGAATGTCCCAGAAATTCCTAAAGGCCGGGGA



TTGTTTGGAGCAATCGCCGGCTTCATCGAAAACGGTTGGGAAGGCTTGATTGATGGCTGG



TACGGCTTCCGCCACCAAAATGCTCAGGGAGAAGGAACTGCAGCTGACTATAAATCAACA



CAGAGCGCCATTGACCAGATCACAGGGAAGCTGAACAGACTTATCGAGAAAACCAATCAG



CAGTTTGAGCTCATAGACAACGAATTTAACGAAGTGGAGAAACAGATTGGCAACGTTATC



AATTGGACCCGGGACTCAATCACTGAAGTCTGGTCCTACAATGCAGAGCTGCTCGTCGCT



ATGGAAAACCAGCACACTATCGATTTGGCTGACAGCGAAATGGATAAACTATATGAAAGG



GTCAAGCGTCAGCTCCGAGAAAATGCAGAAGAGGATGGAACAGGCTGTTTCGAAATCTTC



CATAAGTGTGATGACGATTGCATGGCCAGTATCAGAAACAACACTTACGATCACTCCAAA



TACAGGGAGGAGGCCATGCAGAACCGGATCCAGATTGACCCTGTAAAACTGTCGAGCGGC



TATAAAGATGTTATCCTGTGGTTCAGCTTCGGGGCCAGCTGCTTCATACTGCTTGCCATT



GTGATGGGACTGGTGTTCATTTGCGTTAAAAATGGAAACATGAGATGCACCATCTGTATC





693
ATGAACACACAAATCCTGGTGTTCGCTCTAATAGCGATCATCCCAACCAATGCCGATAAG



ATCTGTCTGGGCCACCACGCCGTATCCAATGGGACTAAGGTTAATACACTGACAGAGCGA



GGAGTCGAAGTGGTGAACGCAACCGAGACAGTCGAAAGGACGAATATTCCCAGGATCTGC



AGCAAGGGGAAGAAGACTGTTGACCTGGGACAATGTGGCCTACTGGGAACTATAACCGGC



CCTCCACAATGCGACCAATTCCTGGAGTTTTCCGCTGACCTGATTATTGAACGGCGCGAA



GGGAGCGACGTATGTTATCCCGGGAAATTCGTGAATGAGGAGGCTCTGCGCCAGATCCTG



CGCGAGAGCGGGGGAATCGATAAGGAGGCCATGGGTTTCACCTATTCCGGAATAAGGACT



AACGGCGCAACCTCAGCTTGTAGACGCAGTGGCTCTTCTTTTTATGCTGAAATGAAATGG



TTATTATCAAACACGGACAACGCCGCTTTTCCCCAGATGACCAAGAGTTATAAGAACACC



CGGAAATCACCTGCTCTGATAGTATGGGGAATTCATCACTCGGTGTCCACTGCGGAGCAA



ACCAAACTGTACGGGAGCGGCAATAAGTTGGTTACAGTAGGAAGCTCCAATTATCAGCAA



AGTTTCGTCCCCTCCCCTGGCGCCAGGCCTCAAGTGAACGGACAGTCAGGGAGAATCGAC



TTCCACTGGCTGATGCTCAATCCAAACGACACCGTAACTTTCTCATTCAATGGGGCATTT



ATCGCCCCAGACCGGGCCTCGTTCTTACGAGGTAAATCCATGGGGATTCAGAGCGGCGTC



CAAGTGGATGCCAACTGCGAAGGCGATTGCTACCACTCTGGTGGGACAATCATCTCGAAC



TTGCCGTTCCAAAACATCGATTCCCGAGCAGTGGGGAAATGCCCCAGATACGTAAAACAA



AGGTCGCTGCTCCTTGCTACCGGCATGAAAAACGTCCCTGAAATCCCAAAGGGTCGTGGT



CTGTTTGGCGCAATTGCTGGGTTTATTGAGAACGGCTGGGAAGGCCTGATAGACGGGTGG



TATGGATTTCGTCATCAGAATGCACAGGGCGAGGGGACCGCAGCCGATTACAAGAGTACC



CAGTCCGCTATTGACCAGATAACAGGGAAACTGAACCGGCTGATTGAGAAGACCAACCAG



CAGTTCGAGTTGATTGACAATGAGTTCAACGAAGTCGAGAAGCAGATCGGGAATGTAATA



AATTGGACAAGAGACAGCATTACAGAGGTGTGGAGCTACAATGCAGAGCTGTTAGTGGCC



ATGGAGAACCAACACACGATTGACCTTGCCGATTCCGAGATGGACAAGTTGTACGAGAGA



GTAAAGAGGCAGCTGAGGGAGAATGCTGAAGAAGACGGAACAGGCTGCTTTGAAATCTTC



CACAAGTGTGATGATGACTGTATGGCTTCGATACGCAATAATACATACGACCATAGCAAG



TATCGGGAGGAAGCCATGCAGAATAGAATTCAGATTGATCCCGTGAAACTAAGCTCGGGA



TACAAGGACGTGATACTATGGTTTTCATTTGGCGCCTCCTGTTTCATCCTCCTGGCTATT



GTCATGGGTTTGGTTTTTATTTGTGTTAAAAACGGCAACATGCGGTGTACTATTTGCATC





694
ATGAACACGCAGATACTGGTTTTCGCACTCATTGCAATCATCCCTACGAACGCCGACAAG



ATTTGTCTGGGCCACCACGCTGTCTCTAACGGCACCAAGGTGAACACCCTGACCGAGCGC



GGAGTGGAAGTGGTCAATGCGACAGAAACTGTGGAACGGACAAACATTCCACGGATCTGT



AGCAAAGGCAAGAAGACAGTGGATCTGGGGCAGTGCGGCCTACTGGGCACCATCACCGGA



CCTCCTCAATGCGATCAGTTTCTTGAGTTTTCCGCCGATTTGATTATAGAAAGACGGGAG



GGATCCGATGTCTGCTACCCAGGCAAGTTTGTCAACGAGGAGGCCCTAAGACAGATTCTG



CGGGAATCTGGCGGGATCGACAAGGAGGCAATGGGCTTCACCTACAGCGGGATCAGGACA



AACGGAGCCACAAGCGCTTGTAGGCGCTCTGGTTCCTCGTTTTACGCAGAAATGAAGTGG



TTACTTTCAAATACGGACAATGCGGCCTTCCCCCAGATGACCAAATCATATAAGAATACT



CGCAAGAGCCCGGCATTGATTGTCTGGGGCATCCATCATTCTGTGTCTACTGCTGAACAG



ACTAAACTGTATGGCTCTGGCAACAAGCTGGTGACTGTCGGAAGCAGTAACTACCAACAG



AGCTTCGTGCCTAGCCCAGGGGCAAGACCCCAGGTCAACGGGCAGAGGGGGCGTATTGAC



TTTCACTGGCTGATGCTGAACCCAAACGACACTGTGACATTCAGTTTCAATGGGGCCTTT



ATAGCCCCTGACAGGGCCAGCTTCTTGAGGGGCAAGTCCATGGGAATACAGTCTGGTGTC



CAGGTCGATGCCAATTGCGAGGGGGACTGTTATCATAGGGGCGGCACAATCATCTCAAAT



CTGCCTTTCCAGAATATCGATAGTCGTGCCGTGGGAAAATGCCCCCGTTATGTAAAGCAA



AGATCCTTGCTGCTAGCTACCGGGATGAAGAATGTGCCAGAAATTCCAAAGGGACGAGGC



CTGTTCGGCGCTATTGCTGGCTTCATTGAGAACGGGTGGGAAGGCCTGATAGATGGGTGG



TACGGGTTCAGGCACCAGAACGCACAGGGCGAGGGTACAGCTGCCGACTATAAATCTACG



CAGAGCGCAATTGACCAGATCACCGGGAAGCTAAACCGTCTGATTGAAAAGACCAATCAA



CAATTTGAGCTCATAGATAATGAGTTCAACGAAGTTGAAAAGCAGATTGGGAACGTCATC



AACTGGACACGGGATAGTATAACGGAAGTGTGGAGTTATAACGCCGAATTACTGGTGGCG



ATGGAAAACCAGCACACTATCGATTTGGCCGACTCCGAGATGGATAAGCTGTACGAGCGG



GTTAAACGCCAGTTAAGGGAGAATGCTGAGGAGGATGGCACAGGTTGCTTTGAGATTTTC



CATAAATGCGATGACGATTGCATGGCCTCTATTCGAAATAACACATACGACCACTCGAAG



TACCGTGAGGAGGCAATGCAAAATCGAATCCAGATTGACCCAGTGAAACTCTCCAGTGGC



TATAAGGATGTGATCTTGTGGTTCTCTTTTGGGGCCTCATGTTTTATTCTCCTTGCGATC



GTGATGGGATTGGTTTTTATCTGTGTCAAGAATGGAAACATGAGATGCACGATCTGTATC





695
ATGAATACACAGATCTTAGTTTTTGCACTAATAGCTATCATCCCCACAAACGCCGACAAA



ATTTGTCTGGGTCATCATGCTGTGTCTAACGGTACCAAGGTTAATACCCTGACCGAACGC



GGGGTTGAGGTGGTTAACGCGACTGAAACGGTGGAACGCACGAATATACCCAGGATCTGT



TCAAAAGGCAAAAAGACCGTTGATCTGGGTCAGTGCGGCCTTCTGGGGACAATCACCGGC



CCCCCCCAGTGCGACCAGTTCCTCGAGTTTAGTGCTGATTTGATCATTGAGCGAAGAGAG



GGGTCCGACGTGTGCTATCCAGGGAAGTTTGTTAATGAAGAGGCGTTGCGCCAGATCCTA



CGCGAATCCGGGGGAATCGATAAGGAAGCAATGGGCTTCACCTATTCTGGCATTAGAACC



AACGGAGCTACATCCGCCTGTAGAAGGAGTGGCTCGTCTTTCTATGCAGAGATGAAATGG



CTGCTGTCCAACACCGACAATGCCGCTTTCCCCCAGATGACTAAAAGCTACAAGAATACC



CGAAAAAGTCCAGCTCTGATCGTCTGGGGCATCCACCACTCAGTTAGTACAGCCGAACAG



ACAAAGTTGTATGGCAGTGGCAACAAACTAGTCACAGTTGGCTCGTCCAACTATCAGCAG



AGTTTTGTGCCCAGTCCCGGGGCACGTCCGCAGGTCAATGGACAGAGCGGCCGGATTGAT



TTCCATTGGCTGATGCTGAACCCTAACGATACAGTGACATTTTCCTTCAACGGCGCGTTC



ATCGCACCCGATCGCGCTTCATTCCTGAGGGGGAAGAGCATGGGGATTCAGTCGGGAGTC



CAGGTTGACGCCAACTGTGAAGGAGACTGCTACCATTCAGGGGGGACAATCATCTCCAAC



CTACCATTCCAGAACATTGATTCAAGAGCTGTTGGAAAGTGTCCAAGATATGTCAAGCAA



AGGTCTCTATTGCTAGCTACCGGTATGAAGAATGTCCCTGAAATACCGAAGGGGAGGGGT



CTGTTCGGTGCCATAGCTGGTTTTATCGAAAATGGGTGGGAGGGTCTTATCGACGGGTGG



TATGGATTTCGCCACCAGAACGCCCAGGGGGAAGGCACTGCAGCTGACTATAAGTCGACT



CAGTCTGCCATCGACCAGATCACCGGTAAATTAAATAGACTGATTGAGAAGACAAATCAG



CAATTCGAGCTCATCGATAATGAGTTCAACGAGGTCGAGAAGCAGATTGGAAATGTGATT



AACTGGACGCGCGATTCCATTACCGAGGTGTGGAGCTATAACGCGGAGTTGTTAGTGGCG



ATGGAGAATCAGCATACAATTGATCTAGCGGACAGTGAAATGGACAAGCTGTACGAGAGA



GTTAAACGACAGCTGCGCGAGAACGCCGAGGAGGATGGGACAGGGTGTTTTGAGATCTTC



CATAAGTGTGACGATGATTGTATGGCTAGCATTAGAAATAACACTTACGATCATAGCAAA



TACAGGGAGGAGGCCATGCAGAACCGAATTCAAATCGACCCCGTGAAGCTGTCTTCGGGC



TACAAAGACGTTATTCTCTGGTTTAGCTTTGGTGCGTCATGCTTCATTCTGCTGGCGATT



GTAATGGGGTTGGTTTTCATATGCGTTAAGAACGGCAACATGCGGTGCACTATTTGTATT
















TABLE 18







Codon Optimized Sequences Encoding H10 Hemagglutinin








Seq



ID



No.
Nucleic Acid Sequence





696
5′7MeGpppG2′OMeGGAAAUAAGAGAGAAAAGAAGAGUAAGAAGAAAUAUAAGAGCCACCA



UGUACAAAAUCGUCGUCAUUAUCGCAUUGCUGGGCGCUGUCAAGGGACUCGACAAGAU



CUGUCUCGGACACCACGCGGUGGCUAACGGAACCAUCGUCAAGACCCUGACUAACGAG



CAGGAAGAAGUGACCAACGCCACCGAAACUGUGGAAUCCACCGGGAUCAACAGAUUGU



GCAUGAAGGGUCGGAAGCACAAGGAUCUGGGAAACUGCCACCCGAUUGGAAUGCUCAU



CGGCACCCCGGCAUGCGAUCUGCAUCUGACUGGGAUGUGGGAUACCCUUAUCGAGCGG



GAAAACGCGAUCGCAUACUGUUACCCCGGUGCCACCGUGAACGUGGAGGCGCUCAGAC



AGAAGAUUAUGGAGUCAGGCGGCAUCAACAAGAUUUCCACGGGCUUCACCUACGGGUC



CUCCAUUAACUCCGCCGGUACCACUCGGGCCUGCAUGCGGAACGGAGGGAACUCCUUU



UACGCCGAGCUCAAGUGGCUUGUGUCAAAAUCCAAGGGACAGAAUUUCCCCCAAACCA



CCAACACCUAUAGGAACACCGACACCGCCGAACAUCUCAUUAUGUGGGGCAUCCAUCA



CCCUUCGAGCACACAGGAGAAGAAUGACCUCUACGGCACCCAGUCGCUGAGCAUCUCC



GUGGGCUCAUCGACCUAUCGCAACAACUUCGUGCCUGUGGUCGGCGCCCGACCUCAAG



UCAACGGACAGUCCGGACGCAUUGACUUCCAUUGGACUCUGGUGCAACCGGGAGACAA



CAUCACUUUCUCCCACAACGGCGGACUGAUUGCCCCAAGCCGCGUGUCAAAGCUGAUC



GGUAGAGGGCUGGGUAUUCAGUCGGAUGCUCCCAUCGAUAACAACUGCGAAUCCAAGU



GCUUUUGGAGAGGCGGCUCCAUCAAUACUCGGCUGCCGUUUCAGAACCUGAGCCCGAG



GACCGUGGGGCAGUGCCCAAAAUACGUGAAUCGCCGGUCACUGAUGCUGGCGACCGGA



AUGAGGAACGUGCCUGAACUCAUCCAGGGACGGGGGCUGUUCGGCGCCAUCGCCGGCU



UCCUGGAAAACGGAUGGGAGGGAAUGGUGGACGGUUGGUACGGCUUCCGCCACCAAAA



CGCCCAGGGAACUGGACAGGCCGCCGACUACAAGUCCACACAGGCCGCAAUAGACCAG



AUCACUGGGAAGCUCAACCGCCUUGUGGAAAAGACUAACACUGAAUUCGAGUCGAUCG



AGUCUGAGUUCUCCGAGAUCGAACACCAGAUUGGGAACGUGAUCAACUGGACGAAGGA



CUCCAUUACCGACAUCUGGACCUACCAGGCGGAACUGCUCGUGGCGAUGGAGAACCAG



CACACUAUCGACAUGGCCGACUCCGAGAUGCUGAAUCUGUACGAACGCGUGCGGAAGC



AACUGAGACAAAACGCUGAAGAAGAUGGAAAGGGUUGUUUCGAGAUCUACCACGCCUG



CGACGACAGCUGCAUGGAAAGCAUUAGGAACAAUACCUACGACCACUCGCAGUACCGG



GAGGAGGCCCUUCUGAACCGGCUGAACAUUAACCCCGUGACCUUGAGCUCCGGCUACA



AGGACAUCAUCCUGUGGUUCUCGUUUGGAGCCAGCUGCUUCGUGCUGCUGGCCGUCGU



GAUGGGAUUGUUCUUCUUCUGCCUGAAAAACGGAAACAUGCGCUGCACCAUCUGUAUU



UGAUAAUAGGCUGGAGCCUCGGUGGCCAUGCUUCUUGCCCCUUGGGCCUCCCCCCAGC



CCCUCCUCCCCUUCCUGCACCCGUACCCCCGUGGUCUUUGAAUAAAGUCUGAGUGGGC



GGCAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA



AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAUCUAGCH3′





697
ATGTACAAGATCGTCGTGATTATCGCCCTTCTGGGGGCAGTCAAGGGACTAGACAAAATAT



GCCTGGGCCATCATGCAGTGGCTAACGGGACGATAGTGAAGACGCTGACCAACGAACAGGA



GGAGGTCACTAACGCCACTGAGACAGTGGAGTCGACGGGCATCAATCGTTTGTGCATGAAA



GGCCGGAAACACAAAGACTTAGGTAATTGTCATCCGATAGGGATGCTGATAGGCACCCCTG



CATGCGACCTCCATCTCACTGGGATGTGGGACACCCTGATCGAAAGGGAAAATGCAATAGC



CTATTGCTACCCCGGTGCTACCGTTAATGTCGAGGCGCTGAGACAGAAAATCATGGAATCC



GGGGGAATCAACAAGATTAGCACGGGGTTTACATATGGGAGCTCAATAAATTCCGCCGGTA



CTACCCGAGCATGCATGCGGAACGGCGGAAATAGTTTTTATGCCGAACTCAAGTGGCTTGT



CTCCAAGTCTAAGGGACAAAATTTCCCGCAGACAACAAATACGTATCGTAACACTGATACC



GCCGAGCATCTTATCATGTGGGGCATCCATCACCCTAGCTCAACGCAGGAGAAAAACGACT



TGTACGGTACTCAGTCTCTATCTATCTCCGTGGGATCTTCCACCTATAGAAACAATTTTGT



GCCCGTCGTAGGGGCCCGCCCTCAGGTGAATGGCCAGTCAGGCCGTATAGACTTCCATTGG



ACTCTCGTACAGCCCGGGGATAATATAACCTTTAGTCATAACGGAGGCCTCATTGCTCCCA



GCAGGGTTTCTAAGTTGATCGGTCGCGGGCTGGGCATTCAGTCTGATGCCCCAATTGATAA



CAACTGTGAAAGCAAGTGCTTCTGGAGGGGTGGGAGTATCAATACTAGACTCCCATTCCAG



AACTTGTCTCCGCGGACTGTAGGACAGTGCCCAAAGTATGTGAATCGTCGGTCTCTCATGC



TGGCAACCGGTATGAGAAATGTTCCTGAGCTAATACAGGGAAGAGGACTTTTTGGAGCAAT



CGCCGGATTTTTAGAAAATGGTTGGGAGGGGATGGTTGACGGATGGTACGGTTTCAGGCAC



CAGAACGCCCAGGGAACCGGCCAGGCCGCGGACTACAAAAGCACACAGGCAGCCATTGATC



AGATTACTGGCAAGCTGAACCGCTTAGTCGAGAAGACCAACACGGAATTTGAATCAATCGA



GTCAGAATTTAGCGAAATCGAACATCAGATTGGGAACGTAATTAATTGGACAAAAGATAGC



ATCACAGATATTTGGACCTACCAGGCTGAGCTACTGGTGGCTATGGAGAACCAACACACTA



TTGATATGGCCGACAGCGAAATGTTAAATTTGTATGAACGGGTACGGAAGCAGCTTAGACA



GAACGCAGAAGAAGATGGCAAGGGCTGCTTTGAAATTTACCACGCTTGCGATGACAGTTGC



ATGGAGTCTATTAGGAACAATACATATGATCACTCTCAGTACAGAGAGGAGGCCTTGCTCA



ATAGGCTGAATATCAACCCTGTCACCCTGAGCAGTGGTTATAAGGACATCATCCTGTGGTT



CAGCTTTGGCGCTTCATGTTTCGTGCTGCTGGCTGTCGTCATGGGCCTTTTCTTTTTTTGT



TTGAAGAACGGCAACATGCGTTGCACTATCTGCATC





698
ATGTACAAGATCGTGGTGATCATCGCTCTGCTCGGCGCCGTTAAGGGACTGGATAAGATTT



GTTTAGGGCACCATGCAGTGGCAAACGGGACCATTGTCAAGACACTCACCAATGAACAGGA



GGAAGTGACCAACGCGACTGAGACTGTTGAGTCCACCGGCATAAACAGGCTTTGTATGAAA



GGCAGAAAGCACAAGGATTTGGGTAATTGTCACCCAATAGGAATGCTAATTGGGACTCCTG



CCTGCGATCTCCACCTGACAGGCATGTGGGACACCCTGATTGAACGGGAGAATGCTATCGC



ATACTGCTACCCAGGTGCAACCGTAAACGTGGAGGCCCTGCGACAGAAGATAATGGAGAGC



GGAGGCATCAACAAGATCAGTACGGGATTTACCTACGGGTCTTCTATCAATTCGGCTGGCA



CAACACGTGCTTGCATGAGAAACGGAGGCAACTCCTTCTACGCTGAACTCAAATGGTTGGT



GAGTAAGAGTAAGGGTCAGAATTTCCCACAGACGACCAACACATACAGGAACACCGATACG



GCCGAACACCTCATCATGTGGGGCATACACCACCCTAGTAGTACACAAGAGAAAAACGACC



TGTATGGGACACAATCCCTTTCAATCAGTGTTGGTAGCTCGACCTACCGTAATAATTTCGT



CCCTGTGGTGGGTGCTAGACCGCAGGTCAATGGCCAGTCAGGAAGGATCGATTTCCACTGG



ACCCTCGTGCAGCCAGGTGATAACATTACTTTTTCTCATAATGGCGGACTAATTGCGCCTA



GCAGGGTGTCAAAGCTTATTGGGAGAGGCCTAGGCATACAAAGCGACGCCCCAATCGATAA



CAATTGCGAGTCGAAGTGTTTCTGGAGGGGGGGATCAATTAACACACGTCTGCCCTTCCAG



AATCTGTCACCAAGGACTGTGGGCCAGTGTCCAAAGTATGTTAATCGACGTTCACTCATGC



TTGCCACCGGCATGCGGAATGTGCCTGAACTGATTCAGGGCCGCGGACTTTTTGGCGCCAT



TGCAGGTTTCTTGGAGAACGGGTGGGAAGGTATGGTCGACGGATGGTATGGCTTCAGACAC



CAGAACGCCCAAGGAACTGGCCAGGCCGCCGATTATAAGAGCACCCAGGCTGCGATCGATC



AAATTACCGGTAAACTCAACCGGCTGGTCGAGAAGACTAATACAGAGTTTGAGTCAATAGA



ATCCGAGTTTTCCGAAATAGAACATCAGATCGGTAATGTAATCAACTGGACCAAGGACAGC



ATCACCGACATATGGACATACCAGGCCGAACTGCTCGTCGCCATGGAGAATCAACACACGA



TTGACATGGCCGATTCGGAAATGCTGAATCTGTACGAAAGGGTGCGTAAACAGTTGCGGCA



GAATGCAGAAGAAGATGGAAAAGGGTGTTTTGAAATCTACCACGCCTGCGACGATAGCTGC



ATGGAATCTATCCGGAATAACACCTATGACCATTCCCAATACCGAGAAGAGGCCCTGCTCA



ACCGCTTGAACATTAATCCCGTTACATTGTCATCCGGATACAAGGACATCATCTTGTGGTT



CTCTTTCGGGGCTTCCTGTTTTGTGCTTCTAGCAGTTGTGATGGGTCTGTTTTTCTTCTGC



TTAAAGAACGGCAATATGAGATGTACTATTTGCATC





699
ATGTACAAGGTAGTGGTAATTATCGCTCTGCTAGGTGCCGTTCGTGGCTTGGACAAGATTT



GTTTGGGGCACCATGCCGTAGCCAACGGAACAATTGTGAAGACACTGACTAACGAACAAGA



GGAAGTAACCAACGCTACAGAAACAGTCGAATCTAAAAGTTTGGGCAAGTTATGTATGAAA



GGGCGGAGTTACAACGACCTCGGAAATTGCCACCCCATCGGAATTTTAATCGGCACTCCAG



CCTGCGATCTGCACTTAACAGGAACCTGGGACACCCTCATCGAACGCGAAAATGCCGTTGC



ATACTGTTACCCAGGTGCGACTGTCAACGAGGAAGCGCTCCGCCAGAAGATCATGGAAAGC



GGGGGGATTTCAAAAATCTCTACCGGGTTTACATACGGGACTTCCATCAACAGCGCTGGCA



CCACAAAGGCCTGCATGCGCAATGGCGGTAACAGCTTCTACGCTGAGCTCAAGTGGCTGGT



CAGCAAAAACAAAGGCCAGAACTTCCCCCAAACTACTAATACCTACAGAAACACAGATACC



GCCGAGCACCTCATAATTTGGGGGATCCATCACCCATCTAGCACTCAGGAGAAAAACGATC



TCTATGGCACACAGTCTCTCAGCATTTCAGTGGGAAGCTCGACATACCAGAATAACTTTGT



TCCCGTGGTGGGCGCAAGACCACAGGTCAACGGCCAGTCCGGGAGAATTGATTTCCATTGG



ACGCTGCTGCAACCTGGAGACAACATCACCTTTTCTCATAATGGCGGCCTAATTGCGCCTT



CCAGAGTTAGCAAGCTGATCGGCCGGGGCCTAGGTATTCAGAGCGAGGCCCCAATTGACAA



CGGTTGCGAATCAAAGTGCTTCTGGAAAGGCGGATCCATTAACACGAAGTTGCCCTTCCAG



AACTTATCACCCAGAACCGTGGGGCAGTGTCCCAAATACGTGAATAAGAGGTCCCTGATGC



TCGCTACCGGTATGCGGAATGTGCCTGAGATAATGCATGGAAGAGGACTGTTTGGGGCAAT



CGCTGGGTTTATCGAAAACGGTTGGGAAGGGATGGTTGATGGATGGTACGGGTTTCGGCAT



CAGAATGCACAGGGAACTGGTCAGGCCGCCGATTACAAATCAACGCAAGCCGCCATCGACC



AGATAACTGGAAAGCTGAATAGGCTCATCGAAAAAACCAACACCGAGTTCGAATCAATTGA



GTCTGAGTTCTCTGAGATCGAGCACCAAATCGGGAATATCATCAATTGGACCAAAGATAGC



ATTACTGATATCTGGACATATCAGGCTGAGCTGCTGGTCGCCATGGAGAACCAGCATACAA



TCGACATGGCAGACTCGGAGATGCTTAACCTGTATGAGAGGGTGCGTAAACAATTGCGACA



GAATGCCGAAGAGGATGGTAAGGGTTGCTTCGAAATCTACCACGCTTGCGACGATTCTTGC



ATGGAAAGTATAAGAAATAATACCTATGATCATTCACAATACCGCGAAGAGGCTTTGCTGA



ACAGACTCAACATCAATCCGGTGAAGCTTTCCTCTGGGTACAAGGATATAATTCTGTGGTT



TTCCTTTGGAGCTTCCTGTCTCATATTATTGGCTGTTGTTATGGGCCTCGTTTTTTTTTGC



CTGAAGAACGGTAACATGCGCTGTACAATATGTATC





700
ATGTACAAAATTATCGTGATCATCGCTCTTCTGGGCGCCGTCAAAGGTCTCGATAAAATTT



GCCTTGGGCACCATGCTGTGGCAAACGGAACTATTGTAAAAACTCTTACGAATGAGCAAGA



AGAGGTGACCAATGCCACCGAAACCGTCGAGTCCACCGGGATCAATAGGTTGTGCATGAAG



GGGCGTAAACACAAGGACCTTGGCAATTGCCATCCGATCGGCATGTTGATCGGAACACCAG



CTTGTGACCTTCACTTGACCGGAACATGGGACACTCTGATCGAGCGAGAGAACGCAATTGC



ATATTGCTATCCGGGAGCAACCGTGAATGTGGAGGCCCTGCGGCAGAAGATCATGGAATCC



GGAGGTATCGACAAAATCTCTACCGGATTCACCTACGGATCTTCAATTAACTCCGCTGGCA



CTACACGCGCTTGCATGCGAAATGGCGGTAACTCATTCTACGCCGAGCTGAAGTGGCTGGT



GTCCAAGTCTAAAGGGCAGAATTTTCCGCAGACCACTAACACCTACAGAAACACTGATACC



GCCGAACATCTCATTATGTGGGGAATCCACCACCCATCAAGCACTCAAGAAAAAAACGACT



TGTATGGTACACAGTCACTAAGCATTTCCGTGGGCAGCTCTACCTACCGCAACAACTTTGT



CCCCGTGGTTGGCGCCCGACCCCAAGTAAATGGTCAGTCCGGCAGGATCGATTTTCATTGG



ACCCTGGTGCAGCCAGGGGATAACATCACTTTTAGCCATAACGGCGGCTTGATAGCGCCGT



CAAGGGTGTCCAAACTGATCGGAAGAGGGCTGGGAATTCAGAGTGACGCACCCATCGATAA



CAACTGCGAAAGCAAATGTTTCTGGGGGGGGGGTTCGATCAACACCCGATTACCTTTCCAG



AACCTCTCCCCCAGGACTGTTGGTCAGTGCCCGAAATATGTTAATCGACGCAGCTTGATGC



TCGCCACCGGGATGCGCAATGTTCCCGAGCTCATTCAGGGGCGGGGCCTCTTTGGCGCAAT



AGCTGGGTTCCTCGAGAATGGTTGGGAAGGCATGGTGGATGGATGGTACGGCTTCCGGCAT



CAAAACGCACAGGGCACAGGCCAGGCCGCAGATTACAAGTCTACACAGGCCGCCATTGATC



AGATTACAGGTAAACTGAACAGGCTAGTGGAAAAGACCAATACCGAGTTCGAATCCATCGA



ATCTGAGTTCTCAGAGATAGAGCACCAGATCGGGAACGTTATCAACTGGACCAAGGACAGC



ATTACCGACATTTGGACCTACCAGGCAGAGCTCCTGGTCGCCATGGAAAATCAGCATACCA



TCGACATGGCCGATTCAGAGATGCTTAACCTTTATGAGCGGGTGAGGAAACAGCTGAGGCA



GAATGCAGAAGAAGATGGTAAGGGTTGCTTCGAAATTTACCATGCTTGTGATGATAGTTGT



ATGGAGAGTATCCGTAACAATACTTACGATCACAGCCAGTACAGGGAAGAAGCACTCCTCA



ATCGCCTCAACATCAATCCTGTAACTCTCTCGTCTGGTTACAAAGATATCATCTTATGGTT



CTCTTTTGGGGCCTCATGTTTCGTGCTCCTGGCCGTGGTGATGGGCCTGTTCTTTTTCTGC



TTAAAGAATGGAAATATGAGGTGCACAATCTGCATT





701
ATGTACAAGATAGTCGTTATCATCGCCTTACTCGGAGCAGTTAAAGGTTTAGATAAGATCT



GCCTGGGGCACCACGCCGTCGCTAACGGCACTATTGTGAAGACGCTGACCAATGAACAAGA



GGAAGTCACTAACGCAACAGAAACCGTGGAGAGCACTGGCATCAATCGCCTCTGTATGAAA



GGGCGCAAGCATAAGGACCTCGGCAATTGCCACCCTATAGGCATGCTGATTGGAACGCCTG



CTTGTGACCTTCACCTGACAGGGATGTGGGATACCCTAATTGAACGAGAGAACGCGATCGC



ATACTGCTATCCTGGTGCCACTGTGAACGTGGAAGCCTTACGCCAAAAAATCATGGAGAGC



GGAGGGATCAATAAAATCAGTACAGGTTTCACCTACGGATCCTCCATCAACAGTGCCGGTA



CTACACGCGCCTGTATGAGAAACGGAGGCAACAGCTTCTATGCTGAGCTGAAATGGTTAGT



GAGCAAATCCAAAGGTCAGAATTTTCCCCAGACCACAAATACTTACCGAAATACGGACACC



GCCGAGCATCTGATAATGTGGGGCATCCACCATCCTAGTTCTACTCAGGAGAAAAACGACC



TTTATGGAACGCAGAGCCTGTCTATAAGCGTGGGGTCTTCAACATACAGGAATAACTTTGT



CCCTGTAGTGGGCGCCGGTCCTCAGGTGAATGGGCAAAGCGGCCGCATCGATTTTCACTGG



ACCCTGGTTCAACCTGGAGACAATATTACGTTCAGTCACAACGGCGGCCTTATTGCCCCTT



CCAGAGTCTCTAAGCTCATTGGCAGGGGACTCGGTATCCAATCCGACGCCCCTATTGACAA



CAACTGCGAGTCCAAATGCTTCTGGAGGGGAGGAAGCATCAACACCCGCCTGCCATTTCAG



AATCTTTCACCTCGAACCGTGGGCCAGTGTCCTAAATACGTCAATCGGAGAAGCTTGATGT



TGGCCACTGGGATGCGGAACGTACCCGAGCTTATCCAAGGCAGAGGCCTTTTCGGTGCCAT



CGCAGGGTTCTTGGAAAATGGCTGGGAAGGCATGGTCGATGGCTGGTATGGCTTTCGCCAT



CAAAATGCTCAGGGCACGGGCCAGGCCGCTGACTACAAAAGTACACAAGCTGCCATCGATC



AGATTACAGGCAAGCTCAATAGGTTGGTGGAGAAGACAAACACCGAGTTTGAGTCAATCGA



GAGCGAGTTTAGCGAGATAGAGCATCAGATCGGCAACGTGATTAACTGGACTAAGGACTCT



ATAACAGACATTTGGACGTACCAGGCAGAGCTCCTTGTAGCAATGGAAAATCAGCACACAA



TTGACATGGCTGACTCTGAAATGCTCAACCTGTATGAGCGGGTTCGGAAGCAGCTGAGGCA



GAATGCAGAGGAAGATGGTAAGGGCTGCTTTGAAATCTACCATGCCTGTGATGACAGTTGC



ATGGAGAGTATTCGAAATAACACATACGATCATTCGCAGTACAGAGAGGAAGCCTTGTTGA



ACCGCCTGAATATCAACCCCGTGACATTATCCTCAGGCTATAAAGACATCATCCTCTGGTT



TTCGTTTGGGGCCTCGTGCTTTGTCTTGCTGGCTGTTGTCATGGGGCTGTTTTTCTTTTGT



TTAAAGAACGGGAACATGCGATGCACAATCTGTATT





702
ATGTACAAGATTGTGCTGGTACTTGCACTTCTGGGTGCCGTTCACGGCCTCGACAAAATCT



GCCTAGGCCACCACGCTGTGCCTAACGGGACCATTGTGAAAACCCTGACTAACGAGAAGGA



GGAGGTTACCAACGCAACCGAGACTGTAGAGTCTAAGTCCTTGGATAAACTGTGCATGAAG



AACCGAAACTACAAAGACCTGGGCAATTGCCATCCTATCGGGATGGTCGTCGGAACTCCAG



CCTGCGATCTCCACCTAACTGGCACCTGGGACACCCTCATCGAGAGGGACAATTCAATTGC



ATACTGCTATCCTGGGGCTACCGTGAGTGAAGAAGCACTGCGACAAAAAATCATGGAGTCA



GGAGGGATCGACAAAATATCGACGGGATTCACATACGGCTCATCTATTAATTCAGCAGGAA



CCACGAAAGCTTGTATGCGCAACGGAGGTAACTCCTTCTATAGCGAACTCAAGTGGTTAGT



GTCTAAGAATAAGGGACAGAACTTTCCACAGACAACAAACACTTACCGGAACACAGACAGC



GTAGAACACCTCATAATATGGGGGATCCACCACCCAAGCTCCACACAGGAGAAGAACGATT



TATACGGCACTCAGTCCCTGAGCATCAGCGTCGGATCAAGCACCTACCAGAACAACTTCGT



CCCCGTGGTGGGAGCTCGCCCACAGGTGAATGGCCAGAGCGGACGCATCGATTTCCACTGG



ACTATGGTCCAGCCGGGTGACAACATCACCTTCTCTCACAATGGGGGGCTGATTGCTCCGA



ACCGAGTGTCCAAGCTGAAAGGGAGGGGGTTAGGAATCCAGAGCGGCGCCTCGGTAGACAA



CGACTGCGAGAGCAAATGTTTCTGGAAAGGTGGCTCGATTAATACCAAGCTTCCATTTCAG



AATTTATCTCCTAGAACTGTCGGCCAGTGTCCAAAATACGTCAACAAAAAGTCTCTGCTCC



TCGCAACAGGCATGCGGAATGTTCCCGAAGTTGCACAGGGCCGAGGCCTGTTTGGTGCCAT



TGCCGGGTTTATCGAGAACGGATGGGAGGGCATGGTGGATGGATGGTACGGATTCCGACAC



CAGAATGCGCAGGGGACGGGCCAAGCAGCGGATTACAAGTCCACACAAGCAGCAATTGACC



AAATCACTGGCAAGTTGAATCGCCTCATAGAGAAAACTAATACAGAGTTCGAATCTATCGA



AAGTGAGTTTTCCGAGATCGAACACCAGATCGGGAATGTGATCAACTGGACGAAGGATTCT



ATTACTGACATATGGACCTACCAGGCCGAGCTCCTGGTGGCTATGGAAAACCAACATACAA



TTGACATGGCTGACTCTGAAATGCTGAATCTGTACGAACGAGTGAGGAAGCAGCTCCGCCA



AAACGCAGAGGAAGACGGAAAGGGTTGTTTTGAGATATATCACAAGTGCGACGACAACTGC



ATGGAGTCCATCCGAAACAATACTTACGACCATACACAATACAGAGAGGAGGCCCTGCTGA



ACCGCCTGAATATCAATCCCGTGAAGCTCAGTTCCGGTTACAAGGACGTCATTTTATGGTT



CAGCTTTGGAGCGTCCTGCTTCGTGCTTCTGGCCGTCATCATGGGCCTTGTCTTCTTTTGT



CTGAAAAACGGTAATATGAGATGCACCATCTGCATT





703
ATGTATAAAATTGTCGTGATCATCGCCCTGCTCGGGGCCGTCAAGGGATTGGATAAGATAT



GTCTCGGTCATCATGCAGTGGCTAACGGCACGATCGTGAAGACCCTGACCAACGAGCAGGA



GGAAGTGACTAATGCCACCGAAACCGTTGAGTCTACTGGTATCAATAGGCTGTGCATGAAA



GGGAGAAAGCACAAGGACCTCGGCAATTGTCACCCAATCGGGATGCTCATTGGGACACCCG



CATGTGACCTCCACCTGACAGGCATGTGGGATACACTGATTGAGCGCGAAAATGCCATCGC



GTACTGCTACCCTGGCGCCACCGTGAATGTGGAAGCTCTGCGACAGAAAATAATGGAGAGT



GGGGGGATTAATAAGATCTCTACAGGGTTTACGTACGGATCAAGTATTAACTCCGCCGGGA



CTACTCGAGCATGTATGCGCAATGGCGGCAATTCCTTTTACGCCGAGCTGAAGTGGCTTGT



GTCGAAGTCAAAAGGACAGAATTTTCCCCAGACAACAAACACATATCGCAATACCGATACT



GCAGAACACTTGATTATGTGGGGGATTCACCACCCGTCATCTACTCAGGAGAAGAACGATC



TGTATGGCACTCAGAGCCTGAGTATCTCAGTAGGCAGCAGCACCTACAGAAATAACTTCGT



GCCGGTTGTCGGGGCCCGCCCACAAGTGAATGGCCAGTCAGGGCGGATCGACTTTCACTGG



ACGCTGGTTCAGCCTGGAGATAACATTACGTTTAGTCACAATGGCGGGCTCATCGCGCCAA



GTCGGGTATCCAAACTGATCGGCCGAGGACTTGGGATACAATCGGACGCCCCCATCGATAA



CAATTGCGAATCCAAATGTTTTTGGAGAGGAGGATCCATAAATACACGACTGCCCTTTCAG



AACCTGTCTCCTCGGACAGTTGGGCAGTGTCCAAAGTACGTAAACCGGAGGTCTCTCATGC



TCGCGACAGGAATGCGTAATGTGCCAGAACTGATTCAGGGCCGCGGCCTCTTCGGTGCGAT



CGCGGGGTTCCTCGAGAATGGTTGGGAAGGCATGGTGGACGGGTGGTATGGTTTTCGTCAT



CAGAACGCTCAAGGCACTGGGCAGGCCGCCGATTACAAGTCCACGCAGGCGGCAATTGACC



AAATCACCGGGAAGTTAAACCGGCTTGTCGAGAAAACCAATACCGAGTTTGAATCCATAGA



GTCCGAGTTTTCCGAGATCGAGCACCAAATCGGAAACGTTATAAATTGGACCAAGGACTCT



ATCACCGACATCTGGACCTACCAGGCCGAACTCCTGGTCGCCATGGAAAATCAGCACACAA



TAGACATGGCAGATTCAGAGATGCTGAACCTGTACGAGCGGGTGCGTAAGCAGCTCCGGCA



GAATGCGGAAGAGGACGGCAAGGGATGTTTCGAAATATACCACGCTTGTGATGATTCATGT



ATGGAGTCGATCAGGAACAATACATACGACCATTCCCAGTACAGGGAAGAGGCCCTCCTGA



ACAGGCTTAACATCAACCCCGTCACCCTGTCCAGCGGCTACAAGGATATTATCCTTTGGTT



TTCATTCGGCGCAAGCTGCTTCGTCTTACTGGCCGTGGTAATGGGACTATTCTTTTTTTGC



CTGAAAAACGGCAACATGAGGTGTACCATTTGTATT





704
ATGTACAAAATCGTGCTCGTTCTGGCCCTGCTCGGCGCCGTGCACGGCCTCGACAAGATTT



GCCTGGGACATCACGCTGTGCCCAACGGTACTATTGTCAAGACACTGACGAACGAAAAAGA



AGAGGTTACAAACGCTACCGAAACCGTTGAATCTAAGAGCTTGGATAAACTGTGCATGAAA



AATCGCAACTATAAAGACCTCGGTAATTGTCACCCTATAGGGATGGTGGTCGGCACCCCAG



CTTGCGACCTGCATTTGACAGGTACTTGGGATACTTTGATCGAACGGGATAACAGTATCGC



CTACTGTTATCCGGGAGCCACGGTGTCGGAAGAGGCTCTGCGTCAGAAAATCATGGAGAGC



GGCGGGATAGACAAGATCTCCACTGGCTTCACTTATGGCTCCAGCATTAATAGCGCAGGTA



CAACCAAGGCTTGCATGAGAAATGGGGGGAACTCCTTCTACTCAGAACTGAAATGGCTGGT



GTCCAAAAATAAGGGACAGAATTTCCCGCAGACGACAAACACCTATAGAAACACAGACTCT



GTAGAGCACCTCATTATTTGGGGTATCCATCACCCAAGCTCCACCCAGGAAAAGAATGACC



TGTACGGCACACAGTCCTTGAGCATTTCAGTGGGCAGCTCCACATATCAGAATAACTTTGT



GCCAGTCGTTGGCGCACGACCCCAGGTGAATGGGCAGTCAGGTCGCATTGACTTCCACTGG



ACTATGGTGCAGCCCGGCGATAACATTACCTTCTCCCATAACGGGGGACTGATAGCCCCCA



ATAGGGTCTCTAAGCTCAAGGGTCGGGGTTTGGGCATCCAGTCCGGAGCATCCGTCGATAA



CGACTGTGAGTCGAAATGCTTTTGGAAAGGTGGATCCATCAATACAAAGCTACCTTTCCAA



AATTTATCCCCTCGAACGGTCGGACAGTGCCCTAAATACGTAAACAAGAAGTCACTGCTCC



TCGCTACCGGCATGCGCAATGTACCTGAAGTTGCCCAAGGACGGGGGCTTTTCGGCGCAAT



CGCTGGCTTCATTGAGAATGGATGGGAGGGCATGGTTGACGGCTGGTACGGCTTTAGGCAC



CAGAATGCTCAGGGTACCGGTCAGGCAGCAGATTATAAAAGCACCCAGGCTGCCATCGATC



AGATAACCGGGAAGTTGAACAGGCTGATCGAGAAGACCAACACTGAGTTTGAGAGCATTGA



ATCGGAGTTCTCGGAAATCGAACATCAAATCGGCAATGTGATCAATTGGACTAAGGATTCT



ATCACCGACATCTGGACGTACCAGGCAGAACTGTTAGTTGCAATGGAAAATCAGCATACTA



TTGATATGGCAGACAGTGAGATGCTGAACCTGTACGAGCGTGTTAGAAAGCAGCTCAGACA



GAACGCCGAGGAGGACGGGAAAGGATGCTTTGAAATCTATCACAAATGTGATGATAATTGC



ATGGAGTCAATCAGGAATAATACATACGATCACACGCAATACAGAGAGGAGGCTCTCCTGA



ACCGCCTTAATATCAACCCCGTGAAACTCAGCTCCGGATATAAAGACGTCATCCTCTGGTT



TTCTTTTGGAGCAAGCTGCTTCGTGCTGCTCGCCGTTATCATGGGGTTGGTGTTCTTCTGC



CTGAAGAATGGTAACATGAGATGCACCATTTGTATA





705
ATGTACAAGATTGTGCTCGTTCTGGCACTATTGGGCGCAGTGCATGGTCTGGATAAAATCT



GTCTGGGTCATCACGCAGTGCCCAACGGTACTATCGTCAAAACACTAACGAACGAGAAGGA



AGAAGTAACTAATGCAACGGAGACAGTGGAGTCAAAAAGTCTGGACAAGTTATGTATGAAG



AACAGAAACTATAAGGATCTCGGTAATTGCCACCCCATCGGTATGGTGGTTGGGACCCCAG



CCTGCGACCTTCACCTGACGGGAACCTGGGACACCCTCATCGAGCGGGACAACTCCATTGC



CTATTGCTATCCTGGGGCCACCGTCTCCGAGGAGGCACTGAGGCAGAAAATTATGGAATCC



GGCGGGATTGACAAGATTTCTACCGGCTTTACCTATGGCTCCTCAATCAACAGCGCTGGGA



CAACTAAAGCCTGCATGAGGAACGGAGGAAATTCTTTTTACTCTGAGTTGAAGTGGTTGGT



GAGCAAAAATAAGGGCCAAAATTTTCCTCAGACGACCAATACCTACCGTAATACTGACTCA



GTTGAGCACCTCATCATTTGGGGAATTCATCATCCCAGCAGCACTCAGGAGAAGAATGATC



TGTACGGGACCCAATCGTTGAGTATATCCGTGGGATCTAGTACTTATCAGAACAACTTTGT



ACCTGTAGTGGGTGCCCGCCCACAGGTAAACGGACAGTCGGGGCGTATTGACTTTCATTGG



ACAATGGTGCAGCCCGGGGATAATATCACTTTTAGCCATAATGGAGGCCTGATCGCACCAA



ACCGAGTGAGCAAGCTGAAGGGTAGAGGATTGGGAATCCAGTCTGGAGCCAGCGTTGATAA



CGACTGTGAGTCTAAATGCTTCTGGAAAGGGGGTAGCATAAATACCAAGCTGCCCTTCCAA



AACCTGAGCCCTCGGACCGTGGGCCAGTGCCCAAAGTACGTGAATAAGAAAAGCCTCCTGC



TCGCTACAGGCATGAGAAATGTGCCCGAGGTTGCACAGGGCAGAGGGCTCTTCGGCGCTAT



AGCTGGATTCATTGAAAATGGCTGGGAAGGTATGGTAGATGGTTGGTACGGCTTCAGACAC



CAGAATGCTCAGGGAACCGGACAGGCTGCTGATTATAAATCTACCCAGGCTGCTATCGATC



AGATCACTGGGAAATTGAACCGGCTGATCGAAAAAACAAACACCGAATTCGAGAGTATTGA



ATCCGAGTTTAGCGAAATTGAACATCAGATCGGCAATGTGATAAACTGGACTAAGGATAGT



ATAACTGACATCTGGACATACCAAGCTGAGCTCCTGGTGGCCATGGAGAATCAACACACGA



TCGACATGGCAGACTCTGAAATGTTGAACCTGTACGAGAGGGTGCGGAAGCAGCTCAGACA



AAACGCTGAGGAGGACGGCAAAGGTTGCTTCGAAATCTACCATAAGTGCGACGATAACTGT



ATGGAGAGTATTAGAAACAATACCTACGACCACACGCAGTATAGGGAGGAGGCTCTGTTGA



ATAGGTTAAATATCAACCCTGTGAAACTATCCAGCGGCTATAAGGACGTGATTTTATGGTT



CTCGTTTGGTGCCAGCTGTTTTGTCCTACTGGCAGTGATCATGGGTCTTGTTTTTTTTTGC



CTGAAGAACGGCAACATGAGATGCACGATATGTATT





706
ATGTACAAGATCGTTGTGATTATCGCCCTGCTCGGCGCCGTCAAAGGATTAGACAAGATCT



GTCTAGGCCATCACGCCGTTGCGAACGGAACCATCGTGAAGACCCTGACAAATGAGCAGGA



AGAAGTTACCAATGCCACTGAGACCGTAGAAAGCACCGGGATCAACAGACTATGTATGAAA



GGCCGCAAGCATAAGGATCTGGGAAACTGCCATCCTATCGGAATGCTCATTGGAACTCCCG



CCTGTGACCTGCACCTGACCGGCATGTGGGACACACTGATTGAGCGGGAGAACGCCATCGC



TTACTGTTATCCTGGTGCAACTGTGAACGTCGAAGCTTTGCGGCAGAAAATAATGGAATCG



GGGGGGATTAATAAAATAAGTACCGGATTCACATATGGAAGCTCAATTAACTCCGCAGGAA



CTACAAGAGCATGTATGCGAAACGGCGGCAACTCATTCTACGCTGAACTTAAGTGGCTGGT



GTCTAAGTCAAAGGGGCAGAACTTTCCGCAAACCACTAATACATATCGCAATACAGACACA



GCCGAGCACCTCATCATGTGGGGAATTCACCACCCAAGTAGTACCCAGGAGAAGAACGACC



TGTACGGCACTCAGTCGCTTAGCATAAGTGTTGGCTCATCGACTTATCGGAATAACTTCGT



CCCAGTGGTTGGTGCTCGTCCCCAAGTGAATGGTCAGTCCGGCAGAATTGATTTTCATTGG



ACACTGGTGCAACCCGGTGACAACATCACTTTTAGCCATAATGGTGGTCTAATCGCCCCGT



CCCGGGTGTCCAAGTTAATTGGGAGAGGTCTGGGTATCCAGAGTGATGCTCCAATCGATAA



TAATTGCGAGAGTAAGTGCTTCTGGCGCGGCGGAAGTATCAACACCCGGCTCCCTTTCCAG



AATCTATCACCTAGAACTGTTGGGCAGTGCCCTAAATATGTTAATCGCCGCTCACTTATGC



TGGCAACCGGGATGCGAAACGTTCCAGAACTGATCCAAGGGGGGGGGCTTTTCGGGGCTAT



TGCCGGGTTTTTGGAGAACGGCTGGGAAGGGATGGTCGATGGTTGGTATGGCTTCCGCCAT



CAGAATGCACAGGGTACCGGCCAGGCCGCCGACTACAAGTCAACGCAGGCTGCAATTGACC



AAATCACTGGGAAACTGAACCGGCTCGTTGAAAAGACTAACACTGAGTTTGAAAGCATAGA



AAGTGAATTCAGTGAAATTGAGCATCAAATCGGCAACGTGATCAATTGGACCAAGGACTCA



ATCACGGATATCTGGACATACCAGGCCGAGCTGCTCGTTGCGATGGAGAACCAACACACCA



TCGATATGGCAGACTCTGAGATGCTAAATCTCTACGAAAGAGTGAGAAAGCAGTTGCGACA



AAATGCGGAGGAGGATGGTAAGGGTTGCTTCGAAATTTACCATGCCTGCGACGACAGTTGC



ATGGAATCCATTAGGAACAATACCTACGATCATTCGCAGTATAGGGAGGAGGCCCTCTTAA



ACCGCCTGAACATCAACCCAGTAACCTTGAGCAGCGGGTATAAAGATATAATCCTGTGGTT



TAGCTTCGGTGCCTCCTGCTTTGTTCTGCTGGCCGTAGTCATGGGTCTGTTTTTTTTCTGC



CTGAAGAATGGTAATATGCGCTGCACCATTTGCATT





707
ATGTACAAGATCATTGTAATCATCGCCTTGTTGGGAGCCGTCAAAGGGCTCGATAAAATTT



GCTTGGGCCATCATGCAGTCGCCAACGGGACAATAGTCAAGACGCTCACGAATGAACAGGA



GGAAGTGACAAACGCCACAGAAACCGTTGAAAGTACAGGGATTAATAGGCTGTGTATGAAA



GGGCGCAAACATAAGGATTTGGGCAATTGTCACCCAATAGGGATGCTTATTGGGACACCAG



CTTGTGATCTCCATCTCACTGGAACATGGGACACCCTAATCGAGCGCGAAAACGCTATTGC



ATATTGCTATCCGGGAGCGACGGTTAACGTGGAGGCACTCCGACAGAAAATCATGGAGAGC



GGGGGGATCGACAAGATTTCCACAGGCTTTACTTACGGCTCTAGTATAAATTCCGCCGGGA



CCACAAGGGCCTGTATGAGAAACGGTGGCAACAGTTTTTACGCTGAGTTAAAATGGCTCGT



TAGCAAGAGCAAGGGTCAGAACTTTCCGCAGACCACAAACACATACCGGAACACCGATACA



GCAGAGCATCTAATCATGTGGGGCATACATCATCCTTCCAGTACCCAGGAGAAGAACGATT



TATACGGGACCCAATCCCTGAGCATCAGCGTTGGGTCATCTACTTACCGCAATAATTTTGT



CCCGGTTGTGGGAGCAAGGCCCCAAGTGAATGGTCAGAGTGGCAGGATTGACTTTCACTGG



ACACTGGTGCAACCTGGTGACAACATTACCTTCAGCCATAACGGAGGACTGATCGCGCCTT



CACGGGTGAGCAAGCTTATTGGTAGAGGACTCGGGATCCAAAGTGATGCCCCAATCGACAA



TAACTGTGAGAGCAAATGCTTTTGGCGAGGGGGATCCATCAATACACGCCTCCCCTTTCAA



AACCTGAGCCCACGCACTGTGGGGCAATGCCCTAAGTACGTAAACCGCAGGTCTCTAATGC



TTGCAACCGGGATGAGAAACGTTCCAGAATTAATTCAGGGACGGGGACTGTTTGGGGCGAT



CGCCGGCTTTCTGGAAAATGGCTGGGAAGGGATGGTGGATGGCTGGTATGGCTTCCGGCAC



CAAAATGCCCAGGGCACAGGGCAGGCTGCAGATTACAAATCAACTCAGGCTGCCATCGACC



AAATCACAGGCAAGCTGAATAGGCTCGTGGAGAAAACGAACACGGAATTCGAGTCTATTGA



ATCTGAGTTCTCCGAAATCGAGCACCAGATCGGGAATGTAATTAACTGGACCAAGGACTCA



ATCACTGACATTTGGACCTATCAGGCAGAATTACTGGTAGCGATGGAGAACCAACACACAA



TTGACATGGCAGATTCTGAAATGCTCAACCTCTATGAACGAGTGAGGAAACAGCTCCGGCA



GAACGCCGAGGAGGATGGAAAGGGATGTTTCGAGATCTATCACGCATGTGACGATAGCTGT



ATGGAATCTATACGGAATAACACATACGATCATTCTCAATATCGGGAGGAGGCTCTGCTTA



ACCGACTCAACATAAACCCAGTCACTCTATCCAGTGGCTACAAGGATATTATCCTGTGGTT



TAGCTTTGGCGCCTCGTGCTTCGTGCTTCTCGCTGTTGTCATGGGCCTGTTCTTCTTCTGT



CTGAAGAACGGGAATATGCGGTGCACCATTTGCATC





708
ATGTATAAAATCGTGGTTATTATCGCATTGCTGGGTGCTGTGAAAGGCCTCGATAAAATTT



GCCTCGGGCATCACGCCGTGGCCAACGGCACAATTGTGAAGACACTGACAAACGAACAGGA



AGAAGTTACCAACGCTACTGAGACCGTGGAATCCACAGGTATTAATAGGCTTTGTATGAAG



GGTCGGAAGCACAAAGACCTGGGGAATTGCCACCCTATCGGAATGCTCATTGGAACTCCGG



CCTGTGACCTGCACCTCACAGGTATGTGGGATACTCTGATTGAGCGAGAGAACGCGATTGC



CTACTGTTACCCGGGAGCAACCGTGAACGTGGAGGCGCTCCGGCAGAAGATCATGGAGTCT



GGCGGCATTAACAAGATCAGTACCGGGTTCACATATGGAAGTTCAATCAATAGTGCCGGCA



CTACCAGGGCATGTATGCGCAACGGAGGAAATAGCTTCTACGCGGAATTGAAATGGTTAGT



CAGCAAGAGCAAGGGACAGAACTTTCCTCAGACTACGAACACTTACCGTAATACTGATACT



GCCGAACATCTAATTATGTGGGGGATCCATCACCCATCCAGCACCCAGGAAAAGAACGATT



TGTACGGCACCCAGTCTTTATCTATTTCCGTGGGGAGTTCGACATATAGAAATAACTTTGT



GCCCGTTGTCGGTGCTGGGCCCCAAGTTAACGGCCAATCGGGACGTATCGATTTCCACTGG



ACACTGGTTCAGCCAGGGGACAATATCACCTTTTCTCACAACGGAGGTCTTATAGCTCCAT



CTCGTGTGTCTAAACTCATTGGACGGGGGCTTGGGATCCAAAGCGATGCCCCCATCGACAA



TAATTGCGAAAGTAAGTGCTTCTGGCGGGGAGGTTCTATTAATACTAGGCTTCCTTTCCAG



AACCTCTCACCACGAACAGTCGGCCAATGCCCCAAGTACGTTAATCGACGTTCACTCATGC



TGGCCACGGGAATGCGCAACGTGCCCGAGCTTATCCAGGGGCGCGGATTGTTCGGCGCCAT



CGCTGGCTTCTTGGAGAACGGTTGGGAGGGTATGGTCGATGGGTGGTACGGCTTTCGCCAC



CAAAACGCTCAAGGGACAGGACAGGCCGCCGATTATAAGAGCACTCAGGCCGCCATAGATC



AGATTACGGGCAAGCTAAACAGGCTGGTCGAGAAAACCAATACGGAATTCGAGTCCATTGA



ATCAGAGTTCTCTGAGATCGAGCACCAGATCGGCAACGTAATCAACTGGACCAAAGATTCT



ATCACCGATATTTGGACATATCAGGCAGAACTACTGGTCGCCATGGAAAACCAGCATACCA



TCGATATGGCGGACAGTGAGATGCTTAATCTCTACGAAAGAGTACGAAAGCAGCTGCGACA



AAACGCCGAGGAAGACGGTAAAGGCTGCTTCGAAATTTATCACGCGTGCGACGACTCTTGT



ATGGAATCTATACGAAACAACACATACGATCACTCCCAATACCGGGAGGAGGCTCTCCTCA



ATAGACTGAATATCAACCCAGTCACTTTGAGTAGTGGGTATAAGGACATTATTCTTTGGTT



CTCCTTCGGGGCTTCTTGTTTTGTCCTTCTGGCAGTGGTTATGGGGCTCTTCTTTTTTTGC



CTCAAGAACGGCAACATGCGCTGTACTATATGTATT





709
ATGTATAAAGTCGTTGTGATCATCGCTTTGTTGGGAGCTGTCCGGGGTTTGGATAAGATCT



GCCTCGGCCATCACGCAGTAGCAAATGGAACCACTGTGAAGACCCTAACTAACGAACAAGA



GGAAGTCACAAATGCCACTGAGACTGTCGAGTCTACTAGCCTGAATAAACTGTGCATGAAG



GGGAGGAGGTACAAAGATCTTGGAAATTGCCACCCAATCGGAATGCTGATAGGCACCCCTG



TGTGTGATCTCCATCTGACCGGAACATGGGATACCCTGATTGAGAGAGAGAATGCTACTGC



ATACTGCTACCCTGGAGTCACTATCAATGAAGAGGCCCTGCGTCAAAAGATCATGGAGTCC



GGGGGTATTTCTAAGATGCGCACCGGCTTTACCTACGGACCATCTATCAATTCGGCAGGTA



CTACCCGGTCATGTATGCGCAATGGAGGCAACTCCTTCTATGCCGAACTGAAGTGGCTGGT



CTCGGGCACTAAGGGTCAGAACTTCCCGCAGACTACTAATACATACCGAAATACCGACACT



GCCGAGCACCTGATTATCTGGGGAATTCACCATCCCTCGTCCACTCAAGAGAAGAATGACC



TTTATGGCACACAGAGCCTCTCGATCAGCGTGGGCTCCTCGACTTACCAGAATAACTTTGT



CCCGGTAATTGGCGCTAGGCCTCAGGTGAACGGCCAGTCCGGCAGAATCGAGTTCCATTGG



ACTCTGGTGCGCCCAGGCGACAATATCACATTCAGCCATAATGGGGGTCTGATCGCACCTG



ACCGAGTTAGTAAACTGATTGGCAAGGGGATCGGGATCCAATCAGGGGCTGTGATCGACAA



AGACTGTGAGTCAAAGTGCTTCTGGAGGGGCGGAAGCATAATTACGGAGCTGCCTTTTCAG



AACCTGAGCCCAAGAACTGTTGGACAATGCCCTAAGTACGTTAAGAAGCGATCTCTCTTGT



TGGCCACTGGAATGAGGAACGTGCCGGAAGTGGTTCAGGGGCGCGGCCTCTTCGGGGCTAT



AGCCGGATTCATAGAAAACGGCTGGGAGGGGATGGTGGATGGCTGGTACGGCTTCAGACAC



CAAAATGCGCAGGGCATCGGCCAGGCTGCTGATTACAAGTCTACCCAAACTGCGATTGATC



AGATCACCGGAAAACTGAATCGACTGATCGAAAAAACTAACACTGAGTTCGAAAGCATCGA



AAGTGAATTTAGCGAGATTGAACATCAGATCGGCAATGTCATAAATTGGACCAAGGATTCC



ATTACAGATATTTGGACATACCAGGCCGAGCTCCTCGTGGCAATGGAAAATCAGCATACTA



TTGATATGGCCGATTCGGAAATGCTGAACCTCTACGAACGTGTCCGGAAACAGCTGCGCCA



GAACGCTGAGGAGGACGGAAAGGGATGCTTTGAGATTTACCACACCTGCGACAATTCTTGT



ATGGAGAGTATACGCAATAATACATATGACCATTCACAATACCGCGAAGAAGCCCTTCTGA



ATCGTCTCAATATCAATCCCGTCAAACTGTCCTCAGGGTATAAAGACATTATCCTATGGTT



CAGTTTTGGTGCCAGCTGCTTTGTGCTGCTGGCTGTCATCATGGGGCTGGGCTTTTTTTGT



CTAAAAAACGGAAACATGCGGTGCACGATCTGCATT





710
ATGTATAAGATCGTAGTGATCATTGCGCTGCTTGGCGCTGTCAAGGGCCTAGATAAGATAT



GTCTCGGACACCATGCTGTTGCCAATGGGACAATTGTGAAGACTCTAACTAACGAACAGGA



AGAAGTTACGAATGCTACAGAAACTGTGGAGTCCACTGGAATCAATAGACTCTGTATGAAA



GGCCGGAAACACAAGGATCTGGGCAACTGCCACCCCATTGGTATGCTTATAGGAACACCTG



CGTGCGATCTGCACCTCACTGGAATGTGGGATACCCTCATCGAGCGGGAGAACGCAATCGC



GTACTGTTACCCCGGAGCTACGGTTAACGTCGAAGCTCTTCGGCAGAAGATCATGGAATCC



GGGGGGATCAATAAGATCTCTACTGGATTCACATATGGGTCTTCAATTAACTCCGCTGGGA



CGACCCGTGCCTGCATGAGGAACGGCGGTAACTCTTTCTATGCTGAGCTGAAGTGGCTGGT



CAGTAAAAGTAAAGGACAGAACTTTCCGCAGACCACCAACACGTATCGGAACACTGATACA



GCAGAGCACCTTATCATGTGGGGAATCCACCATCCCTCTTCTACACAAGAAAAGAATGACC



TGTACGGCACTCAGAGCCTTTCAATCTCAGTGGGCAGTTCCACCTATCGAAACAACTTCGT



GCCCGTGGTTGGAGCACGCCCACAGGTGAACGGCCAATCCGGGCGCATTGATTTTCATTGG



ACCCTGGTTCAGCCAGGGGATAACATAACTTTCAGTCATAATGGTGGGCTCATCGCACCAA



GCCGTGTTTCCAAGTTAATCGGCCGGGGGCTGGGCATCCAGAGCGACGCTCCTATCGACAA



TAACTGCGAAAGTAAATGCTTCTGGCGCGGAGGTAGCATCAACACCCGACTACCCTTCCAG



AATCTTAGCCCACGAACCGTGGGACAATGCCCAAAATACGTCAACCGCAGGTCTCTTATGC



TAGCTACCGGTATGCGTAATGTCCCTGAGCTGATTCAGGGCCGCGGGCTTTTTGGGGCCAT



TGCAGGATTTCTTGAGAATGGATGGGAAGGTATGGTTGACGGATGGTATGGCTTTAGACAC



CAGAACGCGCAGGGCACTGGTCAAGCTGCAGATTACAAGTCCACACAGGCTGCTATAGACC



AGATAACAGGCAAGCTGAATAGATTAGTGGAGAAAACCAACACAGAATTCGAGAGTATTGA



GTCTGAATTTAGCGAGATTGAGCATCAGATTGGGAACGTGATCAATTGGACTAAAGACAGC



ATCACGGACATCTGGACATACCAGGCTGAACTTTTGGTGGCCATGGAGAATCAGCACACAA



TCGATATGGCAGACTCAGAGATGCTCAATTTGTATGAACGGGTGAGAAAGCAATTACGCCA



GAACGCGGAAGAGGATGGCAAAGGCTGCTTTGAGATATACCACGCATGTGACGACTCATGC



ATGGAATCCATCAGGAACAACACCTATGACCATTCCCAGTACCGGGAGGAAGCTCTGTTGA



ACCGCCTCAACATAAACCCGGTGACACTGTCTAGCGGTTATAAAGATATCATCCTTTGGTT



CTCATTCGGGGCGTCTTGTTTTGTTCTCCTTGCAGTGGTTATGGGCCTATTCTTCTTCTGC



CTGAAGAATGGAAATATGAGATGTACAATCTGTATC





711
ATGTATAAAGTTGTTGTTATCATAGCGCTGCTAGGCGCTGTCAAGGGGTTAGACAAAATTT



GTCTGGGCCATCACGCAGTGGCTAACGGCACAATAGTTAAGACATTGACCAATGAACAGGA



GGAGGTTACAAATGCAACCGAGACCGTGGAATCAACCGGCATTAATAGACTATGTATGAAG



GGCCGGAAGCATAAGGATCTGGGGAACTGCCATCCAATCGGTATGCTGATCGGCACGCCAG



CTTGCGATTTGCACCTAACGGGAACCTGGGACACTTTAATCGAGAGGGAGAATGCTATAGC



TTATTGCTACCCCGGCGCTACCGTTAATGTTGAGGCACTTCGGCAGAAGATCATGGAAAGC



GGGGGGATCGATAAAATCAGCACAGGATTCACCTACGGGAGTTCTATCAACTCTGCCGGGA



CTACACGTGCATGTATGAGAAACGGCGGTAATTCCTTCTATGCCGAGCTCAAATGGCTTGT



TTCCAAGAATAAGGGCCAGAACTTCCCACAGACCACTAATACTTACAGGAATACCGACACT



GCGGAGCACCTCATTATGTGGGGCATACATCACCCTTCTTCGATCCAAGAAAAGAATGACC



TCTATGGTACTCAGTCCCTCAGCATATCTGTGGGGAGCAGTACTTACCGGAATAATTTCGT



ACCCGTTGTGGGAGCACGCCCACAGGTGAACGGCCAGTCTGGTAGAATTGATTTCCATTGG



ACTTTGGTGCAGCCGGGGGATAACATCACCTTTTCCCATAACGGGGGACTGATCGCTCCAA



GCAGAGTTTCCAAACTTATTGGGAGAGGTTTAGGGATCCAGTCAGACGCCCCAATTGATAA



CAACTGTGAGTCGAAGTGCTTTTGGAGAGGGGGCAGCATCAATACGGGGCTGCCTTTCCAG



AACCTGTCACCCAGGACTGTCGGCCAGTGCCCAAAGTACGTGAACAGACGATCCTTGATGC



TTGCCACCGGAATGCGTAATGTGCCCGAGCTGATACAGGGCCGTGGACTTTTCGGAGCCAT



CGCGGGATTTCTGGAGAATGGTTGGGAAGGAATGGTCGACGGCTGGTATGGATTCCGCCAT



CAAAACGCCCAAGGAACAGGCCAGGCCGCTGACTATAAAAGCACGCAGGCTGCTATTGACC



AGATCACAGGTAAGCTGAACCGCCTGGTCGAAAAGACCAACACTGAATTTGAGTCCATCGA



GAGCGAGTTTAGCGAAATCGAACACCAAATCGGCAATGTAATCAACTGGACCATGGACAGC



ATAACCGATATTTGGACTTACCAGGCGGAATTACTGGTCGCCATGGAAAATCAGCACACAA



TCGATATGGCAGACAGCGAAATGTTGAACCTCTATGAGAGAGTCAGAAAACAATTGGGGCA



GAATGCTGAAGAGGATGGCAAAGGCTGCTTCGAAATCTATCACGCATGCGATGATAGTTGC



ATGGAATCAATTCGGAATAATACGTATGACCATAGCCAGTACAGGGAAGAGGCCCTTCTCA



ACCGACTTAATATCAATCCTGTGACACTTAGTTCTGGATATAAGGACATTATTCTCTGGTT



CTCTTTTGGAGCATCATGTTTTGTGCTGCTAGCCGTGGTGATGGGCCTGGTGTTCTTTTGT



CTCAAGAACGGTAACATGAGGTGTACTATATGCATC





712
ATGTATAAAATCGTGGTTATTATCGCCTTGCTAGGGGCCGTCAAAGGCCTGGACAAGATCT



GTTTGGGCCACCATGCTGTGGCAAATGGCACAATTGTTAAGACACTTACCAATGAGCAGGA



GGAAGTGACCAATGCTACCGAGACCGTCGAGTCTACCGGCATTAACAGGCTGTGTATGAAG



GGGCGGAAACACAAAGACCTGGGAAACTGCCACCCAATCGGAATGCTGATTGGGACTCCTG



CTTGCGACTTACACCTGACCGGAATGTGGGATACCCTCATAGAGAGAGAGAACGCGATAGC



CTACTGTTATCCTGGGGCGACCGTGAATGTTGAGGCCCTGAGACAGAAGATTATGGAATCT



GGGGGCATCAACAAAATTTCTACCGGATTTACATACGGCAGTTCCATCAACTCAGCCGGCA



CAACCCGCGCGTGTATGAGAAACGGGGGGAACAGCTTTTACGCCGAGCTGAAGTGGCTGGT



TTCCAAAAGCAAAGGGCAGAATTTTCCGCAGACTACGAATACCTACAGAAATACAGATACT



GCCGAACACCTCATAATGTGGGGCATCCATCATCCGTCCAGTACACAGGAGAAAAATGACT



TATATGGTACCCAGTCTTTATCAATTTCTGTAGGCTCCTCAACTTACCGTAACAATTTCGT



GCCCGTGGTCGGAGCTCGCCCGCAGGTGAACGGCCAGAGTGGGCGCATTGACTTTCATTGG



ACCCTCGTACAACCAGGCGACAACATCACTTTTTCTCATAATGGTGGTCTCATCGCCCCAA



GCCGAGTCTCTAAGCTGATTGGGGGGGGTCTTGGGATCCAATCAGATGCACCTATCGATAA



CAACTGCGAAAGTAAATGTTTTTGGCGTGGCGGTTCAATCAACACCCGGCTGCCGTTCCAG



AACCTGAGTCCAAGAACAGTTGGTCAGTGCCCCAAGTACGTAAACCGGAGGTCTTTGATGC



TGGCCACCGGAATGCGGAACGTGCCAGAACTGATCCAGGGCCGAGGCCTTTTCGGAGCCAT



TGCTGGCTTTCTCGAGAACGGTTGGGAAGGAATGGTAGATGGTTGGTACGGGTTCAGACAC



CAGAACGCCCAGGGCACCGGTCAGGCCGCTGATTATAAATCAACCCAGGCCGCTATAGACC



AAATCACCGGCAAGCTCAACAGACTCGTGGAAAAAACGAATACGGAGTTCGAGAGCATCGA



GTCAGAGTTTTCGGAAATCGAACACCAAATAGGGAATGTCATTAACTGGACTAAGGACAGC



ATCACCGACATTTGGACATATCAGGCAGAATTATTAGTGGCGATGGAGAATCAGCATACCA



TCGATATGGCAGACAGCGAAATGCTCAATCTGTACGAACGAGTACGCAAACAACTTCGCCA



AAACGCAGAGGAGGATGGGAAGGGCTGCTTCGAGATATACCATGCATGCGATGATTCTTGC



ATGGAGAGTATCCGTAACAATACATACGATCATTCCCAGTACCGAGAAGAGGCCCTGCTGA



ACCGGCTGAATATCAACCCAGTTACACTCTCATCTGGCTACAAGGATATTATCCTCTGGTT



CAGTTTTGGGGCATCTTGTTTCGTCCTGCTAGCTGTCGTCATGGGCCTGTTCTTTTTCTGT



CTCAAAAACGGCAATATGCGGTGTACCATATGCATC





713
ATGTATAAAATTGTGGTCATTATCGCCCTTCTTGGTGCCGTGAAGGGACTTGACAAAATCT



GCCTGGGCCACCACGCCGTCGCAAACGGTACTATTGTGAAAACTCTTACAAATGAGCAGGA



GGAAGTGACAAATGCTACCGAGACCGTTGAAAGCACAGGTATCAACAGACTTTGTATGAAG



GGACGCAAACACAAGGATCTCGGTAATTGTCATCCAATCGGTATGCTGATCGGCACTCCAG



CATGTGACCTCCACCTCACCGGCATGTGGGATACTCTAATTGAGAGAGAGAACGCGATCGC



TTACTGCTATCCCGGTGCGACTGTCAATGTGGAAGCCCTTCGACAGAAGATCATGGAGTCG



GGCGGCATTAACAAAATTTCTACAGGTTTCACCTATGGCAGCAGTATTAACTCTGCCGGAA



CAACAAGAGCCTGCATGAGGAACGGCGGAAACAGTTTCTACGCTGAACTTAAATGGTTGGT



CAGCAAGAGCAAAGGCCAGAATTTCCCGCAGACCACTAACACATATCGCAACACCGACACC



GCTGAGCACCTTATTATGTGGGGAATACACCACCCCTCCAGCACCCAGGAGAAGAACGACT



TGTACGGTACTCAGAGCCTCTCTATCTCCGTGGGATCCTCCACATACCGCAATAACTTTGT



CCCCGTGGTTGGTGCCCGCCCCCAGGTAAACGGACAGTCAGGCAGGATTGACTTCCACTGG



ACCCTGGTGCAACCCGGTGACAACATTACATTCAGCCATAACGGCGGCCTAATCGCTCCCT



CTCGCGTGAGTAAACTGATTGGACGGGGACTGGGGATTCAATCCGATGCTCCCATCGACAA



CAATTGCGAATCCAAGTGCTTTTGGCGAGGAGGGTCCATTAACACCAGGCTGCCGTTCCAA



AACTTGTCTCCCCGTACGGTGGGGCAGTGTCCCAAATACGTTAACCGCCGGTCCTTAATGC



TCGCTACAGGGATGAGAAATGTGCCCGAGCTGATCCAGGGTAGAGGCCTCTTCGGTGCCAT



TGCTGGATTCCTGGAGAATGGATGGGAGGGTATGGTCGACGGCTGGTACGGTTTTCGGCAT



CAAAATGCTCAGGGAACAGGACAGGCGGCCGATTATAAGAGCACCCAAGCTGCTATCGATC



AGATTACAGGAAAGCTGAATAGGCTGGTCGAGAAGACAAACACGGAGTTCGAAAGTATCGA



ATCAGAGTTTAGCGAGATTGAACATCAGATTGGCAATGTGATTAATTGGACCAAGGACTCA



ATTACCGATATCTGGACCTATCAGGCCGAGCTGCTTGTGGCCATGGAGAATCAGCATACAA



TCGATATGGCCGATTCAGAAATGCTGAACCTGTACGAGCGTGTGCGTAAACAGCTGCGCCA



GAATGCCGAGGAGGACGGAAAGGGGTGTTTTGAGATCTACCACGCGTGTGACGACTCATGT



ATGGAGAGTATCCGGAACAATACTTACGACCATTCACAGTATCGCGAAGAGGCATTATTAA



ACCGCCTTAATATCAACCCCGTGACACTCAGCAGCGGGTATAAGGACATCATTCTGTGGTT



CTCATTTGGGGCCTCCTGCTTCGTTCTGCTGGCCGTGGTGATGGGGTTATTCTTTTTTTGT



CTAAAGAACGGTAATATGAGGTGCACAATATGTATC





714
ATGTATAAGGTAGTAGTGATCATCGCCCTGCTGGGGGCCGTGAGAGGCCTTGATAAGATCT



GTTTGGGTCACCACGCCGTTGCAAACGGGACCACTGTTAAGACCCTTACCAATGAGCAGGA



GGAGGTGACGAATGCAACCGAGACCGTCGAGTCCACAAGTCTGAACAAGCTGTGTATGAAA



GGGAGGAGGTATAAAGATCTGGGGAACTGCCACCCCATCGGAATGTTGATTGGAACCCCAG



TCTGCGATCTGCACTTGACCGGCACCTGGGATACACTGATTGAGCGGGAGAACGCTACCGC



CTACTGCTATCCCGGGGTCACTATTAATGAGGAAGCCTTGAGACAGAAGATCATGGAGAGT



GGAGGGATATCCAAGATGCGGACAGGGTTCACCTACGGTCCCTCCATCAATTCCGCTGGCA



CCACCCGGTCATGCATGCGCAATGGCGGCAATTCCTTTTACGCCGAGCTGAAATGGCTGGT



TAGCGGGACTAAGGGACAGAACTTCCCACAAACCACTAACACCTATAGAAATACTGATACC



GCGGAGCATCTGATCATATGGGGAATTCATCATCCTTCATCGACCCAGGAGAAAAACGACC



TGTACGGGACTCAGTCCCTGTCCATATCCGTGGGAAGTTCCACTTATCAGAACAATTTCGT



GCCTGTTATCGGAGCCCGACCTCAGGTTAACGGACAATCGGGACGGATTGAGTTCCACTGG



ACTTTAGTGAGACCGGGCGACAACATCACCTTTTCTCATAACGGCGGCCTGATTGCCCCCG



ATAGAGTCAGCAAATTAATCGGCAAGGGAATCGGCATACAGAGCGGGGCTGTTATTGACAA



GGACTGCGAATCTAAATGCTTTTGGCGTGGTGGCTCCATTATCACTGAACTGCCCTTCCAG



AATCTCAGCCCTAGAACTGTGGGCCAGTGCCCGAAGTATGTGAAAAAGAGGTCTCTTCTTC



TTGCTACAGGTATGAGGAACGTCCCTGAGGTTGTCCAGGGGCGCGGCTTGTTCGGCGCTAT



CGCCGGGTTCATCGAAAACGGGTGGGAGGGGATGGTGGACGGCTGGTATGGCTTTCGACAC



CAGAATGCTCAAGGGATCGGGCAGGCAGCCGACTACAAATCCACCCAGACAGCTATAGACC



AGATCACGGGGAAACTTAATCGTCTGATCGAAAAGACAAATACGGAGTTTGAGTCTATCGA



GTCCGAATTCTCGGAGATTGAGCACCAGATTGGTAATGTCATCAATTGGACTAAGGACAGT



ATTACTGACATCTGGACTTATCAAGCAGAGCTGCTGGTAGCTATGGAAAACCAACATACAA



TCGATATGGCCGATAGCGAGATGCTGAACCETTACGAACGAGTAAGGAAACAGCTGAGGCA



GAACGCCGAAGAGGACGGCAAAGGTTGCTTTGAAATTTACCACACCTGTGACAATTCCTGT



ATGGAAAGCATACGAAATAATACCTATGATCACTCCCAGTACAGAGAGGAAGCGCTCCTGA



ACCGACTGAATATCAACCCCGTGAAACTGAGTTCCGGATACAAGGATATCATCCTATGGTT



CTCATTCGGCGCCAGCTGTTTCGTTCTGTTAGCGGTTATAATGGGTCTGGGGTTTTTTTGT



CTCAAAAATGGCAATATGCGTTGTACCATTTGTATA





715
ATGTACAAGGTTGTGGTCATCATCGCCCTGCTTGGTGCTGTGAAAGGGCTTGATAAGATAT



GTTTGGGCCACCATGCCGTGGCTAACGGAACCATTGTGAAGACCTTGACCAACGAGCAGGA



GGAAGTGACTAATGCCACAGAAACTGTAGAGTCTACCGGTATAAACAGGCTGTGCATGAAG



GGAAGGAAGCACAAAGATCTCGGCAATTGTCATCCCATAGGCATGCTGATCGGTACCCCCG



CCTGCGATCTGCACTTGACTGGCACCTGGGACACGCTGATCGAGAGGGAAAACGCTATAGC



CTATTGTTACCCTGGGGCTACCGTTAATGTGGAAGCGCTGCGACAAAAGATAATGGAGAGC



GGGGGCATTGATAAAATTTCAACCGGATTTACCTACGGCTCTAGTATCAACTCTGCGGGTA



CTACGCGAGCATGCATGAGAAACGGGGGGAATTCCTTTTATGCAGAGCTTAAGTGGCTGGT



TAGCAAGAACAAGGGTCAGAATTTCCCCCAAACTACTAACACTTACAGAAACACAGATACC



GCCGAACATCTGATCATGTGGGGCATTCATCACCCATCCTCTATTCAAGAGAAGAATGACC



TTTATGGCACTCAAAGCCTCTCTATCTCCGTGGGAAGCAGCACTTACCGCAATAATTTCGT



GCCCGTCGTTGGGGCACGACCGCAGGTCAATGGCCAGAGTGGCAGGATCGATTTCCATTGG



ACCTTAGTCCAGCCGGGCGATAATATTACCTTCAGCCATAACGGAGGACTTATTGCGCCGT



CCAGAGTGTCAAAACTGATCGGGAGAGGACTCGGCATCCAGAGCGATGCTCCTATTGATAA



TAATTGCGAGTCCAAGTGTTTTTGGCGTGGGGGTTCGATCAATACTAGACTACCTTTCCAG



AACTTGAGCCCACGCACTGTGGGCCAGTGCCCCAAATATGTAAATAGAAGGTCCCTTATGC



TCGCTACAGGTATGAGGAACGTCCCAGAACTCATTCAGGGCCGAGGTTTGTTTGGCGCAAT



CGCCGGATTTCTGGAGAACGGGTGGGAGGGCATGGTCGACGGCTGGTACGGATTCCGCCAC



CAGAACGCCCAAGGTACAGGTCAGGCCGCCGACTATAAGAGCACGCAGGCTGCTATAGATC



AGATTACAGGAAAGCTAAACCGACTTGTGGAGAAGACAAATACAGAGTTCGAGTCAATAGA



GAGTGAGTTCAGTGAGATAGAGCATCAGATCGGTAATGTCATTAACTGGACAATGGATAGC



ATCACCGATATTTGGACTTATCAGGCCGAATTGCTGGTGGCTATGGAAAATCAGCACACCA



TTGATATGGCAGACTCTGAGATGCTAAATCTTTACGAGCGGGTGCGAAAGCAGTTGCGGCA



GAACGCAGAAGAAGACGGAAAAGGCTGCTTCGAAATATATCACGCTTGCGACGATTCCTGT



ATGGAAAGCATCAGAAATAACACATATGACCACAGTCAGTATCGCGAGGAGGCTCTCCTGA



ACAGACTCAATATCAATCCGGTCACCCTCTCCTCAGGTTACAAGGACATTATTCTCTGGTT



TTCTTTCGGTGCGTCTTGCTTTGTGCTACTCGCTGTGGTGATGGGCTTGGTGTTCTTCTGC



CTGAAGAACGGCAATATGCGGTGCACTATCTGTATC





716
ATGTACAAAATTGTGGTCATCATCGCTTTACTAGGAGCTGTGAAAGGCTTGGATAAAATTT



GTCTGGGACATCATGCTGTCGCTAACGGGACCATAGTGAAAACACTCACGAACGAACAGGA



GGAAGTTACCAATGCCACCGAAACGGTCGAGTCAACAGGGATTAACCGGCTGTGTATGAAG



GGAAGAAAGCATAAAGATCTGGGGAACTGCCACCCTATAGGAATGTTGATAGGCACGCCTG



CTTGTGACCTGCACCTGACTGGGATGTGGGATACCCTGATCGAAAGAGAGAACGCTATAGC



CTATTGCTATCCCGGTGCAACAGTGAACGTGGAGGCATTGAGACAGAAAATAATGGAAAGT



GGAGGGATCAATAAGATCTCAACCGGTTTTACCTATGGATCTAGTATAAATAGTGCAGGGA



CCACACGTGCCTGCATGAGAAATGGGGGCAATTCTTTCTACGCGGAACTGAAGTGGCTGGT



GAGCAAATCTAAGGGGCAGAATTTTCCACAGACCACGAATACATATCGTAACACAGACACC



GCGGAGCACTTGATTATGTGGGGTATCCACCACCCCAGCAGCACGCAGGAAAAAAACGATC



TCTACGGTACTCAGAGCCTGTCTATCTCAGTAGGCTCATCAACATACCGGAATAACTTTGT



TCCAGTTGTGGGGGCCCGGCCTCAGGTGAATGGCCAGTCTGGACGCATTGATTTTCATTGG



ACGCTGGTACAGCCAGGAGACAATATCACATTTAGTCATAATGGCGGTTTGATCGCCCCGA



GTAGAGTGTCTAAGCTGATCGGCCGAGGCCTTGGCATTCAGTCCGACGCCCCCATCGACAA



TAACTGCGAAAGCAAATGCTTTTGGAGAGGAGGTTCTATTAATACACGCCTGCCATTTCAA



AACTTGAGCCCTAGAACTGTGGGTCAGTGTCCCAAGTACGTGAATCGCCGCTCCCTGATGT



TAGCCACCGGGATGAGGAATGTGCCTGAGCTGATCCAGGGCAGGGGCCTATTTGGAGCCAT



CGCTGGTTTCTTGGAGAATGGTTGGGAGGGTATGGTAGATGGATGGTATGGGTTTCGGCAT



CAGAATGCGCAAGGCACTGGCCAGGCCGCGGATTACAAAAGCACTCAGGCTGCCATTGACC



AGATAACCGGAAAACTCAACAGACTGGTTGAGAAGACCAACACTGAATTTGAGAGCATTGA



GTCAGAGTTTAGCGAAATAGAACACCAGATCGGGAACGTTATTAACTGGACAAAGGACTCC



ATTACGGACATATGGACATATCAGGCAGAGCTGCTAGTGGCAATGGAGAACCAACACACTA



TTGACATGGCCGACTCTGAGATGCTGAACCTCTATGAGCGCGTCAGAAAGCAGCTAAGGCA



GAATGCAGAAGAGGATGGTAAAGGGTGTTTTGAAATCTATCATGCATGCGACGATTCATGC



ATGGAAAGCATCAGGAACAATACTTATGACCATTCCCAATACCGAGAGGAAGCCCTGCTGA



ACAGACTGAATATTAACCCAGTGACCCTATCCAGTGGCTATAAGGATATCATCCTGTGGTT



CAGCTTTGGCGCTAGCTGTTTCGTGTTACTCGCGGTCGTCATGGGACTGTTTTTTTTTTGT



TTGAAGAACGGGAATATGAGATGCACAATCTGTATT





717
ATGTATAAAATCGTAGTGATTATTGCGTTGCTTGGCGCTGTGAAAGGGCTAGATAAGATCT



GCCTGGGCCACCACGCCGTAGCTAACGGAACCATCGTCAAAACTTTGACTAACGAGCAGGA



AGAGGTCACCAATGCTACTGAGACAGTCGAGTCTACAGGCATAAATAGACTCTGTATGAAG



GGTAGAAAGCACAAGGATCTTGGGAATTGCCACCCCATTGGTATGCTGATTGGGACACCCG



CCTGCGACCTGCACCTCACAGGGATGTGGGACACCTTAATTGAGCGAGAGAATGCAATCGC



CTACTGTTACCCCGGGGCTACTGTTAACGTCGAAGCTCTGCGCCAGAAAATCATGGAGAGC



GGGGGGATCAACAAGATCTCCACCGGCTTCACCTATGGCTCATCTATCAATTCTGCAGGCA



CTACCAGAGCGTGCATGAGAAATGGAGGAAATTCCTTCTATGCGGAATTGAAATGGCTTGT



GTCAAAATCTAAAGGGCAAAATTTTCCGCAGACCACCAACACCTACAGGAACACCGATACT



GCAGAGCATCTGATTATGTGGGGGATTCACCACCCTTCATCCACTCAGGAAAAGAACGATC



TCTATGGGACACAATCATTGTCCATTAGCGTGGGCTCTTCCACTTACAGAAACAACTTCGT



GCCTGTCGTTGGGGCGCGACCGCAAGTTAATGGGCAATCCGGGCGAATTGATTTCCACTGG



ACGCTGGTTCAACCTGGAGACAATATCACTTTCTCACATAATGGAGGGTTAATTGCTCCCT



CCCGCGTCTCCAAACTGATTGGAAGAGGCCTGGGCATTCAGTCCGATGCCCCAATCGACAA



CAATTGCGAATCCAAGTGTTTCTGGCGCGGGGGCTCAATCAATACCCGCCTGCCCTTCCAA



AACCTGAGTCCCCGCACAGTGGGCCAATGCCCTAAATATGTCAACCGTCGATCCCTCATGC



TTGCCACAGGCATGAGGAACGTCCCAGAGCTGATCCAGGGCCGCGGACTCTTTGGAGCTAT



CGCAGGCTTTCTTGAAAACGGGTGGGAGGGCATGGTCGATGGTTGGTATGGATTTCGGCAT



CAGAATGCACAAGGTACTGGACAGGCCGCTGATTACAAGTCAACCCAGGCGGCCATTGACC



AGATAACCGGGAAGCTCAACCGGTTGGTCGAGAAGACTAATACTGAGTTTGAATCCATCGA



AAGTGAGTTCTCTGAGATAGAACATCAGATTGGTAATGTCATAAATTGGACTAAAGATAGC



ATAACGGACATTTGGACCTATCAGGCAGAATTACTGGTGGCAATGGAAAATCAACACACCA



TCGACATGGCCGATTCTGAAATGCTCAACCTATACGAAAGAGTCAGAAAGCAGCTCAGACA



GAACGCCGAGGAAGACGGCAAAGGGTGCTTTGAAATTTACCATGCTTGTGACGATTCTTGT



ATGGAGAGTATACGCAATAACACTTATGACCATTCACAGTACCGAGAGGAGGCACTCCTGA



ATCGACTGAACATCAACCCCGTCACACTGTCCTCAGGCTACAAGGATATTATCCTTTGGTT



TAGTTTTGGTGCGTCGTGCTTCGTCCTCCTGGCCGTCGTGATGGGGTTATTCTTTTTTTGC



TTGAAAAATGGAAATATGCGTTGCACCATCTGTATC





718
ATGTATAAGATAGTCGTCATAATCGCTCTGCTCGGCGCAGTGAAAGGGCTGGATAAAATTT



GTCTGGGTCACCACGCCGTAGCGAATGGCACCATCGTGAAGACACTGACTAACGAGCAAGA



GGAGGTGACTAATGCCACAGAAACCGTCGAGTCTACAGGAATTAACCGCCTCTGCATGAAA



GGCAGGAAACACAAAGATCTCGGCAACTGTCACCCGATCGGAATGCTCATAGGGACTCCAG



CCTGTGATCTCCACCTTACCGGAATGTGGGATACTCTCATAGAGAGGGAGAATGCCATCGC



TTATTGTTACCCCGGCGCGACAGTTAACGTGGAAGCTCTCAGACAGAAGATCATGGAAAGT



GGGGGCATTAACAAGATATCCACCGGATTCACTTACGGTTCATCCATTAATTCTGCGGGAA



CCACTCGGGCCTGTATGCGGAACGGTGGCAATTCTTTCTATGCCGAGCTGAAGTGGCTGGT



CTCCAAGTCCAAGGGCCAGAATTTCCCACAGACTACCAACACATATAGAAACACTGACACT



GCCGAGCATCTGATCATGTGGGGGATCCATCACCCAAGTTCAACTCAGGAGAAGAATGACC



TCTACGGTACCCAGAGCTTATCTATTAGTGTTGGCTCCTCTACTTACCGCAATAATTTTGT



GCCAGTAGTCGGTGCTCGCCCTCAGGTGAATGGGCAGTCCGGCAGGATCGACTTCCACTGG



ACTCTAGTCCAACCCGGGGATAACATCACATTCAGTCATAACGGGGGATTGATCGCTCCAA



GTAGAGTTTCAAAACTCATAGGTAGGGGCCTCGGGATTCAGTCGGACGCTCCTATCGACAA



CAATTGCGAGTCTAAGTGTTTCTGGCGAGGGGGAAGCATAAATACCCGACTCCCCTTCCAG



AATCTCAGCCCAAGGACTGTGGGTCAGTGCCCAAAATACGTTAACCGCCGGAGCCTAATGC



TGGCGACTGGCATGAGAAACGTCCCCGAACTGATTCAAGGTCGCGGACTCTTCGGGGCAAT



CGCGGGATTTCTGGAAAACGGCTGGGAGGGAATGGTGGACGGCTGGTACGGCTTCCGACAC



CAGAACGCTCAAGGGACAGGCCAAGCGGCTGACTACAAGTCCACCCAGGCCGCGATTGACC



AAATCACAGGGAAATTGAATAGGCTGGTAGAAAAGACGAATACAGAGTTCGAATCCATAGA



GAGTGAATTTTCCGAGATCGAACACCAAATAGGAAATGTCATCAATTGGACGAAGGACAGC



ATTACGGACATCTGGACATACCAGGCAGAGCTCCTCGTGGCGATGGAAAATCAGCACACAA



TCGACATGGCTGACTCAGAGATGCTCAATCTGTACGAGCGGGTCCGCAAACAGTTGAGGCA



GAATGCTGAAGAAGACGGTAAAGGGTGTTTTGAAATCTATCATGCCTGCGACGATTCATGC



ATGGAATCTATTAGAAACAATACGTACGATCACTCCCAGTATAGGGAGGAAGCTCTGCTGA



ATAGACTGAACATAAACCCCGTCACCCTGTCTTCCGGTTACAAGGACATCATACTTTGGTT



CTCGTTCGGTGCAAGCTGCTTCGTTCTGCTCGCTGTTGTCATGGGCCTGTTCTTCTTCTGT



TTGAAAAACGGCAATATGCGATGCACCATTTGTATT





719
ATGTATAAAATTGTCGTAATCATTGCCCTGCTGGGAGCGGTTAAGGGGCTTGATAAGATAT



GCTTGGGGCATCACGCCGTAGCTAATGGTACAATCGTCAAAACACTAACTAATGAACAGGA



GGAAGTAACAAACGCAACTGAAACTGTTGAGTCTACGGGAATCAACAGGCTCTGTATGAAA



GGCCGAAAGCACAAAGACTTGGGTAATTGTCACCCGATCGGGATGCTCATCGGGACACCTG



CATGCGACCTCCACCTCACCGGCATGTGGGATACACTTATTGAACGGGAGAACGCGATCGC



CTACTGCTACCCTGGGGCAACGGTGAATGTAGAAGCTCTCCGGCAGAAGATCATGGAAAGC



GGCGGAATTAATAAAATTAGTACCGGATTTACCTACGGGTCATCCATAAACAGCGCCGGGA



CCACACGCGCCTGCATGAGGAACGGCGGCAACAGCTTTTATGCCGAGCTCAAGTGGCTTGT



CTCCAAATCCAAAGGACAGAACTTTCCTCAGACAACGAACACATATCGTAATACTGATACC



GCAGAACATCTGATCATGTGGGGAATCCACCACCCCAGTAGCACCCAAGAGAAGAACGATC



TATACGGAACTCAGTCTCTTTCCATCAGCGTTGGGTCCTCTACTTACAGGAACAATTTTGT



ACCGGTCGTGGGAGCCCGCCCCCAGGTGAATGGGCAGTCCGGAAGGATTGATTTTCACTGG



ACTTTAGTACAGCCTGGAGACAACATAACCTTTTCCCACAACGGAGGTCTCATAGCCCCTT



CTCGAGTGAGCAAGTTGATAGGGCGTGGGTTGGGAATCCAGTCTGACGCTCCGATCGACAA



TAATTGTGAGTCCAAGTGCTTTTGGAGGGGCGGCTCTATCAATACGAGATTGCCTTTCCAG



AACCTTAGTCCAAGAACCGTGGGGCAATGTCCAAAGTATGTCAATCGACGCTCACTAATGT



TAGCAACCGGCATGAGGAATGTTCCCGAGCTAATCCAAGGCCGGGGACTCTTTGGCGCCAT



CGCGGGCTTCTTGGAGAACGGTTGGGAAGGAATGGTCGACGGGTGGTATGGCTTCCGGCAC



CAAAACGCCCAGGGTACAGGCCAGGCAGCCGACTATAAATCCACACAGGCAGCCATCGATC



AGATCACCGGCAAGCTCAATAGGCTCGTGGAAAAAACAAACACTGAGTTCGAGTCCATTGA



ATCCGAGTTCTCGGAGATCGAGCACCAAATCGGGAACGTCATCAATTGGACTAAGGACAGT



ATTACAGATATCTGGACATATCAGGCCGAACTTTTGGTCGCTATGGAAAATCAACATACGA



TTGACATGGCAGACTCAGAGATGTTAAACCTGTATGAGAGAGTGCGCAAACAGCTGCGGCA



GAATGCCGAAGAAGATGGGAAGGGATGTTTCGAGATTTACCATGCCTGTGACGATTCCTGC



ATGGAGTCGATTCGTAATAATACTTATGATCATTCCCAATATAGAGAGGAAGCATTATTAA



ACCGGCTGAATATTAACCCCGTGACCCTGAGCTCCGGGTACAAGGACATTATTCTGTGGTT



CTCATTCGGCGCATCTTGTTTCGTCTTACTCGCAGTGGTCATGGGACTGTTTTTCTTTTGT



CTGAAGAATGGGAACATGCGCTGTACCATTTGTATC





720
ATGTACAAGATTGTCGTCATCATAGCCCTCCTAGGTGCTGTTAAAGGGCTCGATAAGATCT



GCCTTGGACATCACGCCGTGGCAAATGGAACAATAGTAAAGACACTCACAAACGAGCAGGA



AGAAGTGACGAATGCCACCGAAACCGTCGAGAGTACCGGCATCAACAGACTGTGCATGAAG



GGCAGGAAGCATAAAGACCTGGGCAACTGCCACCCTATCGGCATGCTAATCGGTACACCAG



CCTGCGATTTACACCTGACCGGAATGTGGGACACACTGATTGAACGAGAAAATGCCATTGC



TTACTGTTATCCTGGCGCTACCGTGAATGTGGAGGCTCTCAGGCAGAAAATTATGGAGAGT



GGGGGGATCAACAAGATTAGTACTGGCTTTACCTACGGCTCTAGCATCAACTCTGCTGGCA



CAACGCGCGCTTGTATGAGAAATGGCGGCAATTCATTCTACGCCGAGCTTAAGTGGCTGGT



TAGCAAGTCCAAGGGACAGAACTTTCCTCAAACGACGAATACATACCGCAACACCGATACT



GCTGAGCATCTGATCATGTGGGGCATCCATCATCCCTCCTCAACTCAGGAAAAAAATGACC



TCTACGGGACTCAGTCCCTATCAATCTCCGTTGGTAGTAGCACTTATCGGAACAACTTTGT



GCCTGTGGTGGGCGCTAGACCTCAGGTCAATGGGCAGTCTGGGCGGATCGACTTTCACTGG



ACTCTCGTACAACCTGGTGACAACATAACTTTCTCACACAATGGCGGCCTCATCGCCCCAA



GCCGAGTCAGTAAATTAATCGGCCGGGGTCTGGGCATCCAGAGCGACGCACCAATTGATAA



CAATTGTGAATCCAAATGCTTCTGGCGGGGGGGGAGCATTAACACTCGGTTACCCTTTCAG



AACTTGAGTCCTCGCACCGTGGGACAATGCCCGAAGTACGTGAACCGCCGCTCACTCATGC



TGGCAACCGGCATGCGGAACGTCCCCGAACTCATCCAGGGCAGAGGGCTCTTTGGCGCCAT



CGCTGGATTTCTGGAGAACGGATGGGAGGGCATGGTCGATGGCTGGTACGGCTTCAGGCAT



CAGAACGCCCAGGGGACCGGCCAAGCCGCTGATTACAAATCTACTCAGGCTGCCATAGACC



AAATCACAGGGAAGCTTAATCGCCTGGTGGAAAAGACCAATACAGAATTTGAAAGCATCGA



GTCTGAGTTCAGTGAAATTGAACATCAGATCGGGAACGTGATCAATTGGACCAAAGACAGC



ATTACCGATATTTGGACCTACCAGGCAGAGTTGCTCGTTGCCATGGAGAACCAGCACACTA



TTGATATGGCCGACTCCGAGATGCTGAATCTCTATGAGAGGGTTCGCAAACAACTGAGACA



AAATGCGGAAGAAGATGGAAAGGGCTGTTTTGAGATCTATCACGCCTGCGATGATAGTTGC



ATGGAAAGTATCAGAAATAACACATACGATCACTCTCAGTACCGGGAAGAGGCCCTCCTGA



ACAGGCTTAATATTAACCCCGTGACGCTTTCATCTGGCTATAAGGACATCATTTTGTGGTT



CTCATTTGGCGCCAGCTGCTTTGTGCTGCTGGCTGTAGTTATGGGCTTATTCTTCTTCTGC



CTGAAGAACGGAAACATGAGATGTACCATTTGCATT





721
ATGTATAAAATTGTGGTCATAATTGCCCTGCTTGGGGCAGTGAAGGGGTTAGACAAAATTT



GCTTGGGGCACCACGCAGTGGCCAACGGGACAATTGTCAAAACACTGACAAATGAACAGGA



GGAAGTGACAAACGCCACAGAAACCGTTGAATCAACCGGAATCAATAGACTTTGTATGAAG



GGCAGAAAGCACAAAGATTTGGGCAATTGCCATCCAATTGGAATGTTGATCGGCACCCCTG



CCTGTGACCTGCATCTGACTGGGATGTGGGACACCCTGATCGAACGGGAGAACGCAATTGC



GTACTGTTATCCCGGCGCTACAGTTAATGTGGAGGCCCTCCGACAGAAGATCATGGAGAGT



GGCGGCATTAACAAGATAAGCACCGGCTTCACCTATGGCTCCAGCATAAACTCAGCTGGCA



CTACTCGGGCATGCATGAGGAACGGCGGGAACTCCTTCTACGCTGAACTCAAGTGGCTGGT



GTCGAAATCTAAGGGACAGAACTTCCCGCAAACCACCAACACTTACCGGAATACGGACACA



GCAGAGCATCTGATCATGTGGGGCATACACCATCCATCCAGCACGCAGGAAAAAAACGACC



TGTATGGAACACAGAGCTTGTCTATCTCGGTGGGGAGCAGCACCTACAGGAACAATTTCGT



CCCTGTTGTTGGAGCCGGGCCCCAAGTTAATGGCCAGAGTGGCAGAATCGACTTTCATTGG



ACACTGGTGCAGCCTGGAGATAATATTACTTTTAGCCACAACGGTGGACTCATTGCTCCCA



GTAGGGTCTCGAAGTTGATCGGTCGTGGCCTGGGTATTCAGAGCGACGCTCCCATTGACAA



TAATTGCGAGAGCAAATGTTTCTGGCGGGGAGGTAGTATTAATACTAGGCTCCCTTTCCAG



AATCTGTCACCGCGCACCGTTGGCCAGTGTCCGAAATATGTCAACCGGCGATCCCTAATGC



TAGCCACTGGCATGCGGAACGTCCCTGAACTCATTCAAGGCAGGGGACTGTTCGGCGCTAT



CGCTGGGTTTCTGGAAAATGGATGGGAGGGCATGGTTGATGGCTGGTATGGCTTCAGGCAC



CAGAACGCTCAGGGCACCGGGCAAGCCGCCGATTATAAATCCACTCAGGCGGCCATCGATC



AAATAACTGGCAAACTAAATAGGCTGGTCGAAAAGACAAACACTGAGTTTGAGAGCATTGA



GAGCGAATTTTCTGAAATTGAGCACCAGATCGGTAACGTTATTAACTGGACCAAGGATTCA



ATTACAGATATTTGGACCTACCAGGCAGAGCTTCTGGTCGCCATGGAAAACCAGCACACAA



TTGATATGGCCGACAGCGAAATGTTGAACCETTACGAGAGAGTGCGGAAGCAGTTGAGACA



GAACGCTGAGGAGGATGGGAAAGGGTGCTTCGAGATTTACCATGCCTGCGATGATTCTTGT



ATGGAGAGCATCAGGAACAATACCTATGACCACAGCCAGTATCGCGAAGAGGCCCTGCTGA



ACAGACTGAACATCAACCCCGTGACACTCTCTTCTGGCTATAAGGATATAATCCTGTGGTT



TAGCTTCGGAGCCAGCTGCTTTGTCCTTCTAGCAGTTGTCATGGGGCTCTTCTTTTTCTGC



CTGAAGAATGGAAACATGAGATGTACAATTTGCATT





722
ATGTACAAAGTGGTGGTCATCATTGCCTTGTTGGGTGCTGTCCGGGGGTTAGACAAGATCT



GTCTGGGGCATCACGCCGTAGCCAATGGAACTACTGTCAAGACCTTAACCAACGAGCAAGA



AGAGGTCACAAATGCGACGGAGACCGTGGAAAGCACATCGCTTAATAAGCTGTGCATGAAG



GGGCGTCGCTACAAAGATCTGGGAAATTGCCATCCAATCGGCATGCTGATTGGAACTCCCG



TCTGTGATCTACACCTGACTGGAACTTGGGATACTTTGATTGAAAGAGAGAACGCTACGGC



TTACTGTTATCCAGGGGTAACCATCAATGAGGAGGCCCTGCGTCAGAAGATTATGGAGAGT



GGGGGAATCAGCAAAATGCGGACAGGATTCACCTATGGGCCGTCCATTAATTCTGCCGGTA



CCACGAGAAGCTGCATGCGGAACGGTGGAAACTCGTTTTACGCAGAACTGAAATGGTTGGT



CTCTGGCACGAAAGGACAGAACTTCCCACAGACTACAAACACCTATCGAAATACCGATACC



GCCGAGCACCTGATCATTTGGGGGATCCACCACCCTAGCAGCACCCAGGAAAAAAATGACT



TATATGGCACTCAATCCCTGAGCATCTCTGTGGGCTCCTCTACTTATCAAAACAATTTTGT



GCCTGTGATTGGAGCCAGGCCCCAGGTGAATGGACAATCCGGACGCATTGAGTTCCACTGG



ACACTTGTCAGACCCGGGGATAATATCACCTTTTCTCACAACGGCGGTCTTATAGCGCCAG



ACCGTGTTAGCAAGCTGATTGGCAAGGGGATCGGCATCCAATCAGGTGCTGTGATCGACAA



GGATTGTGAGTCTAAGTGCTTTTGGAGGCGGGGGTCCATCATTACCGAGCTGCCTTTTCAG



AACCTAAGCCCACGCACCGTCGGACAGTGCCCCAAATATGTGAAAAAAAGATCTTTACTGT



TGGCCACCGGAATGAGAAATGTGCCAGAGGTGGTCCAAGGTCGGGGCTTGTTCGGGGCGAT



TGCAGGCTTTATAGAGAACGGCTGGGAGGGCATGGTGGACGGTTGGTACGGTTTCCGGCAC



CAGAACGCACAGGGAATTGGGCAAGCCGCCGACTACAAGTCAACCCAAACAGCCATAGACC



AGATTACGGGAAAACTGAACAGATTAATCGAGAAAACTAATACAGAATTTGAGAGCATCGA



ATCTGAGTTTTCCGAAATCGAGCACCAGATAGGGAATGTCATCAATTGGACTAAGGACTCC



ATTACAGACATCTGGACTTACCAGGCCGAGTTGCTGGTCGCCATGGAGAATCAGCATACAA



TTGATATGGCTGACAGCGAAATGCTCAACCTGTACGAGCGCGTAAGGAAGCAACTGCGCCA



GAATGCTGAGGAAGACGGGAAGGGTTGCTTTGAGATTTACCACACCTGTGACAACTCATGT



ATGGAAAGCATCCGGAACAACACTTACGATCACTCTCAATATCGCGAGGAGGCCCTTCTGA



ATCGGCTGAATATAAACCCAGTTAAATTGTCTTCAGGCTATAAAGACATCATCCTGTGGTT



CTCGTTCGGGGCTAGCTGTTTCGTGCTGCTGGCCGTGATAATGGGCCTTGGATTCTTTTGT



CTCAAGAACGGCAATATGAGGTGCACCATATGTATC





723
ATGTACAAGGTCGTTGTTATCATCGCCCTGTTGGGCGCGGTGAGGGGACTCGATAAGATTT



GTCTGGGCCACCACGCCGTCGCCAACGGCACGACTGTGAAGACATTGACCAACGAGCAGGA



GGAGGTTACTAATGCCACCGAAACTGTGGAGAGTACCAGTCTGAACAAGTTGTGCATGAAG



GGCCGGCGGTATAAGGATCTGGGAAATTGCCACCCCATCGGAATGCTCATTGGTACCCCAG



TGTGTGATCTTCACCTCACAGGAACCTGGGATACCCTCATCGAGCGTGAGAACGCAACCGC



GTATTGCTATCCCGGCGTGACCATAAATGAGGAAGCCCTGAGACAGAAGATCATGGAGAGC



GGCGGCATAAGTAAGATGAGGACCGGCTTCACTTATGGCCCCTCAATTAACAGTGGGGGAA



CAACCCGGTCCTGCATGAGAAATGGCGGCAATAGTTTCTATGCTGAACTGAAGTGGCTTGT



GAGCGGAACAAAGGGACAGAATTTTCCTCAGACAACGAACACGTATCGCAACACTGATACC



GCTGAACACCTGATCATCTGGGGCATCCATCATCCCAGTTCTACTCAGGAGAAAAATGACT



TGTATGGTACCCAATCTTTGTCTATATCCGTCGGGAGTTCCACATACCAGAACAACTTCGT



CCCTGTGATTGGGGCGCGACCTCAAGTGAACGGCCAGTCGGGCCGCATAGAGTTTCACTGG



ACCTTGGTCCGACCAGGCGATAACATTACATTTTCGCACAATGGCGGCTTGATCGCCCCCG



ATCGCGTGAGCAAACTTATCGGGAAGGGGATCGGAATCCAGAGCGGCGCAGTGATAGACAA



GGACTGCGAAAGCAAATGCTTCTGGCGCGGTGGATCTATCATCACTGAATTGCCTTTCCAA



AACCTGTCCCCCCGAACAGTGGGTCAGTGCCCGAAGTATGTGAAGAAGCGCAGTTTGCTAT



TAGCGACTGGCATGCGGAACGTGCCTGAGGTGGTTCAGGGGCGCGGTCTCTTTGGCGCCAT



CGCAGGATTTATTGAGAATGGCTGGGAGGGCATGGTCGACGGCTGGTACGGATTTAGACAT



CAGAATGCTCAGGGAATTGGGCAGGCCGCCGATTACAAGAGTACCCAGACAGCAATTGACC



AGATCACAGGCAAACTTAACAGGCTTATTGAGAAAACCAACACCGAGTTCGAGTCCATCGA



GTCAGAGTTTAGCGAGATCGAACATCAAATCGGCAATGTGATTAATTGGACAAAAGATTCT



ATTACCGATATCTGGACCTACCAGGCAGAGCTGCTGGTGGCTATGGAAAACCAGCACACCA



TAGACATGGCAGACAGTGAGATGCTGAACCTATATGAGCGTGTGAGGAAACAATTGAGACA



AAATGCCGAGGAAGACGGGAAGGGATGCTTCGAAATATACCACACATGTGATAACTCCTGT



ATGGAATCAATTCGGAACAATACTTACGACCACAGCCAGTATCGCGAGGAAGCCTTACTTA



ATCGTTTAAATATTAATCCCGTTAAGCTGAGCTCCGGTTATAAAGACATCATTCTGTGGTT



CTCCTTTGGAGCCAGTTGCTTCGTTTTGCTCGCCGTTATCATGGGCCTGGGGTTTTTCTGT



CTCAAGAATGGAAATATGCGATGCACCATTTGCATC





724
ATGTATAAGATTGTCGTGATTATCGCTCTCCTTGGTGCCGTTAAGGGCCTGGACAAGATCT



GTCTTGGACACCACGCTGTGGCCAATGGCACTATTGTCAAAACCCTCACTAATGAGCAGGA



GGAGGTCACCAACGCAACGGAGACAGTAGAAAGCACCGGGATCAACCGTCTGTGCATGAAG



GGGCGGAAACATAAAGACCTCGGAAACTGCCATCCGATTGGAATGCTGATCGGGACCCCAG



CTTGCGACCTCCATCTGACAGGGATGTGGGACACGCTTATCGAACGCGAGAATGCCATTGC



CTATTGTTATCCTGGGGCTACTGTGAACGTAGAAGCCCTGCGTCAGAAGATTATGGAGTCC



GGCGGGATCAATAAAATCAGCACAGGGTTCACCTATGGCTCTTCAATCAACAGTGCCGGAA



CAACCCGCGCCTGCATGCGGAACGGCGGGAATTCCTTCTACGCCGAATTAAAGTGGTTGGT



TTCTAAAAGTAAAGGGCAAAACTTCCCTCAGACCACGAACACCTATCGTAACACAGACACC



GCCGAGCATCTCATCATGTGGGGGATCCACCATCCCAGCAGTACACAGGAAAAGAATGATC



TGTACGGCACACAGTCGCTGTCGATCTCAGTTGGGAGTAGCACTTACCGCAACAACTTTGT



GCCCGTCGTGGGGGCGAGGCCGCAGGTAAATGGGCAATCTGGACGTATAGACTTCCACTGG



ACTCTAGTGCAACCCGGCGACAACATCACATTTTCTCATAACGGGGGCCTTATAGCCCCGT



CTCGAGTGTCCAAACTGATTGGCCGCGGCCTCGGAATCCAGTCCGATGCCCCCATCGACAA



TAATTGCGAGTCTAAATGTTTTTGGCGAGGGGGGAGCATTAACACACGGCTCCCATTTCAA



AATTTGAGTCCGCGCACCGTCGGTCAGTGTCCAAAATATGTGAACAGACGCAGCTTGATGC



TCGCAACGGGCATGAGAAACGTTCCTGAATTGATCCAGGGTCGGGGACTGTTTGGGGCCAT



CGCAGGCTTTTTGGAGAACGGTTGGGAAGGAATGGTGGACGGATGGTACGGCTTTAGACAC



CAGAACGCACAGGGAACCGGTCAGGCAGCTGACTACAAGTCAACTCAGGCCGCCATTGACC



AGATCACAGGCAAGCTGAATCGACTCGTCGAGAAGACCAACACCGAATTTGAGTCTATCGA



ATCAGAGTTTTCGGAGATCGAGCACCAGATCGGCAATGTGATCAATTGGACAAAGGATTCT



ATCACCGATATCTGGACGTATCAGGCGGAATTGCTGGTAGCCATGGAGAATCAACACACAA



TAGATATGGCCGATTCTGAGATGCTTAACCTGTACGAACGGGTCCGGAAGCAACTCCGCCA



GAATGCAGAGGAGGATGGGAAGGGCTGCTTCGAGATTTACCACGCTTGTGATGACTCCTGC



ATGGAGTCAATTCGAAACAACACTTACGATCACTCACAGTACCGCGAGGAAGCACTTCTTA



ATAGGCTGAACATCAATCCTGTTACTCTCTCCAGCGGATATAAAGATATCATTCTGTGGTT



CAGCTTCGGTGCCAGCTGCTTTGTGCTACTGGCAGTGGTCATGGGGCTCTTCTTCTTCTGC



CTTAAAAATGGGAATATGCGTTGCACCATTTGCATT





725
ATGTATAAAGTGGTAGTGATCATCGCTCTGCTGGGTGCCGTGCGAGGCCTTGATAAGATCT



GTCTTGGCCACCATGCAGTGGCCAACGGGACCATAGTTAAGACATTAACCAACGAACAGGA



GGAGGTTACCAACGCTACCGAAACTGTCGAGAGCAAATCTCTGGGTAAGCTGTGTATGAAG



GGCCGTAGCTACAATGATCTTGGTAACTGTCATCCTATCGGCATACTAATTGGGACCCCAG



CCTGTGACTTGCACCTTACTGGTACTTGGGACACCTTGATAGAACGTGAAAATGCCGTGGC



TTACTGTTACCCGGGCGCCACTGTGAACGAGGAGGCCCTGCGGCAGAAAATTATGGAGTCA



GGTGGCATCTCTAAGATTTCAACAGGCTTCACCTACGGGACAAGTATTAATTCAGCTGGGA



CTACCAAAGCCTGTATGCGAAATGGGGGTAACTCTTTTTATGCCGAGCTTAAGTGGCTGGT



TTCTAAAAATAAAGGACAGAATTTTCCACAAACTACAAACACTTATCGGAACACGGACACC



GCCGAGCACCTGATTATTTGGGGAATCCACCATCCATCTAGCACTCAGGAAAAAAATGATC



TGTATGGTACTCAGAGCCTGAGCATTAGCGTAGGCAGCTCTACATATCAGAATAACTTTGT



GCCTGTTGTAGGGGCTAGGCCTCAAGTGAACGGGCAGAGCGGTAGGATTGATTTCCACTGG



ACCCTGTTGCAGCCCGGAGACAATATAACCTTCTCGCATAACGGAGGGCTGATAGCCCCGT



CCAGAGTGAGTAAGCTGATCGGTAGAGGACTGGGAATTCAGAGCGAAGCCCCAATTGATAA



CGGCTGCGAGAGTAAGTGCTTCTGGAAGGGCGGTAGCATTAACACGAAGTTGCCATTTCAG



AATCTCAGTCCACGTACGGTGGGCCAGTGTCCCAAATACGTCAACAAACGCTCTCTGATGC



TTGCTACTGGGATGAGGAATGTCCCCGAGATAATGCATGGACGCGGGTTGTTTGGCGCCAT



CGCCGGGTTTATTGAGAATGGCTGGGAGGGCATGGTAGATGGATGGTACGGTTTTCGGCAT



CAGAATGCCCAGGGGACCGGACAGGCTGCGGATTACAAGTCTACACAGGCAGCCATCGATC



AGATCACAGGCAAGTTGAACCGACTGATCGAAAAGACAAACACAGAGTTCGAATCAATTGA



GAGCGAGTTTTCCGAGATAGAGCATCAGATTGGCAACATTATTAATTGGACTAAAGATAGC



ATTACCGATATATGGACCTATCAGGCAGAACTGCTCGTCGCAATGGAGAATCAGCACACTA



TCGATATGGCCGATTCAGAGATGCTAAACCTGTACGAACGCGTTCGCAAGCAACTCAGACA



GAATGCTGAGGAGGATGGCAAGGGTTGTTTCGAGATCTACCATGCGTGCGACGATAGTTGT



ATGGAGAGCATTCGGAATAATACCTACGATCACTCCCAGTACAGGGAAGAGGCTTTGTTAA



ATAGACTGAATATAAACCCTGTCAAGCTATCATCAGGTTACAAAGACATCATTCTTTGGTT



CTCTTTTGGCGCTTCCTGTCTGATCCTTCTAGCCGTGGTGATGGGTCTGGTTTTCTTTTGC



CTCAAAAATGGAAACATGCGTTGTACGATATGTATA





726
ATGTATAAGATAGTTGTGATAATTGCGCTGTTGGGGGCCGTGAAGGGACTCGACAAAATCT



GCCTCGGCCACCATGCAGTCGCCAACGGTACTATTGTGAAAACCCTAACCAACGAACAGGA



GGAGGTTACTAATGCCACCGAGACTGTCGAATCAACCGGCATCAACCGCCTCTGTATGAAA



GGCCGCAAACACAAGGATCTGGGAAACTGCCACCCCATCGGCATGTTAATAGGCACCCCCG



CATGCGATCTGCACCTGACAGGAATGTGGGACACCTTGATCGAGCGTGAAAACGCGATCGC



TTATTGTTACCCTGGCGCGACTGTGAATGTCGAGGCTCTGAGACAGAAGATTATGGAAAGC



GGTGGCATTAATAAGATTAGTACTGGATTTACTTACGGTTCCAGCATAAATTCTGCAGGGA



CCACTCGCGCGTGCATGCGCAATGGTGGCAATAGTTTCTACGCTGAACTTAAGTGGCTTGT



ATCTAAGTCGAAGGGACAAAATTTTCCACAGACGACCAACACATATAGGAACACAGATACA



GCAGAGCACCTTATCATGTGGGGCATTCATCATCCGAGCAGTACTCAGGAGAAGAACGACC



TGTACGGGACTCAGTCTTTGAGCATTAGCGTGGGAAGCAGCACTTACCGGAACAATTTTGT



TCCTGTAGTGGGCGCTCGTCCTCAGGTCAATGGGCAGTCAGGACGGATAGACTTTCACTGG



ACACTCGTGCAGCCCGGCGATAACATTACTTTTTCACATAATGGGGGTCTGATAGCACCAA



GTCGCGTCTCTAAACTGATTGGTAGGGGCCTGGGAATTCAGTCCGACGCTCCCATCGACAA



TAATTGCGAATCCAAATGCTTTTGGGGGGGAGGGTCTATTAACACCAGGTTGCCATTTCAG



AATCTGTCCCCGCGGACAGTTGGCCAGTGCCCCAAGTATGTCAACCGCAGGTCCCTGATGC



TCGCTACAGGAATGCGCAATGTGCCAGAGTTGATCCAGGGACGGGGCTTGTTCGGTGCAAT



TGCAGGCTTTCTGGAAAACGGCTGGGAGGGGATGGTCGATGGCGGGTACGGCTTTCGCCAC



CAGAACGCCCAGGGAACAGGCCAGGCCGCCGATTACAAATCTACCCAGGCTGCCATCGATC



AAATTACAGGGAAATTAAACCGACTAGTCGAGAAGACCAACACTGAATTTGAATCCATTGA



ATCTGAGTTTTCTGAGATAGAGCACCAGATTGGAAATGTTATTAATTGGACAAAGGATAGC



ATCACAGACATATGGACATACCAAGCCGAATTGCTCGTGGCGATGGAAAACCAGCACACAA



TTGATATGGCCGACAGCGAAATGCTAAACCTTTACGAGAGAGTCCGAAAGCAGCTAAGGCA



GAATGCCGAGGAAGACGGTAAAGGCTGTTTCGAAATCTACCATGCATGCGACGATTCATGC



ATGGAAAGTATACGCAACAATACCTATGATCATTCCCAGTACCGCGAAGAGGCCTTGCTGA



ACCGACTCAACATCAACCCTGTAACCCTGAGTTCTGGGTATAAGGACATCATCCTGTGGTT



TAGTTTTGGAGCATCGTGCTTTGTGCTGCTCGCTGTGGTGATGGGATTGTTCTTCTTTTGC



TTAAAGAACGGCAACATGAGGTGCACCATCTGTATA





727
ATGTATAAGATTGTCGTCATCATCGCCCTACTGGGCGCGGTGAAAGGGCTAGATAAGATAT



GTCTCGGGCACCATGCAGTGGCTAACGGAACAATTGTTAAAACCTTAACGAATGAACAGGA



GAAGGTTACCAACGCTACTGAAACAGTTGAGTCAACTGGCCTCAACAGACTGTGCATGAAG



GGTCGCAAACACAAAGATTTAGGCAACTGCCACCCCATTGGTATGTTAATCGGAACCCCAG



CCTGTGATCTCCATCTGACCGGCACATGGGATACGATAATTGAGAGGGAGAATGCTATTGC



CTACTGTTACCCTGGCGCCACCGTCAATGAAGAGGCCCTCAGACAGAAGATCATGGAGTCC



GGGGGTATCGACAAAATTTCCACCGGTTTCACCTACGGTAGCTCCATCAATAGTGCCGGCA



CTACACGCGCATGCATGCGCAATGGGGGCAACTCATTCTACGCGGAGCTAAAGTGGCTCGT



TAGTAAGAGCAAAGGACAGAACTTCCCACAGACTACTAACACTTATAGGAACACTGATACG



GCAGAACATTTAATTATGTGGGGCATACACCATCCTAGCTCAACGCAGGAGAAGAATGACC



TATACGGTACCCAATCCCTCTCCATCAGTGTGGGGAGCTCTACTTATAGAAACAACTTCGT



GCCCGTCGTAGGCGCTCGACCTCAGGTCAATGGACAGTCTGGCAGAATCGACTTCCACTGG



ACTCTGGTACAACCTGGCGATAATATTACCTTTAGCCACAATGGCGGCTTAATAGCACCAT



CTCGTGTGAGCAAGTTGATTGGGCGAGGATTGGGCATTCAGTCGGACGCGCCCATTGATAA



CAACTGTGAATCCAAATGCTTCTGGCGTGGAGGGTCAATCAATACCCGCCTCCCCTTCCAG



AACCTGTCCCCGAGGACTGTGGGCCAATGTCCCAAATATGTGAACAAGAGGTCTCTGATGC



TGGCAACCGGGATGAGAAATGTGCCCGAACTGATCCAGGGACGCGGGCTATTCGGGGCTAT



AGCAGGTTTTCTCGAAAATGGATGGGAGGGCATGGTGGACGGGTGGTACGGCTTTCGCCAC



CAGAATGCACAGGGAACCGGCCAGGCCGCAGATTACAAATCCACCCAGGCGGCCATCGATC



AGATAACCGGCAAATTGAACAGGCTGGTTGAAAAAACAAATACAGAATTCGAATCCATTGA



GTCTGAGTTTAGCGAGATAGAGCACCAGATAGGCAATGTCATAAACTGGACCAAAGATTCC



ATTACAGATATCTGGACATATCAGGCAGAGCTGCTCGTGGCAATGGAGAATCAGCATACTA



TTGATATGGCAGACAGCGAGATGCTCAATCTGTATGAACGGGTAAGGAAACAGCTGCGTCA



GAATGCTGAGGAGGACGGTAAGGGGTGTTTTGAAATATACCACGCTTGCGATGACAGTTGC



ATGGAATCTATTCGCAACAATACGTACGACCACTCTCAGTACCGCGAGGAGGCCCTTCTTA



ACAGGCTGAACATTAATCCCGTCACACTAAGCTCCGGTTATAAGGACATCATTCTTTGGTT



TTCATTTGGCGCTAGCTGCTTCGTTCTGCTTGCCGTGGTTATGGGCCTGGTCTTTTTCTGC



CTTAAGAACGGAAATATGAGGTGTACAATCTGCATT





728
ATGTACAAGATAGTGGTCATTATTGCTCTGTTGGGAGCTGTGAAAGGGCTTGATAAGATTT



GCCTGGGCCACCACGCGGTGGCGAATGGGACGATCGTGAAAACTCTCACAAACGAGCAGGA



AGAAGTGACTAACGCTACAGAGACCGTGGAAAGCACGGGGATCAATAGGCTGTGCATGAAG



GGCCGGAAGCATAAGGATCTAGGCAACTGCCACCCAATTGGCATGCTCATCGGGACGCCCG



CATGCGATCTGCACCTGACAGGGATGTGGGACACCCTTATCGAGCGTGAGAACGCCATCGC



CTATTGCTACCCCGGGGCAACAGTGAATGTGGAAGCACTGAGGCAGAAGATCATGGAGAGC



GGGGGAATCAACAAGATATCCACAGGCTTCACATATGGATCATCAATCAACAGCGCCGGCA



CCACCCGGGCATGTATGCGGAACGGGGGCAATAGTTTCTACGCTGAGCTCAAATGGCTTGT



TAGTAAGTCTAAGGGGCAGAACTTTCCACAGACTACGAATACGTACCGCAATACGGATACT



GCAGAACACTTAATAATGTGGGGAATCCACCACCCAAGTTCCACCCAGGAGAAAAACGATT



TGTACGGAACCCAATCCCTGTCAATATCCGTGGGAAGCTCTACCTATAGGAACAATTTCGT



CCCGGTCGTGGGAGCTCGGCCACAGGTGAACGGACAGAGTGGAAGGATCGACTTCCACTGG



ACGCTCGTGCAACCAGGTGATAATATCACGTTCAGTCACAACGGCGGACTGATTGCTCCAA



GCCGCGTCAGCAAGCTGATAGGCCGGGGGCTGGGGATCCAGTCAGACGCCCCTATTGACAA



TAATTGTGAGTCCAAATGTTTCTGGAGAGGTGGCTCTATCAATACCCGCCTTCCCTTTCAG



AACTTGTCCCCACGGACAGTGGGACAGTGCCCCAAGTATGTCAATCGCAGGTCACTGATGC



TGGCAACCGGGATGAGGAACGTTCCCGAACTCATTCAAGGCCGGGGTCTATTTGGCGCAAT



CGCCGGCTTCCTGGAAAATGGCTGGGAAGGAATGGTGGACGGGTGGTATGGTTTCCGGCAC



CAGAATGCTCAGGGCACAGGCCAGGCTGCTGATTATAAGTCTACTCAGGCAGCCATTGACC



AGATCACCGGTAAGCTCAATAGATTGGTAGAAAAAACAAACACGGAGTTCGAGAGCATCGA



GTCTGAATTTTCCGAGATCGAACATCAGATCGGGAACGTCATCAATTGGACCAAGGACTCT



ATTACGGACATTTGGACTTACCAAGCTGAGCTCCTGGTGGCAATGGAGAACCAGCATACCA



TTGATATGGCCGACTCTGAGATGCTGAACTTATACGAACGGGTGCGAAAGCAACTGAGGCA



GAACGCCGAGGAGGATGGTAAGGGCTGCTTTGAGATATATCATGCCTGTGATGATTCTTGC



ATGGAGAGCATCCGTAATAATACTTACGACCATAGCCAGTATCGAGAGGAAGCGCTACTCA



ATCGATTAAATATCAACCCTGTGACCCTATCTTCGGGTTACAAGGACATAATTCTGTGGTT



CTCATTCGGCGCATCTTGTTTCGTATTGCTCGCAGTGGTGATGGGCCTTTTTTTCTTCTGT



CTGAAAAATGGTAACATGCGCTGTACTATATGCATT





729
ATGTACAAAATAGTGGTGATTATCGCCCTCCTGGGTGCTGTCAAGGGCCTGGATAAGATCT



GTCTTGGCCATCACGCTGTCGCAAATGGCACTATAGTCAAAACTCTGACAAACGAGCAGGA



GGAGGTGACCAACGCAACCGAGACGGTGGAATCTACTGGAATTAACAGGCTGTGTATGAAG



GGTAGGAAGCATAAGGATCTAGGTAATTGCCATCCCATCGGTATGCTGATCGGAACTCCCG



CGTGCGACTTACATCTCACTGGAATGTGGGACACGTTGATCGAGCGGGAGAATGCTATTGC



GTACTGCTACCCCGGCGCTACGGTGAACGTCGAGGCTTTGCGTCAGAAGATCATGGAGAGC



GGGGGTATCAACAAAATAAGTACCGGATTCACATACGGAAGCAGTATCAATTCCGCCGGAA



CAACCCGCGCATGCATGCGGAACGGTGGTAATTCCTTCTATGCTGAACTCAAGTGGCTCGT



GTCAAAGAGCAAGGGACAAAACTTTCCCCAAACGACCAATACCTATAGAAATACAGACACT



GCTGAGCATCTGATCATGTGGGGCATTCACCATCCATCATCTACTCAGGAAAAAAACGACC



TGTACGGTACCCAGAGCCTGTCTATTAGCGTCGGATCATCGACCTACAGGAATAACTTCGT



GCCAGTCGTTGGGGCCCGCCCTCAGGTGAACGGCCAGAGCGGACGGATTGATTTTCACTGG



ACCCTGGTCCAGCCAGGTGATAACATCACCTTCTCACATAACGGAGGCCTGATCGCCCCCA



GCCGAGTTAGTAAACTAATCGGAAGGGGACTTGGTATCCAGAGTGACGCACCCATCGACAA



CAACTGTGAGTCTAAGTGTTTTTGGCGAGGGGGGAGTATCAATACTAGACTGCCGTTTCAG



AATTTGAGTCCCAGAACAGTGGGCCAGTGCCCTAAGTACGTGAACCGGAGGTCTCTGATGC



TCGCAACCGGGATGCGGAATGTTCCCGAGCTGATCCAGGGACGCGGTCTCTTCGGTGCCAT



CGCTGGGTTTCTCGAAAACGGCTGGGAGGGAATGGTGGATGGTTGGTACGGCTTCAGACAT



CAAAACGCTCAAGGAACTGGCCAGGCCGCTGACTATAAGTCAACTCAGGCTGCAATCGATC



AGATCACCGGGAAACTGAATCGCCTCGTGGAGAAGACAAACACCGAGTTCGAGTCAATCGA



GTCCGAGTTCTCCGAGATCGAACACCAAATAGGCAACGTTATAAACTGGACGAAGGACTCC



ATTACGGACATCTGGACATACCAGGCCGAGCTCCTCGTTGCTATGGAGAACCAACACACAA



TCGATATGGCTGATTCCGAGATGCTCAATCTCTACGAGAGGGTGAGGAAACAGTTGAGGCA



GAATGCAGAAGAGGATGGAAAGGGATGCTTTGAAATCTACCATGCCTGCGACGACTCATGC



ATGGAGTCCATTAGAAATAACACTTATGACCATTCGCAATACAGAGAAGAAGCTCTTCTCA



ACAGGCTCAACATCAACCCGGTCACCCTTAGCTCCGGCTACAAGGACATTATCCTCTGGTT



CTCTTTCGGGGCATCATGCTTTGTTCTCCTGGCAGTGGTGATGGGTCTCTTCTTCTTCTGT



CTCAAAAACGGCAACATGAGATGTACGATTTGTATC





730
ATGTATAAGATCGTGGTGATCATAGCGCTCCTGGGCGCCGTGAAAGGACTGGATAAAATTT



GTCTGGGGCATCATGCAGTCGCCAACGGAACCATCGTAAAGACTTTGACTAATGAGCAGGA



AAAGGTTACCAATGCAACCGAAACCGTGGAGAGCACCGGTCTGAACCGCCTCTGCATGAAG



GGCCGTAAACACAAAGATCTGGGCAATTGTCATCCCATCGGAATGCTAATCGGCACTCCTG



CCTGTGACCTACACTTGACCGGGACTTGGGATACCATTATAGAGAGAGAGAATGCTATTGC



CTACTGTTACCCCGGGGCAACCGTGAACGAAGAAGCTTTGAGACAGAAAATTATGGAGAGT



GGCGGAATAGATAAGATTAGCACAGGGTTCACCTACGGAAGCTCTATTAATAGTGCGGGCA



CCACAAGGGCATGCATGCGGAACGGCGGTAACTCTTTCTATGCTGAGTTGAAGTGGCTCGT



GAGCAAGTCTAAAGGGCAGAACTTTCCACAAACCACCAACACTTACAGAAACACGGATACT



GCCGAGCACCTCATCATGTGGGGCATCCACCATCCTTCATCAACACAAGAGAAGAACGACT



TATATGGTACTCAGAGTCTGTCGATTAGCGTCGGCTCTTCAACGTACAGGAACAATTTCGT



TCCTGTAGTCGGGGCCCGGCCACAAGTAAATGGACAGAGGGGGAGGATTGATTTCCATTGG



ACGCTGGTCCAGCCCGGAGATAACATAACTTTCTCTCATAACGGAGGACTCATAGCTCCAT



CAAGGGTGAGCAAACTGATTGGCAGGGGATTGGGAATCCAGTCTGACGCTCCCATCGACAA



CAATTGTGAGAGTAAGTGCTTTTGGCGGGGCGGTTCCATCAACACACGACTGCCTTTCCAG



AATCTGAGTCCCAGAACTGTGGGGCAGTGCCCAAAGTATGTGAATAAAAGATCTTTGATGT



TAGCTACTGGAATGAGAAATGTGCCTGAGCTAATACAGGGTAGAGGTCTGTTCGGAGCAAT



AGCAGGGTTCCTGGAGAATGGGTGGGAAGGCATGGTCGACGGATGGTACGGTTTCCGGCAT



CAGAACGCACAAGGTACAGGGCAGGCGGCTGATTACAAATCTACACAAGCCGCTATTGACC



AAATCACCGGCAAATTGAACCGGCTCGTGGAGAAGACGAATACGGAGTTTGAATCTATTGA



GAGTGAGTTCAGTGAGATTGAACATCAGATTGGCAACGTTATAAATTGGACCAAGGACAGC



ATAACTGATATATGGACCTATCAAGCCGAGCTTCTCGTGGCCATGGAAAATCAGCATACTA



TCGACATGGCTGACTCTGAGATGCTCAACTTATACGAACGTGTAAGGAAGCAGCTGCGGCA



AAACGCCGAGGAAGACGGTAAGGGCTGCTTCGAGATTTATCACGCGTGCGATGACTCTTGT



ATGGAGTCCATCAGAAACAACACCTACGATCACTCACAGTATAGAGAAGAGGCTTTGTTGA



ATCGGCTCAACATCAATCCAGTTACCCTTTCAAGTGGTTACAAGGACATCATCCTATGGTT



TAGCTTCGGTGCCTCTTGTTTCGTGTTGCTGGCGGTCGTTATGGGGTTGGTCTTTTTTTGC



TTGAAAAATGGTAATATGCGGTGTACCATTTGCATC





731
ATGTACAAGATTGTGGTGATCATCGCGCTGCTTGGTGCTGTGAAGGGACTCGACAAAATAT



GCCTGGGGCATCATGCTGTCGCCAATGGGACAATTGTGAAGACATTGACGAACGAGCAGGA



GGAAGTCACTAACGCAACAGAGACAGTTGAGAGCACCGGGATTAACCGACTGTGTATGAAG



GGTCGGAAGCACAAGGACTTGGGTAACTGTCACCCGATCGGCATGTTAATCGGAACCCCTG



CCTGTGACCTGCATCTGACCGGCATGTGGGACACACTGATAGAAAGGGAAAACGCCATTGC



ATACTGCTACCCCGGGGCTACGGTAAATGTGGAGGCTCTCCGGCAGAAGATAATGGAGTCA



GGCGGCATCAACAAGATCTCTACCGGGTTCACGTACGGCTCTTCTATCAATTCAGCTGGAA



CTACCCGCGCATGCATGAGAAACGGTGGGAACTCCTTTTACGCCGAACTGAAATGGCTAGT



GTCCAAATCTAAGGGCCAGAATTTCCCACAGACCACTAATACTTACAGAAACACGGATACA



GCCGAACACTTGATAATGTGGGGGATTCATCACCCATCATCTACACAGGAAAAAAATGATT



TGTACGGTACCCAGAGCCTTAGCATTTCTGTGGGCAGCTCTACCTACAGAAATAACTTCGT



GCCAGTAGTAGGTGCTCGACCGCAGGTTAATGGCCAAAGCGGTAGAATCGATTTTCACTGG



ACATTGGTGCAGCCGGGCGACAACATAACCTTTTCCCATAATGGGGGACTTATTGCACCTT



CCAGGGTGTCCAAACTCATAGGCCGCGGCCTCGGCATTCAAAGCGATGCTCCCATTGACAA



TAATTGTGAATCAAAGTGCTTCTGGCGTGGAGGAAGTATAAACACACGGCTGCCCTTCCAG



AACTTAAGCCCAAGAACCGTGGGGCAGTGCCCTAAGTACGTTAATAGGCGGTCGCTTATGC



TTGCAACAGGTATGAGGAACGTCCCGGAGCTTATCCAAGGCAGGGGACTTTTCGGAGCTAT



CGCCGGTTTTTTAGAGAACGGATGGGAAGGAATGGTGGACGGTTGGTATGGATTCCGGCAC



CAAAATGCTCAGGGCACCGGGCAGGCGGCTGACTACAAATCTACACAGGCGGCTATCGATC



AGATTACGGGAAAGCTGAATAGGTTAGTGGAAAAAACAAACACAGAGTTTGAGAGCATCGA



AAGCGAGTTTTCTGAGATAGAGCATCAGATCGGTAATGTAATCAACTGGACCAAAGACAGC



ATCACAGACATATGGACGTACCAGGCTGAGCTTCTAGTCGCCATGGAAAACCAGCACACTA



TTGATATGGCAGATTCTGAGATGCTTAATCTGTATGAACGAGTGCGAAAACAGCTGCGCCA



GAACGCCGAAGAGGATGGGAAGGGCTGTTTCGAAATCTACCACGCCTGCGACGACTCCTGC



ATGGAAAGCATTAGAAATAATACCTACGATCATTCGCAATATCGGGAAGAGGCCCTCCTGA



ATCGCCTAAATATCAATCCTGTTACACTAAGCAGCGGCTACAAAGACATTATTTTATGGTT



CTCCTTCGGCGCCTCCTGCTTCGTACTATTAGCCGTAGTTATGGGTCTGTTCTTCTTTTGC



CTTAAGAACGGTAACATGAGATGCACAATCTGTATA





732
ATGTACAAAATTGTTGTGATCATTGCCCTCCTGGGGGCAGTGAAGGGACTGGACAAAATCT



GCCTGGGTCACCACGCCGTGGCGAACGGCACCATTGTGAAGACCCTGACCAATGAACAGGA



AGAGGTGACCAATGCTACCGAGACTGTAGAGAGTACAGGCATCAATAGGTTATGCATGAAA



GGCCGCAAACACAAGGACTTGGGAAACTGCCACCCTATAGGCATGTTGATCGGGACGCCAG



CTTGCGACTTGCACCTTACAGGAATGTGGGATACCTTGATAGAAAGGGAAAACGCTATCGC



TTACTGCTACCCGGGCGCTACCGTCAATGTGGAAGCACTGCGACAGAAAATTATGGAGAGT



GGTGGCATAAATAAAATATCAACTGGGTTCACATACGGAAGCTCAATCAATAGCGCGGGCA



CAACACGAGCCTGCATGCGTAACGGAGGAAACAGCTTTTATGCAGAGCTCAAATGGTTAGT



TTCAAAATCTAAGGGGCAGAACTTTCCTCAAACCACTAACACGTATCGGAATACCGACACA



GCAGAGCACTTAATAATGTGGGGCATACATCATCCCTCAAGCACACAGGAAAAGAACGACC



TGTACGGAACGCAGTCCTTATCAATCTCTGTGGGGTCCAGCACATACCGAAACAACTTTGT



ACCAGTCGTGGGTGCTCGCCCACAAGTGAACGGCCAGTCTGGGCGCATCGACTTTCACTGG



ACTTTGGTTCAGCCTGGTGATAATATCACCTTTAGCCATAATGGCGGACTCATAGCGCCAA



GCAGGGTGTCCAAACTTATCGGACGTGGGTTGGGTATTCAGAGCGACGCACCAATCGACAA



TAACTGCGAGTCAAAGTGTTTTTGGAGAGGGGGGTCAATCAACACCCGCCTGCCCTTCCAG



AACCTGTCTCCCCGTACGGTGGGGCAGTGTCCAAAGTACGTGAATAGGCGGAGCCTGATGC



TGGCCACAGGGATGCGCAACGTGCCTGAGCTCATTCAAGGCCGGGGCTTGTTTGGAGCCAT



CGCGGGTTTTCTCGAAAACGGGTGGGAAGGGATGGTCGATGGCTGGTACGGCTTTCGGCAC



CAGAATGCTCAGGGAACGGGGCAGGCTGCCGACTACAAGTCAACGCAGGCGGCCATCGATC



AAATCACCGGCAAGCTCAACAGGCTCGTGGAAAAAACCAATACGGAGTTCGAAAGTATCGA



AAGCGAGTTCAGCGAAATTGAGCACCAGATCGGCAATGTAATCAATTGGACTAAGGATAGC



ATCACCGATATCTGGACATACCAAGCTGAGCTGTTAGTCGCCATGGAGAATCAGCATACAA



TAGACATGGCTGATAGTGAAATGTTGAATCTGTACGAGAGGGTTAGGAAACAGCTGCGCCA



GAATGCTGAGGAAGACGGAAAGGGCTGCTTTGAAATCTATCACGCTTGCGACGATTCCTGT



ATGGAGTCCATACGAAATAATACGTACGACCATTCCCAGTACCGCGAAGAGGCTCTCCTGA



ATCGGCTGAACATCAACCCTGTGACACTTAGCTCGGGCTATAAGGACATAATTTTGTGGTT



CTCTTTTGGGGCATCATGTTTTGTCTTGCTGGCCGTCGTTATGGGGCTCTTCTTCTTCTGT



CTAAAAAATGGAAACATGCGGTGCACCATTTGTATT





733
ATGTATAAAATCGTGGTGATCATTGCTCTGTTAGGCGCCGTGAAGGGCCTGGACAAGATTT



GCCTAGGACATCATGCCGTCGCTAACGGCACTATCGTGAAGACTCTGACCAATGAGAAAGA



GGAGGTGACTAACGCAACAGAAACAGTTGAGTCAACTGGCCTGAACCGGCTCTGCATGAAA



GGGAGAAAGCATAAAGACCTAGGCAATTGCCATCCTATTGGTATGCTCATTGGCTCTCCCG



CCTGTGACCTGCATCTTACTGGAACGTGGGACACCCTGATTGAAAGAGAAAACGCCATCGC



GTATTGCTACCCGGGGGCCACCGTGAACGGAGAAGCGTTACGCCAAAAGATCATGGAGTCA



GGCGGCATCGATAAGATCAGCACTGGCTTTACCTACGAAAGTAGCATCAACAGCGCTGGAA



CCACCCGCGCCTGTATGAGAAACGGGGGTAATTCCTTCTATGCGGAGCTGAAATGGCTTGT



GTCTAAATCCAAAGGCCAGAACTTTCCACAGACAACGAACACTTATCGGAATACTGACACA



GCAGAGCATCTTATCATGTGGGGGATCCACCATCCTAGTTCCACGCAGGAGAAGAATGACC



TGTATGGGACACAAAGCCTGTCTATTAGCGTGGGATCATCAACTTACAGGAACAATTTTGT



CCCTGTGGTGGGCGCCAGGCCCCAGGTAAACGGACAGAGTGGACGCATCGACTTTCATTGG



ACTCTCGTGCAGCCTGGGGATAATATTACCTTCAGCCATAATGGTGGCCTGATAGCACCCT



CAAGAGTGTCAAAACTCATCGGTCGCGGATTGGGGATTCAATCTGACGCCCCTATAGATAA



CAATTGCGAGAGCAAGTGCTTTTGGAGAGGAGGCAGCATCAACACCCGCCTTCCCTTTCAG



AATCTGAGTCCCCGGACGGTTGGGCAGTGTCCTAAATATGTCAATAAGCGGTCACTCATGT



TGGCAACTGGCATGCGCAACGTACCTGAGCTCATGCAGGGAAGGGGCCTCTTTGGAGCTAT



TGCAGGGTTCCTGGAGAACGGCTGGGAGGGGATGGTAGACGGATGGTACGGATTCCGGCAT



CAAAATGCGCAAGGCACTGGTCAAGCTGCTGATTATAAGTCCACCCAGGCCGCTATTGATC



AGATTACCGGAAAGCTGAACCGGCTGGTGGAAAAGACCAATACAGAATTTGAGAGCATTGA



ATCGGAGTTTAGCGAAATCGAACATCAAATTGGGAACGTCATAAACTGGACAAAAGACAGC



ATCACCGATATCTGGACATACCAGGCGGAGCTGCTAGTGGCGATGGAGAATCAGCACACGA



TTGATATGGCCGACTCTGAGATGCTGAATCTGTATGAGCGGGTTAGAAAGCAGCTGAGGCA



AAACGCAGAAGAAGATGGTAAAGGATGCTTTGAGATCTATCATGCCTGCGATGACTCATGT



ATGGAATCTATCCGTAACAATACATACGATCACAGTCAGTATCGGGAGGAAGCTCTGCTGA



ATAGGCTAAACATCAATCCCGTGACCCTCTCGAGTGGCTATAAGGATATCATCTTGTGGTT



CTCTTTCGGCGCCAGCTGTTTCGTGCTACTGGCCGTCGTGATGGGGCTGGTATTCTTCTGC



CTGAAGAACGGTAATATGCGCTGCACCATATGTATT





734
ATGTACAAGATCGTGGTCATCATTGCACTGCTTGGCGCTGTGAAAGGATTAGACAAGATTT



GCCTCGGCCACCACGCCGTCGCCAATGGGACCATCGTTAAGACATTAACAAATGAACAAGA



AGAGGTAACCAACGCCACCGAGACCGTGGAGTCGACAGGCATCAACCGGTTATGCATGAAA



GGGCGGAAACACAAAGATCTGGGGAACTGCCATCCAATCGGAATGCTCATTGGCACCCCAG



CGTGCGATCTCCATCTCACTGGCATGTGGGATACATTAATTGAGAGGGAGAATGCAATCGC



ATATTGCTACCCTGGCGCCACTGTCAACGTCGAGGCCCTGCGCCAGAAAATAATGGAATCA



GGTGGCATAAACAAGATTTCCACCGGATTTACTTATGGCTCTTCCATCAACAGCGCTGGCA



CCACACGGGCTTGTATGCGAAACGGGGGCAACTCATTTTATGCAGAACTGAAGTGGCTTGT



CTCAAAAAGTAAGGGTCAGAACTTTCCACAGACAACAAATACATACAGGAATACCGACACT



GCAGAGCATCTGATCATGTGGGGCATCCACCATCCTAGTTCGACACAGGAGAAGAACGACC



TGTATGGCACCCAATCACTGAGTATCTCTGTGGGGAGTAGTACTTATCGGAACAATTTTGT



GCCAGTCGTGGGCGCAAGACCACAAGTCAATGGCCAGAGTGGCCGTATCGACTTCCATTGG



ACCCTGGTACAGCCTGGTGATAACATCACCTTTAGCCACAACGGAGGACTGATTGCACCGT



CAAGAGTTTCAAAACTGATCGGCCGAGGCCTGGGAATCCAGAGCGACGCTCCCATCGATAA



TAATTGTGAAAGTAAGTGCTTCTGGCGGGGTGGATCCATCAACACCCGTCTACCCTTTCAG



AATCTGTCACCCCGGACCGTCGGACAGTGCCCAAAATACGTGAACAGGCGCAGTTTGATGT



TAGCTACAGGGATGAGAAACGTGCCAGAACTGATTCAGGGACGCGGACTGTTCGGCGCCAT



CGCCGGCTTCCTCGAAAACGGTTGGGAGGGTATGGTGGACGGTTGGTATGGCTTCAGGCAT



CAGAACGCCCAGGGGACAGGCCAGGCCGCTGACTATAAGAGCACTCAGGCGGCTATCGACC



AGATCACTGGGAAGCTCAATCGTCTCGTCGAGAAAACGAATACCGAGTTTGAGAGCATCGA



AAGTGAATTCTCTGAGATAGAGCACCAGATCGGTAATGTGATCAATTGGACAAAGGACTCG



ATTACTGACATCTGGACGTACCAAGCCGAGCTGCTCGTCGCCATGGAAAATCAGCATACCA



TTGATATGGCTGACTCAGAGATGCTTAACTTGTACGAACGGGTCCGGAAACAACTGAGACA



GAATGCCGAAGAGGACGGGAAAGGCTGTTTTGAAATCTATCACGCCTGTGATGATTCTTGT



ATGGAAAGCATTAGAAACAATACATACGACCATTCACAGTACAGGGAGGAGGCTTTACTCA



ATCGCCTGAACATCAATCCCGTAACATTGAGCTCTGGATATAAAGACATTATCCTCTGGTT



CTCCTTTGGTGCCTCTTGTTTTGTACTCCTGGCAGTGGTTATGGGTCTCTTCTTCTTTTGT



CTAAAGAACGGTAATATGAGGTGTACCATTTGCATA





735
ATGTACAAGATCGTGGTGATTATTGCCCTGTTGGGGGCCGTGAAGGGCTTGGACAAGATAT



GCCTTGGTCACCATGCTGTGGCCAACGGCACTATCGTCAAAACACTGACAAACGAGCAGGA



AGAGGTGACCAACGCCACGGAGACTGTAGAAAGCACCGGGATTAACCGACTATGTATGAAA



GGCCGCAAACACAAGGACCTCGGGAACTGCCATCCCATCGGCATGTTAATAGGCACCCCCG



CTTGCGATCTGCACCTGACAGGGATGTGGGATACCCTAATTGAGCGCGAGAACGCAATTGC



CTATTGTTACCCAGGAGCCACAGTAAATGTAGAAGCTTTAAGGCAGAAGATTATGGAGAGT



GGAGGGATTAACAAGATCAGCACGGGCTTCACATACGGTTCCTCCATCAATTCTGCTGGAA



CCACCAGGGCATGCATGCGTAATGGGGGAAACTCATTCTACGCAGAGCTAAAGTGGCTGGT



TTCCAAGTCTAAGGGACAGAACTTCCCGCAGACAACGAATACTTATCGGAACACCGACACT



GCCGAACATTTAATCATGTGGGGGATCCACCACCCCAGTTCTACCCAGGAGAAAAATGATC



TCTACGGTACTCAGTCCCTGTCCATCTCCGTTGGTTCCTCCACCTATCGGAATAATTTTGT



CCCTGTTGTGGGAGCACGGCCACAGGTGAATGGCCAGTCCGGGAGGATAGACTTTCACTGG



ACCCTTGTTCAGCCCGGGGACAATATCACTTTCTCACATAATGGGGGCCTGATTGCTCCTT



CCAGAGTGAGTAAATTGATAGGCCGGGGGCTGGGCATCCAATCAGATGCACCCATTGATAA



CAACTGCGAGTCCAAATGCTTCTGGCGCGGAGGCAGCATCAATACCCGACTGCCCTTCCAG



AACCTGTCTCCTAGGACAGTTGGCCAGTGTCCCAAATATGTAAACCGCAGATCACTGATGC



TGGCTACCGGTATGAGAAACGTCCCAGAGCTAATTCAAGGCCGAGGACTTTTTGGCGCTAT



TGCAGGATTCCTTGAGAACGGGTGGGAGGGCATGGTCGACGGCTGGTACGGGTTCAGACAC



CAAAACGCTCAGGGAACAGGCCAAGCCGCGGACTATAAATCAACACAAGCGGCCATTGATC



AGATAACCGGCAAGCTGAATAGGCTGGTGGAAAAGACTAACACTGAGTTTGAAAGCATCGA



GTCGGAATTCTCTGAGATTGAACACCAGATTGGAAATGTAATCAACTGGACAAAGGATTCC



ATCACCGACATCTGGACTTATCAAGCAGAACTGTTAGTGGCCATGGAAAATCAGCATACCA



TCGACATGGCCGACAGCGAGATGCTGAATCTGTACGAAGGGGTTCGTAAACAGCTGAGGCA



GAACGCAGAGGAGGACGGTAAGGGATGCTTTGAAATTTATCACGCTTGTGACGATAGTTGT



ATGGAGAGCATTAGGAACAACACTTACGACCACTCTCAGTATAGGGAAGAAGCACTCCTTA



ACAGGCTGAACATCAACCCTGTGACGCTCTCTTCCGGGTATAAAGACATCATCCTGTGGTT



TTCATTTGGCGCTTCATGTTTTGTACTGCTAGCAGTGGTGATGGGTCTCTTCTTTTTTTGC



CTCAAAAACGGGAACATGAGGTGCACTATTTGCATC





736
ATGTACAAGATCGTAGTGATAATCGCTCTACTAGGAGCTGTCAAAGGTCTCGATAAGATAT



GTCTGGGGCACCATGCGGTAGCCAATGGAACGATCGTGAAAACACTTACTAACGAGCAGGA



GGAGGTCACCAACGCCACAGAAACGGTGGAATCTACGGGGATCAACCGCTTATGCATGAAG



GGGAGGAAGCATAAGGATTTGGGCAATTGCCACCCGATTGGAATGCTGATTGGGACTCCTG



CTTGCGATCTGCACTTAACCGGCATGTGGGATACGCTAATAGAGCGCGAAAACGCCATCGC



CTACTGTTATCCCGGCGCGACAGTAAACGTAGAGGCACTAAGACAGAAGATTATGGAGTCC



GGGGGAATAAACAAGATAAGCACGGGCTTTACCTATGGATCATCCATCAATTCTGCTGGAA



CAACACGCGCCTGCATGCGGAACGGAGGCAATTCTTTCTATGCAGAGCTGAAATGGCTCGT



GTCCAAAAGTAAAGGTCAGAACTTCCCGCAGACTACAAACACTTATAGGAACACTGACACA



GCTGAGCATCTAATCATGTGGGGTATTCACCACCCAAGTTCAACCCAAGAAAAAAATGATC



TCTACGGCACGCAGTCACTTTCCATCTCTGTGGGCTCTAGCACCTACAGAAACAACTTTGT



CCCAGTGGTGGGAGCTCGGCCTCAAGTGAACGGACAGTCCGGTAGGATCGATTTTCATTGG



ACCCTCGTACAGCCCGGGGATAACATCACTTTTAGTCACAATGGTGGCCTGATTGCCCCCT



CCAGGGTGTCTAAGTTGATTGGGCGCGGCCTAGGTATACAGAGTGACGCCCCCATAGATAA



TAATTGCGAGAGCAAATGTTTCTGGAGGGGCGGAAGTATCAATACTCGGCTGCCTTTTCAG



AACCTTAGCCCACGTACTGTGGGCCAGTGTCCCAAGTACGTTAATCGAAGAAGCCTGATGC



TTGCAACCGGAATGAGGAACGTGCCCGAACTGATCCAAGGTCGTGGCTTATTCGGAGCCAT



CGCCGGATTCCTGGAGAACGGATGGGAAGGGATGGTGGATGGGTGGTACGGGTTCCGACAC



CAGAACGCCCAGGGAACAGGTCAAGCCGCCGATTACAAATCAACACAAGCGGCCATCGATC



AGATTACTGGAAAACTGAACAGGTTGGTGGAGAAGACTAACACAGAGTTCGAGTCAATCGA



AAGCGAATTTAGCGAGATTGAGCACCAAATCGGGAACGTGATCAACTGGACAAAGGATTCC



ATTACCGACATATGGACCTACCAGGCTGAGCTGTTGGTGGCAATGGAAAATCAGCATACTA



TCGATATGGCCGATTCTGAGATGCTGAATCTGTACGAGCGGGTCAGAAAGCAGCTGAGACA



AAATGCTGAGGAAGACGGTAAGGGTTGTTTCGAGATCTACCATGCCTGCGACGACTCTTGC



ATGGAGAGCATCAGGAACAACACATACGATCACTCCCAGTATAGAGAAGAAGCTCTGTTGA



ATAGGCTTAACATCAACCCAGTGACGCTTAGTAGCGGTTACAAAGATATCATTCTGTGGTT



TAGTTTTGGGGCCTCATGTTTCGTGCTTTTGGCAGTAGTTATGGGGCTGTTTTTCTTCTGT



CTCAAAAATGGTAATATGCGATGCACGATTTGTATT





737
ATGTACAAAATCGTGGTCATTATCGCCCTGCTGGGCGCGGTGAAAGGCTTGGATAAAATCT



GCCTCGGGCATCACGCCGTGGTGAATGGAACGATCGTGAAGACTCTGACCAACGAACAGGA



AGAGGTTACCAACGCAACGGAAACAGTCGAATCAACCGGACTCAATCGTTTATGTATGAAG



GGCAGAAATCACAAGGACCTTGGAAACTGCCACCCAATAGGGATGCTTATAGGAACCCCAG



CTTGCGACCTGCACCTAACCGGCACCTGGGACACTCTTATTGAGAGAGAGAACGCAATTGC



TTACTGTTACCCCGGCGCAACAGTGAACGAAGAGGCCCTCAGGCAGAAGATTATGGAGTCT



GGAGGGATAAACAAGATATCGACCGGTTTCACCTATGGATCCTCTATCAATTCTGCAGGGA



CAACCCGCGCCTGTATGAGAAATGGCGGAAACTCCTTTTATGCCGAACTGAAGTGGCTTGT



TTCCAAAAGCAAAGGTCAGAACTTTCCTCAAACAACTAATACGTACAGGAACACCGATACC



GCCGAGCACCTGATCATGTGGGGAATCCATCACCCTAGCAGTACCCAAGAAAAAAACGACC



TATATGGTACCCAGTCCCTCAGCATCTCAGTGGGCTCATCAACCTATCAAAACAACTTCGT



GCCTGTTGTCGGCGCACGACCCCAGGTGAACGGTCAAAGCGGAAGGATCGATTTCCATTGG



ACCCTGGTTCAGCCCGGCGACAATATCACATTTAGTCACAATGGCGGTCTGATTGCACCTT



CCCGCGTGAGTAAACTGATCGGTCGGGGGCTTGGAATTCAAAGCGACGCCCCCATCGACAA



CAATTGTGAGAGCAAGTGTTTTTGGAGAGGCGGGTCAATAAACACCAGGCTGCCCTTTCAG



AACCTAAGTCCCAGGACTGTAGGCCAGTGTCCCAAATACGTCAATAAGCGTTCACTAATGT



TGGCCACGGGAATGAGAAACGTGCCCGAGCTGATGCAAGGCAGAGGCCTGTTCGGGGCCAT



CGCGGGGTTCATCGAGAACGGTTGGGAAGGCATGGTTGATGGTTGGTATGGATTTAGGCAC



CAGAACGCTCAGGGCACAGGACAGGCCGCTGACTATAAGAGTACTCAAGCCGCAATTGACC



AGATCACCGGGAAGTTGAACCGACTCATCGAGAAGACGAACACAGAATTCGAGAGCATAGA



GTCAGAGTTCTCGGAGATCGAACACCAAATTGGCAACGTTATCAATTGGACTAAGGACTCG



ATCACTGACATCTGGACATACCAGGCTGAGCTGTTGGTGGCCATGGAAAACCAGCACACCA



TAGACATGGCCGACAGCGAGATGCTGAATCTCTACGAAAGAGTTCGCAAACAGCTCAGGCA



GAATGCCGAAGAAGACGGTAAAGGATGCTTTGAAATCTATCACGCTTGTGACGATTCCTGC



ATGGAGAGCATCAGAAACAATACCTACGATCACAGCCAGTACCGGGAAGAAGCACTCCTGA



ATAGGCTGAACATAAATCCAGTAACTCTTTCGTCCGGATACAAAGACATAATACTCTGGTT



TTCGTTTGGTGCATCCTGCTTCGTGCTGCTCGCAGTGGTGATGGGGCTTGTCTTTTTCTGT



TTGAAGAACGGAAATATGCGGTGCACCATATGCATC





738
ATGTACAAGATCGTTGTGATAATTGCCTTGCTGGGCGCAGTCAAAGGACTCGATAAGATCT



GTCTCGGCCATCACGCCGTTGCCAATGGAACCATTGTGAAGACTCTCACTAACGAGAAAGA



GGAGGTTACAAACGCTACCGAAACTGTGGAGAGTACTGGTCTGAACCGACTGTGTATGAAG



GGCAGAAAGCATAAGGATCTGGGTAATTGTCACCCCATCGGAATGTTAATCGGTAGCCCAG



CCTGTGATTTGCACCTTACAGGGACCTGGGATACACTCATAGAGAGGGAAAACGCCATCGC



ATATTGTTATCCCGGGGCCACGGTGAACGGAGAAGCTTTACGCCAGAAGATCATGGAGTCC



GGGGGGATCGATAAGATCAGCACCGGATTCACCTACGAGAGTAGTATAAACTCAGCGGGCA



CCACCAGAGCGTGCATGCGGAATGGCGGCAATAGCTTTTATGCTGAGCTTAAGTGGTTGGT



GTCCAAATCTAAGGGACAGAATTTCCCCCAGACCACCAATACGTACCGCAATACAGACACA



GCCGAGCATTTAATCATGTGGGGAATCCACCACCCATCGTCTACCCAGGAAAAGAACGACT



TGTATGGGACTCAGAGTCTTTCCATCTCCGTCGGATCCTCAACCTACCGGAACAATTTCGT



GCCCGTGGTAGGGGCGCGTCCCCAAGTTAACGGCCAATCTGGCAGGATAGATTTCCATTGG



ACTCTGGTGCAGCCTGGCGACAACATTACCTTCTCGCATAACGGGGGACTGATCGCCCCCT



CTCGCGTTTCTAAGCTGATCGGCCGCGGTCTGGGCATCCAGTCTGACGCTCCCATTGACAA



TAACTGCGAATCAAAGTGCTTTTGGAGAGGAGGGTCTATTAATACTAGGTTGCCCTTTCAG



AATCTGTCCCCCCGAACCGTCGGGCAGTGTCCGAAATATGTCAACAAACGCTCATTAATGC



TTGCTACTGGCATGAGGAATGTCCCTGAGTTGATGCAGGGCAGGGGGCTGTTCGGCGCCAT



AGCAGGGTTTCTCGAGAACGGGTGGGAGGGCATGGTAGATGGGTGGTACGGCTTTAGGCAT



CAGAATGCTCAAGGTACCGGCCAAGCCGCCGACTACAAATCCACACAGGCCGCAATTGACC



AGATCACAGGTAAATTGAATCGGCTTGTGGAGAAGACCAATACTGAATTCGAAAGTATTGA



ATCCGAATTTTCTGAGATAGAGCACCAAATCGGTAACGTGATCAACTGGACTAAAGATTCT



ATCACCGACATTTGGACATATCAGGCGGAATTGCTGGTGGCTATGGAGAACCAGCACACGA



TTGATATGGCTGACAGCGAGATGCTGAACCTTTACGAGCGAGTGCGTAAGCAACTGAGGCA



GAACGCAGAGGAGGATGGTAAGGGGTGCTTCGAGATATATCACGCATGTGATGATTCATGC



ATGGAGTCCATTCGCAACAATACATACGATCACAGCCAGTATCGGGAGGAAGCTCTGCTAA



ACCGATTGAACATTAATCCGGTAACTTTGTCCTCCGGTTACAAGGACATTATCCTCTGGTT



CTCGTTCGGGGCAAGTTGCTTCGTTCTTTTGGCAGTCGTTATGGGTCTGGTTTTTTTTTGC



CTGAAGAACGGCAATATGCGCTGCACAATCTGCATC





739
ATGTATAAGATTATAGTAATCATAGCTCTTCTAGGCGCTGTCAAAGGACTAGACAAGATCT



GTTTAGGCCATCATGCTGTTGCAAATGGAACAATCGTGAAAACATTAACAAACGAACAGGA



AGAGGTAACAAATGCTACTGAGACAGTCGAAAGCACTGGCATCAACAGGCTGTGCATGAAG



GGGCGTAAACACAAGGACCTTGGCAACTGCCATCCCATCGGAATGCTCATCGGCACCCCCG



CATGCGATCTGCACCTAACCGGAACCTGGGACACTCTCATCGAGCGCGAAAACGCAATCGC



CTACTGCTACCCCGGCGCTACGGTGAACGTCGAGGCGTTGCGACAGAAGATTATGGAATCA



GGTGGAATCGATAAGATCTCCACTGGATTTACATACGGATCGTCTATCAACAGCGCCGGTA



CAACTCGCGCCTGTATGCGTAACGGCGGAAACTCATTTTACGCCGAATTAAAGTGGCTGGT



GAGCAAAAGTAAAGGGCAGAACTTTCCGCAAACAACAAATACCTATAGAAATACAGACACT



GCCGAGCACCTCATTATGTGGGGTATACACCACCCTAGCAGCACGCAGGAGAAAAACGACC



TCTACGGAACCCAGTCACTGAGCATCTCAGTTGGTTCCTCCACATACCGGAACAATTTCGT



GCCCGTCGTGGGCGCACGCCCTCAGGTCAATGGACAGTCTGGTCGTATAGACTTTCATTGG



ACGCTTGTGCAGCCAGGCGATAACATCACATTTAGCCATAACGGGGGGTTGATTGCTCCCT



CACGGGTGAGCAAGCTAATAGGTAGGGGCCTCGGTATCCAGTCCGATGCACCTATTGATAA



CAACTGCGAGTCTAAATGTTTTTGGCGAGGTGGGTCCATCAATACGCGGCTGCCTTTTCAG



AATCTTTCTCCTCGAACTGTCGGGCAATGCCCAAAATACGTCAACCGTCGTAGTCTTATGT



TGGCTACAGGGATGCGGAACGTACCGGAACTTATTCAGGGCAGAGGCCTGTTTGGTGCGAT



AGCCGGCTTCCTGGAAAACGGATGGGAGGGAATGGTCGATGGATGGTACGGTTTTCGACAT



CAAAATGCCCAGGGAACCGGGCAGGCAGCGGACTATAAGTCTACCCAGGCAGCCATAGACC



AGATTACAGGAAAGCTCAATAGACTCGTGGAGAAAACTAACACAGAGTTTGAATCAATCGA



GAGCGAGTTCAGCGAGATTGAACATCAAATCGGGAACGTGATCAACTGGACCAAAGATTCT



ATCACAGACATTTGGACATACCAAGCTGAACTCCTAGTTGCCATGGAAAATCAACACACTA



TCGATATGGCCGATTCAGAAATGTTGAATCTGTATGAGCGCGTGAGAAAACAACTCCGCCA



AAACGCAGAAGAGGATGGCAAGGGCTGTTTTGAGATCTACCACGCCTGTGATGACTCTTGT



ATGGAGTCCATTCGGAATAATACCTACGATCATAGCCAGTATCGGGAAGAGGCTCTGCTTA



ACCGATTGAACATTAATCCCGTGACCTTGTCAAGCGGTTACAAAGACATAATTCTATGGTT



CTCATTTGGCGCCTCCTGCTTTGTGCTGCTCGCTGTTGTCATGGGCCTCTTTTTTTTTTGT



CTGAAAAATGGAAATATGCGATGTACCATCTGCATT





740
ATGTATAAAATTGTCGTGATCATAGCTCTCCTTGGGGCTGTGAAAGGCCTGGATAAGATCT



GTCTGGGACACCACGCGGTGGCAAATGGCACTATCGTCAAAACCCTGACAAACGAGCAGGA



GGAGGTTACTAACGCCACGGAAACGGTTGAGTCCACCGGGATTAACAGACTTTGCATGAAG



GGCAGGAAACACAAGGATCTCGGTAACTGTCACCCCATTGGCATGCTGATTGGGACTCCCG



CATGTGACCTTCACTTAACCGGAATGTGGGACACTCTGATCGAGCGTGAAAACGCCATTGC



CTACTGTTATCCCGGGGCAACAGTGAACGTCGAGGCGTTGAGGCAAAAGATCATGGAAAGC



GGCGGCATCAACAAAATCAGCACTGGGTTCACATACGGATCTAGCATTAACAGCGCCGGCA



CTACACGTGCATGTATGAGGAATGGCGGCAATTCTTTTTACGCCGAACTGAAGTGGCTTGT



TTCCAAATCCAAGGGTCAGAACTTTCCACAAACCACGAATACCTATCGGAATACTGACACT



GCAGAGCATCTAATTATGTGGGGCATCCACCACCCCAGTTCAACTCAGGAGAAGAATGACT



TGTACGGGACCCAGAGCCTGAGTATTTCTGTTGGGAGTTCAACCTACAGAAATAACTTCGT



CCCTGTCGTCGGGGCTAGACCTCAAGTTAATGGTCAGTCCGGCCGTATCGACTTTCACTGG



ACTCTGGTACAGCCGGGGGATAACATTACATTCTCACACAATGGGGGTCTCATCGCACCCA



GCCGGGTGTCCAAACTCATTGGCCGAGGATTGGGGATCCAATCCGATGCCCCCATAGACAA



CAATTGCGAGTCTAAATGCTTTTGGAGGGGCGGCTCTATAAACACACGCCTGCCATTCCAG



AACCTCAGTCCCCGGACCGTCGGGCAGTGCCCAAAATATGTGAATCGAAGGAGTCTTATGC



TGGCTACTGGCATGCGTAACGTGCCTGAGCTGATACAGGGAAGGGGCCTTTTCGGGGCTAT



CGCCGGATTTTTAGAGAATGGATGGGAGGGGATGGTTGACGGGTGGTATGGATTTCGGCAC



CAGAATGCACAGGGTACAGGACAAGCCGCCGATTACAAGTCTACCCAAGCTGCAATAGATC



AGATCACCGGCAAACTCAACCGGCTTGTTGAAAAGACCAACACAGAATTCGAATCAATCGA



GAGCGAGTTCTCTGAAATAGAGCATCAGATTGGCAACGTGATCAACTGGACAAAAGACTCT



ATTACAGACATCTGGACTTACCAGGCTGAGTTGCTCGTGGCCATGGAGAACCAACATACAA



TCGATATGGCAGACTCAGAGATGCTTAACCTGTATGAACGTGTGAGGAAGCAGCTCCGCCA



GAATGCTGAAGAGGACGGAAAGGGGTGTTTTGAGATATACCATGCCTGCGACGATAGCTGC



ATGGAGTCCATCAGGAACAATACGTACGATCACTCCCAATACAGAGAGGAGGCCTTGCTGA



ATCGGCTTAATATCAACCCCGTCACGCTGAGTTCCGGATACAAGGATATTATACTATGGTT



CTCATTTGGCGCTTCATGCTTCGTGCTCCTCGCCGTGGTGATGGGCCTGTTTTTCTTTTGC



CTGAAGAACGGTAACATGAGGTGTACAATCTGCATT





741
ATGTACAAAATCGTGGTCATTATTGCCCTGCTGGGCGCCGTAAAAGGCCTCGATAAGATTT



GTCTGGGACATCACGCGGTGGCTAACGGAACAATTGTTAAAACCCTGACTAACGAGCAGGA



AGAAGTCACAAACGCTACGGAGACCGTGGAGAGTACCGGAATCAATCGCCTGTGCATGAAG



GGCCGTAAGCACAAGGACCTGGGTAACTGCCATCCAATCGGGATGCTTATCGGCACGCCTG



CTTGCGATTTGCATCTGACTGGGATGTGGGACACTCTGATCGAGCGTGAGAACGCTATAGC



TTACTGCTACCCCGGAGCCACCGTCAATGTTGAAGCACTGCGTCAGAAGATCATGGAAAGC



GGTGGCATCAACAAGATCTCTACCGGATTCACTTATGGCTCTTCCATAAACTCAGCAGGCA



CCACACGGGCATGCATGCGGAATGGCGGCAACTCTTTCTACGCCGAACTAAAATGGCTGGT



GAGTAAGAGCAAGGGGCAAAACTTTCCACAGACCACTAATACATACAGGAATACTGACACC



GCAGAGCACCTCATCATGTGGGGAATCCACCATCCTTCAAGTACCCAAGAGAAAAACGATC



TCTACGGGACACAGTCACTTAGTATATCCGTTGGCTCAAGCACTTACAGAAATAATTTTGT



GCCCGTGGTCGGCGCCCGCCCCCAGGTTAATGGACAGAGCGGACGGATTGACTTTCATTGG



ACCCTGGTCCAGCCCGGAGACAACATAACTTTTAGCCACAATGGGGGGTTGATCGCACCCA



GCAGAGTTTCCAAGCTGATAGGAAGAGGGCTGGGTATCCAATCCGATGCCCCCATCGATAA



CAATTGTGAGTCAAAATGCTTCTGGCGCGGAGGGTCAATCAACACACGCCTTCCCTTTCAA



AACCTCTCACCTCGGACCGTGGGTCAGTGTCCGAAATATGTTAATCGACGGAGCCTGATGC



TGGCCACCGGGATGCGCAACGTGCCCGAGTTGATCCAGGGTAGGGGCTTATTTGGTGCAAT



CGCCGGGTTCCTGGAGAACGGATGGGAAGGCATGGTAGACGGCTGGTATGGATTCCGCCAT



CAGAACGCCCAGGGGACAGGCCAGGCAGCCGATTATAAAAGCACCCAGGCTGCAATCGACC



AGATCACGGGAAAGCTGAACCGGCTGGTGGAGAAGACTAATACGGAATTCGAATCTATTGA



GTCTGAATTCAGTGAGATTGAGCATCAGATCGGCAACGTGATTAATTGGACTAAGGATAGC



ATCACCGACATTTGGACCTATCAGGCCGAGCTGCTGGTGGCTATGGAAAATCAGCATACAA



TCGACATGGCTGACTCTGAGATGCTGAACCTCTACGAGAGAGTCAGAAAACAGTTACGTCA



GAACGCCGAGGAGGATGGCAAGGGGTGCTTTGAGATCTATCACGCGTGCGACGATAGTTGC



ATGGAGTCAATTAGGAACAATACCTATGACCATAGTCAATACCGGGAGGAGGCCCTGTTGA



ACCGGCTGAACATCAACCCTGTGACACTGTCCTCGGGGTATAAGGACATCATCCTTTGGTT



CTCATTTGGAGCTAGCTGCTTCGTGTTATTGGCCGTTGTGATGGGCCTTTTCTTCTTCTGT



CTCAAAAATGGAAACATGCGCTGTACCATTTGTATT





742
ATGTACAAAATCGTGCTCGTTCTGGCTCTTCTTGGGGCTGTGCACGGGCTGGATAAAATTT



GCCTGGGCCACCATGCCGTCCCAAATGGCACTATTGTTAAGACTTTAACCAACGAGAAAGA



GGAAGTGACTAATGCTACCGAGACAGTGGAAAGCAAAAGCCTGGACAAGCTTTGTATGAAA



AATAGGAATTACAAGGATCTGGGCAATTGTCATCCAATTGGCATGGTCGTCGGCACTCCCG



CCTGCGATCTGCACCTTACAGGCACGTGGGATACCCTCATCGAGCGCGATAACAGCATTGC



ATATTGTTACCCAGGGGCCACGGTTAGTGAGGAAGCATTGAGACAGAAGATCATGGAGAGT



GGTGGCATCGATAAGATTTCAACAGGGTTCACCTATGGATCTTCTATCAATAGTGCAGGTA



CCACTAAGGCTTGCATGCGCAACGGCGGCAACTCATTTTACTCTGAGTTGAAGTGGCTCGT



CAGTAAAAATAAGGGCCAGAACTTTCCGCAGACAACAAATACTTACCGAAACACGGATAGT



GTGGAACACCTCATAATTTGGGGAATCCACCACCCCTCCAGCACACAGGAGAAGAACGACT



TGTATGGCACTCAAAGCCTATCAATTAGCGTGGGATCATCTACTTACCAAAACAACTTTGT



CCCAGTCGTGGGTGCCAGGCCACAAGTGAATGGCCAGAGTGGTCGGATTGATTTCCACTGG



ACGATGGTCCAACCCGGCGATAACATTACATTTTCTCATAATGGAGGCCTCATTGCTCCTA



ACAGGGTGTCTAAGCTGAAGGGCAGAGGACTCGGAATCCAATCCGGCGCCTCAGTGGATAA



TGATTGTGAGAGCAAGTGTTTTTGGAAGGGGGGTTCTATCAATACTAAGCTCCCCTTCCAG



AACCTGAGCCCACGCACCGTAGGACAATGCCCCAAATACGTGAACAAGAAGTCCCTGCTCC



TCGCAACAGGCATGCGGAACGTTCCAGAAGTGGCACAGGGCAGGGGGTTATTTGGGGCTAT



CGCTGGTTTTATTGAGAACGGATGGGAGGGGATGGTGGATGGCTGGTACGGTTTCCGCCAT



CAGAACGCCCAGGGGACTGGCCAAGCGGCAGACTACAAGTCCACACAGGCAGCCATAGATC



AGATAACTGGAAAGCTTAATAGGCTCATTGAGAAGACAAATACCGAGTTTGAAAGCATCGA



ATCCGAATTTTCCGAGATTGAGCATCAAATTGGCAACGTAATCAACTGGACAAAGGACAGC



ATTACTGACATCTGGACGTACCAGGCCGAACTGCTGGTGGCGATGGAAAACCAGCACACTA



TCGATATGGCAGATAGTGAAATGCTGAACTTATATGAGCGCGTGCGAAAGCAACTGAGGCA



AAACGCTGAAGAGGACGGCAAAGGGTGTTTCGAAATTTACCATAAGTGCGATGATAATTGT



ATGGAGAGTATCCGGAATAACACGTATGATCATACCCAGTATCGCGAAGAAGCTCTCCTTA



ACAGGCTTAATATTAATCCAGTCAAGCTAAGTTCCGGATATAAGGACGTCATTCTCTGGTT



TAGTTTTGGCGCTTCCTGCTTTGTATTGCTGGCTGTGATCATGGGCCTGGTCTTCTTCTGT



CTCAAGAACGGGAACATGCGATGCACCATATGCATC





743
ATGTATAAAATTGTGGTCATCATCGCTTTATTGGGAGCAGTTAAGGGGCTCGATAAGATCT



GTCTGGGCCACCACGCCGTTGCAAACGGGACCATTGTGAAGACTCTCACCAATGAGCAGGA



GAAAGTTACTAATGCAACAGAGACCGTCGAATCTACAGGCCTGAATCGGCTTTGTATGAAG



GGACGCAAGCATAAGGACCTGGGCAATTGCCACCCTATAGGCATGCTAATTGGGACGCCGG



CCTGCGACTTGCACCTCACAGGTACGTGGGACACTATCATCGAAAGGGAGAACGCTATCGC



CTACTGTTACCCAGGCGCTACCGTGAACGAGGAAGCGCTGAGACAGAAAATCATGGAATCC



GGTGGAATCGATAAGATATCTACTGGCTTTACTTACGGCTCATCCATTAATTCCGCTGGCA



CCACTCGCGCCTGTATGCGGAACGGCGGCAATTCCTTCTACGCTGAACTTAAATGGCTCGT



GTCCAAGAGCAAAGGCCAGAACTTTCCACAGACCACCAATACTTATAGAAATACAGACACG



GCCGAGCACCTGATCATGTGGGGGATCCATCACCCTAGTAGTACACAGGAGAAAAATGACT



TATACGGCACCCAATCCCTTAGTATATCTGTTGGGTCAAGCACGTACAGAAACAATTTCGT



GCCTGTAGTGGGCGCCAGGCCACAGGTCAACGGGCAGTCAGGCAGGATTGATTTCCATTGG



ACACTGGTGCAACCTGGTGATAATATCACTTTCTCCCACAACGGCGGTTTAATTGCTCCCA



GCAGAGTAAGTAAGCTCATCGGCCGAGGACTCGGCATTCAGAGCGACGCACCCATAGATAA



TAACTGCGAATCTAAATGTTTTTGGAGGGGGGGCTCTATCAATACACGCCTCCCTTTTCAG



AACCTGTCTCCTAGGACTGTAGGGCAGTGCCCCAAGTACGTAAACAAAAGATCGCTGATGT



TAGCCACCGGGATGCGGAACGTCCCTGAGCTCATTCAGGGAAGGGGCCTGTTCGGAGCCAT



TGCAGGGTTCTTGGAGAATGGATGGGAAGGAATGGTTGACGGGTGGTACGGGTTCCGACAT



CAGAATGCCCAAGGCACCGGACAGGCCGCTGACTACAAAAGCACCCAGGCAGCCATAGACC



AGATTACCGGCAAACTAAATCGTTTAGTGGAGAAGACCAATACCGAATTTGAATCCATAGA



GAGCGAATTCAGCGAGATAGAGCATCAAATCGGCAATGTGATTAACTGGACAAAAGATTCC



ATAACCGACATTTGGACTTATCAGGCCGAGTTGCTAGTCGCAATGGAGAATCAGCATACAA



TCGACATGGCTGACTCTGAGATGTTGAATCTGTACGAGAGGGTTCGGAAGCAGCTGCGGCA



GAACGCCGAGGAAGACGGGAAAGGGTGTTTTGAGATCTACCATGCGTGTGATGATAGCTGT



ATGGAAAGCATTCGCAATAACACCTATGACCACTCACAGTATCGGGAAGAGGCGTTGTTAA



ACAGGCTGAACATCAACCCAGTAACACTGTCTAGCGGTTATAAGGACATAATATTGTGGTT



CTCCTTTGGTGCAAGCTGCTTTGTCTTGCTGGCGGTCGTGATGGGGCTGGTGTTCTTTTGT



CTGAAAAACGGTAACATGAGGTGTACTATTTGTATC





744
ATGTATAAGATCGTTCTCGTGTTGGCTCTACTGGGTGCCGTCCATGGTTTGGACAAGATCT



GCCTGGGCCACCATGCAGTGCCAAACGGTACCATAGTGAAAACCTTGACTAATGAAAAAGA



AGAGGTGACTAATGCCACCGAGACCGTGGAGTCGAAATCCCTCGATAAACTGTGTATGAAG



AACAGGAACTACAAGGACCTGGGCAATTGCCATCCAATTGGCATGGTGGTGGGGACACCTG



CCTGCGACTTACACCTCACCGGGACATGGGACACTTTGATCGAGAGGGATAATTCAATTGC



GTACTGCTATCCCGGGGCCACTGTGAGTGAGGAGGCGCTGAGGCAAAAGATCATGGAGTCT



GGGGGCATAGACAAGATTAGCACCGGCTTCACATATGGAAGCTCCATCAACTCAGCTGGCA



CGACGAAAGCTTGCATGCGGAACGGTGGGAACTCCTTTTATTCTGAGCTGAAGTGGTTAGT



TAGCAAGAACAAAGGCCAGAACTTCCCCCAGACTACAAACACATATAGAAACACAGACTCA



GTGGAGCATTTGATCATTTGGGGGATTCACCATCCATCGTCCACACAGGAAAAGAACGACC



TGTATGGCACCCAATCGCTGAGCATCTCAGTCGGGTCCAGTACTTATCAGAATAACTTCGT



GCCCGTGGTGGGCGCTCGCCCACAGGTAAACGGGCAAAGCGGGAGAATCGACTTCCATTGG



ACTATGGTGCAGCCTGGGGATAATATTACCTTCTCCCACAATGGAGGTCTTATAGCCCCCA



ATCGAGTTAGCAAACTGAAAGGCCGAGGACTGGGTATCCAGAGCGGCGCAAGCGTGGATAA



TGATTGTGAGTCCAAATGTTTTTGGAAGGGAGGATCAATTAATACCAAATTGCCCTTCCAG



AACTTGAGCCCTCGCACTGTTGGCCAGTGTCCAAAGTACGTTAACAAGAAATCATTACTGC



TAGCCACCGGCATGCGTAACGTGCCTGAGGTCGCCCAGGGGCGCGGTCTCTTCGGAGCAAT



AGCAGGATTCATAGAGAATGGTTGGGAGGGAATGGTGGACGGCTGGTATGGATTCCGCCAT



CAGAATGCTCAAGGAACCGGCCAGGCTGCGGACTATAAAAGCACGCAAGCTGCGATAGACC



AAATTACGGGAAAGCTGAACCGCCTGATTGAAAAGACCAATACTGAGTTTGAATCTATTGA



GTCTGAGTTCTCCGAAATCGAACATCAGATTGGGAATGTTATCAACTGGACTAAAGACAGT



ATAACTGACATTTGGACGTACCAGGCGGAGCTTCTAGTGGCCATGGAAAATCAGCACACCA



TAGATATGGCAGATTCTGAAATGCTGAACCTCTACGAACGAGTGCGAAAGCAATTGCGTCA



GAACGCCGAGGAGGACGGCAAGGGATGTTTCGAGATTTACCACAAATGTGACGACAACTGC



ATGGAAAGCATTAGGAATAACACTTACGACCATACACAGTACAGGGAAGAGGCCCTGCTCA



ACCGCCTCAATATTAACCCGGTGAAACTATCTTCTGGGTACAAGGATGTTATTCTGTGGTT



TAGCTTCGGCGCCTCCTGTTTTGTACTGCTTGCCGTGATTATGGGTTTGGTTTTCTTCTGC



CTCAAGAATGGCAATATGAGATGTACAATTTGCATA





745
ATGTACAAGATCGTGGTCATCATTGCGCTCCTGGGTGCCGTGAAAGGGCTTGACAAGATCT



GCCTGGGTCACCATGCTGTCGCCAATGGGACAATAGTGAAGACTCTTACCAACGAGAAGGA



AGAAGTCACCAACGCAACAGAGACTGTCGAGAGTACCGGCTTAAACAGACTTTGTATGAAA



GGGCGCAAGCACAAGGACCTGGGGAACTGTCACCCAATTGGCATGCTGATAGGGTCTCCAG



CCTGTGATCTGCACCTAACTGGCACATGGGACACCCTGATTGAGAGAGAAAACGCCATTGC



ATACTGTTATCCAGGTGCCACCGTTAATGGGGAGGCATTGAGGCAGAAAATCATGGAGTCC



GGAGGAATAGACAAGATATCAACAGGGTTCACATATGAGAGCTCTATCAACTCGGCTGGGA



CAACCAGGGCATGTATGCGCAACGGAGGAAATTCGTTCTATGCCGAGCTGAAATGGCTTGT



TAGCAAGTCTAAGGGCCAGAATTTTCCTCAGACTACCAATACATACCGCAACACCGACACT



GCCGAGCATCTGATTATGTGGGGGATTCACCACCCCTCTAGTACTCAGGAGAAGAACGACT



TGTACGGGACACAAAGCCTGTCAATTAGTGTCGGGAGCTCTACATACCGGAATAATTTCGT



TCCTGTTGTCGGGGCGAGGCCACAGGTGAACGGCCAGAGTGGGAGGATCGACTTCCACTGG



ACTCTCGTCCAACCAGGGGACAACATCACTTTCAGCCACAACGGAGGCCTTATTGCTCCTT



CGAGAGTCAGTAAGCTGATTGGCAGGGGTTTGGGCATTCAAAGTGATGCCCCAATTGATAA



TAACTGCGAAAGCAAGTGCTTCTGGCGAGGGGGCTCTATTAATACTCGATTGCCTTTTCAG



AACCTGAGCCCGAGAACAGTTGGGCAATGTCCCAAGTACGTTAATAAGAGGTCTCTGATGC



TGGCGACAGGGATGAGAAATGTCCCTGAGCTGATGCAAGGGGGGGGACTGTTTGGCGCTAT



AGCGGGCTTCCTCGAAAACGGATGGGAGGGAATGGTTGATGGATGGTATGGGTTCCGACAC



CAGAATGCACAGGGCACCGGGCAAGCTGCTGATTACAAGTCTACTCAAGCCGCCATCGACC



AGATCACCGGCAAACTTAACCGCCTGGTCGAGAAAACAAATACAGAATTTGAATCTATTGA



ATCCGAGTTCTCTGAGATAGAACACCAAATCGGCAACGTGATTAATTGGACCAAGGATAGT



ATCACAGATATCTGGACCTATCAAGCGGAGCTGCTGGTGGCCATGGAGAACCAGCACACAA



TCGATATGGCTGACTCAGAGATGCTTAATTTGTATGAGCGGGTTCGCAAGCAGCTCCGACA



AAATGCTGAGGAGGATGGAAAGGGATGTTTTGAGATCTATCATGCCTGCGACGACTCATGC



ATGGAAAGCATTCGCAATAATACCTATGATCATTCACAGTACAGAGAAGAGGCTCTCCTGA



ACAGGCTGAACATAAACCCCGTTACACTTTCTAGCGGGTACAAAGACATTATCTTATGGTT



CAGTTTCGGAGCATCTTGCTTCGTACTACTGGCCGTTGTCATGGGCCTGGTGTTCTTCTGT



CTAAAGAATGGGAACATGCGCTGCACCATTTGCATT





746
ATGTACAAGATCGTCGTGATTATCGCCTTATTGGGAGCAGTCAAGGGGCTCGATAAGATCT



GTTTAGGGCATCATGCGGTTGCAAACGGCACTATCGTTAAGACCTTGACAAATGAACAGGA



GGAAGTGACGAATGCCACTGAAACCGTTGAGTCCACTGGGATTAATCGGCTGTGCATGAAA



GGACGAAAGCATAAGGACCTTGGAAACTGCCACCCCATTGGCATGCTGATTGGGACCCCTG



CTTGCGACCTGCATCTGACTGGAACCTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC



CTATTGCTATCCAGGCGCCACAGCAAACGTCGAGGCCCTCAGACAGAAAATCATGGAGTCC



GGTGGAATTGACAAAATCTCTACCGGCTTTACCTACGGGTCTAGCATCAATTCCGCAGGGA



CTACGAGGGCATGTATGAGAAATGGCGGCAACAGCTTCTATGCCGAGCTTAAATGGCTTGT



TTCAAAATCCAAGGGACAGAACTTCCCTCAGACTACAAACACTTATCGGAATACAGATACA



GCAGAACACTTGATTATGTGGGGCATTCACCACCCAAGCAGTATCCAGGAGAAAAATGACC



TCTACGGCACGCAGTCACTGAGTATATCCGTGGGCTCTTCAACCTACAGGAACAATTTTGT



CCCCGTCGTCGGTGCGAGGCCTCAAGTGAAGGGGCAATCGGGAAGGATCGACTTCCATTGG



ACACTGGTGCAACCTGGAGATAATATCACGTTTAGCCACAACGGAGGCTTGATTGCTCCAT



CCAGAGTGAGCAAACTGATCGGCAGGGGCCTAGGGATCCAATCAGACGCACCAATCGATAA



CAACTGTGAGTCTAAGTGTTTCTGGAGAGGTGGCAGCATTAACACCCGGTTGCCCTTCCAG



AATTTGAGCCCCCGGACTGTCGGTCAGTGCCCAAAGTACGTGAATCGGCGCTCTCTTATGC



TGGCCACCGGAATGAGGAACGTCCCCGAGCTCATACAGGGCCGGGGTTTATTCGGGGCAAT



TGCTGGGTTCCTGGAGAACGGCTGGGAAGGCATGGTGGATGGCTGGTACGGATTTAGGCAC



CAGAACGCACAAGGCACTGGCCAAGCCGCGGACTACAAATCAACTCAAGCTGCCATCGATC



AGATAACCGGGAAGTTGAACAGACTGGTAGAAAAAACCAATACCGAGTTCGAGTCAATTGA



GTCCGAGTTTAGTGAGATAGAACACCAGATCGGTAACGTGATCAACTGGACAATGGATAGT



ATTACTGACATTTGGACCTATCAAGCAGAACTGCTGGTGGCGATGGAGAACCAGCACACTA



TCGACATGGCAGACAGCGAAATGCTTAACCTGTACGAACGGGTGCGGAAACAGCTAAGACA



AAACGCCGAAGAGGACGGCAAAGGTTGCTTCGAAATCTACCACGCCTGTGACGACTCTTGT



ATGGAAAGCATAAGGAACAATACCTACGATCACTCCCAGTACCGAGAGGAGGCGTTACTCA



ATAGACTGAACATCAACCCTGTGACCCTGAGCTCTGGATATAAAGACATCATTCTCTGGTT



TTCTTTTGGGGCCAGCTGCTTCGTGCTTCTCGCAGTCGTTATGGGACTCGTGTTCTTCTGC



TTGAAGAACGGTAATATGAGATGCACAATCTGCATA





747
ATGTATAAGATTGTCGTGATTATTGCCCTGTTAGGGGCCGTGAAAGGACTAGATAAAATTT



GCCTGGGCCACCATGCTGTCGCCAATGGCACGATCGTTAAAACTTTAACAAACGAGCAGGA



GGAAGTAACGAACGCAACAGAGACAGTTGAGAGTACAGGAATCAATAGACTGTGTATGAAG



GGGAGGAAACACAAGGATTTAGGAAATTGCCACCCTATCGGAATGCTCATCGGAACTCCAG



CATGTGATCTGCATCTGACAGGCATGTGGGACACACTGATCGAGCGGGAAAATGCGATTGC



CTATTGCTATCCCGGGGCTACAGTGAATGTCGAGGCTCTGCGGCAGAAGATCATGGAATCC



GGCGGCATCAATAAAATTTCTACTGGGTTCACTTACGGGAGTTCTATTAATAGTGCCGGCA



CGACCAGAGCCTGCATGCGGAACGGCGGCAACTCGTTCTATGCAGAGCTGAAATGGCTGGT



TTCAAAATCTAAAGGACAGAACTTTCCACAAACAACAAATACTTATAGGAACACCGACACC



GCCGAGCATCTGATTATGTGGGGAATCCATCACCCAAGTAGCACACAGGAAAAGAACGACC



TTTACGGCACTCAGTCACTGAGCATAAGCGTTGGGTCCTCTACTTACCGCAATAATTTCGT



GCCAGTCGTCGGCGCTAGACCACAAGTCAATGGGCAATCAGGGAGAATCGATTTTCACTGG



ACCCTTGTGCAGCCTGGTGATAATATCACTTTCAGCCACAACGGGGGCCTGATTGCTCCAA



GTAGAGTCTCCAAGCTTATTGGACGGGGACTCGGGATTCAGTCTGATGCTCCCATAGATAA



TAATTGTGAGTCGAAGTGCTTTTGGCGAGGAGGGTCCATCAACACGGGGTTGCCCTTCCAG



AACCTCTCACCTCGGACCGTGGGGCAGTGCCCCAAATACGTGAACAGGAGGAGTCTGATGC



TGGCCACCGGGATGCGCAACGTGCCCGAATTGATCCAGGGGAGAGGCCTTTTCGGCGCTAT



AGCGGGGTTTTTAGAAAACGGGTGGGAGGGCATGGTGGACGGCTGGTACGGATTTCGCCAT



CAGAATGCCCAGGGTACTGGTCAAGCCGCCGATTACAAATCTACCCAGGCTGCCATCGACC



AGATTACAGGAAAGTTGAACCGACTGGTGGAAAAGACCAACACTGAGTTTGAGAGTATTGA



AAGTGAATTCTCTGAGATCGAACACCAGATTGGGAACGTTATCAACTGGACGAAAGATTCC



ATCACAGACATCTGGACCTACCAAGCCGAACTCCTTGTGGCCATGGAGAATCAACACACGA



TCGACATGGCTGACTCAGAAATGCTGAATTTGTACGAAAGAGTGAGAAAACAGCTGAGGCA



AAATGCCGAGGAGGATGGCAAAGGCTGTTTCGAGATTTATCACGCCTGCGATGATTCCTGT



ATGGAATCAATCAGGAATAATACCTACGACCACTCTCAGTACCGCGAGGAAGCCCTATTGA



ACCGACTTAACATAAACCCTGTGACTTTGTCCAGTGGTTACAAGGATATCATTCTTTGGTT



TTCGTTCGGAGCTTCCTGCTTCGTACTCCTCGCGGTGGTAATGGGCTTATTCTTTTTTTGC



CTAAAGAACGGAAATATGAGGTGTACGATCTGCATC





748
ATGTACAAAATTGTGGTGATTATTGCTCTGCTCGGAGCCGTCAAGGGCCTGGATAAGATCT



GTCTGGGCCACCACGCCGTGGCCAACGGAACAATTGTGAAGACACTCACAAACGAGCAGGA



AGAAGTGACTAATGCCACCGAGACCGTTGAAAGTACCGGGATAAACCGCCTTTGCATGAAG



GGTCGGAAACATAAAGACCTGGGGAACTGCCACCCTATAGGTATGCTTATTGGAACACCCG



CTTGTGATCTACACCTTACTGGGATGTGGGACACCCTTATAGAGCGCGAGAACGCCATCGC



ATACTGTTATCCTGGTGCCACGGTTAACGTGGAGGCTCTTAGGCAGAAGATCATGGAGTCA



GGCGGTATTAATAAGATTTCCACAGGCTTTACTTACGGGAGCTCAATAAACAGCGCCGGGA



CCACGAGGGCCTGCATGCGGAACGGGGGGAACTCCTTTTACGCGGAATTGAAATGGCTGGT



GTCAAAGTCCAAAGGACAAAACTTCCCTCAAACCACTAATACCTACAGGAATACCGACACT



GCAGAACATCTTATCATGTGGGGCATACACCACCCGTCGTCTACACAAGAGAAGAACGATC



TTTATGGGACCCAGTCTCTGTCCATCAGCGTGGGGTCATCCACTTACCGAAATAATTTTGT



GCCTGTGGTTGGGGCTAGGCCACAGGTGAATGGGCAGTCTGGCCGTATTGATTTCCACTGG



ACACTTGTGCAGCCAGGGGATAATATAACATTCAGCCACAATGGGGGCCTAATCGCTCCAT



CCCGGGTGTCTAAGTTGATCGGTCGCGGACTTGGAATCCAATCTGACGCTCCAATCGACAA



CAATTGTGAGTCTAAATGCTTTTGGCGCGGGGGCTCTATCAACACTAGACTGCCATTCCAA



AATCTGTCTCCTCGCACCGTTGGGCAGTGTCCTAAGTATGTAAACAGACGGTCCCTGATGC



TTGCGACAGGAATGCGGAATGTACCTGAACTCATCCAGGGAAGAGGGCTGTTCGGAGCTAT



TGCCGGCTTTCTGGAGAATGGTTGGGAGGGAATGGTAGACGGCTGGTACGGCTTTCGGCAT



CAAAATGCGCAGGGAACAGGCCAGGCAGCAGACTACAAATCAACCCAGGCTGCCATTGACC



AGATTACAGGGAAGCTCAATAGACTTGTGGAGAAAACAAACACCGAGTTCGAATCCATCGA



GTCCGAGTTCAGTGAGATCGAGCACCAGATTGGGAACGTGATAAACTGGACGAAAGATTCT



ATCACCGATATTTGGACATACCAGGCTGAGCTCCTGGTCGCCATGGAGAATCAACATACAA



TTGATATGGCGGACAGCGAGATGCTGAACCTATATGAGCGCGTACGAAAGCAATTGAGACA



GAACGCCGAGGAGGACGGTAAGGGGTGCTTTGAAATATATCATGCTTGTGACGACTCATGC



ATGGAATCAATTAGAAATAATACATATGACCACTCTCAATATAGAGAGGAGGCCCTCTTGA



ATCGCTTGAACATCAATCCGGTGACTCTCTCTAGTGGGTACAAAGACATTATACTGTGGTT



CAGTTTCGGGGCCAGCTGCTTCGTGCTGCTGGCAGTAGTTATGGGGCTCTTCTTTTTTTGC



CTGAAAAATGGCAATATGCGATGTACCATTTGTATC





749
ATGTATAAAATTGTCGTGATTATTGCCTTGCTAGGCGCCGTCAAGGGCCTGGACAAAATCT



GCCTGGGACACCACGCTGTGGCGAACGGCACTATCGTTAAGACTCTGACCAATGAGCAGGA



AAAGGTCACAAACGCTACAGAAACGGTCGAATCTACAGGCCTGAACAGGCTGTGTATGAAA



GGTAGAAAGCACAAAGACCTGGGAAATTGCCACCCAATAGGGATGTTAATCGGCACCCCAG



CATGCGATTTGCACCTGACAGGTACATGGGACACCATCATCGAAAGGGAGAATGCCATTGC



TTACTGTTATCCCGGAGCCACAGTGAATGAGGAGGCCCTCAGACAAAAAATAATGGAATCC



GGCGGAATCGACAAGATAAGTACAGGATTTACCTATGGGAGCTCTATTAATTCCGCCGGCA



CTACAAGAGCTTGTATGAGGAACGGTGGAAATTCGTTTTACGCAGAGCTTAAATGGCTAGT



GAGCAAGTCCAAAGGACAGAACTTTCCTCAGACAACAAATACTTATCGGAACACCGATACG



GCTGAACACTTAATAATGTGGGGGATCCACCATCCGTCGTCAACGCAGGAGAAAAATGATC



TGTACGGTACGCAATCACTGTCCATCTCCGTAGGCAGCTCCACCTACAGAAATAATTTTGT



TCCAGTTGTCGGTGCTCGGCCACAAGTGAATGGCCAGAGCGGCCGAATCGACTTTCACTGG



ACCCTGGTGCAGCCAGGGGATAACATCACCTTCAGCCACAACGGTGGCCTTATCGCCCCCT



CTAGGGTGAGTAAGCTGATCGGGGGGGGCCTCGGAATCCAATCTGACGCACCCATTGATAA



CAACTGCGAGAGCAAGTGTTTCTGGGGGGGTGGTTCTATCAATACCCGACTCCCGTTTCAG



AATCTATCTCCTAGGACCGTCGGCCAGTGCCCAAAATATGTGAACAAGCGCAGCCTTATGC



TAGCAACTGGAATGAGGAATGTTCCCGAGCTGATTCAGGGCCGAGGTCTCTTCGGAGCTAT



TGCCGGGTTTCTCGAGAACGGATGGGAAGGCATGGTGGACGGGTGGTACGGTTTTCGGCAC



CAGAACGCCCAGGGAACCGGACAAGCAGCCGATTACAAGAGCACCCAGGCTGCTATCGATC



AGATTACCGGCAAGCTCAATCGCTTGGTGGAGAAAACCAATACTGAATTTGAGTCCATTGA



ATCAGAGTTCAGCGAGATCGAGCATCAGATCGGGAACGTCATTAATTGGACAAAGGATAGC



ATCACCGATATCTGGACATACCAGGCTGAGCTTCTGGTTGCAATGGAAAATCAGCATACTA



TCGACATGGCTGATAGCGAAATGTTGAATTTGTATGAAAGGGTGCGTAAGCAGCTGCGGCA



GAACGCCGAGGAGGACGGCAAGGGATGCTTCGAGATCTACCACGCATGTGACGACTCATGC



ATGGAGAGCATTCGGAACAACACTTATGATCACTCTCAATATCGTGAAGAGGCACTCCTAA



ACAGACTAAATATAAACCCGGTCACCCTCAGCAGCGGCTATAAGGACATCATTCTTTGGTT



CTCTTTTGGTGCAAGCTGTTTCGTCCTCCTCGCCGTGGTTATGGGCCTGGTGTTTTTTTGC



CTGAAGAATGGCAATATGCGGTGCACCATTTGCATC





750
ATGTATAAGATTGTGGTGATTATTGCGTTGCTGGGGGCTGTGAAAGGCCTGGATAAGATCT



GTCTTGGGCATCATGCCGTAGCTAACGGCACAATTGTGAAAACTCTGACAAATGAGCAGGA



GGAGGTGACAAACGCAACCGAGACCGTTGAGAGCACAGGGATTAATCGCCTGTGCATGAAG



GGGCGCAAACACAAGGACCTGGGGAACTGTCACCCTATCGGAATGCTGATCGGGACCCCAG



CCTGTGATTTACACCTAACAGGAATGTGGGACACACTCATTGAAAGAGAGAACGCGATAGC



ATACTGCTACCCCGGAGCTACTGTGAATGTGGAAGCACTGCGCCAGAAGATTATGGAATCC



GGAGGCATAAATAAGATTTCCACTGGGTTCACCTATGGCTCCTCTATCAACAGTGCAGGAA



CGACGAGAGCCTGCATGCGCAATGGGGGAAATAGTTTCTACGCCGAGCTGAAGTGGCTGGT



GTCTAAGTCAAAGGGTCAAAACTTTCCCCAAACTACCAATACGTACCGAAATACTGACACG



GCAGAACACCTAATAATGTGGGGGATTCACCATCCCAGCAGCACCCAGGAGAAGAATGATT



TGTATGGGACTCAGTCTCTGTCGATTTCCGTGGGCAGCAGCACGTACCGAAATAATTTCGT



ACCCGTGGTTGGAGCTCGACCTCAGGTGAACGGCCAGTCCGGCAGAATTGATTTTCACTGG



ACACTAGTTCAGCCAGGCGATAATATAACATTTTCGCACAACGGAGGTCTGATCGCACCTT



CACGCGTGTCCAAGCTTATCGGTCGGGGCCTGGGGATCCAGAGTGATGCTCCCATCGATAA



CAATTGCGAGTCTAAATGTTTTTGGCGAGGTGGATCCATCAATACCCGTCTGCCCTTCCAG



AACCTGTCTCCACGCACAGTCGGTCAGTGCCCCAAGTATGTGAATAGAAGGTCCCTGATGC



TCGCCACAGGAATGAGAAACGTTCCGGAACTAATTCAGGGCCGTGGACTATTCGGGGCCAT



AGCAGGGTTCCTGGAGAATGGCTGGGAGGGTATGGTTGACGGTTGGTACGGCTTTCGGCAT



CAGAACGCCCAAGGGACCGGGCAGGCCGCCGACTACAAAAGTACCCAGGCTGCAATCGACC



AGATCACGGGGAAACTGAACCGACTCGTGGAGAAGACTAACACTGAGTTTGAGTCCATCGA



GTCTGAGTTTAGCGAAATCGAGCATCAGATTGGGAACGTTATTAACTGGACAAAGGACAGC



ATCACCGATATATGGACCTACCAGGCAGAACTATTAGTGGCAATGGAGAACCAGCACACAA



TTGACATGGCGGACAGCGAGATGCTGAATCTTTATGAGCGTGTCCGGAAACAGCTGAGACA



GAACGCCGAAGAAGATGGCAAAGGCTGCTTTGAGATATACCATGCGTGCGATGATTCATGC



ATGGAGTCTATTCGCAATAATACATACGATCACAGTCAGTACAGAGAGGAAGCTCTACTGA



ATCGGCTCAACATCAATCCAGTCACCCTGTCTTCCGGCTACAAGGACATCATTCTGTGGTT



CAGCTTTGGAGCCTCCTGTTTTGTACTTCTAGCCGTTGTGATGGGCTTGTTTTTTTTCTGT



TTGAAGAACGGGAATATGAGATGTACCATCTGCATC





751
ATGTACAAGATCGTGGTAATTATCGCTCTGCTAGGAGCCGTGAAGGGGCTAGACAAGATAT



GTCTCGGGCACCACGCCGTGGTTAACGGAACCATTGTGAAGACATTGACTAACGAACAGGA



GGAGGTGACCAATGCGACGGAAACAGTTGAGTCAACAGGATTGAATAGGCTGTGTATGAAG



GGGCGTAACCACAAAGACCTGGGCAATTGCCATCCAATCGGAATGCTTATTGGAACTCCCG



CTTGCGACTTACACCTGACCGGCACATGGGATACCCTGATAGAAAGAGAAAACGCTATTGC



GTATTGCTACCCAGGAGCTACCGTAAACGAAGAGGCCCTTCGGCAGAAAATAATGGAGTCC



GGGGGAATTAACAAAATATCTACTGGCTTTACTTATGGATCGTCCATCAACAGCGCTGGAA



CTACACGCGCTTGCATGCGTAACGGAGGTAATTCATTTTATGCCGAACTGAAGTGGCTGGT



GTCAAAGTCAAAGGGACAGAACTTCCCCCAAACTACAAATACATACAGGAATACCGACACT



GCTGAACACCTGATTATGTGGGGTATTCACCACCCCTCAAGCACCCAGGAAAAGAATGACC



TGTACGGAACTCAGAGTTTGTCTATCAGCGTGGGAAGTTCAACCTACCAAAATAACTTCGT



TCCGGTGGTTGGCGCCAGGCCCCAGGTGAACGGACAGTCGGGGCGCATCGACTTTCATTGG



ACTTTAGTCCAGCCTGGCGACAATATCACATTCTCCCACAACGGAGGGCTTATCGCCCCGA



GTCGCGTGAGCAAGCTCATTGGTCGGGGGTTGGGAATTCAGAGCGATGCCCCTATTGACAA



CAACTGCGAAAGCAAGTGCTTCTGGAGAGGCGGTTCTATTAACACAAGACTCCCATTCCAA



AACCTGAGCCCACGGACAGTCGGGCAGTGCCCCAAGTACGTAAATAAAAGGTCACTCATGT



TGGCTACCGGGATGCGGAATGTCCCAGAACTGATGCAGGGAAGGGGGCTGTTCGGCGCAAT



CGCCGGCTTTATTGAGAATGGCTGGGAGGGAATGGTTGACGGATGGTATGGTTTCAGGCAC



CAGAATGCCCAGGGTACCGGTCAGGCAGCCGATTATAAATCCACCCAGGCAGCGATTGACC



AGATTACTGGAAAGTTGAACCGGCTTATTGAAAAAACCAACACTGAGTTCGAGAGCATCGA



GAGTGAGTTCAGCGAGATCGAACATCAGATCGGTAACGTGATAAACTGGACCAAGGACTCC



ATCACTGATATTTGGACCTACCAGGCTGAGTTATTGGTTGCCATGGAGAACCAGCACACCA



TCGACATGGCCGATTCTGAAATGCTGAATCTCTATGAGAGAGTTCGGAAACAGCTGAGACA



AAATGCAGAGGAGGATGGGAAGGGCTGTTTTGAGATTTACCACGCCTGTGACGACAGTTGT



ATGGAGTCTATTAGAAATAATACCTACGATCATTCTCAATATCGAGAAGAGGCCTTGTTAA



ATAGGCTGAATATTAACCCAGTCACCCTAAGCAGCGGGTACAAAGATATCATACTGTGGTT



CTCGTTTGGAGCCTCTTGCTTTGTGCTATTGGCAGTCGTGATGGGTTTGGTGTTCTTCTGC



CTCAAAAACGGGAATATGAGATGTACGATTTGCATC





752
ATGTATAAGATTGTCCTTGTGCTCGCCCTGCTCGGAGCAGTGCACGGCCTCGATAAAATCT



GTCTGGGGCACCACGCCGTGCCTAACGGCACCATCGTCAAGACTCTCACAAACGAGAAGGA



GGAAGTGACAAACGCTACTGAAACAGTAGAAAGTAAGAGCCTGGACAAACTTTGCATGAAA



AACAGGAATTATAAAGACTTGGGTAATTGTCACCCGATTGGCATGGTCGTCGGAACGCCTG



CTTGTGACCTCCATCTGACGGGAACCTGGGATACCTTGATCGAGCGGGACAACTCAATTGC



ATACTGCTATCCAGGCGCCACCGTTAGTGAGGAGGCTTTGAGACAGAAGATCATGGAGTCT



GGAGGGATTGACAAAATTTCCACCGGCTTTACATATGGTAGCTCAATCAACTCGGCTGGGA



CTACAAAAGCTTGTATGAGGAACGGTGGAAATAGCTTTTACTCGGAACTAAAATGGTTGGT



GTCTAAAAACAAGGGTCAGAACTTTCCTCAGACGACCAACACTTATCGAAATACTGACTCC



GTGGAGCACCTGATTATTTGGGGGATCCATCATCCCAGCAGCACACAAGAGAAGAATGACC



TGTATGGGACGCAGTCTCTGTCCATTAGCGTCGGCAGTTCAACTTACCAGAATAATTTCGT



GCCTGTGGTGGGAGCGCGCCCCCAAGTCAATGGGCAGAGCGGAAGGATTGATTTCCACTGG



ACTATGGTCCAGCCCGGCGATAACATTACTTTCAGCCACAACGGAGGGCTCATTGCACCAA



ACCGTGTCTCAAAACTGAAGGGCAGGGGGCTTGGTATTCAGAGCGGAGCTAGTGTGGACAA



TGACTGCGAATCTAAGTGTTTTTGGAAAGGAGGATCAATTAACACTAAGCTTCCGTTTCAA



AACCTGAGTCCACGCACAGTCGGACAGTGCCCTAAATATGTGAACAAAAAGTCGCTTCTGC



TAGCTACCGGGATGAGGAACGTGCCAGAGGTCGCCCAGGGCAGAGGTTTGTTCGGCGCGAT



CGCCGGTTTCATCGAAAACGGATGGGAGGGAATGGTGGATGGCTGGTACGGATTTCGTCAT



CAAAACGCACAGGGAACGGGTCAGGCCGCAGATTATAAATCTACTCAGGCCGCTATAGATC



AGATCACAGGCAAGCTGAATAGGTTAATAGAGAAGACGAATACCGAGTTTGAGAGCATCGA



AAGCGAGTTCAGTGAAATAGAGCATCAGATTGGCAATGTGATCAATTGGACAAAAGATTCG



ATCACTGATATTTGGACATATCAGGCAGAACTTCTTGTGGCAATGGAGAACCAGCATACGA



TTGATATGGCCGATTCGGAAATGCTGAATCTTTACGAGAGAGTCAGAAAACAGCTGCGCCA



AAATGCTGAGGAAGACGGGAAGGGGTGCTTTGAAATATACCATAAATGTGACGACAACTGC



ATGGAGTCGATCCGCAACAACACATATGACCATACCCAGTACCGTGAGGAAGCTCTGTTAA



ATAGACTTAACATCAATCCAGTTAAACTGTCCTCTGGGTATAAAGATGTGATTTTGTGGTT



CTCTTTCGGCGCTTCATGCTTTGTCCTCCTCGCCGTCATCATGGGACTGGTGTTTTTTTGC



CTCAAAAACGGGAATATGCGATGTACGATATGCATC





753
ATGTATAAAATAGTAGTGATCATCGCTCTGTTAGGAGCGGTGAAAGGGCTCGACAAGATTT



GTCTGGGCCACCACGCCGTTGCTAACGGCACCATCGTCAAGACCCTCACTAATGAACAGGA



GGAGGTCACTAACGCCACTGAGACAGTTGAATCGACCGGGATTAACCGGTTGTGTATGAAA



GGCCGGAAGCATAAAGATCTCGGGAATTGCCACCCAATAGGGATGCTTATCGGCACACCAG



CATGCGACCTCCATCTCACGGGCATGTGGGACACCCTTATCGAAAGAGAAAATGCCATTGC



CTATTGCTATCCGGGCGCAACCGTGAATGTGGAGGCCCTTCGACAAAAAATCATGGAAAGC



GGCGGCATTAACAAAATCAGCACGGGATTCACCTACGGGTCTAGTATCAATTCAGCAGGCA



CGACCAGAGCTTGTATGCGTAACGGGGGTAATTCTTTCTACGCAGAGCTGAAATGGCTCGT



GTCTAAGAGCAAAGGTCAGAATTTTCCCCAGACTACTAATACATATAGGAATACCGACACT



GCGGAGCATCTTATAATGTGGGGCATCCACCACCCATCCTCCACACAGGAAAAGAACGACC



TGTATGGTACGCAGTCACTGAGTATAAGCGTTGGGTCCAGCACTTATCGAAATAACTTTGT



GCCCGTAGTGGGAGCCCGCCCACAGGTTAACGGCCAGAGTGGCAGAATCGACTTCCATTGG



ACCCTGGTGCAGCCCGGCGACAACATCACTTTCTCACATAACGGAGGGTTAATAGCTCCAT



CCAGGGTATCCAAACTCATTGGTAGGGGGCTGGGCATCCAATCCGACGCCCCCATTGACAA



TAATTGTGAGAGCAAATGTTTCTGGAGGGGTGGAAGCATCAATACCAGACTCCCATTCCAG



AATTTATCTCCCCGCACAGTAGGGCAGTGCCCCAAATATGTTAACAGAAGATCCCTGATGC



TCGCGACAGGAATGCGGAATGTGCCCGAGCTGATCCAGGGCCGCGGGTTGTTTGGCGCCAT



AGCTGGTTTTCTCGAGAATGGTTGGGAAGGGATGGTTGACGGCTGGTATGGGTTTCGCCAT



CAGAACGCTCAGGGAACAGGACAAGCTGCCGACTACAAGAGCACTCAAGCAGCAATCGATC



AAATCACGGGGAAGCTCAACAGGCTTGTTGAAAAGACTAATACTGAGTTCGAAAGCATTGA



GTCCGAGTTTTCCGAGATTGAGCATCAGATTGGGAACGTCATCAACTGGACCAAAGACAGT



ATCACGGACATATGGACTTATCAAGCCGAACTCCTGGTGGCCATGGAAAACCAGCACACAA



TCGATATGGCTGATTCTGAGATGCTTAACCTGTACGAGCGCGTGCGGAAACAACTGCGGCA



AAACGCAGAGGAAGACGGAAAAGGATGTTTTGAAATATACCACGCATGTGATGATAGCTGC



ATGGAGAGCATTCGTAACAACACTTATGATCATTCTCAGTACCGCGAGGAAGCTCTCCTAA



ACAGACTCAACATTAATCCAGTGACCCTGAGCTCTGGATATAAAGACATTATTCTGTGGTT



TAGTTTCGGCGCCAGCTGCTTTGTGCTGCTGGCGGTGGTTATGGGACTGTTCTTCTTCTGT



TTGAAAAACGGAAATATGAGATGTACTATTTGCATC





754
ATGTATAAGATAGTAGTAATTATTGCTCTCTTGGGGGCGGTGAAAGGGCTGGATAAAATCT



GCCTGGGGCATCACGCCGTGGCCAATGGCACCATTGTAAAAACGCTTACAAATGAGCAGGA



AGAAGTGACCAACGCCACAGAAACTGTGGAGAGCACTGGCATCAACCGGCTCTGTATGAAG



GGTAGAAAGCACAAGGATCTGGGGAATTGCCACCCCATCGGCATGTTAATAGGCACTCCGG



CTTGCGATTTGCACCTTACCGGAATGTGGGACACACTAATCGAGAGGGAAAATGCCATTGC



GTACTGCTACCCAGGTGCCACCGTGAATGTCGAGGCACTGAGGCAGAAAATCATGGAATCA



GGAGGAATAAACAAGATCTCTACCGGCTTTACGTATGGCTCATCCATCAACTCTGCAGGTA



CCACTCGAGCTTGCATGCGGAACGGCGGCAATTCCTTCTACGCAGAACTAAAGTGGCTTGT



GTCCAAAAGTAAGGGTCAGAATTTCCCCCAAACTACCAATACGTACAGGAACACTGACACG



GCAGAACACCTGATCATGTGGGGCATCCATCATCCCTCCTCTACCCAGGAAAAAAATGACC



TGTACGGGACACAGAGCCTGTCCATATCTGTAGGCTCAAGTACATATCGTAACAACTTCGT



GCCCGTTGTGGGCGCACGTCCACAGGTTAACGGCCAAAGCGGACGCATTGATTTCCATTGG



ACCCTAGTCCAGCCCGGAGACAATATAACCTTCTCGCATAATGGAGGACTGATCGCTCCCT



CTCGCGTGTCTAAGCTGATCGGTCGGGGATTGGGGATTCAGAGCGACGCTCCTATTGATAA



CAACTGCGAATCCAAGTGCTTTTGGAGAGGGGGCAGCATCAATACTAGATTGCCTTTTCAG



AACCTTTCTCCCCGCACAGTGGGGCAATGCCCTAAATACGTCAATAGAAGGTCTCTTATGC



TTGCCACCGGAATGCGTAATGTACCAGAACTCATACAAGGTAGAGGGTTATTCGGCGCCAT



CGCTGGCTTTCTGGAAAATGGCTGGGAGGGGATGGTTGACGGCTGGTATGGTTTCAGACAC



CAAAATGCTCAGGGTACAGGTCAGGCCGCCGATTACAAGTCCACACAGGCAGCTATTGATC



AGATCACAGGCAAGTTGAACCGCCTCGTGGAAAAGACTAACACAGAGTTTGAGTCTATTGA



ATCCGAATTCTCTGAGATTGAACACCAAATTGGAAATGTTATCAACTGGACAAAGGACTCT



ATTACCGATATTTGGACCTATCAAGCCGAGTTGTTGGTCGCCATGGAGAATCAACATACTA



TTGACATGGCGGACTCTGAAATGCTAAATCTCTACGAGAGAGTAAGAAAGCAGCTTCGACA



GAACGCAGAGGAAGACGGAAAGGGATGTTTTGAGATCTATCATGCTTGTGACGATTCGTGC



ATGGAATCCATTCGGAATAATACATATGACCATTCTCAGTATAGAGAAGAAGCCCTGCTTA



ACCGGCTAAACATCAATCCCGTGACGCTATCATCCGGGTATAAAGATATCATCCTGTGGTT



CTCATTCGGGGCTTCGTGTTTTGTGCTCCTGGCGGTCGTGATGGGCCTGTTCTTTTTCTGT



CTTAAAAACGGGAACATGCGATGCACCATATGCATC





755
ATGTACAAGGTCGTAGTTATTATCGCGCTGCTAGGTGCAGTTCGGGGGCTCGATAAGATTT



GCCTGGGGCACCATGCGGTCGCCAACGGAACTATCGTTAAGACATTAACCAACGAACAGGA



GGAGGTGACAAATGCAACCGAGACCGTGGAATCTAAATCCCTGGGTAAGCTGTGCATGAAA



GGGAGGAGTTATAACGACCTTGGAAACTGTCACCCAATCGGCATTCTTATCGGGACCCCCG



CTTGTGATCTCCATTTAACCGGCACCTGGGATACACTCATTGAGCGCGAAAATGCTGTTGC



CTACTGTTACCCAGGAGCTACAGTAAACGAGGAAGCTCTTAGACAGAAGATAATGGAGTCC



GGAGGGATTTCCAAGATCAGCACTGGCTTCACCTATGGCACATCAATCAACAGCGCAGGGA



CGACAAAGGCCTGTATGAGGAACGGCGGCAACTCATTCTACGCCGAGCTGAAATGGCTGGT



GTCAAAGAACAAAGGCCAGAACTTCCCACAAACCACGAACACCTACAGGAACACCGATACC



GCAGAGCATCTTATAATATGGGGAATCCACCACCCCTCTTCCACCCAGGAGAAAAATGATC



TTTATGGCACTCAATCTTTATCTATATCAGTAGGGTCTTCAACTTACCAGAACAATTTCGT



GCCTGTGGTGGGAGCGCGGCCGCAAGTGAACGGTCAGAGCGGTCGTATAGACTTTCACTGG



ACCCTGCTGCAGCCAGGTGACAACATCACCTTCTCTCACAATGGTGGGCTAATTGCTCCCT



CCAGAGTCAGCAAGCTTATAGGGAGAGGCCTCGGGATACAGTCAGAAGCCCCTATCGACAA



TGGGTGCGAGTCGAAGTGTTTCTGGAAGGGTGGATCTATTAACACAAAACTTCCTTTTCAG



AACTTATCTCCGAGGACTGTGGGCCAATGCCCTAAATACGTTAACAAGCGCAGTTTAATGC



TTGCTACGGGTATGAGGAATGTCCCAGAGATCATGCACGGCCGCGGGCTCTTCGGGGCCAT



TGCCGGATTTATTGAGAACGGGTGGGAGGGCATGGTAGATGGATGGTACGGGTTCCGCCAC



CAAAACGCACAGGGAACGGGACAGGCAGCTGACTACAAATCAACACAAGCGGCTATCGACC



AGATAACAGGCAAGCTGAATAGACTGATCGAGAAAACTAATACAGAGTTCGAGAGCATAGA



GAGCGAATTTTCCGAGATCGAGCATCAGATCGGTAACATTATAAATTGGACTAAGGATAGC



ATTACTGATATTTGGACCTATCAGGCTGAGCTGCTGGTTGCCATGGAAAACCAACATACAA



TCGATATGGCCGATTCAGAAATGCTGAATCTATATGAGAGAGTGAGGAAGCAGCTGAGACA



GAACGCTGAGGAGGACGGTAAAGGCTGTTTCGAAATTTACCATGCATGCGACGACTCTTGT



ATGGAATCTATCCGCAACAACACATACGACCACTCCCAGTACAGGGAGGAAGCCCTGCTGA



ATCGACTGAACATTAATCCAGTCAAGCTTTCCTCTGGTTATAAGGACATCATCTTATGGTT



CAGCTTCGGGGCTTCGTGTCTCATTCTCTTGGCTGTGGTAATGGGCTTAGTTTTCTTTTGT



CTTAAGAACGGCAACATGAGGTGCACAATTTGCATC





756
ATGTATAAAATCGTGGTTATTATTGCACTGCTAGGGGCCGTCAAGGGCTTAGATAAGATTT



GCCTGGGCCACCACGCGGTGGCCAATGGGACCATTGTGAAAACTCTGACCAACGAGCAGGA



AGAAGTGACTAACGCCACCGAGACTGTGGAATCAACAGGAATCAATCGTCTGTGCATGAAA



GGCAGAAAGCATAAGGACCTTGGAAACTGTCATCCTATTGGGATGCTGATCGGCACCCCAG



CTTGTGATTTGCACCTCACCGGTATGTGGGATACTCTTATCGAAAGGGAAAACGCTATCGC



TTATTGTTACCCAGGAGCGACTGTCAATGTCGAGGCCCTACGCCAGAAAATAATGGAAAGT



GGAGGGATTAATAAGATAAGCACTGGTTTCACGTATGGCAGTTCGATCAATAGTGCCGGAA



CAACTCGCGCTTGCATGCGTAATGGTGGAAACTCATTTTACGCAGAGCTCAAATGGCTAGT



TTCGAAGTCCAAAGGTCAGAACTTTCCACAGACGACCAACACCTATCGCAATACCGACACT



GCAGAGCACCTGATCATGTGGGGAATTCATCACCCGTCAAGCACTCAAGAGAAGAACGATC



TTTATGGAACCCAGAGTCTCAGTATTTCCGTTGGCTCGAGTACGTACCGCAATAACTTCGT



TCCTGTCGTGGGTGCCAGGCCTCAGGTTAACGGGCAGTCCGGGCGCATCGATTTTCACTGG



ACTCTCGTTCAGCCCGGGGATAATATCACATTCAGTCACAACGGTGGGCTGATCGCGCCGT



CCAGAGTGTCAAAACTGATCGGCAGGGGCCTGGGCATTCAGAGCGACGCACCAATTGATAA



CAATTGTGAGAGCAAATGTTTCTGGCGTGGAGGCAGCATCAATACCCGACTCCCGTTTCAG



AATCTGAGCCCCAGAACTGTCGGACAATGTCCTAAATATGTGAATCGGCGCTCCCTGATGC



TCGCAACTGGCATGCGGAACGTGCCCGAGTTGATTCAAGGACGCGGGCTGTTCGGTGCCAT



CGCTGGGTTCCTGGAAAACGGCTGGGAAGGCATGGTAGATGGATGGTACGGGTTCAGGCAC



CAGAACGCCCAAGGGACAGGACAGGCCGCCGACTACAAGAGTACTCAAGCTGCTATTGACC



AAATTACCGGAAAACTGAATAGGCTGGTGGAAAAGACCAATACAGAGTTCGAGTCTATCGA



GAGCGAGTTTAGCGAGATCGAGCATCAGATTGGTAATGTGATTAACTGGACGAAAGATAGT



ATCACCGACATCTGGACATATCAAGCAGAACTTCTTGTGGCTATGGAGAATCAACATACTA



TTGACATGGCTGATAGCGAGATGTTGAATCTTTACGAGAGAGTGCGCAAACAGCTGCGGCA



GAATGCTGAGGAAGATGGCAAAGGTTGTTTCGAGATCTACCATGCCTGCGACGACAGTTGT



ATGGAGAGCATTAGGAATAACACTTACGACCACTCACAATATCGAGAAGAGGCTCTACTCA



ACAGGCTAAACATCAATCCAGTGACCCTCTCCTCCGGTTATAAGGATATCATTCTCTGGTT



CTCCTTCGGAGCTTCCTGTTTTGTCCTTCTGGCAGTGGTGATGGGATTATTTTTTTTCTGC



CTTAAGAATGGGAATATGAGATGTACAATCTGTATT





757
ATGTACAAGATCGTAGTGATTATCGCATTACTTGGCGCCGTGAAGGGACTCGATAAGATTT



GCTTGGGCCATCATGCTGTGGCCAATGGCACTATAGTGAAGACACTCACCAATGAACAGGA



AGAAGTGACCAACGCCACCGAGACCGTGGAGTCTACAGGCATCAACAGGCTCTGTATGAAG



GGCCGTAAGCACAAGGATCTTGGCAACTGCCATCCTATCGGAATGCTCATTGGAACACCAG



CTTGTGATCTCCACTTAACAGGCATGTGGGACACACTGATTGAGCGGGAGAATGCGATTGC



CTACTGTTATCCCGGGGCCACCGTGAACGTTGAGGCTCTCAGACAGAAAATCATGGAGAGC



GGCGGGATAAACAAGATAAGCACAGGCTTCACTTACGGTTCTAGCATTAATTCGGCAGGAA



CCACACGGGCCTGCATGCGCAACGGCGGCAATTCATTTTACGCCGAACTTAAGTGGCTGGT



GTCCAAGAGCAAGGGCCAGAACTTCCCCCAGACCACTAATACTTACCGCAACACCGACACA



GCAGAGCACCTTATCATGTGGGGTATACACCATCCTAGCAGTACCCAAGAAAAAAACGATC



TGTACGGAACACAAAGCCTTTCAATTTCTGTAGGAAGTTCCACATATAGGAACAACTTTGT



CCCGGTGGTGGGCGCTGGCCCTCAGGTTAATGGCCAGTCCGGGAGGATCGATTTCCATTGG



ACACTCGTGCAGCCTGGGGACAACATTACTTTCTCTCACAACGGGGGTTTAATCGCCCCCT



CAAGGGTCTCTAAGCTCATCGGGCGCGGTCTGGGAATCCAATCCGACGCTCCTATTGACAA



CAACTGCGAGTCAAAGTGCTTCTGGAGAGGTGGATCCATCAACACGCGCCTCCCATTTCAG



AACTTGTCCCCGCGTACAGTGGGCCAGTGTCCCAAGTATGTGAATCGACGGAGCTTGATGC



TGGCCACTGGGATGAGGAACGTGCCTGAACTTATCCAGGGAAGGGGCCTCTTCGGAGCCAT



CGCTGGCTTCCTGGAAAACGGCTGGGAGGGGATGGTGGACGGGTGGTACGGCTTTCGACAT



CAGAATGCCCAGGGGACTGGACAGGCAGCAGATTATAAGAGTACCCAAGCCGCCATTGACC



AGATCACAGGGAAGCTAAACAGGTTGGTCGAAAAGACTAACACAGAATTCGAATCCATCGA



GAGCGAGTTTTCCGAGATTGAGCACCAGATCGGTAACGTGATTAACTGGACGAAAGACTCA



ATAACCGATATCTGGACATATCAGGCGGAGTTGCTTGTGGCGATGGAGAACCAGCACACTA



TTGATATGGCAGACTCTGAGATGCTCAACCTGTATGAGCGGGTTCGGAAGCAGCTGCGACA



AAATGCTGAGGAAGACGGAAAGGGGTGTTTCGAAATCTATCACGCCTGTGATGACTCTTGC



ATGGAGTCGATTAGGAACAATACCTATGATCACTCTCAATATAGAGAGGAGGCTTTACTAA



ATCGGCTCAACATAAATCCAGTGACCCTGTCCAGCGGATATAAAGACATTATTCTATGGTT



CTCTTTCGGAGCGAGCTGCTTTGTGCTTCTCGCTGTGGTGATGGGTCTCTTCTTTTTTTGC



CTGAAGAATGGTAACATGCGCTGCACTATTTGTATT





758
ATGTACAAGGTGGTAGTGATTATTGCCCTGCTGGGAGCAGTTAGAGGCTTAGATAAAATTT



GCCTCGGGCATCATGCTGTTGCTAATGGTACAATTGTCAAGACCTTAACAAATGAGCAGGA



GGAGGTAACCAATGCGACCGAGACGGTGGAGTCTAAGTCTTTGGGGAAACTGTGTATGAAG



GGAAGATCATATAACGACCTAGGCAATTGCCACCCCATCGGGATTCTGATTGGGACCCCCG



CCTGTGATCTGCACCTGACAGGCACATGGGACACCCTGATCGAACGGGAAAACGCGGTGGC



CTATTGCTACCCTGGGGCGACAGTCAACGAGGAAGCTTTGAGGCAGAAAATCATGGAGAGC



GGGGGCATCTCTAAAATCTCCACCGGGTTCACGTATGGTACCTCCATTAATTCAGCCGGAA



CGACCAAGGCATGTATGCGTAATGGAGGCAACTCCTTCTACGCCGAGCTCAAGTGGCTTGT



TTCCAAAAATAAGGGGCAGAATTTCCCTCAGACAACGAACACATACCGGAATACTGACACT



GCAGAGCACCTAATCATCTGGGGAATTCACCACCCATCCAGTACGCAGGAAAAAAACGACC



TCTACGGGACTCAGTCTCTGTCAATTTCTGTGGGCTCCTCAACATACCAAAATAACTTCGT



TCCAGTGGTGGGCGCCCGGCCCCAGGTCAATGGACAGAGCGGAAGGATAGACTTCCACTGG



ACACTCCTTCAGCCGGGGGACAATATCACGTTCTCTCACAACGGGGGACTGATAGCTCCAT



CTAGGGTGAGCAAACTGATTGGACGGGGATTGGGCATACAATCAGAAGCGCCCATAGACAA



TGGATGCGAAAGCAAATGCTTTTGGAAGGGAGGTTCAATAAACACAAAACTCCCATTCCAG



AATCTGTCTCCTAGAACAGTGGGGCAGTGCCCCAAATATGTTAATAAGAGATCTCTCATGC



TTGCTACTGGCATGCGGAACGTCCCCGAAATTATGCATGGGAGGGGCCTCTTCGGGGCGAT



TGCCGGCTTCATTGAAAATGGCTGGGAAGGAATGGTCGATGGATGGTATGGCTTTCGACAT



CAGAACGCACAGGGCACTGGGCAGGCAGCAGACTACAAAAGTACTCAGGCCGCAATAGACC



AGATAACCGGAAAGCTCAATCGCCTCATCGAAAAGACAAACACTGAATTCGAAAGTATTGA



ATCCGAATTCTCTGAAATAGAGCACCAGATTGGTAATATCATCAACTGGACCAAGGATAGT



ATTACTGATATCTGGACATACCAAGCCGAACTGCTGGTAGCAATGGAGAATCAGCACACGA



TTGATATGGCAGATTCTGAAATGCTGAACCTGTATGAGCGAGTGCGCAAGCAGCTGCGCCA



AAACGCTGAAGAGGATGGGAAAGGCTGCTTCGAAATCTACCACGCTTGCGACGATTCCTGC



ATGGAGAGTATCCGGAATAACACCTACGATCATAGCCAGTACAGGGAGGAAGCCCTTCTGA



ACAGACTGAACATTAACCCAGTTAAGCTTAGTAGTGGATACAAAGACATAATCCTCTGGTT



CTCCTTTGGCGCTTCATGCTTAATTTTACTTGCCGTCGTAATGGGACTGGTGTTTTTCTGC



CTTAAGAACGGCAATATGAGGTGCACGATTTGCATC





759
ATGTACAAGATCGTGGTTATTATTGCCTTGTTGGGCGCCGTGAAGGGTCTCGATAAGATTT



GTCTGGGCCATCATGCTGTAGCCAATGGCACCATTGTGAAGACGCTCACTAACGAGCAGGA



AGAGGTTACGAACGCAACCGAGACAGTGGAGAGCACTGGGATAAACAGACTGTGCATGAAA



GGACGTAAACACAAGGACCTTGGTAATTGCCACCCTATCGGGATGCTGATTGGGACACCCG



CATGCGACTTGCATTTGACCGGAATGTGGGATACATTGATTGAGCGCGAGAACGCAATTGC



CTACTGTTACCCAGGAGCCACCGTCAATGTTGAGGCCCTGCGGCAGAAGATCATGGAGAGC



GGCGGCATTAACAAGATATCTACAGGCTTTACATATGGATCATCCATAAATTCAGCAGGAA



CTACGCGCGCATGCATGCGCAACGGCGGCAACAGCTTTTACGCTGAGCTTAAGTGGCTCGT



CAGTAAGTCAAAGGGCCAGAATTTCCCCCAAACCACCAATACATACAGAAACACCGACACG



GCAGAGCACCTGATCATGTGGGGAATCCATCACCCATCTTCCACGCAAGAGAAGAATGACC



TATACGGGACTCAGAGCCTCTCCATATCCGTCGGGTCCTCCACCTACAGGAACAACTTTGT



ACCTGTTGTAGGGGCTCGCCCCCAGGTGAATGGCCAGAGCGGACGGATCGACTTTCATTGG



ACACTTGTTCAGCCCGGCGACAACATTACTTTCTCCCACAACGGAGGTCTGATCGCCCCCA



GCAGGGTAAGTAAACTGATTGGCCGCGGCTTAGGAATACAGAGCGACGCCCCAATCGATAA



CAATTGTGAATCTAAGTGCTTTTGGAGGGGGGGCAGTATAAACACCCGGCTACCCTTTCAG



AATCTGAGTCCACGCACCGTGGGGCAGTGTCCAAAGTATGTGAACCGGAGAAGTTTAATGC



TGGCAACCGGCATGAGAAATGTCCCTGAGCTAATTCAGGGTCGCGGGCTTTTCGGCGCAAT



CGCAGGCTTTCTCGAAAACGGTTGGGAGGGCATGGTGGACGGGTGGTACGGGTTCCGGCAC



CAAAACGCCCAGGGAACTGGGCAGGCCGCCGATTACAAAAGCACTCAGGCAGCTATAGACC



AGATCACAGGCAAACTGAATCGGCTGGTGGAAAAGACAAATACAGAGTTCGAGAGCATTGA



GAGCGAGTTTAGCGAGATCGAACATCAGATCGGGAACGTTATTAACTGGACCAAGGATAGC



ATCACTGATATTTGGACCTACCAGGCTGAACTGTTGGTCGCCATGGAGAACCAGCACACAA



TCGACATGGCAGACTCGGAGATGCTTAACCTCTATGAGCGGGTGAGAAAGCAGCTCCGACA



GAACGCCGAAGAGGACGGGAAGGGGTGCTTCGAAATTTATCATGCATGTGACGATAGTTGT



ATGGAGTCAATCCGCAATAATACTTATGATCATAGCCAGTATCGTGAGGAGGCCCTGCTCA



ATCGTCTGAATATAAATCCCGTGACCCTGAGTTCGGGCTACAAAGACATAATACTCTGGTT



TTCGTTTGGCGCGAGTTGCTTCGTGCTGTTAGCTGTTGTAATGGGATTGTTCTTTTTCTGC



CTAAAAAACGGCAACATGAGGTGTACTATTTGCATC





760
ATGTACAAGATTGTCCTGGTGCTTGCTCTGCTGGGAGCCGTGCACGGCCTCGATAAAATCT



GCTTAGGCCACCACGCTGTCCCTAATGGCACCATTGTTAAGACCTTGACAAACGAAAAGGA



AGAGGTGACCAACGCCACTGAGACTGTGGAATCCAAGTCACTCGACAAATTATGTATGAAG



AACAGGAACTATAAAGATCTTGGTAACTGCCATCCAATTGGCATGGTGGTAGGAACTCCTG



CTTGCGATCTACACCTGACGGGCACATGGGACACCCTGATTGAGAGGGACAACTCTATTGC



ATACTGCTATCCAGGTGCGACCGTTTCCGAAGAAGCACTCCGGCAGAAGATTATGGAGTCC



GGCGGCATCGATAAAATCTCCACCGGCTTCACATACGGAAGTAGCATCAACTCTGCTGGGA



CGACCAAAGCGTGTATGAGGAACGGGGGGAATAGTTTCTACTCAGAACTCAAGTGGCTGGT



CAGTAAGAACAAGGGGCAGAACTTCCCTCAAACGACCAACACATACCGAAATACAGATTCT



GTGGAGCACTTAATCATCTGGGGGATTCATCATCCATCCAGCACGCAGGAGAAAAACGATC



TCTATGGTACACAGTCTCTCAGCATCAGTGTGGGAAGCAGTACGTATCAGAACAATTTTGT



CCCCGTCGTTGGCGCCCGGCCACAAGTGAACGGACAAAGTGGTCGTATTGATTTTCATTGG



ACCATGGTCCAACCTGGTGATAATATAACATTTTCACACAATGGAGGACTGATAGCTCCTA



ACAGAGTATCCAAGCTGAAGGGAAGGGGGTTGGGGATTCAGTCCGGAGCATCAGTGGACAA



TGATTGCGAGAGCAAGTGCTTCTGGAAGGGAGGTTCCATCAACACGAAGCTGCCTTTCCAG



AATCTGAGCCCACGAACAGTGGGACAGTGCCCGAAGTATGTGAATAAGAAGAGCCTTCTGC



TTGCGACTGGCATGAGGAATGTTCCTGAAGTTGCGCAGGGAAGGGGGCTATTCGGGGCAAT



CGCCGGATTCATCGAGAACGGCTGGGAGGGCATGGTGGACGGGTGGTACGGGTTCAGGCAC



CAGAACGCCCAGGGTACAGGGCAGGCCGCTGATTACAAGTCAACACAGGCGGCGATAGACC



AGATCACCGGCAAACTGAATAGGCTAATAGAGAAGACTAACACTGAATTTGAATCTATTGA



GAGCGAGTTCTCGGAAATTGAACACCAGATCGGAAATGTGATCAATTGGACCAAGGATTCC



ATTACCGATATCTGGACTTATCAGGCAGAGCTGTTAGTGGCAATGGAAAACCAGCATACCA



TAGACATGGCTGATTCTGAGATGTTGAACCTCTACGAGGGGGTACGGAAACAACTGAGACA



GAATGCAGAGGAAGACGGCAAGGGCTGTTTCGAAATCTACCACAAGTGCGACGATAATTGT



ATGGAAAGTATACGCAACAATACCTATGATCACACACAATATAGGGAAGAGGCTCTTCTGA



ACCGACTGAACATCAATCCCGTGAAACTTAGCTCAGGATACAAGGACGTGATCCTTTGGTT



TTCTTTCGGGGCTAGTTGCTTCGTGCTGCTTGCGGTTATCATGGGGCTTGTTTTCTTTTGT



CTAAAGAATGGGAATATGAGATGCACAATCTGCATC





761
ATGTACAAAATCGTGGTGATCATCGCCCTCCTGGGAGCTGTGAAGGGCCTTGACAAAATCT



GCCTCGGCCACCACGCCGTCGCCAATGGAACCATCGTGAAGACTCTGACCAATGAGCAGGA



GGAAGTTACCAATGCAACTGAGACCGTGGAAAGTACCGGGATAAATCGCCTCTGCATGAAG



GGAAGGAAACATAAAGACCTGGGGAACTGTCATCCGATTGGGATGCTGATTGGGACCCCTG



CCTGTGATTTGCACCTTACCGGCACATGGGACACACTGATCGAGCGAGAAAATGCTATCGC



ATATTGTTATCCCGGGGCAACCGCAAACGTAGAGGCCCTACGGCAGAAAATTATGGAGTCC



GGTGGCATAGACAAAATAAGCACAGGATTTACCTACGGCTCGAGCATCAACTCTGCTGGCA



CCACCAGAGCTTGCATGAGGAATGGGGGGAACTCCTTTTACGCTGAGTTGAAGTGGCTGGT



GAGCAAGAGTAAAGGGCAGAACTTTCCTCAGACGACTAATACATATAGAAACACCGACACA



GCAGAGCACCTCATAATGTGGGGAATCCATCACCCATCTTCAATTCAGGAGAAGAATGACC



TTTATGGTACTCAGAGCCTCAGTATTTCCGTGGGATCTTCTACGTACAGAAACAACTTTGT



GCCAGTTGTCGGCGCAAGACCTCAGGTCAACGGGCAGTCAGGGAGAATTGACTTTCATTGG



ACACTGGTGCAACCTGGGGATAATATCACTTTTAGCCATAATGGAGGACTGATTGCTCCCA



GTAGAGTCTCTAAACTGATTGGGAGGGGACTCGGTATCCAGTCGGATGCTCCTATCGATAA



TAACTGTGAGAGCAAGTGTTTTTGGCGAGGGGGATCTATCAATACACGGTTGCCATTTCAG



AATCTATCGCCCCGCACGGTTGGTCAGTGCCCCAAGTACGTTAATCGTCGGTCGCTGATGC



TGGCTACGGGAATGAGGAATGTTCCAGAACTGATTCAAGGACGCGGTTTGTTCGGCGCCAT



CGCAGGTTTCCTTGAAAACGGCTGGGAAGGTATGGTTGACGGTTGGTACGGATTCCGACAT



CAGAACGCCCAGGGTACGGGACAGGCGGCTGACTACAAAAGCACCCAGGCAGCAATTGATC



AGATCACGGGGAAGCTCAATAGACTGGTGGAAAAGACCAACACGGAATTTGAATCAATTGA



GTCCGAATTTTCCGAGATTGAACATCAGATCGGCAATGTCATTAATTGGACAATGGATAGC



ATCACTGACATATGGACTTATCAGGCCGAGCTGCTGGTTGCAATGGAGAATCAGCACACTA



TCGACATGGCTGATTCCGAGATGCTGAACCTTTACGAGAGAGTGCGCAAGCAGCTCCGGCA



GAACGCCGAAGAAGATGGAAAGGGGTGCTTTGAGATTTATCACGCGTGCGACGACAGTTGC



ATGGAATCCATCCGGAACAATACTTATGATCATTCTCAGTACCGCGAGGAAGCACTGCTCA



ACAGACTGAATATTAACCCAGTGACCCTAAGCTCAGGGTACAAGGACATCATTCTGTGGTT



CTCTTTCGGCGCGTCATGCTTCGTGCTGCTGGCAGTTGTGATGGGACTCGTGTTCTTTTGC



CTCAAAAATGGAAACATGAGATGTACCATTTGTATC





762
ATGTATAAAGTCGTAGTGATCATCGCACTGTTAGGAGCTGTAAAGGGACTGGACAAGATCT



GCTTAGGACACCACGCAGTGGCAAACGGGACCATAGTCAAGACATTGACTAATGAACAAGA



GGAAGTCACCAACGCGACTGAAACAGTCGAATCTACAGGAATCAACAGACTTTGTATGAAA



GGACGGAAACATAAAGATCTGGGCAACTGTCACCCCATAGGAATGCTGATTGGTACACCAG



CTTGTGACTTGCATCTGACCGGCACATGGGACACGCTGATCGAGAGAGAAAATGCCATTGC



CTACTGTTACCCTGGGGCTACAGTAAACGTCGAGGCGCTGCGTCAGAAGATCATGGAATCT



GGGGGCATCGATAAAATCAGCACGGGGTTCACATACGGATCCAGTATTAATTCTGCTGGCA



CTACCCGTGCTTGTATGCGGAACGGTGGAAACTCCTTCTATGCAGAGCTCAAATGGCTGGT



TTCTAAGAACAAGGGGCAGAATTTTCCCCAGACGACAAATACATATAGAAATACAGACACT



GCTGAGCACCTAATCATGTGGGGCATCCACCACCCAAGTAGTATCCAGGAGAAAAACGACC



TGTACGGCACACAAAGCCTGTCAATCTCAGTGGGCTCCTCAACTTACCGCAATAATTTTGT



GCCAGTTGTGGGCGCCAGGCCCCAGGTTAATGGTCAGTCTGGGCGCATCGATTTTCATTGG



ACTCTGGTGCAACCTGGCGACAATATTACATTCTCTCACAACGGAGGACTCATCGCCCCAT



CCAGAGTGTCTAAGTTGATAGGACGAGGGTTAGGCATCCAAAGCGATGCCCCCATTGACAA



TAACTGCGAATCAAAGTGCTTTTGGCGGGGAGGATCCATTAACACACGGTTGCCTTTCCAG



AATCTGTCTCCAAGGACCGTAGGGCAGTGCCCAAAATACGTGAACAGGCGGTCTCTTATGC



TGGCCACGGGGATGCGCAACGTGCCAGAGCTCATCCAGGGGCGTGGATTATTTGGAGCTAT



TGCCGGATTTCTGGAAAATGGCTGGGAGGGGATGGTTGACGGTTGGTACGGTTTCAGGCAC



CAGAACGCACAGGGCACAGGACAGGCCGCCGACTATAAAAGTACCCAGGCAGCGATTGATC



AGATAACCGGAAAGCTGAACAGGTTGGTGGAAAAAACCAATACTGAGTTCGAGTCTATCGA



GAGCGAATTCTCGGAAATCGAACACCAGATTGGAAATGTAATCAACTGGACTATGGATAGC



ATCACCGATATCTGGACCTACCAGGCTGAACTGTTGGTGGCTATGGAGAATCAACACACGA



TCGATATGGCTGACAGCGAGATGCTCAACCTGTATGAACGTGTTAGGAAACAGCTAAGGCA



AAACGCTGAAGAAGACGGAAAGGGATGTTTTGAAATATATCATGCATGCGATGACTCATGT



ATGGAGTCAATCCGGAACAATACATATGACCATTCTCAGTATAGGGAGGAGGCCCTCCTGA



ACAGACTGAATATTAATCCCGTTACCCTATCCAGCGGGTATAAGGACATCATCCTCTGGTT



CTCTTTTGGTGCCAGTTGTTTCGTTTTGCTTGCTGTTGTGATGGGACTCGTCTTTTTCTGT



CTGAAGAACGGGAACATGAGATGCACCATTTGCATC





763
ATGTACAAAATTGTCGTCATCATAGCACTTCTAGGTGCCGTGAAAGGTTTGGATAAGATCT



GTCTAGGCCATCATGCTGTCGCAAACGGCACTATCGTGAAAACTTTGACTAACGAACAAGA



GGAAGTGACTAACGCTACGGAGACAGTCGAATCGACCGGGATCAACAGACTGTGCATGAAA



GGCCGCAAACACAAAGATTTGGGGAACTGCCATCCTATAGGCATGCTGATTGGGACACCAG



CTTGCGACCTCCACCTGACGGGAATGTGGGACACCCTCATTGAGCGGGAGAATGCGATCGC



GTACTGTTACCCGGGGGCTACCGTCAATGTGGAGGCACTCAGGCAAAAGATCATGGAGTCT



GGCGGCATCAATAAGATTTCCACTGGGTTCACCTATGGATCTAGCATTAATTCTGCAGGTA



CAACTAGAGCTTGTATGAGAAATGGGGGGAATAGTTTCTACGCCGAACTTAAATGGCTGGT



GAGCAAGTCAAAGGGACAAAACTTCCCCCAGACAACGAATACTTACAGGAATACGGATACC



GCAGAGCACTTGATCATGTGGGGGATTCATCATCCATCAAGCACACAGGAAAAAAACGATT



TGTATGGGACTCAGTCACTGTCTATTAGCGTGGGATCTAGTACTTACAGAAACAACTTCGT



ACCTGTGGTGGGAGCCCGACCACAGGTGAATGGACAGAGTGGGAGGATTGACTTTCACTGG



ACCCTGGTGCAACCTGGTGATAATATTACATTTAGCCACAATGGCGGATTGATCGCACCAT



CCCGAGTCAGTAAGCTCATAGGCCGGGGACTTGGCATACAGAGCGACGCTCCTATCGATAA



CAATTGCGAGTCCAAATGCTTCTGGCGGGGAGGAAGTATAAACACACGGCTGCCATTTCAG



AACCTTTCGCCCCGCACGGTCGGCCAGTGCCCCAAATATGTGAATAGGCGTTCACTCATGC



TCGCAACAGGAATGAGAAATGTGCCTGAGCTGATTCAGGGCAGGGGGCTTTTCGGTGCTAT



AGCGGGATTTTTAGAGAACGGCTGGGAAGGGATGGTTGATGGGtGGTACGGGTTCCGGCAC



CAAAATGCGCAGGGAACAGGACAGGCTGCCGACTACAAATCTACCCAGGCTGCAATTGATC



AAATAACTGGCAAACTCAATAGGTTGGTGGAAAAGACGAACACCGAGTTCGAGTCAATCGA



ATCTGAATTCAGCGAGATTGAACACCAAATCGGAAATGTGATTAACTGGACCAAGGACTCC



ATCACCGACATCTGGACCTATCAGGCCGAACTGCTCGTCGCTATGGAGAACCAGCATACCA



TAGATATGGCCGACAGCGAGATGCTCAACCTTTACGAGCGCGTCAGGAAACAGCTTAGGCA



GAATGCTGAAGAAGACGGGAAGGGATGTTTTGAGATCTATCACGCTTGCGATGATTCCTGT



ATGGAGTCCATAAGGAACAACACCTATGACCATTCACAGTACCGTGAAGAGGCCTTGCTTA



ACCGCCTCAACATAAATCCCGTTACTCTCAGCTCAGGTTATAAGGATATCATCCTGTGGTT



TAGCTTTGGAGCCTCCTGCTTTGTGCTCCTCGCCGTCGTGATGGGCCTATTCTTTTTTTGT



CTGAAAAACGGGAATATGCGATGCACTATATGTATA





764
ATGTATAAGATCGTGGTGATCATTGCACTCCTGGGAGCCGTCAAGGGCCTGGATAAAATAT



GCCTGGGGCACCACGCCGTTGCCAACGGAACTATAGTAAAGACCCTGACCAATGAACAGGA



AGAAGTGACCAACGCAACCGAAACCGTGGAGAGTACAGGCATAAATCGCCTTTGCATGAAG



GGTCGAAAGCACAAAGACCTGGGGAATTGCCACCCCATAGGGATGCTGATCGGCACCCCGG



CTTGTGATTTGCACTTGACTGGGATGTGGGATACACTCATTGAGCGCGAAAACGCAATCGC



ATATTGCTACCCCGGGGCAACCGTGAACGTCGAGGCCCTGCGGCAGAAAATTATGGAGTCT



GGCGGAATAAATAAGATTTCAACCGGTTTTACATACGGAAGTTCTATTAATAGCGCAGGCA



CAACAAGGGCGTGTATGAGGAACGGTGGTAATAGTTTCTATGCAGAACTAAAATGGTTGGT



GTCTAAATCGAAAGGTCAAAATTTCCCCCAAACTACCAACACCTACCGCAATACTGATACT



GCCGAACACTTGATTATGTGGGGTATTCACCACCCATCCTCAACACAGGAAAAGAACGATT



TGTACGGGACACAGAGTCTGAGTATTAGTGTAGGCTCTAGCACCTACAGAAATAACTTTGT



CCCAGTGGTGGGCGCTCGGCCTCAGGTGAATGGCCAATCTGGAAGAATTGACTTCCATTGG



ACACTTGTGCAGCCAGGTGATAACATCACTTTTAGCCATAATGGTGGGCTGATTGCCCCTT



CCAGGGTGAGTAAACTTATTGGTCGCGGGCTGGGGATACAATCGGATGCCCCTATCGACAA



TAATTGCGAATCCAAGTGTTTTTGGAGGGGGGGGTCAATCAATACCAGGCTACCTTTCCAG



AATCTGAGTCCACGTACCGTCGGGCAGTGTCCTAAGTATGTCAATCGACGGTCACTGATGC



TCGCTACCGGCATGCGGAATGTCCCAGAGCTGATCCAAGGGCGTGGTCTGTTCGGCGCAAT



TGCCGGCTTCCTCGAGAATGGATGGGAGGGCATGGTAGATGGATGGTATGGTTTTAGACAC



CAAAACGCCCAAGGAACTGGGCAGGCGGCCGATTATAAATCCACTCAGGCCGCAATTGATC



AGATTACTGGCAAGCTAAACCGTTTAGTTGAGAAAACGAACACCGAATTCGAGAGCATAGA



GAGTGAATTTAGTGAGATCGAGCATCAAATTGGGAATGTGATTAACTGGACCAAAGACTCA



ATAACCGATATCTGGACCTACCAGGCAGAGTTACTGGTAGCTATGGAGAACCAGCATACCA



TCGACATGGCCGACTCTGAGATGCTCAATTTGTATGAGAGGGTCAGGAAACAACTGCGGCA



GAATGCTGAAGAAGATGGAAAAGGGTGCTTTGAAATATATCACGCATGCGACGATAGTTGC



ATGGAGTCCATACGAAACAATACCTACGATCACTCACAGTATAGAGAGGAAGCCCTCTTAA



ATAGGCTAAATATAAACCCTGTCACACTGAGCTCTGGGTACAAAGATATTATCTTATGGTT



CTCATTTGGGGCTAGTTGTTTCGTGCTCCTGGCGGTCGTGATGGGCCTGTTCTTCTTCTGT



CTAAAGAACGGTAATATGAGATGTACTATCTGCATT





765
ATGTATAAAGTGGTGGTTATTATAGCGTTGCTGGGCGCTGTTAAAGGTTTGGACAAGATCT



GCTTGGGACATCATGCTGTCGCCAACGGGACAATCGTCAAGACCCTGACAAACGAACAGGA



AGAGGTCACAAACGCGACTGAAACCGTGGAGAGCACAGGAATTAATCGGCTCTGTATGAAA



GGCCGCAAACACAAAGATCTTGGAAATTGCCACCCAATTGGGATGCTCATTGGCACACCAG



CCTGTGATCTACATCTGACCGGCACATGGGACACTCTCATCGAACGCGAGAACGCTATCGC



ATATTGTTACCCCGGGGCGACCGTGAATGTTGAGGCCCTGCGCCAGAAGATTATGGAGAGT



GGAGGCATCGATAAGATATCGACCGGCTTCACTTACGGAAGCTCCATTAACTCCGCTGGTA



CCACCCGGGCCTGCATGAGGAACGGCGGCAATTCCTTTTACGCCGAACTGAAGTGGTTAGT



GTCTAAAAATAAGGGGCAGAATTTTCCCCAAACCACAAACACATACCGAAACACCGACACG



GCCGAGCATCTGATCATGTGGGGGATTCACCATCCTTCTTCCATCCAGGAAAAGAACGATC



TGTACGGAACTCAATCTCTCTCCATCTCCGTTGGTTCCTCCACGTATAGGAACAATTTCGT



ACCCGTGGTCGGCGCCCGACCACAAGTAAACGGCCAGTCCGGCCGCATCGACTTCCACTGG



ACACTTGTGCAGCCAGGAGACAACATTACATTCTCCCATAATGGCGGGCTGATTGCACCCA



GCCGGGTCTCCAAGCTTATCGGCCGCGGCCTGGGGATCCAGTCAGACGCGCCCATCGATAA



CAACTGCGAAAGCAAGTGTTTTTGGCGGGGtGGATCTATTAACACCCGTCTGCCTTTCCAG



AATCTTAGTCCCCGGACAGTGGGGCAGTGCCCCAAGTATGTGAATCGAAGGTCTCTGATGC



TGGCCACAGGCATGAGAAATGTGCCAGAGTTGATTCAGGGCCGGGGTCTCTTTGGAGCCAT



TGCCGGTTTTCTTGAAAACGGTTGGGAGGGTATGGTCGACGGTTGGTACGGTTTCCGGCAC



CAGAACGCACAGGGCACTGGTCAGGCTGCAGATTATAAATCTACACAAGCCGCTATCGACC



AGATCACGGGCAAACTAAATAGACTGGTCGAGAAGACTAACACTGAATTTGAGAGCATTGA



GTCGGAGTTTTCCGAGATTGAACACCAGATCGGAAATGTGATTAATTGGACAATGGACTCA



ATTACTGACATCTGGACATACCAAGCCGAACTGCTGGTTGCGATGGAGAACCAGCACACCA



TCGATATGGCCGATAGCGAAATGCTAAATCTGTATGAGAGGGTAAGGAAGCAGCTGCGCCA



GAATGCCGAAGAAGACGGGAAGGGTTGTTTTGAGATCTACCATGCTTGTGACGACAGTTGC



ATGGAAAGCATTCGAAACAACACTTATGACCACTCGCAATATCGCGAAGAGGCCCTTTTGA



ATCGGCTCAACATAAACCCAGTGACACTTTCTTCCGGTTACAAGGATATTATCCTGTGGTT



CTCTTTTGGAGCATCGTGTTTTGTACTGCTCGCTGTCGTTATGGGCTTGGTCTTCTTTTGT



CTGAAAAATGGCAATATGCGGTGTACCATCTGCATT





766
ATGTATAAGATTGTGGTGATCATTGCACTGCTGGGGGCTGTGAAGGGACTCGACAAGATTT



GCCTGGGCCACCATGCCGTTGCAAACGGGACCATCGTCAAAACATTGACAAACGAGCAGGA



AGAGGTGACAAACGCCACTGAAACAGTCGAAAGTACGGGGATTAACCGGCTATGTATGAAG



GGGAGGAAACATAAAGATCTAGGCAACTGCCACCCCATAGGCATGCTTATCGGCACCCCGG



CCTGCGACCTTCACCTGACCGGAATGTGGGATACCTTGATCGAGAGGGAAAACGCCATCGC



TTATTGCTACCCAGGAGCCACGGTGAACGTAGAGGCTCTACGACAAAAGATTATGGAGAGC



GGCGGAATAAATAAAATATCCACGGGATTCACCTACGGTTCCTCGATAAATTCAGGGGGCA



CCACCAGAGCCTGCATGCGCAACGGCGGCAATTCCTTTTATGCCGAGCTTAAGTGGCTCGT



TTCCAAAAGCAAGGGGCAGAACTTTCCTCAGACCACAAACACCTATAGGAATACCGACACC



GCGGAGCACCTGATTATGTGGGGGATCCACCATCCCTCAAGTACACAGGAAAAGAACGATC



TCTATGGAACCCAGAGCCTGAGTATCAGCGTGGGGTCCAGCACATATCGCAACAACTTTGT



CCCAGTGGTCGGAGCCCGCCCACAGGTTAACGGCCAATCCGGTCGCATTGACTTTCACTGG



ACCTTGGTGCAACCAGGGGATAATATTACCTTCAGCCACAATGGTGGACTGATTGCCCCAA



GTCGTGTTTCCAAGCTGATCGGAAGAGGGTTAGGTATCCAGAGTGACGCCCCAATTGATAA



TAACTGCGAGAGCAAATGCTTCTGGCGGGGGGGATCGATTAATACGCGTCTCCCCTTTCAG



AACCTCTCCCCACGTACGGTCGGGCAGTGTCCAAAGTATGTGAACAGACGTTCACTGATGC



TGGCAACAGGGATGAGAAACGTACCCGAGCTGATCCAGGGGAGAGGGCTGTTCGGTGCCAT



TGCCGGATTTCTCGAAAATGGTTGGGAGGGAATGGTGGACGGTTGGTACGGATTCCGGCAC



CAGAACGCTCAGGGGACCGGCCAAGCAGCTGATTATAAATCTACCCAGGCCGCCATTGATC



AGATCACCGGGAAGTTGAACCGCCTCGTGGAGAAGACTAACACAGAGTTCGAGTCTATCGA



ATCAGAGTTCAGCGAGATTGAACACCAGATTGGGAACGTGATTAACTGGACCAAGGACTCC



ATCACCGACATTTGGACATATCAAGCCGAGCTGCTGGTAGCCATGGAGAACCAGCACACCA



TAGATATGGCAGATAGTGAGATGCTGAACCTCTATGAACGCGTGCGAAAGCAACTGCGACA



AAATGCTGAGGAGGATGGGAAGGGATGCTTTGAAATCTACCACGCGTGCGACGATTCTTGT



ATGGAAAGTATCCGGAATAATACTTATGATCACTCTCAGTATAGGGAGGAGGCACTACTAA



ATCGTCTGAATATCAACCCAGTGACCTTATCCTCCGGATACAAGGACATTATCCTGTGGTT



CAGTTTTGGCGCTTCCTGTTTCGTGCTCCTGGCTGTAGTGATGGGCTTATTTTTCTTCTGC



CTGAAAAACGGAAATATGCGGTGCACCATTTGCATT





767
ATGTATAAGATAGTCGTAATTATCGCACTCCTCGGGGCTGTTAAGGGCCTGGACAAAATCT



GTCTGGGTCACCATGCAGTCGCCAACGGAACAATAGTCAAGACTCTGACCAATGAACAGGA



GGAGGTTACGAATGCCACGGAAACCGTGGAAAGTACAGGGATCAACCGCCTGTGTATGAAA



GGGAGAAAGCATAAAGACTTGGGTAATTGCCATCCAATCGGGATGCTGATTGGAACACCCG



CTTGTGACCTCCATTTGACCGGTATGTGGGACACACTGATCGAAAGAGAGAATGCCATCGC



GTATTGTTACCCTGGTGCCACTGTGAACGTGGAGGCACTGCGCCAGAAGATCATGGAATCC



GGCGGAATCAATAAGATCTCCACCGGATTTACCTACGGATCCAGTATAAATTCAGCCGGGA



CGACAAGAGCATGCATGAGAAACGGCGGCAACAGTTTTTACGCCGAGCTGAAGTGGCTTGT



GTCCAAGTCTAAAGGCCAGAACTTTCCTCAGACAACCAACACCTACCGTAACACTGATACA



GCAGAGCATCTGATCATGTGGGGCATTCACCATCCATCTTCCACCCAAGAAAAGAATGATC



TGTACGGAACACAGAGCCTGTCTATTAGTGTTGGATCGTCAACCTACCGGAATAACTTTGT



TCCCGTAGTGGGCGCACGCCCCCAGGTGAATGGGCAGTCAGGTCGAATTGATTTTCACTGG



ACCCTCGTGCAGCCTGGCGACAATATTACATTCAGTCATAACGGGGGACTGATCGCCCCAA



GCCGCGTTTCTAAGCTGATTGGGAGAGGTTTGGGAATTCAGAGCGACGCACCTATCGATAA



CAATTGCGAATCAAAGTGCTTTTGGGGGGGGGGCAGCATAAATACCAGACTGCCCTTTCAG



AACCTTAGCCCTAGGACAGTCGGGCAGTGTCCCAAATACGTCAACCGCCGGAGTCTGATGC



TCGCTACAGGAATGAGAAATGTTCCAGAGCTAATCCAGGGACGAGGACTCTTCGGAGCCAT



CGCTGGATTTCTGGAGAATGGCTGGGAGGGGATGGTTGATGGGTGGTATGGCTTTAGACAT



CAGAACGCCCAGGGGACAGGTCAGGCCGCCGATTACAAGTCTACCCAGGCCGCGATTGACC



AGATCACTGGCAAATTGAATAGGCTGGTTGAGAAAACTAACACTGAATTTGAGTCAATCGA



GAGCGAGTTTTCTGAGATCGAACACCAGATCGGGAACGTGATTAATTGGACTAAAGACTCT



ATAACGGACATTTGGACCTATCAAGCCGAGTTATTAGTCGCGATGGAGAACCAGCACACAA



TAGATATGGCAGACTCTGAGATGCTGAACCTGTACGAGAGGGTGCGGAAGCAATTAAGGCA



GAATGCCGAAGAGGATGGGAAGGGATGCTTCGAAATATACCATGCCTGCGACGACTCGTGC



ATGGAGAGCATTAGAAACAATACATACGACCATAGCCAGTATCGCGAGGAAGCACTACTGA



ATCGGCTGAATATCAATCCAGTCACACTCTCTTCTGGGTACAAAGATATCATTCTGTGGTT



TAGCTTCGGCGCCTCCTGCTTCGTCCTTCTGGCCGTGGTTATGGGGCTGTTTTTTTTCTGT



CTTAAGAACGGAAATATGAGGTGTACCATCTGTATT





768
ATGTATAAGATTGTGGTGATCATTGCCCTCCTAGGCGCCGTAAAAGGGTTAGATAAAATCT



GCCTGGGACACCACGCCGTGGCCAACGGCACTATAGTCAAGACCCTCACTAACGAGCAGGA



AAAAGTGACCAATGCTACGGAAACAGTGGAATCTACAGGCCTGAATCGCCTTTGCATGAAA



GGCAGGAAACACAAAGACTTAGGGAATTGTCACCCCATTGGAATGTTAATTGGGACTCCAG



CTTGCGATCTGCACCTCACTGGTACATGGGATACAATTATTGAACGGGAGAATGCCATCGC



ATACTGCTACCCTGGGGCGACCGTCAATGAGGAAGCTCTGCGGCAGAAGATCATGGAGTCT



GGTGGCATTGATAAAATCTCCACCGGGTTCACGTATGGGTCTTCAATTAATAGCGCTGGAA



CGACTAGAGCTTGTATGCGCAATGGTGGAAATTCCTTTTACGCTGAGCTTAAATGGCTCGT



CTCGAAATCCAAGGGACAGAACTTTCCGCAAACTACAAACACTTATAGAAACACAGACACC



GCAGAACACCTCATCATGTGGGGGATTCACCACCCTTCTAGTACCCAAGAAAAGAATGACC



TCTATGGCACACAGAGCCTGTCCATCTCGGTCGGCAGCAGCACCTACCGGAACAACTTTGT



GCCCGTGGTGGGCGCGCGCCCCCAAGTTAACGGACAGTCCGGTCGGATAGATTTCCACTGG



ACACTGGTCCAGCCCGGGGATAACATAACGTTCTCTCACAACGGAGGGCTGATAGCTCCTT



CTCGAGTGTCAAAATTGATTGGAAGGGGCTTGGGGATCCAGTCCGATGCCCCAATAGACAA



TAACTGCGAGTCTAAATGTTTTTGGAGGGGCGGTTCTATAAATACCCGTCTGCCTTTTCAG



AATCTTAGCCCCAGAACAGTGGGACAGTGTCCCAAGTACGTAAATAAAAGAAGTCTGATGC



TTGCAACCGGCATGAGGAATGTCCCTGAGCTGATCCAGGGTCGTGGCTTGTTCGGTGCCAT



TGCGGGCTTCTTGGAAAATGGTTGGGAGGGAATGGTAGACGGATGGTATGGGTTCCGCCAC



CAAAATGCTCAGGGGACGGGCCAAGCTGCCGACTATAAGAGTACGCAAGCCGCTATTGACC



AGATCACTGGCAAATTGAACAGACTTGTTGAAAAAACAAATACAGAATTCGAAAGCATCGA



ATCAGAATTTAGCGAGATTGAGCACCAAATCGGCAACGTGATCAATTGGACAAAAGACTCC



ATAACCGATATTTGGACCTACCAGGCCGAGCTGCTCGTGGCTATGGAGAACCAGCACACCA



TCGACATGGCTGATAGCGAGATGCTGAATCTATATGAAAGGGTTCGGAAGCAGTTGCGTCA



GAATGCGGAGGAGGATGGGAAGGGTTGCTTTGAAATCTATCACGCCTGCGATGACAGCTGT



ATGGAGAGCATACGAAATAATACCTATGACCATTCACAGTACCGCGAGGAGGCCCTGCTCA



ATCGGCTGAACATCAATCCGGTGACACTGAGCTCTGGCTACAAGGACATCATTCTGTGGTT



CTCATTCGGGGCGAGCTGCTTTGTTTTGTTAGCCGTCGTGATGGGCCTCGTTTTCTTCTGC



CTGAAGAATGGGAATATGCGCTGTACAATCTGCATC





769
ATGTACAAGATTGTCGTGATTATCGCTTTGCTCGGCGCCGTGAAGGGACTGGATAAAATCT



GTCTGGGGCATCACGCTGTGGCTAATGGAACAATTGTGAAGACCCTCACCAATGAGCAGGA



GGAAGTGACAAACGCTACAGAGACAGTCGAGTCCACCGGAATCAACAGGCTGTGCATGAAG



GGCCGGAAACATAAGGACCTCGGGAACTGCCACCCTATTGGGATGCTGATAGGCACACCTG



CCTGTGACTTACACCTTACCGGGATGTGGGATACACTGATAGAACGGGAGAATGCCATAGC



ATACTGCTACCCAGGAGCTACGGTGAATGTGGAAGCTCTCCGCCAGAAAATTATGGAATCA



GGCGGGATTAATAAGATTTCTACGGGCTTCACTTATGGAAGTTCAATAAATTCAGCCGGAA



CAACCCGGGCTTGTATGAGAAATGGTGGAAATTCTTTCTACGCAGAACTCAAGTGGCTTGT



TAGCAAGTCCAAGGGCCAAAACTTCCCTCAGACCACTAATACTTACAGGAATACTGACACC



GCCGAACACCTTATCATGTGGGGTATCCACCATCCATCTAGCACCCAGGAGAAAAATGATC



TTTACGGTACCCAATCACTGAGCATCAGCGTGGGGAGCTCAACTTATCGCAACAATTTCGT



GCCTGTGGTGGGTGCCCGACCACAGGTTAACGGACAAAGTGGACGAATTGACTTTCATTGG



ACCCTGGTGCAGCCTGGCGACAACATCACATTCTCGCATAATGGAGGTTTGATCGCTCCCT



CCCGTGTGTCTAAGCTGATAGGGAGAGGCCTCGGTATACAGTCCGACGCTCCCATCGATAA



TAATTGTGAAAGCAAGTGCTTTTGGCGAGGTGGCAGCATTAACACGCGGTTACCCTTTCAG



AACCTCAGCCCACGCACAGTCGGCCAATGCCCTAAGTATGTAAACCGCCGGAGCTTGATGC



TGGCAACGGGCATGAGAAACGTCCCCGAGCTAATCCAGGGCAGAGGACTGTTCGGCGCCAT



TGCTGGCTTTCTTGAGAACGGATGGGAGGGAATGGTGGACGGCTGGTACGGATTCCGGCAC



CAGAACGCCCAGGGCACCGGCCAGGCCGCCGATTATAAGTCCACCCAAGCTGCCATCGACC



AGATCACCGGCAAACTGAATCGGCTTGTAGAGAAAACCAACACCGAATTCGAGTCAATCGA



GTCCGAATTTAGCGAGATCGAACACCAGATCGGCAATGTGATTAACTGGACAAAGGACAGT



ATCACTGATATCTGGACCTACCAAGCAGAATTACTGGTCGCTATGGAAAATCAGCACACCA



TTGATATGGCCGACAGCGAGATGCTCAACCTATATGAACGCGTCCGCAAGCAGCTGCGTCA



GAACGCAGAGGAAGATGGAAAAGGCTGCTTCGAGATCTACCATGCTTGCGATGACTCTTGT



ATGGAGTCCATCCGCAATAACACATACGACCACTCCCAGTACAGGGAGGAGGCGCTTTTGA



ACAGACTGAATATAAATCCTGTTACTCTTTCATCGGGGTATAAAGACATCATCCTGTGGTT



CTCCTTCGGCGCCTCCTGTTTCGTCCTGCTGGCGGTAGTTATGGGCCTATTTTTTTTTTGT



CTGAAGAATGGGAACATGCGCTGTACAATTTGTATC





770
ATGTACAAAATTGTTGTCATCATTGCTCTGCTGGGGGCTGTGAAAGGACTGGACAAAATCT



GCTTAGGCCATCACGCTGTAGCCAATGGTACCATTGTGAAGACACTGACCAATGAACAGGA



AAAAGTAACAAATGCTACCGAGACGGTCGAGTCCACAGGGCTGAACCGATTGTGCATGAAG



GGACGCAAGCACAAGGATCTGGGAAATTGCCACCCGATTGGTATGCTGATTGGGACTCCAG



CCTGCGATCTGCATCTGACCGGGACTTGGGATACTATCATAGAACGGGAGAACGCCATCGC



CTACTGCTACCCAGGTGCCACTGTAAACGAGGAAGCCTTGCGCCAGAAAATTATGGAGTCA



GGTGGGATTGACAAGATTTCCACTGGGTTCACTTATGGGAGCAGTATTAACTCAGCTGGCA



CAACCCGTGCTTGTATGCGGAACGGAGGAAACTCATTCTACGCAGAGCTGAAATGGCTGGT



TAGCAAAAGCAAGGGCCAGAATTTCCCACAGACAACCAATACATATCGGAACACTGATACC



GCAGAGCACCTGATTATGTGGGGCATTCACCACCCATCCTCCACGCAAGAGAAGAATGATC



TGTATGGAACTCAGAGCCTGTCAATCTCCGTGGGATCTAGCACATATAGAAATAATTTTGT



GCCTGTGGTCGGCGCGCGACCACAGGTTAATGGACAATCAGGACGCATTGATTTCCACTGG



ACCTTGGTTCAGCCCGGGGACAATATAACATTCAGCCACAACGGTGGCCTGATCGCCCCCT



CGCGGGTGAGTAAGCTGATTGGCAGAGGACTCGGTATTCAGAGCGATGCCCCTATTGATAA



TAACTGCGAAAGCAAATGTTTTTGGAGAGGGGGGTCGATCAACACCAGATTACCCTTTCAG



AATCTCTCTCCTAGAACCGTTGGTCAGTGCCCGAAATATGTCAACAAGCGTAGTTTGATGC



TAGCCACTGGAATGCGCAACGTACCAGAACTCATCCAGGGAAGGGGTTTGTTCGGAGCGAT



TGCAGGTTTCCTGGAAAATGGGTGGGAGGGAATGGTGGACGGGTGGTATGGGTTTCGCCAT



CAGAACGCACAGGGAACAGGTCAGGCAGCCGACTATAAGTCTACACAAGCCGCCATAGATC



AGATCACGGGAAAGCTAAACCGCTTGGTGGAGAAGACAAATACCGAGTTCGAGTCTATAGA



GAGTGAGTTTTCCGAGATAGAACATCAAATCGGTAATGTGATCAACTGGACTAAAGACTCG



ATAACAGACATCTGGACCTACCAGGCGGAACTGCTCGTCGCCATGGAGAACCAGCACACTA



TCGATATGGCTGATTCAGAAATGCTGAACCTGTATGAACGCGTACGGAAACAGCTGCGCCA



GAATGCAGAGGAGGATGGGAAAGGCTGTTTTGAAATCTACCACGCCTGCGACGATAGCTGC



ATGGAAAGCATCCGCAATAACACATATGACCACTCTCAGTATCGCGAGGAAGCTCTTCTGA



ACCGTCTCAACATCAATCCAGTGACGTTGTCATCTGGATACAAAGACATCATATTATGGTT



TTCCTTCGGCGCAAGTTGCTTCGTGCTCCTGGCAGTTGTCATGGGCCTGGTCTTCTTCTGT



CTCAAGAATGGGAATATGAGATGCACGATCTGTATC





771
ATGTACAAGATTGTTGTGATCATCGCTCTGCTCGGTGCCGTCAAAGGGTTGGATAAGATTT



GCCTCGGCCACCATGCAGTAGCCAACGGCACAATTGTGAAAACTCTCACCAACGAGCAGGA



AGAGGTCACCAATGCCACCGAAACAGTCGAGTCAACTGGCATTAATCGATTATGTATGAAA



GGAAGAAAGCATAAAGACTTGGGAAACTGTCATCCTATCGGGATGCTCATCGGAACACCAG



CATGTGACCTCCATTTAACCGGAATGTGGGACACATTAATCGAGCGTGAGAACGCAATTGC



CTATTGCTACCCTGGCGCAACAGTTAACGTCGAAGCTTTGAGACAGAAGATTATGGAGTCA



GGAGGCATCAATAAAATCTCGACCGGGTTTACCTACGGCTCCTCCATCAACTCGGCTGGCA



CAACCAGAGCCTGCATGCGTAACGGAGGCAATAGTTTCTACGCTGAGCTTAAGTGGCTGGT



AAGTAAATCAAAAGGTCAAAATTTCCCACAGACTACGAATACTTACAGAAATACAGACACA



GCCGAACACCTTATCATGTGGGGGATCCACCACCCTAGCAGTACTCAGGAAAAAAACGATC



TGTACGGCACCCAGAGCCTGTCGATCTCTGTGGGAAGTTCAACTTACCGAAATAATTTCGT



CCCTGTCGTTGGTGCAAGGCCTCAGGTCAATGGCCAGTCAGGACGCATCGATTTCCATTGG



ACTCTGGTGCAACCGGGCGACAACATTACCTTTTCACATAATGGCGGCCTTATCGCCCCCT



CCCGAGTGAGTAAGCTGATCGGTCGGGGATTGGGAATCCAGTCTGATGCACCCATTGATAA



TAACTGTGAATCTAAATGTTTCTGGAGAGGAGGTTCCATTAATACACGGCTGCCCTTTCAG



AACCTGTCCCCTCGAACCGTCGGACAGTGCCCCAAGTACGTGAACAGGAGAAGTCTCATGC



TGGCGACAGGGATGAGAAACGTTCCCGAACTGATTCAGGGACGGGGCTTATTCGGGGCTAT



TGCAGGCTTTCTGGAAAACGGCTGGGAGGGGATGGTGGACGGCTGGTACGGATTCAGGCAT



CAGAACGCACAGGGCACCGGCCAAGCAGCCGACTACAAGAGCACTCAGGCAGCCATCGACC



AGATTACAGGAAAACTTAATAGGCTTGTGGAGAAAACCAATACCGAATTCGAGTCAATTGA



ATCCGAGTTTAGCGAGATCGAACATCAAATCGGCAACGTGATTAACTGGACAAAGGACTCC



ATCACGGACATATGGACTTACCAGGCCGAACTGTTGGTGGCCATGGAAAATCAACATACAA



TTGATATGGCAGACAGTGAGATGCTGAACCTGTACGAGAGGGTCAGAAAGCAGCTACGTCA



GAACGCTGAAGAGGACGGGAAGGGCTGTTTCGAAATTTATCACGCCTGTGACGACTCCTGC



ATGGAATCTATCCGCAATAATACTTATGACCACAGTCAGTATCGCGAAGAGGCCCTCTTAA



ACAGATTAAACATCAATCCGGTGACTCTTAGCAGTGGCTACAAGGACATTATTTTATGGTT



TTCGTTCGGAGCTAGCTGTTTCGTCCTCCTCGCCGTGGTGATGGGTCTGTTCTTCTTTTGC



CTCAAGAATGGAAATATGAGATGTACAATCTGTATA





772
ATGTATAAGATAGTCGTGATCATTGCGCTTCTGGGAGCAGTAAAGGGTCTTGACAAGATTT



GTCTGGGCCACCATGCTGTGGCCAACGGGACTATTGTTAAGACTCTGACTAATGAACAGGA



AGAAGTTACAAACGCTACTGAGACGGTGGAGAGCACTGGCATAAATAGATTGTGTATGAAA



GGGAGGAAACACAAAGACTTGGGTAATTGCCACCCGATTGGGATGCTAATTGGGACTCCCG



CTTGTGACCTGCACCTTACTGGCATGTGGGATACCCTAATAGAACGTGAGAACGCCATTGC



CTATTGTTACCCAGGCGCTACTGTCAATGTGGAGGCACTTAGGCAGAAGATCATGGAAAGC



GGCGGCATCAACAAGATCTCCACCGGATTTACCTATGGTTCAAGTATCAACAGTGCCGGTA



CCACCCGCGCTTGTATGCGCAACGGAGGAAACAGTTTTTATGCTGAGCTCAAATGGCTAGT



AAGTAAGTCTAAGGGACAAAATTTCCCTCAGACCACCAACACTTATCGTAACACAGACACC



GCAGAGCATCTCATTATGTGGGGGATACACCATCCCAGCAGCACACAGGAGAAGAACGATC



TGTATGGCACCCAATCGCTCTCCATCTCAGTGGGTTCTTCTACCTATAGAAATAACTTCGT



GCCTGTCGTGGGCGCACGGCCACAGGTGAACGGGCAGAGTGGCAGAATCGATTTTCATTGG



ACGCTGGTCCAGCCCGGCGATAACATTACCTTCTCACACAATGGGGGATTGATCGCCCCTT



CTAGGGTATCAAAATTGATCGGCAGGGGACTTGGGATCCAAAGCGATGCCCCTATTGACAA



CAACTGCGAATCGAAATGCTTCTGGCGGGGGGGCAGCATTAATACACGGCTGCCCTTCCAA



AATTTATCCCCAAGAACAGTTGGCCAGTGCCCTAAATACGTCAACCGTCGCAGCCTTATGT



TAGCCACAGGAATGCGGAACGTCCCGGAGCTTATTCAGGGCAGGGGCCTGTTCGGCGCAAT



CGCGGGCTTTCTGGAAAATGGTTGGGAAGGGATGGTTGACGGCTGGTACGGGTTCAGGCAC



CAGAATGCCCAGGGAACAGGTCAGGCCGCTGACTATAAGTCAACACAAGCAGCCATCGACC



AAATTACCGGCAAGCTGAATAGACTTGTGGAAAAAACGAATACAGAATTCGAGAGTATTGA



AAGTGAATTTAGTGAGATTGAACACCAAATTGGCAATGTCATTAACTGGACGAAAGATTCA



ATCACCGACATCTGGACCTATCAGGCTGAACTCTTGGTCGCAATGGAAAACCAACATACCA



TCGACATGGCTGATTCTGAGATGCTCAACTTATACGAGCGAGTTCGAAAGCAACTGCGGCA



GAATGCCGAGGAGGATGGGAAGGGGTGTTTCGAAATTTATCATGCCTGCGACGACAGTTGT



ATGGAGAGCATCCGTAATAATACTTATGACCATAGTCAATACAGAGAGGAGGCTCTTCTGA



ACAGGCTGAACATCAACCCTGTGACCTTAAGCTCCGGATACAAGGACATTATCTTGTGGTT



CAGTTTTGGAGCCTCATGTTTCGTTCTGTTGGCAGTTGTGATGGGCCTCTTCTTCTTCTGC



CTGAAAAACGGAAACATGCGTTGCACTATATGCATC





773
ATGTACAAGATTGTGGTCATCATTGCCCTGCTTGGGGCCGTCAAGGGCCTGGACAAAATTT



GCTTGGGGCACCATGCCGTGGTTAATGGCACCATCGTCAAAACCCTTACGAACGAACAAGA



AGAGGTCACCAACGCCACTGAGACAGTTGAAAGTACAGGCCTCAATCGATTGTGCATGAAA



GGTAGGAATCACAAAGATCTGGGGAACTGTCACCCCATAGGGATGCTGATTGGCACACCAG



CCTGTGATCTGCATTTGACAGGGACCTGGGATACTCTAATTGAGAGAGAGAACGCTATTGC



CTACTGCTACCCCGGCGCCACAGTTAACGAAGAGGCTCTGCGGCAGAAAATAATGGAATCC



GGTGGTATTAACAAGATTAGTACAGGGTTTACATACGGATCGTCTATTAATTCAGCTGGTA



CAACTCGGGCTTGCATGAGGAACGGTGGCAACTCATTCTATGCAGAACTGAAGTGGTTGGT



AAGTAAGTCGAAAGGTCAAAATTTTCCCCAGACAACAAATACATATCGCAATACCGACACC



GCGGAACATTTGATCATGTGGGGCATCCACCATCCATCAAGTACACAGGAGAAGAATGACC



TTTACGGTACTCAGAGTCTGAGCATTTCAGTTGGATCCAGTACATACCAAAATAACTTCGT



TCCTGTCGTCGGAGCCCGCCCGCAGGTAAATGGTCAGTCCGGGCGCATTGACTTTCATTGG



ACCCTCGTGCAGCCCGGCGATAACATAACCTTCTCACACAATGGAGGACTGATCGCACCCA



GCAGAGTGAGCAAACTTATCGGGAGAGGTCTGGGGATCCAAAGTGACGCCCCCATTGATAA



CAACTGTGAGTCCAAATGTTTCTGGCGAGGGGGTTCAATTAACACCCGCTTGCCTTTCCAA



AACCTGAGCCCTCGGACGGTGGGCCAGTGTCCAAAGTATGTGAATAAACGGTCTCTGATGT



TAGCTACTGGCATGAGAAACGTTCCTGAGTTGATGCAGGGAAGGGGTCTCTTCGGCGCAAT



CGCTGGCTTTATTGAGAACGGGTGGGAGGGAATGGTGGACGGCTGGTATGGTTTTAGGCAT



CAGAATGCCCAGGGCACCGGACAGGCGGCTGATTATAAATCAACTCAAGCCGCCATCGACC



AAATCACCGGGAAACTAAACCGTCTGATCGAAAAAACCAATACTGAGTTCGAGTCTATCGA



GAGCGAGTTTAGTGAAATCGAACACCAGATTGGAAACGTGATCAATTGGACAAAAGATAGC



ATTACCGATATTTGGACCTACCAGGCCGAATTGCTGGTGGCGATGGAAAATCAGCACACAA



TCGACATGGCAGACTCGGAGATGTTGAATCTGTATGAGAGAGTGAGGAAGCAGCTGCGCCA



GAATGCCGAAGAGGATGGAAAGGGATGCTTCGAGATCTACCATGCATGTGACGACTCCTGT



ATGGAAAGCATCAGAAATAATACATACGATCACTCTCAATATCGAGAGGAGGCGCTTCTTA



ATCGTTTAAATATCAATCCCGTCACACTGTCCTCTGGTTATAAGGACATAATTTTGTGGTT



CTCGTTCGGTGCCAGTTGTTTCGTCCTGCTAGCGGTCGTGATGGGCCTGGTGTTTTTTTGC



CTTAAAAACGGGAACATGCGGTGCACCATCTGCATC





774
ATGTACAAGATTGTCGTCATTATCGCGCTGTTGGGGGCCGTCAAGGGACTGGATAAGATTT



GTCTGGGCCATCACGCCGTGGCCAACGGCACAATCGTCAAGACTCTGACCAACGAACAGGA



AGAGGTCACCAACGCCACAGAAACCGTGGAGAGTACGGGTATTAACCGCCTCTGCATGAAG



GGTCGGAAGCATAAGGACCTCGGTAACTGTCATCCAATCGGCATGTTGATTGGCACACCCG



CCTGCGACCTGCACCTGACTGGCATGTGGGACACACTGATTGAAAGGGAAAACGCAATCGC



GTACTGTTACCCAGGTGCAACGGTGAACGTTGAAGCACTGAGGCAGAAGATCATGGAGAGC



GGGGGCATCAACAAAATTAGCACGGGCTTCACATACGGTAGCAGTATCAACAGCGCTGGCA



CCACACGGGCCTGCATGCGGAATGGAGGGAACAGTTTCTACGCTGAACTGAAGTGGTTAGT



GAGCAAATCTAAGGGTCAGAATTTCCCCCAAACCACTAATACCTACCGCAACACTGACACC



GCCGAGCACTTAATAATGTGGGGCATCCATCATCCTTCAAGCACGCAGGAGAAGAACGACC



TGTACGGCACCCAGTCTCTGAGTATCTCGGTGGGTTCGTCCACCTATAGAAACAATTTTGT



GCCAGTGGTGGGGGCCAGGCCACAGGTCAATGGACAATCGGGACGTATCGACTTTCATTGG



ACCCTCGTGCAGCCTGGTGATAACATTACATTCAGCCATAATGGGGGCCTCATCGCCCCCA



GTAGGGTCTCCAAGCTCATTGGGAGAGGACTCGGAATCCAGAGTGATGCACCTATTGACAA



CAACTGTGAGAGCAAATGTTTTTGGAGAGGCGGGTCTATTAACACTCGATTGCCTTTCCAA



AATCTCTCACCTAGGACCGTCGGTCAGTGTCCTAAGTACGTGAATAGGAGAAGCCTCATGC



TCGCGACAGGCATGAGAAACGTGCCCGAACTGATCCAGGGCAGGGGACTCTTCGGGGCTAT



CGCAGGATTCTTAGAGAATGGGTGGGAAGGAATGGTGGATGGATGGTATGGCTTTAGGCAT



CAGAACGCTCAGGGCACTGGCCAAGCTGCGGACTACAAGAGCACTCAGGCCGCAATAGACC



AGATTACCGGCAAGTTGAATCGCCTAGTTGAAAAGACTAATACAGAGTTTGAGAGCATTGA



AAGCGAGTTTAGCGAAATTGAACATCAGATCGGCAATGTTATAAACTGGACAAAGGACTCC



ATAACTGATATATGGACTTACCAGGCAGAGCTACTAGTCGCCATGGAGAACCAGCATACTA



TCGACATGGCCGACTCAGAGATGCTGAACCTATACGAAAGAGTTCGGAAGCAGTTAAGACA



AAACGCCGAGGAGGACGGAAAGGGTTGCTTCGAAATCTACCACGCATGTGACGACTCATGC



ATGGAATCTATCAGGAATAACACATACGATCATTCACAGTATAGGGAGGAGGCTTTGCTGA



ATCGCCTCAATATCAATCCCGTCACTTTATCTAGCGGCTACAAGGACATTATCTTGTGGTT



CAGTTTTGGTGCCTCTTGCTTTGTGCTCCTGGCAGTGGTGATGGGACTCTTTTTTTTCTGT



TTGAAGAACGGTAATATGCGTTGTACAATTTGCATC





775
ATGTACAAGATTGTGGTGATCATCGCACTGCTGGGTGCTGTGAAAGGCCTGGACAAAATAT



GTTTGGGTCACCACGCCGTGGCAAATGGCACCATAGTCAAAACCCTCACCAACGAACAAGA



GGAAGTGACGAATGCGACTGAAACAGTGGAGTCGACCGGCATCAACCGTCTGTGTATGAAA



GGCAGAAAACATAAGGATCTCGGCAATTGCCATCCCATTGGAATGTTAATAGGGACGCCTG



CGTGCGATTTGCATCTGACTGGGATGTGGGATACCCTAATAGAGCGGGAGAACGCCATAGC



CTATTGCTACCCAGGAGCTACCGTCAATGTGGAAGCCCTACGGCAGAAAATTATGGAAAGC



GGTGGTATCAATAAGATTTCCACCGGATTTACATACGGGTCCTCCATCAATTCAGCCGGGA



CGACTCGTGCTTGCATGCGCAACGGAGGTAACTCGTTCTATGCCGAACTCAAATGGCTGGT



GAGCAAGTCTAAGGGACAGAATTTTCCACAAACAACCAACACCTACCGTAATACCGATACC



GCTGAACACCTTATCATGTGGGGCATTCACCACCCTTCCAGCACACAGGAGAAAAACGACT



TGTACGGCACACAGTCCCTCAGTATTTCCGTTGGTAGCTCTACTTACAGAAACAATTTTGT



TCCCGTCGTCGGTGCCCGTCCTCAAGTCAACGGACAGTCCGGCAGAATTGACTTTCATTGG



ACGTTAGTGCAGCCTGGGGACAACATTACCTTCAGCCACAATGGGGGTCTGATTGCGCCGT



CCCGCGTTAGCAAGCTGATAGGCCGAGGGCTGGGCATTCAGAGCGATGCACCCATCGACAA



TAATTGCGAATCCAAATGCTTTTGGCGGGGTGGGAGTATTAATACTCGCCTCCCCTTTCAA



AATCTCTCACCACGCACTGTTGGGCAGTGTCCCAAATACGTGAATCGGCGTAGCTTAATGC



TGGCTACAGGGATGAGGAACGTGCCCGAACTGATTCAAGGCCGTGGTCTTTTTGGAGCCAT



TGCCGGCTTTTTAGAGAATGGCTGGGAGGGCATGGTTGACGGTTGGTATGGGTTTAGGCAC



CAGAACGCCCAGGGCACTGGACAGGCAGCCGATTATAAGTCCACACAGGCCGCTATTGATC



AGATTACTGGAAAATTGAATAGACTCGTGGAGAAAACTAACACCGAGTTCGAGTCTATTGA



GTCAGAATTTTCTGAGATTGAGCACCAGATCGGTAATGTTATCAATTGGACAAAGGACAGC



ATCACTGACATTTGGACGTACCAGGCCGAGCTGCTGGTGGCAATGGAGAACCAGCACACCA



TCGACATGGCGGACTCAGAGATGCTGAACCTATATGAAAGGGTGCGTAAACAGCTTAGGCA



AAATGCTGAGGAGGACGGCAAAGGATGTTTCGAGATTTATCATGCCTGCGATGACTCCTGC



ATGGAATCAATTCGCAATAATACTTATGACCATTCACAGTATCGCGAAGAAGCGCTTCTGA



ATCGGCTAAATATTAACCCCGTAACTCTGTCTTCTGGATACAAGGATATTATCCTGTGGTT



TAGTTTTGGAGCTTCATGTTTCGTATTGTTGGCCGTGGTGATGGGGCTGTTCTTTTTCTGT



CTTAAGAACGGCAACATGAGGTGTACAATTTGCATT





776
ATGTACAAGATCGTCGTGATCATTGCCCTGCTCGGGGCCGTGAAGGGCCTTGACAAGATTT



GTCTAGGCCACCATGCAGTTGCTAACGGAACTATTGTCAAGACATTGACCAACGAACAGGA



GGAAGTGACAAATGCCACAGAGACAGTTGAGTCTACTGGGATAAACAGATTGTGTATGAAA



GGCAGGAAACACAAAGATCTCGGAAATTGTCATCCTATCGGAATGCTGATAGGAACTCCCG



CTTGCGATTTGCATTTGACAGGAATGTGGGACACACTGATCGAACGAGAAAACGCCATCGC



GTACTGCTACCCCGGTGCCACTGTGAACGTGGAGGCCCTTCGGCAAAAGATCATGGAATCA



GGAGGAATCAATAAGATCTCTACCGGGTTCACTTATGGCAGCTCTATCAACTCCGCCGGTA



CTACTAGGGCCTGCATGAGAAATGGGGGAAATAGCTTCTACGCAGAACTGAAGTGGCTGGT



GAGCAAGTCGAAGGGGCAGAACTTCCCTCAGACTACGAATACCTATCGCAATACCGATACT



GCTGAGCATTTGATTATGTGGGGCATCCATCATCCGTCGTCGACGCAAGAGAAAAATGACC



TTTATGGCACACAGTCCTTGTCTATTTCTGTAGGGTCTTCTACCTATCGCAATAACTTTGT



GCCTGTTGTCGGCGCCAGGCCACAGGTAAATGGACAGTCTGGCAGAATTGATTTCCACTGG



ACGCTCGTACAGCCTGGGGATAATATTACATTCTCACACAACGGCGGACTTATCGCCCCGA



GCCGTGTCTCAAAGCTGATTGGAAGGGGACTCGGCATTCAGTCCGATGCGCCCATTGACAA



CAATTGCGAGAGCAAGTGTTTTTGGCGCGGTGGATCCATCAATACCCGCCTTCCTTTTCAG



AATTTATCACCACGTACCGTCGGCCAGTGTCCCAAATATGTGAATCGAAGATCTCTGATGC



TGGCCACAGGCATGCGGAACGTCCCTGAGCTGATCCAGGGAAGGGGGCTTTTCGGAGCGAT



TGCCGGGTTTCTGGAAAATGGATGGGAAGGAATGGTGGACGGCTGGTACGGCTTCAGACAT



CAGAATGCCCAGGGAACCGGGCAGGCTGCGGATTACAAATCTACCCAAGCTGCTATCGACC



AGATCACAGGTAAGCTGAATCGGCTCGTGGAGAAAACTAACACTGAATTTGAGTCCATAGA



AAGCGAATTTAGTGAAATCGAACACCAAATCGGAAATGTGATTAACTGGACAAAAGATAGC



ATTACCGATATCTGGACCTACCAAGCTGAATTGCTGGTCGCCATGGAGAACCAACACACTA



TTGACATGGCAGACTCCGAAATGCTAAATTTGTACGAGCGCGTCCGCAAACAGTTGCGGCA



AAACGCAGAAGAAGATGGAAAGGGCTGCTTTGAGATCTACCACGCCTGTGACGATTCCTGC



ATGGAATCGATACGAAACAATACTTATGACCATAGCCAGTATCGTGAAGAAGCTCTGCTAA



ATCGCCTCAACATTAACCCTGTGACATTGAGCAGTGGGTACAAGGATATTATTCTCTGGTT



TTCTTTCGGTGCCTCGTGCTTTGTTCTGCTGGCGGTGGTGATGGGACTCTTCTTCTTCTGC



CTCAAAAATGGGAATATGCGGTGTACAATCTGTATC





777
ATGTACAAGATCGTCGTTATCATTGCCCTGCTGGGAGCAGTAAAAGGACTGGACAAAATTT



GCTTAGGCCATCACGCGGTGGCAAATGGGACCATCGTAAAGACACTGACCAACGAGCAGGA



GGAGGTGACAAACGCTACAGAAACAGTAGAATCGACCGGGATCAACAGGCTCTGTATGAAG



GGCCGGAAACATAAGGATCTGGGGAATTGCCATCCTATCGGAATGCTCATTGGTACGCCTG



CTTGTGACCTCCACCTCACTGGAATGTGGGACACACTCATCGAGCGCGAGAACGCAATAGC



ATATTGTTATCCGGGCGCAACTGTCAACGTTGAGGCACTGAGGCAGAAGATTATGGAGAGT



GGGGGCATCAACAAGATATCAACAGGCTTTACATATGGATCGAGCATCAATTCAGCAGGGA



CGACCCGGGCGTGCATGAGGAATGGAGGGAATAGCTTTTACGCCGAATTGAAATGGCTCGT



GTCTAAGAGCAAAGGCCAAAATTTTCCACAGACAACTAATACCTATCGCAACACCGATACG



GCCGAACATCTAATCATGTGGGGAATTCACCACCCAAGTTCGACCCAGGAAAAGAACGATC



TCTACGGCACCCAGAGTCTGAGCATCTCGGTGGGATCCTCGACGTACCGGAACAATTTCGT



GCCTGTCGTGGGAGCGCGACCGCAGGTTAATGGGCAATCCGGGAGGATCGATTTTCACTGG



ACGCTAGTCCAACCCGGGGACAACATCACTTTCAGCCACAACGGTGGACTTATTGCTCCTT



CCCGAGTCAGTAAACTCATCGGCCGGGGACTTGGGATTCAAAGCGATGCACCAATAGATAA



TAACTGTGAGTCTAAGTGCTTCTGGCGGGGAGGTAGTATTAACACACGACTCCCATTTCAG



AACCTGTCCCCAAGGACCGTGGGTCAGTGCCCTAAGTACGTGAACAGACGAAGCCTGATGT



TGGCAACCGGAATGAGAAACGTCCCCGAGCTGATCCAGGGGAGGGGACTGTTTGGGGCAAT



AGCGGGATTTCTGGAGAACGGATGGGAAGGGATGGTTGACGGATGGTACGGGTTTAGGCAC



CAGAACGCCCAAGGGACTGGACAGGCTGCAGATTATAAAAGTACACAAGCGGCCATCGATC



AGATCACCGGTAAACTGAATAGACTTGTCGAGAAAACCAATACAGAGTTCGAGTCGATAGA



ATCGGAATTCAGCGAGATCGAACACCAGATCGGCAATGTGATCAATTGGACTAAAGACAGC



ATCACCGATATCTGGACCTATCAAGCTGAGCTCCTAGTAGCTATGGAGAATCAACACACAA



TAGACATGGCTGACTCGGAAATGTTGAACCTGTATGAACGTGTCCGCAAGCAGCTGAGGCA



GAACGCCGAGGAGGACGGTAAGGGATGCTTCGAGATCTACCATGCTTGTGACGATTCTTGT



ATGGAAAGTATCAGAAACAACACCTACGACCATAGCCAGTACAGGGAAGAGGCCCTGCTGA



ATAGACTGAATATCAACCCAGTGACCCTCAGCTCTGGGTATAAAGATATCATTCTGTGGTT



CTCATTCGGTGCATCGTGCTTCGTACTGCTGGCCGTTGTCATGGGACTCTTTTTCTTTTGT



CTTAAAAATGGCAATATGCGATGCACAATTTGCATT





778
ATGTATAAAATAGTTGTCATCATCGCCCTCCTAGGTGCAGTTAAGGGGCTCGACAAAATTT



GTTTAGGCCACCACGCCGTGGCAAACGGCACCATCGTCAAGACCCTTACTAATGAACAAGA



GGAGGTGACTAATGCTACAGAGACCGTGGAGTCTACCGGCATAAATCGACTATGTATGAAA



GGCCGAAAGCACAAAGATTTGGGGAACTGTCATCCTATCGGAATGCTGATTGGAACCCCAG



CCTGCGATCTGCACCTCACCGGCATGTGGGATACCCTGATCGAACGTGAAAATGCTATCGC



ATACTGTTACCCTGGAGCCACAGTCAACGTTGAGGCATTGAGGCAAAAGATCATGGAGAGC



GGTGGAATCAATAAGATCTCAACAGGGTTTACCTACGGCAGCTCTATAAACTCCGCTGGCA



CAACAAGAGCCTGTATGCGCAATGGGGGAAATTCCTTTTATGCCGAACTGAAATGGCTTGT



ATCAAAGAGCAAGGGCCAGAACTTCCCCCAAACGACTAATACTTATCGCAACACAGATACA



GCTGAGCACCTGATAATGTGGGGTATCCACCATCCATCATCAACGCAAGAAAAGAACGATC



TGTACGGGACTCAAAGCCTGTCTATCTCCGTCGGCAGCAGCACATATAGGAATAACTTTGT



GCCCGTCGTCGGCGCTAGACCGCAGGTTAACGGACAGAGTGGCCGGATAGACTTCCACTGG



ACTCTGGTCCAGCCTGGCGATAACATCACCTTCAGCCACAATGGCGGTTTGATAGCACCCT



CTCGTGTGTCTAAGCTGATCGGAAGAGGCCTCGGGATTCAGTCCGACGCCCCGATCGACAA



TAACTGCGAGAGTAAATGTTTTTGGAGAGGAGGATCCATTAACACCCGGCTGCCGTTCCAG



AATTTGAGCCCTAGGACAGTGGGGCAGTGTCCCAAATATGTCAACCGCCGAAGTCTGATGC



TAGCGACTGGCATGAGGAACGTTCCCGAGCTCATCCAGGGACGCGGGCTGTTTGGCGCCAT



TGCCGGTTTTCTGGAAAACGGATGGGAAGGTATGGTAGATGGCTGGTATGGATTTCGCCAC



CAGAACGCGCAGGGCACTGGGCAGGCGGCGGATTACAAGTCCACACAGGCAGCGATTGATC



AGATCACCGGCAAACTGAATCGCCTGGTGGAGAAAACAAATACAGAGTTTGAGTCCATCGA



AAGCGAGTTTAGCGAAATTGAGCATCAAATTGGCAACGTCATTAATTGGACAAAAGACAGC



ATTACCGATATCTGGACATACCAGGCGGAGCTACTGGTCGCAATGGAGAACCAGCATACCA



TCGATATGGCCGACAGTGAAATGCTGAACCTCTATGAGAGAGTGCGAAAGCAGTTAAGACA



GAATGCGGAAGAGGATGGGAAAGGTTGTTTTGAGATCTATCACGCCTGTGACGACTCTTGC



ATGGAAAGCATTCGAAATAATACCTACGACCATAGTCAGTATCGAGAAGAGGCTCTGTTAA



ACCGATTAAATATTAACCCGGTAACTTTGTCGAGTGGGTACAAGGATATTATCCTTTGGTT



TTCCTTCGGGGCATCCTGTTTTGTGTTGCTGGCTGTGGTAATGGGACTGTTCTTTTTTTGC



TTAAAGAACGGTAATATGAGATGCACAATCTGTATA





779
ATGTATAAAGTAGTTGTGATCATCGCTTTACTGGGCGCAGTCAAAGGTTTGGACAAGATTT



GTCTGGGTCACCATGCCGTTGCCAATGGGACCATAGTTAAAACCTTAACAAATGAGCAGGA



AGAGGTCACAAACGCTACAGAGACTGTGGAGTCCACTGGGATAAACAGACTGTGTATGAAA



GGACGCAAGCACAAGGACCTCGGAAATTGTCACCCAATTGGAATGCTGATTGGCACTCCTG



CCTGCGATTTACATCTAACCGGCACATGGGACACCCTGATCGAGCGGGAGAACGCGATCGC



CTACTGCTACCCCGGAGCCACCGTCAACGTAGAGGCATTACGGCAGAAGATCATGGAGAGT



GGAGGCATAGATAAGATCTCCACCGGATTCACCTATGGTTCTAGCATTAACTCCGCAGGTA



CAACAAGAGCTTGCATGCGAAATGGAGGGAATAGCTTTTACGCTGAGCTCAAATGGCTTGT



GAGCAAAAACAAGGGACAGAATTTTCCCCAGACCACTAATACTTATAGAAACACTGACACC



GCTGAGCACTTAATCATGTGGGGAATCCACCACCCCTCCAGTATCCAAGAAAAGAACGACC



TGTATGGAACACAGAGCTTAAGTATCAGCGTGGGGTCATCTACCTACCGGAACAACTTCGT



TCCTGTGGTTGGGGCTAGACCACAGGTGAATGGTCAGAGCGGCAGAATCGATTTCCACTGG



ACCCTCGTCCAGCCAGGAGACAACATCACCTTCAGCCATAATGGCGGCCTGATTGCCCCTT



CTAGGGTTTCCAAATTGATTGGACGCGGCCTCGGGATTCAATCAGACGCTCCCATTGATAA



TAATTGTGAGAGCAAATGCTTCTGGAGGGGAGGATCCATTAACACCCGATTGCCATTCCAG



AATTTATCCCCACGGACCGTGGGCCAGTGCCCTAAATACGTGAATAGGCGATCCCTGATGT



TGGCAACAGGCATGAGAAACGTCCCTGAGCTGATCCAAGGGCGCGGACTATTTGGAGCAAT



AGCCGGCTTCTTAGAGAACGGATGGGAAGGAATGGTGGATGGTTGGTACGGTTTCCGACAC



CAGAACGCCCAAGGAACTGGACAGGCTGCCGATTACAAATCTACTCAGGCCGCTATAGATC



AGATTACAGGAAAACTGAATAGGCTGGTTGAGAAGACGAATACGGAATTTGAATCCATTGA



GAGTGAATTCAGTGAGATCGAACACCAGATTGGCAATGTGATTAACTGGACAATGGACTCC



ATCACTGATATTTGGACTTACCAGGCCGAGCTGCTTGTAGCGATGGAGAATCAACATACTA



TCGACATGGCAGACTCCGAGATGCTGAACCTGTATGAAAGAGTGCGCAAGCAGCTGAGACA



GAACGCCGAAGAAGACGGCAAAGGCTGTTTTGAAATTTACCATGCCTGCGACGACTCCTGT



ATGGAGTCCATTCGCAACAATACATACGATCACAGCCAGTACAGGGAGGAAGCGTTGCTGA



ACAGGTTGAACATAAATCCCGTGACACTTAGCTCTGGTTACAAGGATATTATACTCTGGTT



TTCCTTTGGAGCTTCTTGCTTCGTGCTGCTCGCAGTCGTGATGGGTCTGGTTTTTTTTTGC



CTCAAGAATGGCAACATGCGTTGCACTATATGTATC





780
ATGTACAAGATCATCGTCATCATCGCTCTCCTCGGTGCGGTGAAGGGTCTGGATAAGATTT



GCTTGGGTCACCACGCTGTTGCCAATGGCACGATTGTAAAGACCCTGACTAACGAGCAAGA



AGAAGTTACTAATGCCACAGAAACCGTGGAGTCTACCGGCATTAACAGATTATGCATGAAA



GGTCGGAAACATAAAGATTTGGGGAATTGCCACCCTATAGGGATGCTCATCGGGACTCCTG



CGTGCGACCTCCACCTTACCGGAACCTGGGACACTCTGATTGAGCGCGAAAATGCAATTGC



CTATTGTTATCCCGGGGCAACAGTGAACGTCGAGGCCTTGCGGCAGAAGATAATGGAATCC



GGCGGAATCGACAAGATTAGCACCGGCTTCACCTACGGCTCCTCTATTAATTCTGCTGGAA



CAACTAGGGCTTGCATGAGAAACGGCGGCAACTCATTCTACGCCGAGCTCAAGTGGCTTGT



GTCTAAGTCTAAAGGACAAAATTTCCCACAGACCACCAATACGTATCGCAATACAGACACT



GCGGAACATCTAATCATGTGGGGCATCCATCACCCGAGTAGTACCCAGGAAAAGAACGACC



TCTACGGCACTCAATCACTGTCCATCAGCGTTGGCTCTAGCACATACCGGAACAATTTCGT



CCCTGTGGTAGGAGCTAGACCCCAGGTTAACGGACAGTCAGGCCGTATCGACTTTCATTGG



ACCTTAGTACAACCAGGGGATAACATTACCTTTTCCCATAACGGGGGACTGATCGCCCCTA



GCCGCGTCAGTAAGCTCATCGGACGTGGACTCGGAATCCAGTCAGACGCCCCCATCGATAA



CAACTGCGAGTCAAAATGCTTTTGGCGAGGAGGATCTATCAACACTAGGCTGCCCTTTCAA



AATCTGTCCCCTCGCACAGTGGGTCAGTGTCCTAAATACGTGAACCGCAGATCACTCATGC



TCGCCACCGGAATGAGGAATGTGCCCGAACTCATCCAAGGGAGGGGCCTCTTCGGTGCCAT



CGCGGGATTCCTCGAAAATGGATGGGAGGGGATGGTGGATGGATGGTACGGCTTTCGGCAC



CAAAACGCTCAGGGCACCGGGCAGGCCGCCGATTATAAATCTACGCAGGCAGCTATAGACC



AAATAACCGGCAAATTAAATCGGCTGGTAGAAAAGACCAACACCGAATTCGAGAGCATAGA



GAGCGAATTTTCAGAAATAGAGCACCAGATTGGGAACGTAATTAACTGGACAAAGGACTCT



ATAACCGATATCTGGACATACCAGGCGGAACTCTTGGTGGCCATGGAGAATCAGCACACCA



TTGACATGGCCGATAGTGAGATGCTGAATCTCTACGAGAGGGTGCGAAAACAGCTAAGGCA



AAATGCCGAAGAGGACGGCAAGGGTTGCTTTGAGATCTACCACGCCTGCGACGACTCTTGT



ATGGAGTCCATTCGAAACAACACCTACGACCATTCTCAATACAGGGAGGAAGCTTTGCTCA



ATCGGCTCAACATCAATCCAGTCACGCTGTCTTCCGGTTATAAGGACATCATCCTCTGGTT



TAGTTTCGGAGCTTCTTGTTTTGTACTCTTAGCCGTGGTGATGGGCCTGTTCTTCTTCTGC



CTAAAAAACGGCAACATGCGGTGCACAATCTGTATT





781
ATGTACAAAATAGTGGTCATCATAGCCCTTCTGGGTGCCGTGAAGGGGCTAGACAAAATCT



GTTTGGGACATCACGCAGTAGCGAACGGCACCATCGTCAAAACGCTGACGAACGAGCAAGA



AGAGGTTACCAATGCTACAGAGACTGTGGAGTCTACTGGCATCAATAGGCTCTGCATGAAA



GGACGGAAACACAAGGACCTGGGCAATTGTCACCCTATCGGCATGTTGATCGGAACTCCCG



CCTGTGATCTGCACCTTACAGGGATGTGGGATACGCTGATCGAGCGGGAAAATGCCATAGC



TTACTGCTACCCCGGAGCGACCGTTAACGTGGAGGCCTTAAGACAGAAGATCATGGAGTCC



GGCGGGATCAATAAGATTTCCACTGGCTTTACGTACGGTTCCAGTATCAACTCCGCAGGGA



CGACGCGCGCGTGCATGAGAAACGGCGGCAACAGCTTTTACGCTGAACTCAAGTGGCTGGT



TAGCAAGTCAAAGGGCCAGAATTTCCCTCAGACCACTAACACATACAGGAATACTGACACC



GCCGAGCACCTCATCATGTGGGGAATTCACCACCCTTCCTCCACCCAGGAAAAGAACGATC



TATACGGGACCCAGTCTTTGTCCATATCTGTGGGCAGTTCAACATACCGGAACAACTTTGT



GCCTGTGGTGGGTGCTAGGCCACAGGTCAACGGGCAATCCGGTAGGATTGATTTTCACTGG



ACTCTGGTCCAGCCCGGGGACAATATAACTTTTTCGCATAATGGCGGGCTGATCGCTCCCT



CCCGGGTGTCAAAGCTGATTGGACGGGGCCTTGGTATACAGTCTGACGCGCCCATTGATAA



CAACTGCGAGTCTAAGTGTTTTTGGCGGGGAGGCAGCATCAATACTCGCCTCCCTTTTCAA



AACCTCTCCCCTAGAACAGTGGGGCAATGCCCAAAATACGTCAATAGGAGGTCCCTCATGC



TAGCAACCGGTATGCGCAACGTTCCCGAACTGATCCAGGGCCGAGGGCTGTTCGGAGCTAT



CGCAGGGTTTCTCGAAAACGGCTGGGAAGGAATGGTCGATGGCTGGTATGGGTTCAGACAT



CAGAATGCCCAGGGCACAGGACAGGCAGCAGATTACAAAAGTACTCAGGCCGCCATCGACC



AGATCACCGGCAAACTTAATAGGCTGGTGGAAAAAACCAACACCGAGTTTGAGAGTATAGA



GAGCGAGTTTTCAGAGATCGAGCATCAGATTGGGAATGTTATCAACTGGACCAAGGATTCC



ATTACTGATATTTGGACTTACCAGGCGGAACTGCTGGTTGCCATGGAGAATCAGCACACGA



TCGATATGGCCGACTCCGAAATGTTGAATTTATATGAGCGGGTGAGAAAGCAGCTCAGGCA



GAACGCAGAAGAGGACGGAAAGGGGTGCTTCGAGATCTACCATGCTTGTGACGATTCCTGT



ATGGAGTCAATTAGAAACAATACCTACGACCACTCCCAGTATAGAGAGGAGGCTCTGCTAA



ACCGCCTTAATATCAACCCGGTTACCCTGTCAAGCGGATACAAGGATATTATATTGTGGTT



TTCTTTTGGCGCATCTTGCTTCGTGTTACTCGCTGTGGTGATGGGTTTATTCTTCTTTTGT



CTGAAGAATGGGAACATGCGGTGTACCATTTGCATA





782
ATGTACAAGGTGGTGGTCATCATTGCCCTGCTGGGGGCAGTCAGGGGCTTAGATAAGATTT



GTCTTGGGCATCACGCCGTGGCCAACGGAACGACCGTGAAAACCCTCACAAATGAGCAGGA



GGAAGTTACGAATGCCACCGAGACTGTGGAGTCTACTTCTCTGAACAAACTGTGCATGAAA



GGCCGGCGTTATAAAGATCTGGGAAATTGTCATCCTATCGGCATGCTGATTGGTACTCCTG



TATGTGACCTGCACCTCACGGGCACTTGGGATACACTGATCGAGAGGGAAAATGCCACAGC



TTACTGCTACCCCGGAGTCACAATTAACGAGGAGGCACTCAGACAGAAAATCATGGAGAGC



GGTGGTATCAGCAAAATGCGCACCGGCTTTACTTATGGCCCAAGCATCAACTCTGCCGGTA



CAACACGAAGTTGCATGAGGAACGGCGGCAATAGCTTCTACGCTGAACTCAAGTGGTTAGT



CTCCGGTACGAAGGGGCAGAATTTTCCGCAGACTACAAATACATACCGAAATACAGATACA



GCTGAGCACCTGATCATCTGGGGCATCCACCACCCTAGTTCAACCCAGGAGAAAAACGATT



TGTATGGAACGCAATCTCTCTCCATTTCCGTAGGGTCCTCCACCTATCAAAACAACTTTGT



CCCGGTTATTGGGGCTAGACCTCAGGTCAATGGCCAGAGCGGTAGGATTGAGTTTCATTGG



ACTCTCGTCAGACCAGGGGACAACATCACGTTTTCCCATAATGGCGGACTCATCGCTCCAG



ACAGGGTTTCCAAGCTCATCGGAAAGGGGATTGGGATTCAGTCAGGGGCAGTAATAGATAA



GGACTGTGAGTCTAAATGTTTTTGGCGGGGAGGTTCCATAATTACCGAACTGCCATTTCAG



AATCTCTCCCCTAGAACAGTGGGGCAGTGTCCCAAATACGTTAAAAAAAGGAGTTTGCTGC



TGGCAACAGGCATGCGGAACGTCCCTGAGGTAGTACAGGGGGGGGGATTATTCGGAGCAAT



AGCCGGGTTTATCGAAAACGGGTGGGAAGGTATGGTGGATGGATGGTACGGCTTCCGTCAC



CAAAATGCTCAGGGGATCGGACAGGCCGCCGACTACAAATCTACTCAGACTGCCATAGATC



AGATTACCGGTAAACTCAACAGGCTCATCGAAAAAACAAATACTGAGTTTGAAAGCATTGA



GTCTGAGTTTTCTGAGATTGAGCATCAGATTGGCAACGTCATCAACTGGACCAAGGATTCC



ATTACAGATATCTGGACGTACCAAGCCGAGCTGCTCGTGGCAATGGAGAACCAGCATACAA



TAGACATGGCTGATTCTGAAATGCTGAATCTGTACGAACGTGTGAGAAAGCAACTGAGGCA



GAACGCTGAGGAGGACGGCAAGGGCTGTTTCGAGATCTATCATACCTGCGATAACTCATGT



ATGGAATCCATCCGGAATAATACTTATGATCACAGTCAGTATCGCGAGGAAGCCCTGCTGA



ATAGATTAAATATCAATCCTGTGAAACTGAGTTCTGGGTACAAAGATATCATCCTGTGGTT



CAGCTTTGGGGCCAGCTGTTTCGTACTGCTGGCCGTAATCATGGGGCTAGGATTCTTTTGC



CTGAAGAACGGCAATATGCGCTGCACGATTTGCATT





783
ATGTACAAAATTGTGGTGATAATTGCCCTTTTAGGCGCCGTGAAGGGCCTCGATAAAATTT



GCCTTGGCCATCATGCAGTCGCTAACGGGACTATCGTAAAGACCCTGACCAACGAACAGGA



AGAAGTTACCAATGCCACTGAAACTGTGGAGAGTACAGGCATTAACAGGCTGTGCATGAAG



GGACGCAAGCACAAGGATTTAGGGAATTGCCATCCGATCGGAATGCTGATCGGGACCCCCG



CGTGCGACCTGCACCTGACAGGAATGTGGGACACCCTTATTGAGAGAGAAAATGCTATCGC



TTATTGCTACCCTGGTGCCACTGTCAACGTGGAGGCCTTACGTCAGAAGATTATGGAATCC



GGAGGCATAAATAAGATTAGTACCGGGTTCACATATGGCTCTTCCATAAACTCTGCGGGCA



CCACTAGAGCATGTATGAGGAACGGTGGGAATAGCTTCTATGCTGAGCTCAAGTGGTTGGT



CAGCAAGTCCAAAGGTCAGAACTTTCCGCAGACAACTAATACCTACCGAAATACAGACACC



GCTGAGCACCTCATTATGTGGGGCATTCACCACCCGAGCTCAACTCAAGAGAAGAATGACT



TGTACGGAACACAATCTCTGTCCATCTCTGTGGGCAGCAGTACCTATCGGAATAATTTCGT



CCCAGTAGTGGGCGCAGGACCTCAGGTCAATGGTCAGTCCGGTCGCATCGACTTCCATTGG



ACCCTGGTGCAACCAGGCGACAACATCACCTTTTCTCACAACGGGGGGCTGATCGCACCCT



CGCGTGTGTCTAAGCTAATCGGCCGTGGCCTGGGGATCCAGTCTGATGCACCCATTGACAA



TAACTGCGAGTCTAAATGTTTCTGGAGAGGCGGATCCATTAACACGCGGCTGCCATTTCAG



AACCTGAGTCCAAGAACGGTAGGCCAGTGTCCGAAGTACGTCAATCGGAGGTCATTGATGC



TGGCAACCGGCATGAGAAATGTCCCGGAGCTGATACAGGGAAGGGGACTATTTGGAGCTAT



CGCTGGCTTCCTAGAAAATGGATGGGAGGGTATGGTCGATGGATGGTATGGGTTTCGCCAC



CAAAACGCACAGGGGACTGGGCAGGCCGCAGATTATAAGAGCACTCAAGCTGCAATCGACC



AGATCACTGGCAAACTGAATCGGCTTGTGGAGAAAACCAACACAGAATTCGAGTCAATTGA



GTCCGAGTTTAGCGAAATTGAACACCAGATCGGAAATGTTATTAACTGGACTAAGGATTCC



ATCACAGATATCTGGACCTACCAGGCAGAGCTATTGGTAGCCATGGAGAACCAACATACAA



TCGACATGGCGGATTCAGAAATGCTGAACCTGTATGAACGCGTTAGGAAGCAGCTCAGGCA



GAACGCCGAGGAGGATGGGAAAGGTTGCTTCGAGATATATCATGCCTGCGACGACAGCTGT



ATGGAGTCCATACGAAATAACACGTATGACCACAGCCAGTACCGAGAAGAGGCTCTTCTTA



ATCGGCTCAATATAAACCCAGTGACACTGTCATCCGGATACAAGGACATCATACTATGGTT



CAGCTTTGGTGCCTCTTGTTTCGTGCTACTTGCTGTGGTGATGGGCCTTTTTTTTTTCTGC



CTCAAGAACGGGAACATGAGGTGTACGATATGCATC





784
ATGTACAAGATAGTCGTGATCATTGCCCTCCTTGGTGCAGTAAAGGGATTAGACAAGATTT



GCTTGGGACACCACGCGGTTGCTAACGGAACAATAGTTAAGACACTCACTAATGAGCAAGA



GGAAGTCACAAATGCTACCGAAACCGTAGAGTCTACGGGCATCAACAGGCTTTGTATGAAA



GGCAGGAAGCACAAGGACCTTGGGAATTGTCACCCTATTGGTATGCTTATTGGCACCCCAG



CCTGCGATCTACATCTGACTGGGATGTGGGACACCCTCATCGAACGAGAGAATGCCATAGC



CTATTGCTACCCTGGCGCAACTGTGAATGTGGAAGCTTTGAGGCAGAAGATAATGGAATCC



GGCGGAATCAACAAGATATCAACAGGCTTTACTTACGGCTCGAGTATCAATTCAGCCGGCA



CAACTCGGGCCTGCATGCGGAATGGGGGAAACTCTTTCTACGCAGAACTGAAATGGCTGGT



ATCCAAGTCTAAGGGCCAGAATTTCCCGCAGACCACCAACACCTATCGCAACACTGACACA



GCAGAACATTTGATAATGTGGGGTATCCACCACCCGTCTAGTACCCAGGAGAAGAACGACT



TGTATGGCACGCAGTCATTATCTATCAGCGTGGGCTCCAGCACGTACCGGAACAACTTTGT



CCCCGTGGTTGGCGCACGACCACAAGTGAACGGACAATCCGGCCGGATCGATTTTCATTGG



ACACTCGTTCAGCCCGGCGACAATATCACCTTTTCTCACAATGGGGGCCTGATCGCGCCAA



GCCGGGTTTCCAAGCTGATCGGCAGAGGCCTCGGCATACAGAGCGATGCCCCGATCGATAA



CAATTGTGAGTCGAAATGTTTTTGGAGAGGCGGCTCTATTAACACGCGACTGCCCTTTCAG



AATCTGAGCCCGCGGACAGTGGGACAATGCCCAAAATACGTAAACAGGAGGAGTCTGATGC



TCGCGACTGGCATGAGGAACGTTCCTGAGTTGATCCAGGGCCGGGGCCTATTTGGCGCCAT



CGCAGGGTTCCTGGAGAATGGTTGGGAGGGTATGGTAGATGGATGGTACGGGTTCCGCCAC



CAGAATGCCCAGGGAACAGGCCAGGCTGCGGACTACAAATCCACTCAGGCCGCCATCGATC



AAATTACCGGAAAGCTTAACAGACTCGTCGAGAAAACGAATACAGAGTTTGAGTCAATTGA



GTCCGAGTTCAGTGAAATCGAGCACCAAATAGGAAACGTGATCAATTGGACAAAGGACAGT



ATCACCGATATCTGGACTTACCAGGCTGAACTGCTCGTAGCTATGGAGAATCAGCACACCA



TAGATATGGCAGACTCCGAGATGTTGAATTTATACGAGAGAGTCCGGAAACAGCTGCGCCA



GAACGCCGAAGAGGATGGGAAGGGCTGCTTCGAGATATACCACGCCTGTGACGACTCATGC



ATGGAGTCTATCCGAAACAATACCTACGATCATTCCCAGTATAGGGAAGAGGCCTTGCTGA



ACCGGTTGAATATTAATCCTGTCACATTGTCTAGCGGCTACAAAGACATCATCTTATGGTT



TTCGTTTGGTGCTTCATGTTTCGTGCTTCTGGCTGTGGTGATGGGACTCTTTTTCTTTTGC



CTTAAGAATGGCAATATGAGATGCACCATTTGTATT





785
ATGTATAAGATCGTGGTGATCATTGCCCTACTGGGTGCCGTGAAAGGGCTGGACAAAATTT



GCCTCGGCCACCATGCTGTCGCCAACGGCACCATCGTCAAAACGCTTACGAATGAGAAGGA



GGAAGTGACCAATGCTACCGAGACTGTGGAAAGTACAGGCCTCAACAGGCTCTGTATGAAG



GGCAGGAAACACAAAGACTTGGGTAACTGCCATCCTATAGGAATGCTCATTGGCAGCCCGG



CTTGTGACCTGCACCTTACTGGGACCTGGGATACTCTGATCGAGAGGGAGAATGCCATTGC



GTATTGTTATCCAGGAGCCACCGTAAACGGCGAGGCACTAAGGCAAAAGATTATGGAAAGC



GGGGGTATTGACAAAATTTCAACAGGGTTCACATATGAGTCTAGCATCAACTCAGCCGGCA



CAACGAGAGCATGCATGCGGAACGGGGGCAATTCCTTTTACGCTGAGTTGAAGTGGCTGGT



GTCCAAGAGCAAAGGGCAGAATTTCCCACAGACTACCAACACCTATAGAAATACGGATACA



GCAGAGCACCTGATTATGTGGGGTATCCACCACCCAAGCTCCACGCAAGAAAAGAATGATC



TGTATGGAACTCAAAGCCTCTCTATTAGTGTGGGGTCTAGCACTTACCGGAACAACTTCGT



CCCTGTGGTGGGCGCTCGCCCTCAGGTTAATGGCCAGTCCGGAAGAATTGACTTTCATTGG



ACTCTCGTCCAGCCAGGGGATAATATAACATTCTCTCACAATGGAGGACTGATTGCACCTT



CTCGGGTGAGCAAGCTGATAGGCCGCGGGCTGGGGATCCAGAGCGATGCTCCAATAGATAA



TAATTGCGAATCAAAGTGCTTTTGGAGGGGGGGATCTATTAATACGCGGCTTCCATTCCAG



AACCTCAGTCCTCGGACTGTTGGACAATGCCCCAAATATGTGAACAAGCGCAGCCTTATGC



TCGCTACCGGGATGAGGAATGTCCCTGAATTAATGCAGGGACGCGGCCTATTCGGAGCAAT



TGCCGGATTTCTCGAGAACGGTTGGGAAGGCATGGTTGACGGGTGGTATGGTTTCAGACAC



CAGAACGCCCAGGGGACAGGGCAGGCCGCCGATTATAAATCCACCCAGGCCGCCATCGACC



AGATTACCGGTAAATTAAACAGGCTAGTTGAAAAAACCAATACCGAGTTTGAATCCATAGA



ATCTGAATTCTCCGAAATTGAACACCAGATCGGTAATGTTATCAACTGGACCAAAGACAGC



ATCACCGACATATGGACTTATCAGGCTGAGCTGCTTGTCGCTATGGAGAACCAGCACACCA



TCGACATGGCCGATTCTGAAATGCTGAACCTGTACGAAAGGGTGCGGAAGCAGCTACGGCA



GAACGCTGAGGAGGACGGCAAGGGGTGCTTTGAAATCTACCACGCCTGCGATGATTCCTGT



ATGGAGTCCATCCGTAACAACACGTACGACCACTCACAGTATAGAGAGGAAGCCCTCCTAA



ACCGCCTGAATATCAACCCCGTAACCCTCTCATCTGGTTATAAAGACATCATCCTCTGGTT



TAGTTTCGGCGCCTCATGTTTCGTACTGCTCGCAGTGGTGATGGGCCTGGTATTCTTCTGT



CTAAAGAACGGGAATATGAGATGCACCATCTGCATT





786
ATGTATAAGATCGTGGTGATCATTGCACTCCTTGGGGCAGTCAAAGGCTTGGACAAAATTT



GTTTGGGACACCACGCAGTCGCTAACGGTACAATAGTCAAAACACTGACAAATGAGCAGGA



AGAAGTGACTAACGCCACAGAAACAGTGGAGTCCACAGGCATTAATCGCCTTTGTATGAAG



GGTCGCAAGCATAAGGATCTGGGGAACTGTCACCCTATAGGTATGCTGATAGGGACTCCAG



CCTGTGATTTACACCTGACAGGGATGTGGGACACGCTCATCGAGAGGGAAAACGCCATCGC



CTACTGCTATCCTGGGGCTACAGTCAACGTCGAGGCCCTACGACAAAAAATTATGGAGAGC



GGCGGGATCAATAAGATTTCCACTGGCTTTACTTATGGCTCATCTATAAACTCCGCAGGCA



CAACACGCGCCTGTATGCGCAACGGCGGAAACTCATTTTACGCGGAACTGAAGTGGCTGGT



TTCTAAAAGCAAGGGCCAGAATTTCCCACAGACTACAAATACCTATCGCAACACTGACACC



GCAGAACACTTAATAATGTGGGGGATTCACCACCCCTCGAGCACCCAAGAGAAGAACGACC



TTTATGGAACGCAGTCTCTCAGCATCAGCGTGGGATCATCCACATACCGGAACAACTTTGT



GCCTGTGGTGGGAGCTCGACCACAAGTCAACGGCCAGTCTGGTAGAATTGATTTTCACTGG



ACCCTTGTGCAACCTGGGGATAATATAACTTTCTCGCACAATGGTGGTTTAATAGCCCCAT



CTCGCGTCAGCAAACTGATCGGTAGAGGCCTCGGAATACAGTCCGATGCACCTATCGATAA



CAATTGTGAATCCAAGTGCTTCTGGAGGGGGGGATCCATTAATACTCGGCTGCCTTTCCAA



AATTTGTCACCCCGCACTGTGGGCCAGTGTCCAAAGTACGTGAACAGAAGGAGCCTGATGT



TGGCAACCGGGATGCGCAACGTTCCCGAACTCATCCAGGGGAGAGGTTTGTTTGGAGCTAT



CGCGGGCTTTCTCGAAAACGGCTGGGAGGGGATGGTGGATGGATGGTACGGCTTTCGTCAC



CAGAACGCCCAGGGAACGGGGCAAGCAGCCGATTACAAGAGCACCCAGGCCGCTATCGACC



AGATTACGGGGAAGCTGAACCGCCTAGTAGAGAAGACCAACACAGAATTCGAATCTATTGA



ATCAGAGTTTAGCGAAATAGAGCATCAGATCGGAAACGTGATCAATTGGACTAAAGATTCT



ATCACAGATATCTGGACTTACCAGGCTGAACTGCTTGTAGCAATGGAGAATCAACACACAA



TAGACATGGCCGATTCTGAGATGCTGAACCTGTACGAGCGTGTACGCAAACAGCTGAGACA



GAACGCCGAAGAGGATGGTAAAGGATGTTTCGAAATCTACCATGCTTGCGACGACTCTTGC



ATGGAAAGTATCCGGAACAATACATACGATCACTCCCAATATCGCGAGGAGGCGCTGCTGA



ACAGACTGAACATTAACCCCGTGACTCTATCCTCAGGGTACAAGGATATCATATTATGGTT



CTCTTTCGGCGCCTCCTGTTTCGTCCTGCTGGCCGTCGTAATGGGCCTTTTCTTTTTCTGT



TTGAAGAATGGAAATATGCGGTGCACCATCTGTATA





787
ATGTACAAAATCGTGGTAATTATTGCTCTTCTTGGGGCTGTTAAAGGGTTGGACAAGATTT



GTCTCGGGCATCACGCCGTGGCCAATGGAACGATTGTGAAGACACTGACCAACGAACAGGA



GGAGGTAACTAACGCCACGGAAACTGTCGAGTCCACTGGCATCAATCGGCTCTGTATGAAG



GGCCGCAAACACAAGGACTTGGGGAACTGCCACCCAATCGGCATGCTTATCGGCACACCCG



CTTGTGACTTACATCTGACTGGGATGTGGGACACGCTTATAGAACGGGAAAACGCCATTGC



CTACTGCTACCCAGGTGCAACTGTTAACGTCGAAGCTCTGCGCCAAAAGATCATGGAAAGC



GGCGGTATCAACAAAATTAGTACGGGCTTTACCTATGGCTCAAGCATTAACTCAGCTGGCA



CCACCCGTGCCTGTATGAGGAATGGAGGCAACTCCTTTTACGCTGAGCTCAAGTGGCTCGT



GTCCAAGTCCAAGGGACAGAATTTCCCCCAGACTACCAATACCTATAGAAATACTGACACC



GCTGAACACTTGATTATGTGGGGTATCCATCACCCTAGCTCCACTCAGGAAAAAAACGATC



TATACGGCACCCAGTCGTTGTCCATCTCAGTCGGCAGTTCCACTTATCGCAACAACTTTGT



GCCCGTGGTCGGAGCACGTCCTCAGGTTAATGGCCAGTCTGGCCGTATCGATTTTCACTGG



ACACTGGTACAGCCTGGCGATAATATTACTTTTAGCCACAACGGGGGCCTGATCGCCCCGA



GTCGTGTGTCCAAGCTTATCGGACGAGGTCTTGGGATTCAATCTGATGCCCCAATTGACAA



TAACTGTGAAAGCAAATGCTTTTGGCGCGGGGGATCCATTAACACGCGGCTTCCTTTCCAG



AATCTATCCCCTCGTACTGTCGGGCAATGCCCTAAGTACGTCAACCGGAGGTCCCTGATGC



TGGCCACTGGCATGCGTAACGTCCCAGAGCTCATTCAGGGCAGAGGTTTATTCGGAGCAAT



TGCAGGGTTCCTGGAGAACGGCTGGGAGGGAATGGTCGATGGCTGGTATGGTTTCCGCCAT



CAAAACGCTCAAGGCACAGGCCAGGCGGCCGATTACAAATCGACTCAGGGGGCCATTGACC



AAATCACAGGCAAACTGAATAGACTGGTGGAAAAAACAAACACCGAGTTTGAGTCTATTGA



ATCTGAGTTTAGCGAAATCGAGCACCAAATCGGCAATGTTATTAACTGGACTAAGGATTCA



ATTACGGATATTTGGACATACCAGGCGGAGTTATTAGTTGCCATGGAGAATCAGCACACTA



TTGATATGGCTGATAGTGAGATGTTAAATTTGTACGAGAGGGTTAGGAAGCAGTTGAGGCA



GAACGCGGAGGAAGACGGGAAAGGCTGCTTCGAGATTTACCACGCCTGCGACGATTCCTGC



ATGGAGAGCATCCGGAATAATACCTACGACCATTCACAGTATCGAGAAGAAGCTCTATTAA



ACCGTTTGAACATCAACCCAGTGACCTTAAGTAGCGGATACAAAGACATTATTCTATGGTT



CTCCTTCGGCGCCTCCTGTTTCGTGTTGCTCGCCGTTGTAATGGGATTGTTTTTCTTCTGT



CTGAAGAATGGAAACATGAGATGCACAATTTGTATC





788
ATGTACAAGATTGTTGTGATCATCGCCCTTCTGGGGGCCGTGAAGGGACTTGACAAAATAT



GCCTCGGTCATCACGCTGTTGTGAATGGCACAATAGTTAAAACGCTGACCAACGAGCAAGA



AGAGGTGACCAACGCAACCGAGACAGTGGAGAGTACAGGTCTGAACCGACTGTGCATGAAG



GGCCGAAACCACAAGGACCTCGGCAATTGTCACCCCATCGGAATGTTAATTGGTACCCCCG



CCTGCGATCTGCATCTGACCGGTACTTGGGATACCTTAATTGAAAGGGAAAACGCCATCGC



GTACTGTTATCCCGGAGCAACCGTGAACGAGGAAGCCCTCAGACAGAAGATCATGGAGTCG



GGAGGCATCAACAAGATCTCCACAGGCTTCACGTACGGCTCCTCTATTAATTCTGCCGGAA



CAACTCGGGCCTGTATGCGCAACGGAGGCAACTCCTTCTACGCAGAACTGAAATGGCTTGT



CAGCAAGAGCAAGGGTCAGAATTTCCCCCAAACTACCAATACTTATAGGAATACGGACACC



GCAGAACACCTGATAATGTGGGGCATTCATCATCCCTCTTCAACTCAGGAGAAAAATGATT



TGTATGGGACTCAATCCTTATCAATCTCCGTGGGTAGCAGCACCTATCAGAATAACTTTGT



TCCAGTCGTAGGGGCCCGGCCTCAGGTGAACGGGCAGTCAGGCAGAATTGATTTCCACTGG



ACCCTTGTGCAACCCGGAGACAACATTACCTTTAGTCACAATGGCGGTCTCATCGCCCCTT



CCAGAGTGTCTAAACTGATCGGTCGGGGCCTGGGCATCCAGAGCGACGCACCAATCGACAA



TAATTGCGAGAGTAAGTGCTTCTGGAGAGGTGGTAGTATCAATACTAGGCTCCCATTCCAA



AATTTATCGCCTAGGACCGTCGGACAGTGTCCCAAATATGTAAATAAAAGGTCCTTAATGC



TTGCGACGGGAATGCGTAACGTTCCTGAACTGATGCAGGGCAGAGGCCTATTTGGCGCAAT



AGCCGGTTTTATCGAGAACGGCTGGGAGGGGATGGTGGACGGTTGGTATGGATTTAGGCAC



CAAAATGCCCAGGGAACTGGGCAGGCGGCGGATTACAAGAGCACACAAGCTGCTATCGACC



AGATCACGGGCAAACTGAATCGATTGATTGAAAAGACCAACACTGAGTTTGAATCAATTGA



GAGTGAGTTTTCAGAGATTGAACACCAGATCGGGAACGTGATAAACTGGACTAAAGATTCC



ATCACTGACATCTGGACATATCAGGCGGAGCTCCTGGTGGCCATGGAGAACCAACACACCA



TCGACATGGCAGACTCTGAAATGTTAAATCTGTACGAGAGAGTCAGGAAACAGCTGCGCCA



GAATGCCGAGGAAGATGGCAAGGGTTGCTTCGAGATCTACCACGCATGTGACGACAGCTGC



ATGGAGTCAATTCGCAACAACACCTACGACCACTCCCAATACAGGGAGGAGGCACTGCTTA



ACAGGCTGAACATTAATCCGGTCACCCTCTCTAGCGGCTATAAGGATATTATTCTGTGGTT



CAGTTTTGGCGCTTCTTGTTTTGTCCTGCTGGCAGTGGTGATGGGCCTGGTCTTCTTTTGC



CTAAAAAATGGGAATATGAGGTGCACCATCTGTATT





789
ATGTATAAAATTGTGGTCATCATTGCTCTGCTGGGTGCAGTAAAGGGGCTGGACAAAATTT



GTCTGGGACACCATGCCGTTGCCAACGGAACAATCGTGAAGACGCTTACTAACGAACAGGA



AGAAGTTACCAACGCTACCGAAACCGTCGAATCCACGGGTATCAACAGGCTGTGTATGAAA



GGGAGGAAGCACAAAGATTTGGGGAACTGCCACCCAATCGGCATGTTGATTGGCACTCCCG



CCTGTGATCTGCATTTAACTGGTATGTGGGATACCCTGATCGAGCGAGAAAATGCTATTGC



ATACTGTTATCCAGGCGCGACTGTGAATGTCGAAGCTCTGCGACAGAAAATCATGGAATCC



GGCGGTATCAATAAAATTTCGACAGGCTTCACATATGGGAGTTCTATTAACTCTGCCGGGA



CCACCAGAGCCTGCATGCGCAACGGAGGAAATAGCTTCTACGCTGAGTTAAAGTGGCTAGT



CTCTAAATCTAAAGGACAAAACTTCCCACAGACCACTAACACCTACCGGAATACCGATACC



GCGGAACACTTAATTATGTGGGGGATCCACCACCCAAGCTCTACGCAGGAAAAGAACGATC



TCTACGGGACTCAGTCTTTATCAATTTCCGTGGGCTCCTCTACATACCGCAATAATTTCGT



GCCCGTGGTTGGCGCTAGGCCTCAGGTAAACGGGCAGAGTGGAAGGATAGATTTTCACTGG



ACCCTGGTTCAGCCGGGCGACAACATCACTTTCAGTCACAATGGCGGCCTTATCGCTCCCA



GCCGGGTGTCTAAATTGATCGGCAGGGGACTGGGTATCCAGTCGGACGCTCCAATTGACAA



CAATTGTGAGTCAAAGTGCTTTTGGCGAGGGGGGAGCATCAACACTCGCCTCCCTTTCCAA



AACCTGTCTCCTCGGACGGTCGGACAATGCCCTAAGTACGTAAACAGGCGGTCGCTGATGC



TGGCCACTGGGATGAGAAACGTGCCAGAACTTATTCAGGGCCGTGGCTTGTTCGGCGCAAT



CGCTGGGTTTCTTGAAAATGGCTGGGAAGGGATGGTGGATGGTTGGTATGGGTTCCGACAT



CAGAACGCTCAGGGCACTGGGCAGGCCGCTGATTATAAGTCCACCCAGGCAGCTATAGACC



AAATAACAGGGAAACTAAATCGCCTGGTCGAAAAGACAAATACAGAGTTCGAATCTATCGA



GAGCGAATTCTCAGAAATCGAGCACCAGATTGGGAATGTGATTAATTGGACCAAGGATAGT



ATCACAGATATCTGGACATACCAGGCAGAACTGTTGGTTGCCATGGAAAACCAGCACACCA



TTGATATGGCAGATTCAGAGATGCTTAACCTGTATGAGAGAGTGCGAAAGCAGCTGCGCCA



GAACGCAGAAGAGGATGGAAAGGGGTGCTTCGAAATTTACCACGCTTGCGATGATAGCTGT



ATGGAGTCAATAAGAAACAACACCTATGACCACAGCCAGTACAGGGAGGAGGCACTACTTA



ATAGGCTGAATATCAATCCAGTTACTTTGTCCAGCGGCTATAAGGACATTATACTGTGGTT



TAGCTTTGGGGCGTCCTGCTTTGTGCTCCTGGCTGTAGTGATGGGGCTATTTTTCTTCTGT



TTAAAGAACGGTAATATGCGGTGCACAATCTGTATC





790
ATGTACAAAATAGTGCTGGTGCTCGCCCTCCTCGGTGCTGTGCATGGTCTTGACAAGATAT



GTCTCGGACATCACGCCGTCCCGAACGGAACTATTGTGAAAACCCTAACCAACGAGAAGGA



AGAGGTGACTAACGCGACCGAAACTGTGGAAAGCAAGAGTCTGGATAAACTGTGTATGAAG



AATAGGAATTACAAGGACCTGGGCAATTGTCATCCTATTGGGATGGTGGTCGGTACCCCCG



CTTGTGATCTTCATCTGACCGGAACCTGGGATACCCTGATAGAGCGCGACAATTCAATTGC



GTATTGCTACCCCGGTGCCACAGTTAGCGAGGAAGCCTTGCGCCAGAAGATCATGGAGAGT



GGCGGCATAGATAAAATCAGCACCGGATTCACGTACGGGAGTAGTATCAATTCAGCCGGCA



CAACAAAAGCCTGCATGAGAAATGGCGGAAACTCCTTTTATTCTGAACTGAAATGGCTCGT



GTCCAAGAACAAGGGCCAGAACTTTCCTCAGACGACCAATACTTATCGCAACACAGATTCC



GTCGAACATTTGATCATTTGGGGCATTCACCATCCTAGCTCTACCCAGGAGAAAAACGATC



TGTACGGCACCCAAAGCCTGTCCATTAGCGTCGGGTCCAGTACATACCAGAACAACTTCGT



GCCAGTCGTCGGGGCGCGGCCGCAGGTCAACGGCCAGTCAGGGAGAATAGACTTTCATTGG



ACCATGGTGCAGCCCGGGGACAACATTACTTTTTCCCATAATGGAGGCCTGATCGCACCAA



ATCGGGTCTCTAAGCTGAAAGGGAGAGGTCTCGGGATCCAGTCCGGAGCATCTGTGGACAA



CGACTGTGAATCCAAATGCTTCTGGAAGGGTGGGTCTATCAATACCAAGCTCCCCTTTCAG



AATCTCTCGCCTAGGACCGTGGGACAGTGCCCAAAATACGTGAACAAAAAAAGTCTCCTCC



TGGCTACTGGTATGCGGAATGTCCCAGAGGTTGCACAGGGGCGAGGCCTGTTCGGTGCCAT



AGCGGGTTTTATTGAGAACGGTTGGGAGGGAATGGTGGATGGCTGGTATGGGTTTCGGCAC



CAAAATGCACAGGGCACAGGTCAGGCCGCCGATTATAAGAGCACACAGGCAGCCATTGATC



AGATTACAGGGAAGCTGAATCGACTGATAGAAAAAACAAATACCGAGTTTGAGTCCATTGA



AAGCGAATTTAGCGAGATTGAGCACCAGATAGGGAATGTCATCAATTGGACCAAAGATTCA



ATCACTGATATTTGGACTTACCAGGCTGAGCTGCTGGTTGCAATGGAAAATCAGCACACAA



TTGACATGGCCGACAGCGAGATGCTGAACCTCTACGAGAGAGTGCGTAAACAGCTGCGCCA



GAACGCAGAAGAGGATGGGAAGGGATGTTTCGAAATTTATCACAAGTGTGATGACAACTGT



ATGGAGAGCATTCGAAACAACACGTACGACCATACTCAGTATCGGGAGGAAGCCCTGTTGA



ATCGCCTCAATATTAATCCCGTGAAACTCTCATCCGGTTATAAAGACGTCATACTGTGGTT



TTCCTTCGGGGCCAGCTGCTTCGTACTGCTGGCCGTCATTATGGGCCTTGTTTTTTTCTGT



CTGAAAAATGGAAACATGAGGTGTACCATCTGTATT





791
ATGTATAAAATCGTGGTGATCATCGCACTGCTGGGTGCGGTTAAGGGGCTCGACAAGATTT



GCCTGGGACACCATGCAGTGGCAAATGGCACTATTGTCAAAACACTTACTAACGAGCAGGA



GGAAGTGACAAACGCCACGGAGACCGTTGAGAGCACGGGCATCAATCGGCTGTGCATGAAA



GGCAGGAAGCATAAGGACCTCGGCAACTGCCATCCTATTGGTATGCTGATTGGCACGCCCG



CTTGCGATCTGCATCTGACCGGAATGTGGGATACGCTTATAGAGAGAGAGAACGCGATTGC



CTACTGCTACCCCGGCGCTACAGTCAATGTCGAAGCTCTGCGCCAAAAAATTATGGAATCT



GGCGGGATTAACAAGATCTCCACTGGCTTCACGTATGGATCTTCAATAAACTCAGCCGGCA



CCACACGGGCCTGCATGCGCAATGGGGGAAACTCATTCTATGCTGAACTGAAATGGCTTGT



CTCAAAATCTAAGGGGCAGAATTTTCCTCAAACTACCAACACCTACAGGAATACGGATACC



GCTGAGCACCTGATCATGTGGGGTATCCACCACCCTTCGTCCACCCAGGAAAAAAATGACC



TATATGGTACCCAGTCACTGAGTATCAGCGTAGGCAGTTCTACATATCGTAACAACTTTGT



CCCAGTAGTCGGGGCCCGCCCTCAAGTGAACGGCCAATCTGGACGTATTGATTTCCACTGG



ACACTGGTGCAACCCGGAGACAACATCACTTTCTCCCACAACGGAGGGCTGATAGCCCCCT



CCAGGGTCTCCAAGTTGATCGGACGTGGACTTGGGATACAGTCTGATGCCCCAATTGATAA



TAACTGTGAGTCTAAATGCTTCTGGAGGGGGGGCAGTATCAATACACGCCTGCCTTTCCAG



AACCTGTCGCCACGGACAGTTGGACAGTGTCCAAAATATGTGAACCGCAGGTCGCTGATGT



TGGCAACCGGAATGAGGAATGTGCCCGAGCTGATTCAGGGTCGGGGATTATTTGGCGCCAT



CGCAGGGTTCCTGGAAAATGGATGGGAAGGCATGGTGGATGGATGGTACGGCTTTAGACAC



CAAAACGCCCAGGGAACAGGGCAAGCAGCAGACTACAAATCCACGCAAGCTGCTATAGACC



AGATTACTGGTAAGCTCAACCGTCTCGTTGAGAAAACAAATACGGAATTTGAGAGTATCGA



GTCAGAGTTTTCTGAAATCGAACATCAAATAGGGAATGTAATTAATTGGACAAAAGACTCA



ATCACTGACATATGGACCTATCAGGCTGAACTGCTAGTTGCAATGGAGAATCAACATACCA



TCGACATGGCTGACAGCGAGATGCTGAATTTGTACGAAGGGGTCAGAAAACAACTGCGGCA



GAATGCTGAGGAAGATGGAAAGGGGTGTTTCGAAATATATCACGCTTGTGATGACTCTTGC



ATGGAATCCATCCGGAATAATACCTACGATCACTCGCAGTATCGAGAGGAGGCCCTGCTGA



ATCGCTTAAACATTAATCCAGTGACACTGTCTTCCGGGTATAAAGATATCATTCTGTGGTT



TTCCTTTGGCGCATCCTGCTTCGTATTACTAGCCGTTGTCATGGGATTGTTTTTCTTTTGT



CTGAAAAACGGGAACATGCGGTGTACCATTTGTATT





792
ATGTACAAGATCGTGGTCATCATCGCTCTGTTGGGCGCCGTGAAAGGGCTTGATAAGATCT



GTCTTGGGCACCACGCCGTGGCCAACGGGACCATTGTGAAAACCCTCACGAACGAGCAGGA



GGAAGTGACAAACGCAACTGAGACCGTTGAGTCAACCGGTATTAATCGCTTGTGCATGAAA



GGACGAAAGCACAAGGACTTGGGCAACTGCCATCCAATTGGGATGCTGATCGGTACCCCAG



CATGTGATCTGCATTTAACAGGCATGTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC



GTATTGCTATCCTGGAGCCACTGTGAATGTGGAGGCACTGCGTCAGAAGATTATGGAATCT



GGCGGGATCAATAAAATAAGCACCGGCTTTACATACGGCAGCTCGATTAATTCCGCTGGCA



CCACTAGAGCTTGCATGCGCAATGGGGGCAACTCATTCTATGCCGAGCTGAAGTGGTTGGT



GAGTAAGAGCAAAGGGCAGAACTTTCCTCAGACCACCAACACCTATCGAAATACGGACACA



GCTGAACACCTTATAATGTGGGGGATCCACCACCCGTCATCTACCCAGGAAAAGAACGACT



TATACGGAACACAGTCTCTGTCCATCTCGGTTGGATCCTCTACTTACCGAAATAATTTTGT



GCCCGTCGTGGGGGCCAGACCCCAGGTAAACGGACAGTCTGGCAGGATCGATTTCCATTGG



ACTCTGGTCCAGCCCGGAGATAATATCACCTTTAGTCACAACGGTGGACTGATCGCTCCCA



GTAGAGTGTCCAAGCTGATAGGCAGAGGGCTTGGAATCCAAAGCGACGCCCCAATCGATAA



TAACTGCGAAAGCAAGTGTTTCTGGCGGGGCGGATCCATCAACACCAGGCTTCCCTTCCAG



AACTTGTCCCCAAGGACTGTTGGACAGTGCCCAAAGTATGTTAATCGACGGAGTCTGATGC



TCGCTACTGGCATGAGAAACGTACCCGAGCTGATACAAGGGCGCGGGCTGTTCGGCGCAAT



AGCCGGATTCCTGGAGAACGGATGGGAGGGTATGGTGGACGGCTGGTATGGCTTTCGGCAT



CAGAATGCCCAGGGTACTGGTCAGGCAGCCGATTATAAGTCAACCCAGGCTGCCATCGATC



AGATTACAGGGAAACTGAATCGGCTGGTGGAAAAAACCAATACCGAATTTGAGTCCATTGA



ATCTGAATTCAGCGAGATCGAGCACCAGATCGGTAATGTCATAAATTGGACTAAGGATTCC



ATCACAGATATCTGGACATACCAAGCTGAGCTGCTTGTGGCCATGGAAAACCAGCATACAA



TAGACATGGCCGACAGTGAGATGCTAAATCTGTATGAGAGAGTGAGAAAACAACTAAGACA



GAATGCTGAGGAGGACGGCAAAGGTTGTTTTGAGATCTACCACGCTTGCGACGACTCGTGT



ATGGAATCCATACGCAACAATACTTACGACCACTCTCAGTACCGCGAGGAAGCTTTACTTA



ACCGCCTGAATATTAACCCTGTTACCTTATCCAGTGGGTACAAAGACATAATATTGTGGTT



CAGTTTTGGCGCGTCGTGTTTTGTTCTCCTGGCCGTTGTGATGGGCCTGTTTTTTTTCTGC



CTGAAGAACGGGAATATGCGCTGTACTATCTGCATA





793
ATGTACAAGATAATCGTCATTATCGCACTGTTGGGCGCCGTTAAAGGACTGGATAAAATCT



GCCTGGGCCATCACGCAGTCGCTAACGGTACAATCGTGAAAACTCTGACCAATGAGCAGGA



GGAAGTCACCAACGCAACCGAAACCGTAGAGTCCACCGGCATCAACCGGCTCTGTATGAAG



GGCCGCAAGCATAAAGACCTGGGTAACTGCCACCCCATAGGCATGCTTATTGGCACTCCGG



CATGCGACTTGCACCTGACGGGGACCTGGGACACATTGATTGAACGGGAAAATGCTATTGC



TTATTGCTATCCTGGAGCCACAGTGAATGTGGAGGCTCTCCGCCAAAAGATCATGGAATCT



GGGGGGATAGATAAGATTAGTACTGGGTTTACGTATGGGAGTTCTATCAACAGCGCCGGGA



CCACAAGAGCCTGTATGAGAAACGGAGGAAACAGCTTTTACGCAGAGTTGAAATGGCTTGT



TAGTAAATCTAAGGGGCAGAATTTCCCTCAGACCACGAACACTTACAGGAATACGGATACT



GCGGAGCACCTTATTATGTGGGGCATCCATCATCCCTCCTCTACTCAGGAGAAAAACGACC



TCTATGGCACTCAATCCTTGTCCATCTCCGTCGGTTCCTCAACCTATAGGAACAACTTTGT



GCCAGTTGTAGGCGCAAGGCCACAGGTTAACGGGCAGAGCGGTCGCATCGACTTCCACTGG



ACCCTGGTGCAGCCAGGCGATAACATCACCTTTTCACACAACGGCGGGCTGATCGCACCTT



CCCGAGTGTCTAAGCTGATAGGGAGGGGCCTCGGCATCCAGTCTGACGCACCAATTGACAA



TAATTGTGAGTCCAAGTGTTTTTGGCGCGGAGGTTCAATTAACACGCGCCTGCCCTTTCAG



AATCTGTCTCCCCGTACTGTGGGCCAGTGTCCAAAGTATGTTAATAGGCGGTCCCTCATGC



TGGCTACGGGAATGAGAAACGTGCCTGAGCTGATACAGGGCCGAGGACTATTCGGGGCGAT



CGCCGGCTTTTTAGAAAACGGGTGGGAGGGCATGGTCGACGGATGGTATGGCTTCAGACAC



CAGAATGCGCAGGGGACTGGCCAGGCTGCTGACTATAAGAGTACCCAGGCCGCTATAGACC



AGATCACGGGTAAGCTGAATCGTCTGGTTGAAAAGACTAATACTGAATTTGAAAGCATCGA



AAGCGAGTTTAGCGAAATTGAGCATCAGATCGGGAACGTCATTAATTGGACTAAAGACTCC



ATTACTGATATCTGGACGTACCAGGCTGAGTTGTTAGTGGCCATGGAAAATCAGCATACCA



TTGATATGGCAGATAGCGAAATGCTGAATCTGTACGAGAGAGTTCGTAAGCAGCTGCGCCA



GAACGCTGAAGAGGACGGAAAGGGATGCTTTGAGATCTACCACGCCTGCGACGACAGCTGT



ATGGAATCGATCCGGAACAACACCTATGACCACTCCCAGTATAGGGAAGAAGCCCTGTTAA



ACCGCCTGAATATTAATCCCGTCACTCTGTCATCCGGCTATAAGGACATAATTCTTTGGTT



TAGCTTCGGCGCTAGTTGCTTTGTGCTACTGGCTGTCGTGATGGGCCTCTTTTTTTTTTGC



CTTAAAAATGGCAATATGAGGTGTACAATCTGTATC





794
ATGTATAAGATCGTCGTAATCATCGCCCTGCTGGGCGCTGTTAAGGGGCTGGATAAGATCT



GCCTAGGCCACCATGCCGTAGCCAATGGTACAATCGTTAAGACATTAACCAATGAGCAGGA



GGAGGTTACAAACGCTACCGAAACCGTTGAGAGCACCGGGATTAACCGACTCTGTATGAAG



GGTAGGAAACATAAGGACCTCGGCAATTGCCATCCTATTGGCATGCTCATAGGGACCCCAG



CGTGTGACTTGCACCTCACTGGAATGTGGGACACTCTGATCGAGAGGGAAAATGCCATAGC



TTATTGTTACCCAGGAGCCACAGTGAATGTGGAAGCCCTGAGACAGAAGATCATGGAGTCC



GGCGGAATCAACAAGATCAGCACTGGTTTCACCTATGGGAGTAGCATAAACAGCGCTGGTA



CTACCCGAGCATGCATGCGGAATGGAGGCAATAGCTTTTACGCTGAACTGAAATGGCTGGT



CTCAAAATCGAAAGGGCAGAATTTTCCTCAGACGACAAATACCTATCGCAATACGGACACC



GCAGAACACCTGATTATGTGGGGTATCCACCATCCTAGCTCCACACAGGAGAAAAATGATC



TGTACGGAACCCAGTCCCTGTCTATCTCCGTGGGATCCTCCACTTACCGGAACAATTTTGT



TCCTGTCGTGGGGGCTCGGCCGCAAGTGAACGGTCAGAGCGGACGAATTGATTTCCACTGG



ACTCTGGTGCAGCCTGGGGACAATATCACGTTCTCCCATAACGGAGGACTGATCGCCCCCA



GCCGCGTGAGCAAGTTGATTGGGCGCGGCCTTGGAATTCAGTCAGATGCGCCAATAGATAA



TAATTGTGAATCTAAGTGTTTCTGGAGGGGAGGCTCCATCAATACCCGGCTCCCTTTCCAA



AATTTGTCCCCGAGAACAGTGGGTCAGTGCCCAAAATATGTGAACCGCCGATCTCTGATGC



TGGCCACCGGCATGAGGAACGTGCCTGAGCTGATTCAGGGTAGAGGCCTGTTTGGAGCCAT



CGCCGGCTTTTTAGAGAACGGCTGGGAAGGAATGGTCGACGGATGGTATGGCTTCAGGCAC



CAGAACGCCCAAGGGACTGGCCAGGCGGCTGACTACAAGTCCACTCAAGCGGCTATTGACC



AAATTACAGGAAAGCTGAATAGACTCGTTGAAAAAACTAATACAGAGTTTGAAAGTATAGA



ATCTGAGTTCTCAGAAATAGAGCATCAGATTGGAAACGTGATCAACTGGACTAAAGACTCT



ATCACCGATATTTGGACGTATCAGGCGGAGTTGCTCGTCGCGATGGAGAACCAACACACAA



TAGATATGGCTGATTCTGAGATGCTGAACTTGTACGAACGGGTGCGTAAACAACTGCGCCA



AAATGCTGAGGAGGACGGGAAGGGGTGTTTTGAGATCTACCATGCTTGCGACGATAGCTGC



ATGGAGTCAATTCGAAATAACACGTATGACCACAGCCAGTACAGGGAAGAGGCCCTGCTGA



ACAGGCTGAATATAAATCCCGTTACCCTCTCCTCTGGATACAAAGACATCATCCTCTGGTT



TTCATTCGGAGCTAGTTGCTTCGTACTACTAGCTGTTGTAATGGGCCTGTTCTTCTTCTGT



CTCAAGAATGGTAACATGCGGTGTACGATCTGCATC





795
ATGTATAAGATCGTGGTGATCATTGCCCTCTTGGGCGCCGTGAAGGGTCTGGATAAAATAT



GTCTTGGTCACCACGCTGTGGCTAATGGTACCATCGTGAAGACGCTTACCAACGAACAAGA



GGAAGTGACAAATGCTACCGAGACCGTGGAGTCTACCGGGATCAACCGACTGTGCATGAAA



GGACGAAAGCACAAAGACCTCGGCAATTGCCACCCTATTGGGATGTTGATTGGCACTCCAG



CTTGCGACCTTCACCTGACCGGAATGTGGGACACGCTCATCGAGCGCGAGAACGCCATTGC



CTACTGCTACCCCGGGGCCACCGTTAACGTGGAAGCACTTAGGCAAAAAATTATGGAATCC



GGTGGAATAAACAAGATTAGCACTGGTTTCACTTATGGGAGTAGTATTAACTCTGCCGGGA



CAACCAGGGCTTGTATGAGAAATGGCGGCAATTCATTTTACGCAGAGCTCAAGTGGCTGGT



TTCAAAAAGTAAAGGGCAGAATTTCCCGCAAACCACTAATACCTACAGGAACACAGACACG



GCCGAGCACCTGATCATGTGGGGTATTCACCACCCTAGCAGCACGCAAGAGAAAAATGACC



TTTATGGAACCCAGAGCCTCAGTATTTCAGTGGGAAGCAGCACGTACCGTAATAATTTTGT



TCCGGTAGTCGGCGCCCGACCCCAGGTGAACGGGCAGTCGGGACGAATCGACTTTCATTGG



ACGCTTGTGCAGCCTGGCGACAACATCACCTTTAGCCACAATGGCGGCCTGATTGCTCCCA



GCCGCGTCAGCAAGCTGATCGGGCGCGGACTGGGCATTCAGTCTGATGCCCCTATTGATAA



CAACTGCGAGAGCAAGTGTTTTTGGCGGGGAGGCTCCATAAATACTCGCTTACCTTTCCAG



AACCTCAGTCCAAGGACCGTAGGGCAGTGTCCTAAGTATGTTAACAGAAGGAGTCTCATGT



TAGCCACAGGAATGCGCAATGTACCAGAACTCATTCAGGGCAGGGGACTCTTTGGTGCAAT



TGCTGGGTTTCTGGAGAACGGTTGGGAAGGTATGGTCGACGGCTGGTACGGCTTTCGACAT



CAAAATGCACAGGGCACAGGCCAGGCGGCTGATTATAAATCCACTCAGGCCGCCATCGACC



AAATCACAGGAAAGCTCAACCGTCTGGTCGAGAAGACCAATACTGAGTTCGAAAGCATCGA



GTCAGAGTTTAGCGAGATTGAGCATCAGATTGGCAATGTCATCAACTGGACTAAAGATAGC



ATAACCGATATTTGGACGTACCAAGCAGAGCTACTTGTTGCTATGGAGAATCAGCATACCA



TTGATATGGCCGATAGCGAGATGCTGAATCTGTATGAGAGAGTGAGAAAGCAGTTGAGACA



AAACGCGGAGGAGGATGGGAAGGGCTGTTTCGAGATCTACCACGCCTGCGACGACTCCTGT



ATGGAGTCTATACGCAACAACACATACGACCACAGCCAGTATAGGGAGGAAGCCTTGCTGA



ATAGGCTGAATATCAATCCTGTAACGCTGTCGAGTGGGTACAAAGACATCATTTTATGGTT



CAGTTTTGGAGCCTCTTGTTTCGTTTTGCTGGCCGTCGTCATGGGACTATTTTTTTTTTGT



TTAAAGAACGGGAACATGAGATGCACTATTTGCATC





796
ATGTACAAGATTGTGTTGGTCCTAGCCCTCCTCGGCGCTGTGCATGGGCTGGATAAGATCT



GCCTTGGGCACCACGCCGTGCCTAATGGCACTATCGTGAAAACACTCACAAACGAAAAAGA



GGAAGTAACAAATGCCACCGAGACTGTGGAAAGCAAGAGCCTTGATAAACTCTGTATGAAA



AACAGAAATTATAAAGATTTAGGCAACTGTCATCCCATTGGTATGGTTGTGGGAACGCCCG



CTTGTGATCTGCATTTAACGGGTACATGGGATACCCTCATCGAGCGAGATAACTCAATCGC



CTACTGCTACCCGGGCGCCACTGTGTCAGAGGAAGCCTTGAGACAGAAGATTATGGAATCC



GGCGGTATTGACAAGATTTCTACCGGGTTTACGTATGGGTCTTCCATAAACTCCGCAGGCA



CCACAAAGGCATGCATGAGAAATGGTGGTAATTCTTTCTACTCAGAGCTTAAATGGCTGGT



GTCTAAGAACAAAGGCCAGAACTTTCCCCAGACGACCAACACATACCGTAACACGGACAGC



GTCGAGCACCTGATCATCTGGGGCATTCACCATCCTTCCTCAACTCAGGAGAAAAACGATC



TCTATGGTACCCAAAGCCTCTCTATTTCAGTCGGATCAAGCACATACCAGAACAACTTTGT



GCCCGTCGTTGGAGCCAGGCCACAGGTGAACGGCCAGAGTGGTCGAATTGATTTTCACTGG



ACAATGGTGCAACCTGGGGATAATATCACATTCAGCCATAATGGTGGTCTGATCGCCCCAA



ATAGAGTTTCAAAGCTTAAGGGCAGGGGTCTGGGGATTCAAAGCGGTGCTTCCGTCGATAA



TGACTGTGAGTCAAAATGCTTTTGGAAGGGGGGCAGCATCAATACAAAGCTACCGTTTCAG



AACCTCAGTCCCAGGACAGTTGGGCAGTGTCCTAAGTATGTGAATAAAAAATCCTTACTGT



TGGCCACTGGAATGAGAAACGTTCCAGAGGTAGCTCAGGGCCGTGGTCTCTTTGGGGCCAT



CGCCGGCTTTATTGAAAACGGGTGGGAAGGAATGGTTGATGGGTGGTATGGGTTCAGGCAT



CAGAACGCCCAGGGCACTGGACAAGCAGCTGACTATAAGAGCACACAGGCTGCTATTGACC



AGATTACTGGAAAACTGAATAGGTTGATAGAGAAGACCAACACTGAGTTCGAGTCTATCGA



GTCAGAGTTTTCAGAAATCGAGCATCAGATCGGTAACGTAATCAACTGGACCAAGGACTCA



ATAACCGACATCTGGACATATCAAGCCGAGTTGCTGGTAGCTATGGAGAATCAACATACTA



TCGACATGGCTGATTCCGAAATGCTCAACTTGTATGAGCGCGTGCGTAAGCAGTTGAGACA



GAATGCTGAGGAAGATGGCAAGGGCTGCTTCGAGATTTACCACAAGTGTGACGATAATTGT



ATGGAGAGCATTCGAAACAACACTTACGACCACACCCAATACCGCGAGGAAGCCCTGTTGA



ATCGGCTCAACATCAATCCCGTAAAGTTGTCCAGTGGTTATAAAGACGTCATCTTATGGTT



TAGTTTTGGAGCTTCTTGTTTTGTGCTCCTGGCAGTCATTATGGGACTGGTATTCTTCTGC



CTGAAAAATGGGAATATGAGATGCACTATCTGTATC





797
ATGTATAAAATTGTCGTGATTATTGCTCTGCTCGGTGCCGTTAAGGGACTCGATAAGATCT



GCTTAGGACATCACGCTGTAGTGAACGGCACAATCGTGAAAACACTCACGAACGAGCAGGA



AGAGGTCACAAACGCCACAGAAACTGTCGAGAGCACCGGTCTAAACCGACTGTGTATGAAA



GGAAGGAATCATAAGGACCTAGGCAATTGTCACCCAATCGGAATGCTTATCGGCACCCCTG



CATGCGATTTGCACCTGACAGGTACATGGGATACGCTGATCGAGCGCGAGAATGCCATCGC



CTATTGTTACCCCGGTGCAACCGTAAACGAGGAGGCCCTGAGGCAAAAGATAATGGAGTCA



GGCGGCATAAATAAGATTAGCACCGGTTTTACCTATGGGAGCAGTATAAATAGTGCCGGTA



CTACGCGCGCATGTATGCGCAATGGGGGCAACTCTTTTTACGCCGAACTCAAGTGGCTAGT



GTCAAAATCGAAGGGCCAGAACTTTCCACAGACCACTAACACTTATAGGAACACGGACACA



GCCGAACATTTAATAATGTGGGGTATCCATCACCCAAGTTCCACTCAGGAGAAAAACGATT



TATACGGAACTCAGTCGCTGTCAATCAGCGTAGGGAGCTCAACATACCAGAACAACTTTGT



TCCAGTGGTGGGCGCACGTCCCCAGGTGAACGGTCAAAGCGGCCGGATAGATTTTCACTGG



ACCCTGGTGCAGCCTGGAGATAATATTACTTTTAGTCACAACGGTGGCCTAATCGCACCCA



GTCGTGTATCGAAGCTTATCGGACGGGGCCTCGGGATACAGTCTGATGCTCCCATAGACAA



CAACTGTGAGTCTAAGTGCTTTTGGCGGGGGGGGTCTATTAACACCAGGCTCCCATTTCAG



AACCTCAGTCCTCGGACCGTGGGTCAGTGTCCGAAGTATGTTAATAAGCGTTCTCTCATGC



TCGCCACTGGAATGAGGAACGTGCCAGAGCTAATGCAGGGAAGAGGACTGTTCGGGGCCAT



AGCCGGCTTCATTGAAAATGGCTGGGAGGGTATGGTTGACGGATGGTACGGCTTCCGACAC



CAGAATGCTCAAGGCACAGGCCAGGCTGCAGATTATAAATCAACACAGGCTGCTATTGACC



AAATCACTGGCAAGCTCAATCGATTAATTGAAAAAACAAATACCGAGTTTGAAAGCATCGA



GAGTGAATTTTCCGAGATCGAACACCAAATCGGAAACGTGATCAACTGGACCAAGGACTCT



ATCACCGATATATGGACCTATCAGGCAGAACTTTTAGTTGCCATGGAGAACCAGCATACCA



TTGATATGGCCGACAGCGAAATGCTGAACTTGTATGAGCGGGTCCGGAAACAATTACGCCA



GAATGCCGAGGAAGACGGAAAAGGGTGCTTTGAGATCTATCATGCTTGCGACGACTCTTGT



ATGGAGTCAATCAGAAATAATACTTATGACCATAGTCAGTATAGGGAAGAGGCGCTGCTCA



ACAGACTAAATATCAACCCCGTTACGCTGAGCTCCGGTTATAAGGACATCATTCTTTGGTT



TTCCTTTGGCGCAAGCTGCTTTGTTCTGCTAGCTGTAGTGATGGGACTCGTCTTTTTCTGC



CTGAAGAACGGAAACATGCGCTGTACAATCTGTATT





798
ATGTATAAGATCGTTGTGATCATCGCCCTGCTGGGCGCCGTGAAAGGGCTGGACAAGATTT



GTCTGGGTCACCACGCCGTCGCCAACGGGACAATTGTTAAAACACTGACTAACGAGAAGGA



GGAGGTGACTAACGCAACCGAGACAGTTGAGTCCACAGGATTGAATCGGCTTTGTATGAAA



GGCCGGAAGCACAAAGACCTGGGAAACTGCCACCCTATAGGGATGCTGATCGGAAGTCCTG



CTTGTGATCTACACCTGACAGGTACTTGGGACACACTGATCGAGCGGGAGAATGCCATTGC



TTACTGCTACCCAGGAGCCACCGTGAATGGTGAAGCTCTGAGACAGAAGATTATGGAATCC



GGAGGCATTGATAAAATCTCTACAGGATTTACATACGAGTCCTCAATCAATTCAGCTGGCA



CAACTCGAGCATGTATGCGCAATGGCGGGAATAGTTTTTATGCCGAGCTCAAGTGGCTCGT



CTCTAAAAGCAAGGGGCAGAACTTTCCCCAGACCACGAACACCTATAGAAATACCGATACA



GCCGAGCATCTTATTATGTGGGGCATACATCATCCCTCCTCTACACAAGAGAAGAATGATC



TTTACGGAACGCAGTCCCTCTCGATCAGCGTGGGAAGCTCCACATATAGGAACAATTTTGT



TCCCGTGGTTGGCGCTCGTCCTCAGGTGAACGGACAGAGTGGCCGAATCGACTTTCACTGG



ACCCTTGTTCAGCCCGGCGACAACATAACGTTTTCGCATAATGGCGGCCTCATTGCACCTT



CCCGTGTCAGCAAACTGATTGGCCGCGGGCTGGGCATCCAATCTGACGCTCCCATCGATAA



CAACTGCGAATCAAAATGCTTCTGGAGGGGAGGGTCTATTAATACTCGGCTGCCATTCCAA



AACCTTTCCCCCCGGACAGTTGGCCAGTGTCCGAAATATGTGAACAAACGGAGTTTGATGC



TCGCTACCGGGATGCGGAACGTGCCTGAATTGATGCAGGGAAGAGGTCTTTTCGGCGCCAT



TGCCGGCTTCTTGGAAAATGGTTGGGAAGGGATGGTCGACGGATGGTATGGATTTCGGCAT



CAGAACGCTCAAGGCACTGGGCAGGCAGCTGATTATAAATCAACCCAGGCTGCCATTGACC



AGATAACTGGCAAACTCAACAGGCTGGTGGAGAAGACCAACACCGAATTCGAGAGTATTGA



GTCTGAATTCAGCGAGATCGAGCACCAGATAGGGAACGTTATTAACTGGACCAAGGATTCT



ATTACGGACATTTGGACATACCAAGCTGAGCTCTTAGTGGCCATGGAGAATCAGCATACCA



TTGACATGGCCGATTCTGAGATGCTTAATCTCTATGAGAGGGTGAGAAAGCAGCTGCGGCA



GAATGCCGAAGAAGATGGCAAGGGGTGCTTTGAGATTTACCACGCTTGCGATGATTCATGT



ATGGAATCTATTCGCAATAACACCTACGATCATTCTCAGTATCGGGAGGAAGCCCTGCTGA



ATCGCCTGAACATTAATCCCGTGACACTTTCAAGTGGTTACAAGGACATAATTCTATGGTT



CAGTTTTGGGGCTAGTTGTTTTGTGCTCCTAGCCGTTGTGATGGGTCTTGTCTTCTTTTGT



TTGAAGAACGGAAATATGCGGTGTACAATCTGTATA





799
ATGTACAAGATCGTGGTGATCATTGCGCTCCTGGGCGCCGTCAAGGGACTGGACAAGATCT



GCCTGGGCCATCACGCTGTGGCAAATGGGACAATCGTGAAAACGCTGACTAACGAGCAAGA



GGAGGTGACAAATGCGACGGAGACAGTGGAATCGACTGGGATTAACCGACTGTGTATGAAA



GGAAGAAAACATAAAGACCTCGGAAATTGCCATCCCATTGGGATGCTGATCGGAACTCCAG



CCTGTGACCTGCACCTGACAGGAATGTGGGATACCCTGATTGAGCGGGAGAATGCTATCGC



ATATTGTTACCCCGGGGCTACCGTAAACGTCGAAGCCCTTAGGCAGAAGATAATGGAAAGC



GGTGGCATCAATAAGATTTCGACAGGCTTCACTTATGGAAGTAGTATTAATAGCGCAGGAA



CCACTCGAGCCTGTATGAGAAACGGCGGTAACAGCTTTTATGCTGAGCTCAAGTGGCTTGT



CTCCAAGTCTAAGGGACAGAATTTCCCACAGACTACAAACACTTACAGGAATACCGATACA



GCTGAGCATCTAATTATGTGGGGAATACATCACCCTTCTTCCACCCAGGAAAAAAACGACC



TCTACGGCACTCAATCTCTCAGCATATCGGTGGGGAGTTCGACTTACCGAAACAACTTTGT



CCCGGTTGTCGGTGCCAGGCCCCAGGTGAACGGACAAAGCGGTCGGATCGATTTTCATTGG



ACTTTGGTCCAGCCTGGGGACAATATCACATTCTCACATAACGGCGGATTAATTGCCCCCT



CTCGCGTGTCAAAGCTCATAGGCCGGGGCCTGGGGATTCAGTCTGACGCTCCAATTGATAA



TAATTGCGAGTCAAAATGCTTCTGGCGCGGGGGGTCTATTAATACTCGATTGCCATTCCAG



AATCTCAGTCCCCGGACCGTGGGGCAGTGCCCAAAGTATGTGAACCGGCGGAGCCTGATGC



TGGCTACTGGAATGCGGAATGTGCCCGAACTTATTCAGGGCCGAGGTCTGTTCGGCGCCAT



CGCCGGGTTCCTGGAGAATGGGTGGGAGGGCATGGTCGATGGATGGTATGGATTTCGTCAC



CAGAACGCACAGGGCACAGGACAGGCTGCCGACTATAAGTCTACACAAGCGGCTATCGACC



AGATTACTGGTAAACTCAACCGGCTGGTGGAGAAGACCAACACTGAGTTCGAATCCATTGA



ATCTGAATTTTCGGAGATCGAACACCAGATTGGAAACGTGATCAACTGGACCAAGGACTCA



ATCACTGACATCTGGACTTACCAGGCCGAACTGCTTGTGGCTATGGAGAATCAGCATACTA



TCGATATGGCCGACTCCGAAATGCTCAACCTTTACGAGCGAGTGCGGAAACAATTGAGACA



AAACGCCGAAGAGGATGGGAAGGGCTGTTTTGAAATATACCACGCCTGCGATGATAGTTGT



ATGGAGTCAATCAGGAATAACACTTATGATCATAGTCAGTATAGAGAGGAAGCTCTTCTGA



ATCGACTGAACATCAACCCAGTAACACTTAGTAGTGGGTACAAAGACATCATCTTGTGGTT



CTCATTCGGAGCCTCTTGTTTTGTGCTGCTTGCCGTCGTAATGGGACTGTTTTTTTTTTGT



CTCAAGAACGGCAACATGAGGTGCACTATTTGCATT





800
ATGTACAAAATCGTGGTGATCATCGCACTGCTAGGGGCAGTGAAAGGCCTGGATAAAATCT



GCCTGGGACACCACGCAGTAGCCAACGGTACCATTGTGAAAACACTGACAAACGAACAGGA



GGAGGTCACAAATGCTACAGAGACCGTGGAGTCTACAGGTATTAATCGGCTGTGCATGAAG



GGAAGAAAGCACAAGGATCTGGGGAACTGCCACCCCATTGGAATGCTCATCGGGACACCTG



CATGCGATCTGCACCTCACTGGCATGTGGGACACATTGATCGAAAGAGAAAATGCCATTGC



ATATTGCTATCCTGGAGCAACGGTCAATGTGGAAGCACTGAGGCAAAAGATCATGGAGTCC



GGAGGCATCAACAAAATCTCAACCGGTTTCACATACGGAAGCAGTATTAACTCTGCCGGCA



CAACCCGTGCTTGCATGCGAAATGGAGGGAACTCTTTCTACGCGGAACTCAAATGGTTGGT



GTCTAAGTCGAAAGGACAGAACTTTCCGCAAACTACAAATACTTACAGGAATACTGACACT



GCAGAACATCTGATCATGTGGGGCATCCACCACCCCTCTTCAACACAGGAAAAGAATGACC



TGTACGGGACCCAGAGTCTGTCAATCTCCGTGGGCTCCTCAACTTATCGTAACAACTTTGT



CCCTGTTGTGGGAGCACGACCTCAAGTGAACGGACAGAGCGGGAGAATCGATTTTCACTGG



ACCCTCGTGCAGCCTGGAGATAACATCACATTTAGCCATAACGGAGGGTTGATCGCTCCGT



CCCGTGTGTCTAAACTTATCGGACGGGGCCTGGGTATCCAGAGTGATGCACCAATCGATAA



CAACTGTGAGAGCAAGTGTTTCTGGCGTGGTGGTTCTATAAACACACGACTGCCCTTCCAG



AACCTGTCGCCTAGAACCGTGGGACAGTGTCCTAAATACGTCAACCGAAGAAGCCTAATGC



TGGCCACAGGAATGCGCAACGTGCCCGAGCTAATTCAGGGCAGGGGCCTCTTCGGCGCAAT



CGCAGGCTTTCTGGAGAATGGGTGGGAGGGGATGGTGGATGGTTGGTACGGGTTCCGACAT



CAGAACGCCCAGGGGACGGGGCAGGCAGCCGACTACAAATCCACTCAGGCCGCAATAGACC



AGATTACCGGGAAACTGAATAGACTGGTGGAGAAAACAAATACTGAGTTCGAGAGTATTGA



ATCAGAGTTCTCCGAAATCGAGCATCAGATCGGCAACGTGATTAACTGGACTAAGGACTCT



ATCACAGATATATGGACATATCAGGCCGAGCTGCTGGTGGCCATGGAGAACCAGCACACCA



TCGACATGGCCGACTCAGAAATGTTAAACCTCTATGAGCGGGTTCGTAAGCAGTTACGCCA



AAACGCCGAAGAGGATGGCAAGGGGTGCTTCGAAATTTATCACGCTTGTGATGATTCCTGT



ATGGAGTCCATTCGGAACAACACCTACGACCACAGCCAGTACCGCGAGGAGGCCCTTCTGA



ATCGTCTGAACATAAACCCGGTCACCCTCAGTTCAGGATACAAGGACATAATTCTTTGGTT



CTCCTTTGGCGCCTCATGCTTCGTGCTCCTGGCCGTGGTGATGGGGCTCTTTTTCTTCTGC



TTGAAGAACGGGAACATGCGGTGTACTATCTGCATT





801
ATGTACAAAGTGGTGGTGATCATCGCCTTACTCGGGGCAGTGCGAGGGCTGGATAAGATTT



GCCTGGGTCACCACGCTGTGGCAAACGGGACAACAGTGAAAACTCTCACAAATGAACAGGA



GGAAGTCACCAACGCAACAGAGACCGTCGAAAGTACCTCACTCAATAAGTTGTGTATGAAA



GGTCGCCGGTACAAGGACCTCGGGAACTGCCACCCAATTGGAATGCTGATTGGTAGGCCCG



TGTGTGACCTGCACCTGACCGGGACGTGGGACACCCTGATCGAGCGCGAGAATGCAACTGC



TTACTGCTACCCCGGCGTGACCATTAACGAAGAAGCGCTGCGCCAGAAAATCATGGAATCA



GGGGGGATTAGCAAAATGAGGACAGGGTTCACATATGGTCCTAGCATCAATAGCGCCGGAA



CGACACGGAGCTGCATGCGCAACGGAGGCAACTCATTTTATGCCGAACTTAAGTGGCTGGT



GTCTGGGACAAAGGGGCAGAACTTCCCACAGACTACTAATACATATCGAAATACCGACACT



GCCGAGCACCTTATCATCTGGGGAATCCACCATCCTAGCTCAACTCAGGAAAAGAATGACC



TCTACGGTACTCAGTCTCTGTCCATTAGCGTGGGATCCAGCACCTACCAAAACAATTTTGT



TCCTGTTATCGGGGCAAGACCCCAAGTGAATGGCCAATCTGGGAGAATCGAATTCCACTGG



ACACTGGTCAGACCAGGCGACAACATAACTTTTTCACACAATGGAGGACTTATCGCCCCAG



ACAGGGTGTCAAAGCTGATCGGAAAGGGCATCGGAATTCAGAGTGGTGCGGTGATTGATAA



GGATTGTGAAAGCAAGTGCTTTTGGCGCGGGGGCTCCATTATCACCGAGCTCCCTTTTCAA



AACCTTAGCCCCCGGACAGTCGGCCAATGCCCAAAATATGTCAAAAAGCGCTCACTGCTCC



TTGCCACGGGGATGCGGAACGTGCCGGAAGTGGTGCAAGGTCGAGGCCTCTTTGGCGCGAT



CGCCGGATTCATCGAGAATGGTTGGGAAGGCATGGTGGACGGGTGGTACGGGTTTAGACAC



CAGAATGCGCAGGGCATTGGGCAGGCTGCTGACTACAAATCAACTCAGACTGCGATTGATC



AGATCACGGGAAAACTGAACCGTCTCATCGAAAAAACAAACACTGAGTTCGAATCCATCGA



GTCGGAATTTAGTGAAATCGAACACCAGATCGGCAACGTCATTAATTGGACGAAGGACTCT



ATTACAGATATCTGGACCTATCAGGCTGAGCTCTTGGTAGCAATGGAAAACCAACACACTA



TCGATATGGCCGATAGCGAGATGCTGAACCTGTATGAAAGGGTTAGAAAGCAGCTGAGACA



GAACGCTGAAGAAGACGGTAAGGGCTGCTTTGAGATCTATCATACATGCGACAATTCATGT



ATGGAGTCCATACGGAATAATACATATGACCATTCGCAGTACCGAGAGGAGGCCTTACTGA



ACAGACTGAACATCAATCCTGTTAAGCTGTCAAGCGGTTACAAGGACATAATTCTCTGGTT



CTCCTTTGGTGCCTCCTGTTTCGTACTTCTCGCCGTCATCATGGGGTTGGGCTTCTTTTGC



CTGAAAAATGGCAACATGAGATGCACTATATGCATT





802
ATGTATAAGATAGTGGTAATAATTGCCCTCTTGGGGGCAGTGAAAGGACTCGATAAGATAT



GCCTGGGACACCATGCCGTGGCTAACGGCACAATTGTGAAAACGCTAACAAACGAGCAGGA



GGAAGTTACCAACGCTACCGAAACCGTTGAGAGTACCGGCATTAATAGACTTTGTATGAAG



GGCCGAAAACACAAAGATCTCGGGAACTGTCATCCGATCGGCATGTTGATTGGAACACCTG



CATGTGATCTCCATTTAACAGGCATGTGGGATACATTGATTGAGCGGGAGAACGCTATAGC



CTATTGCTATCCCGGAGCCACAGTGAATGTTGAGGCGCTTCGTCAGAAAATCATGGAGAGC



GGAGGCATCAACAAGATCTCCACCGGGTTTACCTATGGCTCGTCTATAAACTCAGCTGGTA



CAACCAGGGCTTGCATGAGAAATGGGGGAAATTCCTTTTATGCAGAGCTGAAGTGGCTGGT



GTCAAAGAGCAAAGGACAGAATTTCCCGCAGACCACAAACACCTATCGTAATACCGACACC



GCCGAGCACCTTATTATGTGGGGCATACACCATCCAAGCTCAACCCAGGAGAAGAACGATC



TGTACGGCACGCAGAGTCTGAGCATCTCAGTCGGCTCTTCCACTTATAGGAACAACTTCGT



TCCAGTTGTCGGGGCGCGCCCTCAAGTCAACGGACAATCTGGCAGGATCGACTTCCACTGG



ACTCTTGTACAACCCGGCGATAACATCACCTTCTCCCATAACGGGGGTCTTATCGCCCCAT



CCCGGGTGAGCAAGCTCATTGGTCGCGGACTGGGGATTCAGAGCGATGCGCCTATTGACAA



TAACTGCGAGAGTAAATGCTTTTGGAGGGGCGGTAGCATCAACACCCGGTTGCCTTTCCAA



AACCTTTCCCCTAGAACAGTTGGCCAGTGTCCGAAGTATGTAAACAGGCGAAGTCTCATGC



TCGCGACAGGCATGCGGAATGTTCCCGAGCTGATTCAGGGCAGGGGACTGTTTGGAGCTAT



CGCGGGATTTCTGGAAAACGGTTGGGAAGGGATGGTGGACGGATGGTATGGATTCCGCCAC



CAGAATGCACAAGGAACGGGCCAGGCCGCCGACTACAAGTCCACTCAGGCCGCTATTGATC



AGATTACCGGCAAGCTCAATCGCCTGGTGGAGAAGACTAATACCGAGTTCGAGAGCATCGA



GTCCGAATTCTCGGAAATTGAGCATCAGATCGGCAATGTCATAAATTGGACCAAAGACTCA



ATCACAGATATATGGACTTATCAGGCTGAGTTGCTTGTGGCTATGGAAAACCAGCACACAA



TCGATATGGCTGATTCCGAGATGCTTAATCTGTATGAACGCGTAAGGAAGCAGTTACGGCA



AAATGCAGAAGAAGATGGCAAGGGCTGTTTTGAGATCTATCATGCCTGCGATGACAGTTGC



ATGGAGTCAATTAGGAATAATACGTATGATCACTCTCAGTATCGTGAGGAAGCTCTGCTGA



ACCGTCTGAACATCAATCCTGTGACCTTATCGTCCGGATATAAGGATATCATTCTATGGTT



CAGCTTTGGCGCTAGCTGCTTTGTCTTACTCGCTGTGGTCATGGGCCTGTTTTTTTTCTGC



TTAAAGAACGGGAACATGCGTTGTACAATCTGCATT





803
ATGTATAAAATCGTCGTTATAATCGCGTTATTGGGAGCAGTGAAGGGCTTAGACAAGATTT



GTCTGGGACATCATGCAGTGGTGAACGGAACCATCGTGAAGACACTAACAAATGAACAGGA



GGAAGTCACCAACGCAACCGAAACTGTGGAATCTACAGGTCTAAACAGGTTGTGTATGAAA



GGCAGGAATCATAAAGACCTCGGCAACTGCCATCCAATTGGTATGCTTATTGGAACGCCCG



CATGTGACCTGCATCTCACAGGTACATGGGACACACTCATTGAGCGCGAAAATGCTATCGC



CTACTGCTATCCTGGCGCTACCGTCAATGAGGAGGCACTGAGACAGAAGATCATGGAGAGC



GGCGGAATAAACAAAATTTCTACAGGCTTCACCTATGGGAGCAGCATCAATTCTGCCGGCA



CAACAAGGGCCTGTATGCGTAACGGGGGAAACTCCTTTTACGCCGAGCTGAAATGGTTGGT



GTCCAAGAGCAAGGGGCAGAACTTTCCCCAGACCACAAATACATATAGGAATACGGATACT



GCCGAGCACCTCATCATGTGGGGCATCCATCACCCAAGCTCCACCCAGGAGAAGAATGACC



TCTACGGGACCCAGTCCCTTAGCATTTCTGTGGGCAGTAGCACTTATCAAAATAACTTCGT



CCCCGTCGTAGGGGCGAGACCACAGGTTAACGGACAAAGCGGCAGAATTGACTTCCACTGG



ACACTCGTTCAGCCAGGTGATAATATTACTTTTAGCCATAATGGGGGACTGATAGCACCCA



GCAGAGTGAGTAAGTTGATAGGCAGGGGGCTTGGTATTCAGTCAGATGCGCCCATTGATAA



CAACTGTGAGAGTAAGTGCTTCTGGAGAGGGGGCTCCATTAATACCCGCTTGCCATTTCAA



AACCTGTCCCCCAGGACTGTAGGGCAGTGCCCTAAGTACGTGAACAAACGGTCCTTAATGC



TGGCCACTGGTATGCGCAATGTGCCAGAGCTCATGCAGGGCAGAGGGCTCTTTGGAGCCAT



AGCAGGGTTTATTGAAAATGGGTGGGAGGGCATGGTGGACGGATGGTACGGATTTAGACAC



CAAAACGCGCAGGGCACTGGACAGGCGGCCGACTATAAGTCCACCCAGGCCGCGATCGATC



AGATCACCGGAAAGTTGAACCGCTTAATAGAGAAGACAAACACCGAGTTCGAAAGCATAGA



GTCCGAATTTTCCGAAATCGAACACCAGATCGGCAACGTGATCAACTGGACGAAGGATTCG



ATTACCGACATTTGGACTTATCAGGCTGAACTACTCGTGGCTATGGAGAACCAACATACTA



TCGATATGGCAGATTCTGAAATGCTTAACCTCTATGAAGGGGTTAGGAAACAGCTGAGGCA



GAACGCAGAAGAAGACGGCAAGGGGTGCTTCGAAATTTATCATGCATGTGACGATAGTTGC



ATGGAAAGCATTAGAAACAACACCTATGACCATTCTCAGTATCGGGAGGAGGCACTCCTGA



ATCGTCTGAATATCAACCCAGTCACACTGAGTTCAGGGTATAAAGACATAATTCTCTGGTT



CTCATTCGGAGCCTCCTGTTTTGTGCTACTCGCAGTTGTGATGGGACTGGTCTTTTTTTGC



CTGAAAAATGGCAATATGAGATGTACAATTTGCATC





804
ATGTATAAAATTGTGGTCATAATTGCACTGCTCGGCGCAGTAAAGGGGCTCGATAAGATTT



GCCTGGGCCACCACGCCGTCGCTAACGGGACGATTGTCAAGACCCTGACTAACGAACAAGA



GGAGGTGACTAATGCTACCGAAACCGTCGAATCCACCGGCATTAACAGACTCTGTATGAAA



GGCAGAAAACATAAGGATCTGGGAAATTGCCACCCAATCGGAATGCTGATCGGGACACCCG



CCTGCGACCTGCACCTGACTGGGACTTGGGATACACTTATCGAAAGGGAGAATGCCATTGC



TTATTGTTACCCCGGCGCAACAGCGAATGTTGAAGCCCTGCGGCAAAAAATTATGGAATCC



GGTGGCATTGACAAGATCAGCACCGGGTTCACCTACGGCTCATCTATTAACAGTGCTGGGA



CCACCAGAGCTTGCATGCGGAACGGTGGCAACAGTTTCTACGCTGAACTCAAGTGGTTAGT



CTCAAAGTCTAAAGGACAGAACTTCCCCCAGACTACTAATACGTATAGGAACACTGATACT



GCTGAACATCTGATTATGTGGGGCATTCACCATCCAAGCTCAATTCAGGAGAAAAACGACC



TGTATGGCACCCAGTCGCTGTCTATCAGCGTGGGTTCCAGCACCTACCGGAACAATTTTGT



ACCGGTGGTTGGCGCGCGTCCTCAGGTCAATGGTCAATCTGGGCGGATTGACTTCCACTGG



ACTCTGGTTCAACCCGGCGACAACATAACTTTCTCTCACAATGGTGGATTGATCGCTCCTT



CCCGCGTTTCAAAACTGATAGGCCGCGGCTTAGGAATTCAGAGCGACGCCCCGATAGACAA



TAATTGCGAGTCCAAGTGCTTCTGGAGGGGAGGAAGCATTAACACGCGGTTGCCTTTCCAG



AACCTGTCCCCAAGGACAGTGGGACAATGCCCAAAATATGTCAATAGAAGAAGTCTCATGC



TGGCGACTGGTATGCGCAACGTGCCTGAGCTTATCCAGGGCCGCGGATTGTTCGGGGCAAT



CGCCGGCTTCCTGGAAAATGGGTGGGAAGGAATGGTGGATGGTTGGTACGGTTTTCGACAT



CAGAATGCCCAGGGTACTGGCCAGGCTGCAGACTATAAAAGCACTCAGGCTGCCATTGACC



AGATCACGGGTAAACTGAATAGGCTGGTGGAGAAGACGAACACAGAGTTCGAGTCTATTGA



ATCTGAGTTTTCTGAGATAGAGCACCAGATCGGAAACGTCATCAACTGGACCATGGATTCC



ATAACTGACATCTGGACTTACCAGGCGGAACTGCTGGTTGCAATGGAGAATCAGCACACTA



TTGACATGGCCGATTCCGAGATGCTCAATCTTTACGAGGGGGTCCGTAAACAGCTAAGGCA



GAATGCCGAGGAAGATGGGAAGGGTTGCTTCGAAATATATCATGCATGTGATGATTCTTGT



ATGGAGTCGATTCGTAATAACACCTACGATCACAGTCAATACAGAGAAGAAGCTCTTCTTA



ATCGGCTAAACATTAACCCAGTCACATTGAGCTCAGGATACAAGGACATCATCCTGTGGTT



CTCATTCGGGGCTTCCTGTTTTGTCCTGCTGGCCGTGGTCATGGGGCTGGTTTTTTTTTGC



CTGAAGAACGGCAATATGAGATGCACAATTTGCATC





805
ATGTATAAGGTGGTTGTGATTATTGCGCTGCTCGGGGCCGTTCGAGGCCTGGATAAAATCT



GTCTGGGCCATCACGCTGTCGCCAATGGCACGACTGTGAAAACTTTAACAAATGAGCAGGA



AGAGGTGACAAATGCCACTGAAACCGTCGAGAGTACATCACTGAATAAACTGTGCATGAAG



GGACGCCGCTATAAGGACCTGGGTAATTGCCATCCAATTGGTATGTTGATCGGGACCCCTG



TGTGCGACTTACACCTAACTGGCACTTGGGACACACTGATCGAGAGGGAGAATGCCACCGC



CTATTGTTACCCTGGTGTGACCATTAACGAAGAGGCTCTCAGACAAAAGATTATGGAGTCT



GGAGGAATCTCTAAGATGCGTACTGGGTTTACCTATGGGCCAAGCATCAACTCGGCTGGCA



CTACTCGCTCCTGTATGAGAAATGGAGGAAACTCCTTTTATGCTGAGTTGAAGTGGCTCGT



TTCCGGCACCAAGGGGCAAAACTTTCCACAGACGACCAATACTTATAGGAATACGGACACC



GCTGAACACCTGATTATTTGGGGAATCCATCACCCCAGCTCTACGCAGGAGAAGAACGACC



TTTACGGTACCCAGAGTCTTTCGATTAGCGTGGGCAGCAGCACATACCAGAATAATTTCGT



GCCCGTAATAGGTGCACGGCCTCAGGTGAATGGACAGTCGGGCCGGATAGAATTCCACTGG



ACGCTCGTTAGGCCCGGAGACAACATAACTTTTTCTCATAATGGCGGACTTATCGCTCCAG



ATCGGGTCAGCAAGCTTATAGGGAAGGGGATCGGCATCCAGTCCGGTGCTGTCATCGATAA



GGACTGTGAATCCAAGTGTTTCTGGCGTGGCGGTTCAATTATCACCGAACTACCTTTTCAA



AACTTGTCACCAAGAACCGTGGGACAGTGTCCAAAGTATGTCAAAAAAAGATCCTTGTTAC



TGGCTACCGGGATGAGGAATGTGCCTGAAGTCGTTCAGGGCCGCGGGCTGTTCGGAGCCAT



CGCGGGATTTATCGAAAACGGGTGGGAGGGGATGGTGGACGGTTGGTACGGATTCAGGCAT



CAGAATGCTCAGGGGATTGGGCAGGCTGCCGACTACAAGTCTACCCAGACGGCTATTGACC



AGATCACCGGCAAGTTGAATCGCCTGATAGAAAAAACTAATACGGAATTCGAAAGCATCGA



ATCCGAGTTCTCAGAAATCGAGCACCAGATAGGTAATGTAATCAATTGGACAAAGGACTCT



ATCACCGATATCTGGACCTATCAGGCAGAATTGCTGGTGGCAATGGAGAACCAGCACACAA



TCGATATGGCTGATTCAGAAATGCTGAATTTGTACGAGAGGGTCCGGAAGCAGCTCCGACA



GAACGCAGAAGAAGATGGGAAGGGTTGTTTCGAGATATATCATACCTGCGACAACTCGTGT



ATGGAATCAATACGCAATAATACATACGATCACAGTCAGTATCGTGAGGAGGCTCTCCTGA



ACAGGCTGAATATTAATCCTGTGAAACTGAGCTCCGGGTACAAGGATATTATTCTGTGGTT



CAGTTTTGGCGCTTCATGTTTCGTGTTGCTGGCAGTTATTATGGGGCTTGGTTTCTTCTGC



CTGAAGAATGGGAACATGCGCTGCACGATTTGCATA





806
ATGTATAAGGTGGTCGTAATCATCGCCCTTCTGGGTGCTGTCCGGGGCTTGGACAAAATTT



GTCTCGGGCATCACGCAGTGGCTAACGGCACAATAGTGAAGACCCTCACTAACGAACAGGA



GGAAGTGACAAACGCGACAGAAACAGTTGAGAGTAAATCCCTCGGCAAGCTGTGCATGAAA



GGGAGGAGTTATAATGACCTCGGCAATTGTCATCCGATAGGTATTCTGATCGGCACTCCTG



CGTGCGACCTGCACCTGACCGGGACCTGGGATACCCTCATCGAGAGGGAGAACGCCGTGGC



CTACTGCTACCCAGGCGCCACAGTAAATGAGGAAGCGCTGCGGCAGAAAATTATGGAATCT



GGAGGAATTAGCAAGATTTCTACTGGCTTCACCTATGGGACAAGCATCAACAGCGCCGGTA



CCACGAAGGCCTGTATGAGAAACGGTGGGAATTCTTTTTACGCAGAGCTCAAATGGCTGGT



GAGCAAAAACAAGGGGCAAAATTTCCCCCAGACCACAAACACATATAGGAATACAGACACA



GCTGAGCATTTAATTATTTGGGGCATCCATCACCCCTCCAGCACACAAGAAAAGAATGACC



TGTACGGTACCCAGTCTCTCTCTATTAGCGTTGGCTCTTCTACATACCAGAATAACTTTGT



TCCAGTCGTCGGAGCACGGCCACAGGTTAACGGGCAGAGTGGACGTATCGATTTCCACTGG



ACTCTTCTACAGCCTGGCGACAATATTACTTTTAGTCACAACGGCGGCCTTATAGCCCCGT



CCAGAGTCTCCAAGCTGATCGGCAGAGGGCTGGGCATTCAGTCCGAGGCTCCAATTGATAA



TGGCTGCGAAAGCAAATGCTTTTGGAAAGGCGGGAGTATCAACACAAAACTGCCCTTTCAG



AATCTGAGCCCTCGAACTGTGGGTCAGTGCCCAAAATACGTTAATAAGCGGAGTCTGATGT



TAGCTACTGGCATGCGGAACGTTCCAGAAATCATGCACGGCCGCGGACTCTTTGGAGCTAT



CGCCGGGTTTATAGAAAATGGCTGGGAAGGCATGGTTGACGGCTGGTACGGATTCAGGCAC



CAAAACGCCCAGGGAACCGGACAGGCCGCCGATTACAAAAGCACGCAAGCAGCTATTGATC



AGATCACTGGAAAACTCAATCGACTGATCGAAAAGACTAACACAGAATTTGAATCCATTGA



GTCCGAATTTAGTGAGATCGAGCACCAAATCGGCAACATCATTAACTGGACGAAGGACAGC



ATAACAGACATATGGACATATCAGGCAGAGCTCCTGGTCGCAATGGAAAACCAGCATACCA



TAGATATGGCTGATTCTGAGATGCTCAATCTGTATGAACGAGTCAGAAAGCAATTAAGACA



AAACGCTGAGGAGGATGGTAAGGGATGCTTCGAGATTTACCATGCTTGCGACGATTCCTGC



ATGGAAAGCATCCGTAATAACACCTACGACCACAGCCAATACCGTGAAGAAGCCCTCCTAA



ATCGATTGAACATTAATCCTGTGAAATTGAGTTCCGGCTACAAGGACATCATCCTGTGGTT



CTCATTTGGCGCATCATGCTTGATTCTTTTGGCCGTGGTGATGGGCCTGGTTTTCTTCTGT



CTGAAAAATGGCAACATGAGATGTACTATCTGCATT





807
ATGTACAAGATCGTGGTTATAATTGCCCTCCTGGGCGCCGTTAAGGGCCTTGATAAGATAT



GTCTGGGGCACCATGCCGTGGCTAATGGGACCATAGTGAAAACCCTGACTAATGAGCAGGA



GGAGGTCACTAACGCCACCGAGACTGTGGAATCCACCGGCATCAACAGGCTGTGTATGAAG



GGGCGCAAACACAAGGACCTAGGGAATTGCCACCCCATCGGTATGCTTATCGGCACGCCAG



CCTGTGACCTTCACCTGACTGGGATGTGGGACACTCTGATTGAAAGAGAAAACGCTATAGC



GTACTGCTACCCCGGCGCAACTGTGAACGTAGAAGCGTTGCGGCAGAAGATCATGGAGTCT



GGGGGAATCAATAAGATCTCAACAGGGTTTACATACGGCTCATCTATCAATTCCGCGGGCA



CGACCAGGGCGTGCATGAGGAACGGCGGGAACTCTTTTTACGCCGAGCTTAAATGGTTAGT



ATCTAAGAGCAAGGGGCAGAACTTTCCACAAACGACCAACACATACCGCAACACCGATACC



GCAGAACACCTCATCATGTGGGGAATCCACCATCCCAGTTCCACTCAAGAAAAAAACGATC



TATACGGCACTCAGTCCCTCTCAATCTCCGTGGGAAGTAGCACATATCGGAACAACTTCGT



GCCCGTGGTTGGGGCCCGCCCCCAGGTCAATGGCCAGTCAGGAAGAATTGACTTCCATTGG



ACACTTGTGCAGCCAGGCGACAATATCACATTTTCCCACAACGGCGGATTGATCGCCCCCT



CCAGAGTTAGCAAGCTGATCGGGAGAGGCCTGGGTATCCAGAGTGACGCGCCAATCGATAA



CAACTGCGAGAGCAAGTGCTTTTGGCGCGGAGGCTCAATTAACACACGGCTACCTTTCCAA



AACCTCAGTCCGCGTACAGTTGGCCAGTGCCCCAAGTATGTGAACCGGAGATCTTTGATGC



TCGCTACCGGCATGCGAAATGTCCCGGAGCTGATTCAAGGCCGCGGGCTCTTTGGAGCGAT



TGCGGGGTTTCTGGAGAACGGATGGGAAGGAATGGTGGATGGTTGGTACGGATTTCGGCAT



CAAAATGCACAGGGGACTGGCCAAGCCGCAGACTATAAGAGCACCCAGGCTGCGATCGACC



AGATCACCGGAAAGCTCAACCGCCTGGTGGAGAAGACCAATACGGAATTTGAATCAATCGA



AAGCGAGTTTAGTGAAATAGAACACCAGATTGGTAATGTGATTAATTGGACAAAAGACAGC



ATTACTGATATTTGGACATATCAGGCTGAGTTACTGGTAGCTATGGAGAATCAGCACACCA



TTGATATGGCCGACTCCGAAATGCTGAATCTGTACGAACGGGTTCGGAAACAGCTCAGGCA



GAACGCCGAAGAAGACGGTAAGGGATGCTTCGAAATCTACCACGCCTGCGATGATAGTTGC



ATGGAGTCTATACGGAACAACACCTATGACCATTCTCAGTATAGAGAAGAGGCCCTACTGA



ACCGTTTGAACATTAATCCAGTGACCCTGTCCTCCGGTTACAAGGACATAATCCTGTGGTT



CTCGTTTGGTGCTAGCTGCTTTGTGCTGCTGGCGGTGGTAATGGGACTGTTTTTCTTTTGC



CTGAAAAATGGCAATATGAGATGCACCATTTGCATC





808
ATGTACAAGATTGTGGTGATTATAGCCCTTCTGGGGGCTGTCAAGGGACTGGACAAAATCT



GCCTGGGACATCATGCTGTGGCAAACGGAACTATTGTGAAGACTTTGACTAACGAACAGGA



GGAGGTGACCAACGCCACCGAAACCGTGGAATCCACAGGCATCAACCGGCTCTGCATGAAA



GGAAGAAAGCACAAGGACCTGGGCAATTGTCATCCAATCGGAATGCTTATCGGGACTCCGG



CCTGTGATTTGCATCTGACCGGCATGTGGGATACGTTAATCGAACGAGAGAACGCCATTGC



CTATTGCTACCCTGGCGCGACCGTGAATGTCGAGGCCTTGAGGCAGAAGATCATGGAGAGC



GGCGGAATCAACAAAATAAGCACTGGTTTCACCTACGGTAGTAGCATAAATTCCGCTGGGA



CCACGCGGGCCTGCATGCGGAACGGCGGCAATTCCTTTTACGCAGAGCTTAAATGGTTAGT



GAGCAAAAGCAAGGGACAGAATTTCCCCCAGACCACAAACACATATCGTAACACCGACACC



GCGGAACATCTGATTATGTGGGGCATACATCACCCCTCTTCCACGCAAGAAAAGAATGACC



TGTACGGAACACAATCCTTATCCATTAGCGTAGGAAGCAGCACTTATCGGAACAACTTTGT



GCCCGTGGTGGGAGCTCGGCCTCAGGTAAACGGCCAGTCCGGTCGGATAGATTTCCATTGG



ACTTTGGTTCAGCCGGGGGATAACATTACATTTTCCCATAACGGCGGCCTCATTGCTCCCT



CGCGGGTCTCTAAACTTATTGGGGGGGGCCTGGGGATCCAGTCAGATGCCCCTATCGATAA



TAATTGCGAATCCAAATGTTTTTGGAGAGGAGGCAGTATTAACACCCGGCTGCCTTTCCAG



AATCTCAGCCCCCGTACAGTCGGACAGTGTCCCAAATATGTGAATAGACGCTCGCTAATGC



TGGCCACCGGCATGCGGAACGTTCCTGAGCTGATCCAGGGACGGGGGCTCTTTGGTGCAAT



TGCTGGATTTCTGGAAAATGGCTGGGAAGGCATGGTGGATGGCTGGTACGGCTTTAGGCAC



CAGAATGCCCAAGGCACGGGGCAGGCAGCCGACTACAAATCCACACAAGCCGCCATTGACC



AAATCACCGGGAAATTAAATAGGCTTGTGGAGAAAACCAATACCGAATTCGAAAGCATCGA



GAGCGAATTTTCAGAGATCGAGCACCAGATCGGGAATGTGATAAATTGGACCAAAGATTCC



ATTACCGATATTTGGACTTACCAAGCTGAGCTGCTCGTGGCCATGGAAAACCAGCACACAA



TCGATATGGCCGACTCTGAAATGTTGAACTTGTATGAAAGAGTGCGAAAACAGTTGCGTCA



AAACGCCGAGGAAGACGGGAAAGGTTGTTTCGAAATCTATCACGCGTGCGATGACAGCTGT



ATGGAAAGTATTAGGAACAATACATATGACCACTCACAGTATCGCGAGGAGGCACTGTTGA



ATCGCCTAAACATCAACCCCGTTACATTGTCTTCTGGTTACAAAGACATTATCTTATGGTT



TTCGTTTGGAGCCTCGTGTTTCGTGCTCCTAGCGGTAGTGATGGGGCTCTTCTTCTTCTGT



CTGAAGAACGGGAACATGCGCTGCACTATCTGTATC





809
ATGTACAAGATCGTAGTCATCATCGCCCTGCTGGGGGCCGTCAAAGGACTGGACAAGATTT



GCCTGGGCCATCATGCAGTCGCAAATGGCACTATCGTGAAGACTCTGACAAACGAACAGGA



AGAGGTGACAAATGCCACTGAAACAGTCGAGTCTACTGGGATCAACAGACTTTGCATGAAG



GGCCGCAAGCACAAGGACCTGGGTAATTGCCACCCCATTGGAATGCTTATTGGCACACCCG



CTTGCGACETACACCTAACCGGTATGTGGGATACTCTGATCGAAAGGGAAAACGCCATTGC



ATACTGCTACCCCGGCGCTACAGTGAACGTCGAGGCTCTGCGCCAGAAAATTATGGAGTCT



GGTGGAATCAATAAGATCTCAACTGGCTTCACCTATGGGAGTTCCATCAACAGCGCTGGGA



CTACGCGTGCGTGCATGCGTAACGGCGGAAACAGCTTTTACGCAGAGCTGAAATGGCTCGT



CAGCAAGTCCAAGGGTCAGAATTTCCCACAGACTACGAATACCTACCGAAATACTGACACT



GCGGAGCATCTCATCATGTGGGGAATCCACCATCCAAGCAGCACCCAGGAAAAGAACGATC



TGTACGGCACTCAGTCCCTAAGCATCTCCGTCGGCAGCAGTACTTATCGCAATAACTTTGT



CCCCGTGGTAGGAGCCCGTCCTCAGGTGAACGGACAGAGCGGACGTATCGACTTTCATTGG



ACACTCGTGCAACCCGGGGACAATATAACGTTCAGCCATAACGGAGGTTTAATAGCGCCTA



GCCGTGTGTCCAAACTCATCGGCCGTGGCCTGGGGATCCAATCCGATGCACCAATCGACAA



TAACTGCGAGTCTAAGTGCTTCTGGCGGGGAGGCTCAATTAATACCCGCCTACCCTTCCAG



AATCTGTCACCCAGGACCGTGGGCCAGTGTCCTAAGTACGTCAACAGGCGATCTCTCATGT



TGGCCACTGGCATGCGAAACGTGCCTGAGCTGATCCAAGGTAGAGGGCTGTTCGGAGCAAT



CGCCGGATTCCTGGAGAACGGCTGGGAGGGAATGGTGGACGGATGGTATGGTTTCAGGCAC



CAAAACGCTCAAGGAACTGGCCAGGCAGCTGACTATAAGTCCACTCAGGCTGCAATCGATC



AAATCACCGGCAAGCTGAACAGGCTCGTTGAGAAAACGAACACGGAATTTGAGTCCATCGA



ATCTGAATTTTCCGAGATCGAACATCAGATAGGCAACGTTATCAACTGGACGAAGGACTCT



ATCACTGACATTTGGACGTATCAGGCGGAGCTCTTAGTGGCCATGGAAAACCAGCACACTA



TCGACATGGCCGACAGTGAAATGCTGAACCTCTACGAAAGAGTTCGCAAGCAGCTCCGGCA



GAATGCAGAAGAGGATGGAAAAGGCTGTTTTGAAATCTACCACGCATGTGACGACTCATGC



ATGGAGTCTATACGAAATAATACTTACGACCATTCGCAATATCGCGAGGAGGCTCTGCTAA



ATAGGTTGAACATCAATCCCGTCACACTGTCCAGTGGCTACAAGGATATCATTCTGTGGTT



CTCATTTGGAGCCTCCTGCTTCGTTCTGCTGGCCGTGGTTATGGGATTATTCTTCTTTTGC



CTCAAGAACGGAAATATGCGCTGCACAATCTGCATC





810
ATGTACAAGATTGTGGTGATTATCGCATTGCTGGGCGCCGTGAAGGGGCTGGATAAAATAT



GTCTGGGGCACCATGCCGTAGCAAACGGTACGATAGTTAAGACTCTTACCAACGAACAGGA



AGAGGTGACGAACGCGACAGAGACCGTTGAGAGTACAGGTATTAATCGACTCTGTATGAAG



GGCCGCAAGCACAAGGACCTGGGCAATTGCCACCCCATCGGGATGCTGATCGGCACTCCTG



CGTGTGATCTGCACTTGACCGGCACTTGGGACACTTTGATTGAGAGAGAAAACGCGATTGC



TTATTGCTACCCTGGAGCAACCGCCAATGTTGAAGCCCTGAGGCAGAAGATTATGGAGTCG



GGAGGTATTGATAAGATCTCCACTGGATTCACTTACGGCTCATCTATAAATAGCGCCGGGA



CTACCCGCGCTTGCATGAGGAACGGGGGGAACAGCTTCTATGCCGAGCTCAAATGGCTTGT



GTCTAAGTCGAAAGGTCAAAACTTCCCACAGACAACTAACACATACCGCAACACCGACACT



GCAGAGCACTTGATTATGTGGGGCATCCATCATCCGTCTAGCATCCAGGAGAAGAATGATC



TCTATGGGACCCAGAGCCTCAGCATTTCAGTCGGAAGTTCCACCTACAGGAATAATTTCGT



GCCTGTGGTGGGCGCACGGCCTCAAGTGAACGGCCAGTCCGGAAGAATAGACTTTCACTGG



ACTCTGGTGCAGCCGGGGGATAACATTACATTCTCGCACAACGGTGGGCTTATAGCCCCCA



GCAGAGTAAGTAAACTTATCGGTCGGGGTTTGGGCATTCAGTCGGATGCCCCTATCGATAA



TAATTGTGAATCTAAATGTTTTTGGAGGGGGGGGAGCATCAACACCAGGCTGCCTTTCCAG



AATCTGTCCCCCCGAACTGTGGGACAGTGCCCCAAGTATGTTAACAGACGGTCCCTTATGC



TGGCCACTGGCATGCGCAACGTCCCCGAACTCATTCAGGGGCGCGGTCTGTTTGGTGCAAT



TGCCGGGTTTCTGGAGAACGGCTGGGAAGGGATGGTAGACGGTTGGTATGGCTTCCGGCAC



CAAAACGCCCAGGGAACTGGCCAAGCTGCCGACTACAAATCTACCCAGGCTGCCATAGATC



AGATCACTGGCAAACTCAATCGCCTGGTGGAAAAAACCAACACAGAGTTTGAGAGCATCGA



GTCCGAATTCTCCGAAATCGAACACCAGATCGGTAATGTGATTAACTGGACCATGGATAGT



ATCACCGACATATGGACATATCAGGCTGAACTCCTGGTGGCCATGGAGAACCAACATACTA



TTGATATGGCCGACTCAGAAATGTTAAATCTGTATGAGCGTGTGAGAAAACAGCTCAGGCA



GAACGCTGAGGAAGACGGAAAGGGCTGCTTCGAAATCTACCACGCATGCGATGACTCTTGC



ATGGAATCAATCCGGAACAACACATATGACCACAGCCAGTACCGGGAGGAGGCCCTTTTGA



ATAGGCTGAATATCAATCCCGTCACGCTTTCTTCCGGTTACAAAGATATAATTCTGTGGTT



CTCATTCGGGGCAAGCTGCTTTGTGCTTCTCGCTGTCGTGATGGGCCTCGTTTTCTTTTGC



TTGAAGAATGGAAATATGCGGTGCACGATCTGTATC





811
ATGTACAAGATCATCGTTATAATCGCACTCCTGGGCGCCGTCAAAGGCCTGGACAAGATTT



GCCTAGGGCATCACGCCGTAGCCAATGGAACCATTGTCAAGACCCTGACCAACGAGCAGGA



AGAGGTGACAAACGCCACAGAGACAGTAGAGTCCACCGGAATCAATCGCTTGTGCATGAAA



GGACGGAAGCATAAAGACTTAGGAAATTGTCATCCAATCGGCATGCTGATTGGGACACCCG



CCTGTGACTTGCATTTGACAGGGACCTGGGACACCCTTATCGAGCGTGAGAATGCCATCGC



GTACTGCTACCCCGGGGCTACGGTGAACGTCGAGGCTTTAAGACAGAAGATCATGGAGTCC



GGCGGAATCGATAAGATTTCTACCGGTTTCACTTACGGGAGTTCTATCAACTCTGCAGGAA



CCACTCGGGCCTGCATGAGGAATGGAGGCAACTCATTCTACGCAGAATTGAAATGGCTGGT



AAGCAAGAGCAAGGGCCAAAATTTCCCCCAGACCACGAATACCTATAGGAATACTGACACT



GCGGAGCATCTGATTATGTGGGGCATCCACCACCCGAGCTCAACTCAAGAGAAAAATGATC



TTTACGGAACCCAGAGCCTGTCAATTTCCGTGGGGAGCAGTACTTATCGCAATAATTTCGT



ACCTGTCGTAGGTGCCAGACCGCAGGTCAATGGACAGAGCGGCCGTATCGACTTCCACTGG



ACACTGGTGCAGCCAGGGGATAACATCACTTTTTCCCACAACGGCGGCCTGATCGCTCCCA



GCAGGGTGTCGAAGCTGATCGGTCGGGGGCTGGGGATACAGTCAGACGCACCCATTGATAA



CAATTGCGAGAGCAAATGTTTCTGGCGTGGTGGAAGCATAAACACAAGACTTCCGTTTCAG



AACCTTAGTCCACGCACTGTCGGCCAGTGCCCAAAATACGTAAACCGACGTTCCCTGATGC



TCGCTACGGGGATGCGAAACGTACCAGAGTTAATCCAGGGCCGCGGGCTGTTCGGAGCTAT



TGCCGGCTTCCTCGAAAACGGGTGGGAAGGCATGGTAGACGGGTGGTACGGGTTTAGGCAT



CAAAACGCCCAGGGCACAGGCCAGGCGGCCGACTATAAAAGCACCCAGGCTGCAATTGACC



AGATTACCGGGAAACTGAACAGACTTGTAGAAAAAACCAATACAGAATTTGAGTCTATCGA



ATCAGAGTTCTCTGAGATAGAGCATCAGATCGGTAACGTGATCAATTGGACTAAAGATTCA



ATAACTGACATATGGACTTACCAGGCCGAACTTCTGGTGGCTATGGAAAACCAGCATACAA



TTGACATGGCCGACTCCGAGATGTTGAACCTTTACGAGCGCGTGCGTAAACAGCTGAGGCA



AAATGCTGAAGAAGACGGAAAAGGCTGCTTCGAGATATATCACGCTTGTGACGATTCATGT



ATGGAATCCATACGGAATAATACTTACGACCATTCGCAATATAGGGAGGAGGCCTTGTTGA



ACCGGCTGAATATCAATCCAGTGACCCTTAGCTCCGGCTATAAAGATATTATTTTGTGGTT



CTCTTTTGGAGCTTCCTGCTTTGTCCTATTAGCTGTGGTCATGGGCCTCTTTTTTTTCTGC



CTTAAAAATGGGAATATGCGGTGCACTATCTGTATC





812
ATGTATAAGATCGTGGTGATAATCGCCCTGCTGGGGGCTGTTAAAGGTCTCGACAAAATCT



GCTTAGGGCATCACGCCGTGGCCAATGGCACCATAGTTAAGACCCTGACCAATGAACAGGA



AGAGGTTACCAACGCAACGGAGACCGTCGAATCTACCGGCATCAACCGATTATGCATGAAG



GGTCGCAAGCACAAAGATCTCGGAAACTGCCACCCCATTGGCATGCTCATCGGGACCCCTG



CTTGCGACCTGCATTTAACAGGTATGTGGGACACGCTGATTGAAAGAGAGAACGCGATCGC



CTACTGTTACCCAGGCGCTACAGTGAACGTGGAGGCTCTGCGACAGAAAATTATGGAGTCG



GGCGGCATCAATAAAATCAGCACGGGTTTCACTTATGGCAGTTCAATCAACTCCGCCGGTA



CTACCAGGGCCTGTATGCGGAATGGGGGCAACTCTTTTTATGCCGAGCTGAAGTGGCTGGT



CTCCAAGAGTAAGGGCCAGAATTTCCCACAGACCACAAACACTTACAGGAACACGGACACC



GCCGAGCATCTGATTATGTGGGGCATTCACCACCCATCTAGTACCCAGGAGAAGAACGACT



TGTACGGCACACAGTCTCTGTCAATTAGTGTTGGGTCTTCCACATATCGTAATAATTTTGT



ACCGGTCGTGGGCGCGGGGCCCCAAGTGAACGGTCAAAGCGGTAGGATTGATTTTCATTGG



ACCCTCGTGCAACCAGGAGATAATATCACTTTTTCGCACAATGGCGGTCTCATAGCCCCGA



GCCGGGTCAGCAAGCTAATCGGACGGGGGCTCGGGATCCAGTCCGATGCTCCCATCGATAA



TAACTGTGAATCTAAGTGTTTTTGGCGGGGCGGATCCATAAACACCAGGCTTCCCTTCCAG



AACTTGTCCCCAAGGACGGTAGGCCAATGCCCAAAGTACGTTAACCGCCGCTCACTCATGT



TGGCCACTGGGATGAGAAACGTCCCGGAACTGATTCAGGGCCGGGGCCTGTTTGGCGCAAT



CGCTGGGTTCTTAGAGAACGGCTGGGAGGGCATGGTGGACGGATGGTACGGGTTCCGCCAT



CAGAACGCTCAAGGCACTGGGCAGGCTGCAGATTACAAGAGTACCCAGGCTGCCATTGATC



AGATTACCGGAAAACTGAATAGGCTGGTCGAAAAGACAAACACTGAGTTCGAAAGCATCGA



GAGCGAATTTTCTGAGATCGAGCACCAGATCGGGAATGTGATTAACTGGACTAAAGATAGC



ATAACGGATATTTGGACATATCAAGCAGAGTTGTTGGTGGCCATGGAGAATCAGCATACAA



TCGACATGGCCGATAGTGAAATGCTGAATCTTTATGAAAGGGTACGGAAGCAGCTGCGCCA



AAACGCCGAGGAAGATGGGAAGGGGTGTTTTGAAATCTATCATGCCTGTGACGATTCCTGC



ATGGAATCTATTCGTAATAATACTTACGACCATAGCCAATATCGAGAGGAGGCATTGTTGA



ACAGGCTAAACATCAATCCGGTGACACTCAGTTCCGGATATAAAGATATAATCCTCTGGTT



CTCTTTTGGCGCTTCTTGTTTCGTGCTGCTTGCTGTCGTAATGGGACTGTTCTTTTTTTGT



CTCAAAAACGGCAACATGAGATGCACCATTTGCATA





813
ATGTATAAAATCGTTGTGATCATTGCCCTGCTGGGCGCCGTAAAGGGCCTGGACAAAATAT



GCCTGGGGCACCATGCAGTAGTGAATGGCACAATTGTCAAGACACTCACTAACGAACAGGA



AGAAGTCACCAATGCCACGGAGACGGTGGAGAGTACCGGTCTGAACCGTCTGTGCATGAAG



GGCCGCAACCATAAAGACTTGGGTAACTGTCATCCTATAGGTATGCTAATCGGTACTCCGG



CCTGCGATCTGCACCTCACCGGTACCTGGGACACCCTGATCGAGCGTGAGAACGCGATCGC



CTATTGCTATCCAGGCGCTACTGTAAATGAGGAAGCCCTGAGACAGAAGATCATGGAGTCC



GGAGGGATCAATAAGATCTCTACTGGATTCACCTATGGCAGCAGTATTAACTCCGCCGGAA



CTACGCGGGCCTGCATGAGAAATGGCGGGAATAGCTTCTACGCTGAACTGAAATGGCTCGT



TTCGAAGTCAAAAGGACAGAACTTCCCTCAGACAACGAACACATACCGCAACACCGACACC



GCGGAGCATCTAATCATGTGGGGTATCCATCACCCCAGCTCTACACAGGAAAAAAATGATC



TTTATGGAACCCAGTCTTTGTCCATTTCTGTGGGCAGCTCCACCTACCAGAACAATTTCGT



CCCAGTCGTGGGCGCGCGGCCACAGGTGAACGGACAGTCGGGGCGCATTGACTTTCACTGG



ACCCTGGTGCAGCCCGGTGACAATATCACTTTTTCTCACAACGGCGGACTTATTGCTCCCT



CCCGGGTGAGCAAACTGATCGGGGGGGGGCTGGGGATCCAGTCCGATGCACCTATCGATAA



CAATTGCGAGAGTAAATGCTTCTGGCGTGGGGGATCAATAAATACCAGGCTCCCATTCCAA



AATCTTTCACCCCGTACAGTTGGACAGTGCCCCAAATACGTGAACAAGCGCTCTCTTATGC



TGGCAACAGGAATGAGAAACGTTCCAGAGCTAATGCAGGGTCGAGGGCTTTTCGGAGCTAT



TGCTGGATTTATCGAAAATGGCTGGGAGGGAATGGTCGATGGATGGTATGGATTCCGACAC



CAGAACGCTCAGGGGACCGGCCAGGCCGCGGACTACAAGAGCACACAGGCTGCAATTGATC



AGATCACAGGGAAGTTAAATAGGCTCATCGAAAAGACGAACACCGAGTTCGAGTCAATCGA



GTCCGAATTCTCTGAGATCGAACACCAAATTGGCAATGTCATCAATTGGACAAAGGATAGT



ATCACCGATATTTGGACGTACCAAGCAGAGCTTCTGGTTGCCATGGAGAACCAACACACCA



TCGATATGGCCGACAGCGAGATGCTTAATCTGTACGAGCGCGTGCGAAAGCAACTTAGGCA



AAACGCCGAAGAAGATGGTAAGGGCTGCTTTGAGATTTATCACGCTTGCGATGACTCCTGC



ATGGAGTCTATTAGAAATAATACCTACGATCATTCTCAGTATAGAGAGGAGGCCCTGCTGA



ACCGGTTGAACATTAACCCAGTTACACTGAGCTCCGGATACAAAGATATTATTCTGTGGTT



TTCCTTTGGCGCGTCCTGCTTTGTGCTGTTAGCCGTGGTGATGGGGCTGGTATTCTTCTGT



CTCAAGAACGGTAATATGCGTTGTACCATATGCATC





814
ATGTATAAGATCGTGGTCATAATTGCACTCTTGGGGGCAGTGAAAGGGCTGGATAAAATTT



GTCTGGGACACCACGCCGTTGCTAATGGCACCATCGTGAAAACCCTTACCAACGAGCAGGA



AGAGGTTACTAACGCAACCGAGACGGTCGAGTCCACTGGAATCAATCGTCTTTGCATGAAG



GGCCGTAAACATAAGGATTTAGGAAATTGTCATCCCATTGGCATGCTGATCGGAACACCTG



CCTGCGACCTGCACCTGACAGGGATGTGGGACACGCTGATCGAGAGGGAGAATGCAATTGC



GTACTGTTATCCTGGAGCTACCGTGAATGTTGAAGCACTGCGTCAAAAAATCATGGAATCC



GGCGGGATCAACAAAATTAGCACTGGGTTCACATATGGAAGCAGCATAAACTCCGCCGGCA



CTACAAGGGCCTGCATGAGAAACGGCGGCAATAGTTTCTACGCTGAACTTAAGTGGCTTGT



GTCAAAATCAAAGGGGCAAAACTTTCCTCAGACTACAAATACATATAGAAACACTGACACC



GCCGAGCACCTGATCATGTGGGGCATTCACCATCCTAGCTCTACCCAGGAGAAAAATGATT



TATACGGCACTCAGAGTCTGTCTATTTCTGTGGGGTCGTCCACATATAGAAATAATTTCGT



GCCAGTCGTGGGGGCTCGGCCGCAAGTGAATGGGCAGAGTGGTAGAATCGATTTCCACTGG



ACACTTGTGCAGCCCGGGGATAACATTACTTTCTCTCATAACGGGGGCCTGATCGCACCCT



CCAGGGTGAGTAAACTAATAGGCAGGGGTCTGGGCATTCAGTCCGACGCTCCAATCGATAA



CAACTGCGAGTCCAAGTGCTTCTGGCGCGGGGGTTCCATCAACACCCGGTTACCTTTTCAG



AACCTGTCCCCCCGCACCGTTGGCCAGTGCCCTAAATACGTAAATCGAAGATCATTAATGC



TGGCGACCGGTATGAGGAACGTACCTGAGCTGATTCAGGGGAGGGGGTTATTTGGTGCCAT



TGCCGGGTTTCTCGAAAACGGGTGGGAGGGAATGGTTGATGGCTGGTACGGGTTCAGGCAC



CAGAATGCCCAGGGCACAGGACAGGCTGCCGATTACAAGAGCACTCAGGCCGCTATTGACC



AGATCACCGGCAAGCTGAATCGGCTGGTAGAGAAAACCAATACGGAGTTTGAGTCCATTGA



GTCCGAGTTCTCAGAGATCGAGCACCAGATTGGCAATGTCATCAATTGGACCAAGGATTCA



ATTACGGATATATGGACATACCAGGCTGAGCTGCTTGTAGCAATGGAGAACCAACATACCA



TAGACATGGCTGATTCTGAGATGCTGAACCTCTACGAAAGGGTCAGAAAACAACTCAGACA



AAACGCAGAAGAAGACGGGAAAGGGTGTTTCGAAATTTACCATGCTTGTGATGACTCCTGC



ATGGAGAGCATCAGAAACAACACTTATGACCACAGCCAGTACCGTGAAGAGGCATTGTTGA



ACCGACTCAACATCAACCCTGTTACGCTGTCATCTGGGTATAAAGACATTATTCTATGGTT



CTCTTTTGGCGCTTCATGTTTTGTTCTGTTGGCGGTAGTGATGGGTCTGTTCTTTTTCTGT



TTAAAAAATGGCAATATGAGGTGCACCATCTGCATA





815
ATGTACAAGATCGTGGTTATTATCGCTCTTCTGGGTGCCGTTAAAGGGCTGGACAAAATTT



GTCTGGGGCATCACGCCGTGGCGAATGGTACTATCGTCAAGACATTGACCAACGAGCAGGA



GGAGGTTACAAATGCAACCGAGACCGTTGAGAGTACTGGAATCAACCGGCTGTGCATGAAG



GGAAGAAAGCACAAGGATCTGGGGAATTGTCACCCTATCGGAATGTTAATTGGTACACCTG



CTTGTGACCTGCACCTGACAGGCATGTGGGACACCCTGATCGAACGGGAGAACGCCATTGC



CTATTGTTATCCAGGGGCCACTGTTAATGTCGAGGCACTCAGGCAGAAGATTATGGAATCC



GGTGGAATTAATAAAATTAGCACAGGGTTTACTTACGGTTCCTCAATAAATTCAGCCGGCA



CTACACGGGCGTGTATGAGGAATGGAGGAAACTCCTTCTATGCCGAACTGAAATGGCTCGT



CAGCAAATCCAAGGGTCAAAATTTTCCTCAAACAACTAACACCTATAGAAATACCGATACC



GCAGAGCACCTCATAATGTGGGGGATACACCATCCGAGCTCCACACAAGAAAAAAACGACC



TGTATGGCACTCAAAGTCTTAGCATTTCCGTCGGAAGTTCTACATACCGGAATAACTTTGT



GCCGGTGGTAGGTGCCCGACCCCAAGTCAACGGCCAGAGTGGCCGCATCGATTTCCATTGG



ACACTGGTGCAGCCAGGAGATAACATTACCTTTTCTCACAATGGCGGCTTGATCGCTCCTT



CGAGGGTGAGCAAGCTGATTGGCCGGGGTCTGGGCATTCAATCCGACGCGCCTATCGACAA



TAATTGTGAGTCTAAATGCTTTTGGAGAGGAGGGTCAATCAACACAAGACTACCCTTCCAG



AATCTTTCCCCCCGAACAGTGGGACAGTGCCCCAAATATGTGAATCGGCGCTCTCTTATGC



TGGCCACTGGGATGAGAAACGTGCCTGAGTTAATACAGGGCCGGGGACTTTTCGGAGCAAT



CGCCGGATTCCTAGAGAACGGTTGGGAGGGGATGGTCGACGGATGGTACGGGTTCAGACAC



CAAAATGCTCAGGGGACAGGGCAGGCAGCAGACTATAAATCAACGCAGGCCGCTATCGACC



AGATCACCGGTAAACTGAACCGGCTTGTCGAAAAGACCAACACTGAGTTCGAGAGTATTGA



ATCCGAGTTTAGCGAGATCGAACACCAGATAGGCAATGTTATCAATTGGACAAAGGATTCA



ATCACGGACATATGGACATACCAAGCAGAACTGCTGGTAGCTATGGAAAATCAACATACAA



TCGATATGGCCGACTCAGAGATGCTCAACCTCTACGAAAGAGTAAGGAAACAACTCAGACA



AAATGCCGAAGAGGACGGCAAGGGTTGCTTTGAAATATATCATGCGTGCGACGACAGCTGC



ATGGAGAGCATACGGAACAATACGTACGACCATTCCCAGTATCGCGAAGAAGCCTTACTGA



ACCGCTTGAACATTAACCCCGTGACCCTTTCCTCCGGATATAAAGATATCATTCTCTGGTT



CAGTTTTGGAGCCTCATGCTTTGTCCTTTTGGCTGTGGTAATGGGATTATTTTTCTTCTGT



CTCAAGAATGGTAACATGCGATGTACAATTTGCATC





816
ATGTACAAGATCGTGGTGATCATAGCACTGCTGGGCGCCGTGAAAGGCTTAGACAAAATCT



GCTTAGGGCATCATGCCGTCGCTAATGGGACTATAGTCAAGACATTGACCAACGAGCAAGA



AGAGGTGACAAACGCAACTGAAACTGTTGAAAGTACCGGGATAAACCGGTTGTGCATGAAA



GGGCGAAAGCACAAGGACCTTGGCAACTGTCATCCCATCGGCATGCTTATAGGAACACCTG



CTTGCGATCTCCATCTGACTGGCATGTGGGACACCCTGATAGAACGAGAAAATGCCATTGC



CTACTGTTACCCAGGCGCCACCGTTAATGTTGAGGCCCTCAGACAGAAGATAATGGAATCT



GGAGGCATCAACAAAATCTCTACGGGCTTTACCTACGGTTCTAGCATTAACTCTGCCGGGA



CTACCCGAGCTTGTATGCGCAACGGGGGCAACTCTTTCTACGCCGAACTTAAGTGGCTGGT



GAGCAAGAGCAAGGGACAGAATTTCCCTCAAACTACTAACACTTATAGGAACACAGACACC



GCCGAACATCTAATAATGTGGGGAATACACCATCCCTCATCCACACAGGAAAAAAACGACC



TTTATGGGACCCAGTCTCTGAGCATTTCAGTCGGCTCATCCACTTATCGTAACAACTTTGT



GCCCGTGGTTGGGGCTCGGCCCCAGGTGAATGGCCAGTCTGGGCGTATTGATTTCCACTGG



ACCCTAGTGCAACCCGGAGACAACATCACCTTTAGTCATAATGGTGGCCTTATAGCCCCTA



GCAGGGTGTCAAAACTTATTGGGAGAGGCCTCGGGATTCAGAGTGACGCACCCATCGACAA



CAACTGCGAGAGTAAGTGTTTTTGGAGAGGGGGTTCGATCAACACCCGCCTCCCCTTCCAG



AACCTATCGCCACGCACTGTTGGTCAGTGCCCAAAATACGTCAACAGGAGGTCACTTATGC



TGGCTACAGGGATGCGGAACGTGCCGGAGCTGATACAGGGACGCGGTCTGTTCGGAGCCAT



TGCCGGATTCTTGGAGAATGGCTGGGAGGGGATGGTGGACGGCTGGTACGGCTTCCGACAC



CAGAATGCCCAGGGTACAGGTCAGGCAGCGGACTATAAGAGTACTCAAGCCGCTATCGATC



AAATCACTGGGAAGCTCAACCGACTGGTCGAGAAGACAAACACAGAATTCGAGTCTATCGA



GTCAGAATTCTCTGAAATCGAGCACCAGATTGGTAACGTAATCAATTGGACCAAGGATAGT



ATTACCGACATCTGGACATACCAAGCAGAACTGCTCGTGGCAATGGAAAATCAGCACACAA



TAGACATGGCCGATAGTGAGATGCTCAACCTGTACGAACGCGTTCGAAAACAGCTGAGACA



GAACGCTGAAGAAGACGGGAAAGGGTGCTTCGAGATCTATCACGCCTGCGACGATTCATGC



ATGGAGAGCATTAGAAACAATACCTACGACCACAGCCAGTATAGGGAGGAGGCTCTGCTAA



ACAGGCTCAACATTAATCCCGTAACACTCTCAAGCGGATATAAAGACATAATTCTGTGGTT



TTCCTTCGGAGCTTCCTGCTTCGTCCTGCTGGCGGTAGTCATGGGGTTATTCTTTTTTTGT



CTGAAGAACGGGAATATGCGATGTACAATATGCATT





817
ATGTACAAGGTTGTGGTTATTATAGCACTCCTCGGGGCTGTGCGCGGACTGGATAAGATCT



GCCTGGGACATCATGCCGTGGCAAATGGTACCACTGTAAAAACTCTCACCAATGAGCAGGA



AGAGGTGACCAACGCCACTGAGACAGTGGAATCTACAAGCCTGAACAAGCTGTGTATGAAG



GGCAGACGATATAAGGATCTGGGTAATTGCCATCCCATCGGCATGTTGATCGGAACACCAG



TTTGCGATCTGCATCTAACTGGAACCTGGGACACGCTTATCGAGCGGGAAAACGCCACCGC



GTACTGCTACCCAGGAGTCACCATCAACGAAGAAGCACTGAGACAGAAGATCATGGAGAGT



GGGGGGATCTCCAAGATGCGCACCGGGTTCACTTATGGGCCCAGCATTAACAGCGCTGGGA



CAACCAGATCCTGCATGAGGAATGGAGGGAACTCTTTTTATGCCGAATTAAAATGGCTGGT



TTCAGGAACAAAAGGACAAAATTTCCCGCAGACCACCAATACATATAGAAACACCGATACA



GCAGAACACTTAATCATCTGGGGGATCCATCACCCTTCATCTACGCAGGAAAAGAATGATC



TGTATGGTACCCAGTCTTTGAGTATTAGTGTAGGCTCTTCCACGTACCAGAATAACTTTGT



CCCTGTTATAGGTGCTCGACCTCAGGTCAATGGGCAGTCTGGGCGTATCGAGTTCCATTGG



ACCCTCGTACGACCCGGCGACAACATCACATTTAGCCACAACGGCGGATTGATAGCCCCCG



ACAGAGTGTCCAAGTTAATCGGCAAAGGAATTGGTATCCAGTCCGGCGCCGTGATCGATAA



GGATTGTGAGTCAAAATGCTTCTGGAGAGGCGGCAGCATCATAACAGAGCTTCCGTTTCAA



AACCTGAGTCCCCGCACCGTTGGGCAATGTCCTAAGTACGTGAAAAAACGAAGCCTCCTGC



TGGCAACCGGCATGCGGAATGTTCCCGAGGTGGTCCAGGGAAGAGGCCTGTTTGGCGCGAT



TGCTGGGTTCATCGAGAATGGCTGGGAAGGCATGGTTGACGGATGGTATGGGTTCAGGCAT



CAGAACGCGCAGGGCATCGGGCAGGCTGCTGACTACAAGAGCACTCAGACCGCCATCGATC



AGATCACAGGGAAGCTAAATCGGCTGATTGAAAAGACTAACACGGAGTTTGAGAGCATTGA



AAGCGAATTTAGTGAAATCGAACACCAGATAGGAAACGTTATTAACTGGACAAAGGATAGT



ATTACCGACATATGGACGTATCAAGCAGAGCTGCTGGTCGCCATGGAGAACCAGCATACTA



TAGATATGGCAGACAGCGAAATGCTCAATTTGTACGAGAGGGTAAGAAAACAACTGAGACA



AAATGCTGAAGAGGATGGCAAAGGCTGCTTTGAAATATACCACACCTGTGACAATTCCTGT



ATGGAGTCCATTCGGAACAATACGTATGATCATTCCCAGTATCGCGAGGAAGCCCTACTCA



ACCGCCTCAATATCAACCCCGTTAAGCTATCATCAGGCTACAAGGACATTATCCTGTGGTT



CAGCTTCGGAGCCTCCTGTTTCGTGCTACTTGCTGTGATCATGGGTTTGGGGTTCTTTTGC



CTGAAAAATGGAAATATGAGATGCACAATTTGTATT





818
ATGTATAAGATAGTCGTGATAATCGCCCTTTTGGGAGCGGTGAAGGGACTGGACAAGATTT



GTCTCGGCCATCATGCAGTCGCCAACGGTACAATTGTTAAAACCCTCACCAACGAACAAGA



AAAAGTGACAAATGCCACAGAAACTGTGGAGAGCACCGGCCTTAACCGGTTGTGCATGAAG



GGGCGAAAGCATAAGGACTTGGGTAATTGTCATCCAATTGGGATGCTGATTGGGACTCCCG



CCTGCGATCTGCACCTGACCGGCACATGGGATACCATTATCGAGAGGGAGAACGCGATCGC



TTACTGCTATCCTGGGGCTACAGTCAATGAGGAGGCCCTAAGGCAGAAAATAATGGAGTCA



GGGGGAATCGATAAAATTTCTACAGGCTTCACTTACGGATCTTCTATTAACAGCGCAGGCA



CCACGCGCGCCTGCATGAGAAATGGCGGGAATAGTTTTTATGCCGAGCTGAAATGGCTGGT



GTCCAAGAGCAAGGGACAGAACTTTCCGCAAACCACTAATACATACCGTAATACTGACACA



GCAGAACATCTGATTATGTGGGGAATCCACCACCCCTCCAGCACTCAAGAGAAAAATGATC



TTTACGGAACACAGTCCCTCAGCATAAGCGTGGGTTCGAGTACATATAGGAACAATTTCGT



GCCAGTGGTAGGCGCGCGACCGCAGGTCAATGGACAGTCAGGAAGGATCGACTTCCATTGG



ACTCTAGTGCAACCTGGGGATAATATTACCTTTAGCCATAATGGAGGTCTGATAGCCCCAT



CTCGCGTCTCCAAGCTGATTGGGCGCGGTCTGGGGATTCAGAGTGACGCTCCTATTGATAA



CAACTGCGAGAGTAAATGTTTCTGGCGCGGCGGCTCGATTAACACCCGTCTTCCCTTTCAG



AACCTGAGTCCCCGGACAGTAGGACAGTGCCCTAAATACGTGAACAAAAGAAGTCTTATGC



TCGCCACTGGGATGCGAAACGTTCCGGAACTGATCCAGGGTCGCGGCCTGTTCGGCGCAAT



TGCTGGTTTCCTCGAAAATGGATGGGAAGGTATGGTGGATGGGTGGTACGGGTTCAGACAT



CAAAACGCTCAGGGCACGGGCCAGGCTGCCGACTACAAGAGCACACAGGCTGCCATCGACC



AGATTACTGGGAAACTCAATAGACTCGTGGAAAAAACTAATACGGAATTCGAAAGCATCGA



ATCTGAGTTCAGTGAGATCGAACATCAGATCGGAAACGTGATCAACTGGACAAAGGATTCG



ATTACTGATATTTGGACGTACCAGGCAGAGTTGTTGGTCGCCATGGAGAATCAACACACAA



TCGATATGGCCGACTCAGAGATGTTGAATCTTTACGAGAGGGTGCGAAAGCAGCTGAGGCA



GAATGCCGAGGAAGATGGAAAGGGGTGTTTTGAGATCTACCACGCCTGCGACGATTCTTGC



ATGGAATCCATCCGCAATAATACATACGATCACTCACAGTATAGGGAGGAGGCCCTACTCA



ACAGACTGAACATCAATCCCGTGACACTTTCAAGTGGTTACAAGGATATCATACTTTGGTT



CAGCTTCGGCGCCAGTTGCTTTGTTCTGCTTGCCGTTGTGATGGGCCTGGTGTTCTTTTGC



CTGAAGAATGGTAACATGAGATGTACCATCTGCATT





819
ATGTATAAAATTGTCGTTATCATTGCCTTGCTCGGCGCTGTGAAGGGGCTGGATAAAATTT



GTCTGGGACATCACGCCGTGGCGAACGGGACTATCGTCAAGACGCTTACTAACGAACAGGA



AGAGGTGACTAACGCGACGGAAACCGTGGAGTCAACTGGGATTAATCGCTTGTGCATGAAG



GGCAGAAAGCACAAGGACTTAGGCAACTGTCATCCTATCGGCATGCTGATCGGTACCCCAG



CCTGCGACCTTCACTTGACTGGCACCTGGGATACCCTGATCGAAAGAGAGAACGCAATAGC



ATACTGTTATCCAGGCGCCACAGCCAACGTAGAGGCCCTGAGACAGAAGATCATGGAATCT



GGAGGTATCGATAAAATTAGCACCGGATTTACATATGGATCAAGTATAAACTCGGCAGGAA



CGACGCGGGCGTGCATGCGAAATGGCGGAAATTCCTTCTACGCCGAATTGAAATGGCTAGT



GTCCAAAAGCAAAGGCCAAAACTTTCCACAGACTACTAACACCTACAGAAATACTGACACC



GCTGAACATTTGATTATGTGGGGGATCCACCACCCAAGTAGCATTCAGGAGAAGAACGATC



TGTATGGCACTCAGTCACTAAGTATTTCCGTGGGCAGCTCTACCTACCGCAATAACTTCGT



GCCGGTTGTGGGCGCCAGACCTCAGGTGAACGGACAAAGTGGTCGCATTGATTTCCACTGG



ACACTTGTGCAACCTGGGGACAATATCACTTTCAGCCACAACGGGGGGCTGATCGCCCCAT



CAAGAGTGAGCAAATTGATAGGGAGAGGCTTGGGAATCCAGTCAGATGCACCTATCGATAA



TAATTGTGAAAGCAAATGCTTTTGGCGTGGGGGATCCATAAACACTCGACTGCCATTCCAG



AATTTGTCCCCCCGCACCGTTGGCCAGTGTCCCAAGTACGTTAATCGCAGAAGTCTGATGC



TGGCCACCGGCATGAGAAACGTGCCCGAACTGATACAGGGACGCGGGCTCTTTGGAGCAAT



TGCCGGCTTTCTGGAGAACGGATGGGAGGGAATGGTGGACGGATGGTACGGCTTTCGGCAC



CAGAATGCCCAGGGGACAGGACAAGCCGCCGATTATAAGTCAACACAGGCCGCAATCGACC



AGATTACCGGCAAGCTCAACAGGCTCGTGGAAAAGACAAACACTGAGTTTGAGTCAATCGA



GTCAGAATTTTCCGAGATCGAGCATCAAATCGGCAACGTGATCAATTGGACTATGGATTCT



ATCACCGACATTTGGACTTACCAGGCAGAGCTCCTGGTGGCAATGGAGAACCAACACACTA



TCGACATGGCAGATTCAGAGATGCTCAACCTCTATGAAAGGGTACGAAAACAGCTTCGGCA



GAACGCCGAGGAGGACGGTAAGGGGTGTTTTGAAATCTATCATGCGTGCGACGATAGCTGT



ATGGAAAGTATCCGGAATAATACATACGATCACTCCCAGTACCGCGAAGAGGCTCTCTTGA



ACCGGCTTAACATCAACCCGGTAACTCTCAGTAGCGGGTACAAGGACATCATTCTGTGGTT



TTCTTTTGGTGCCTCCTGTTTTGTGCTGCTGGCCGTGGTGATGGGACTCGTGTTTTTTTGC



CTCAAGAACGGGAATATGCGGTGCACAATATGCATT





820
ATGTATAAGATTGTGGTGATTATTGCTCTCTTGGGGGCAGTCAAAGGACTTGATAAGATTT



GTCTGGGCCACCATGCTGTCGCAAATGGGACAATCGTCAAGACCCTTACCAACGAGCAAGA



AAAGGTAACCAACGCAACCGAGACTGTTGAGAGTACAGGGCTGAATAGACTCTGTATGAAG



GGCCGCAAACATAAGGACCTAGGTAACTGTCATCCAATAGGGATGCTGATTGGAACACCGG



CATGTGACTTACACCTCACAGGTACATGGGATACTATTATAGAGAGAGAAAATGCCATTGC



CTACTGTTATCCTGGGGCTACCGTTAACGAGGAAGCCTTACGTCAGAAAATTATGGAATCC



GGGGGCATTGATAAAATATCCACTGGATTTACTTATGGAAGCTCAATCAACTCCGGGGGCA



CTACTCGAGCATGTATGCGCAACGGAGGTAACTCCTTCTACGCCGAACTGAAGTGGCTCGT



TTCAAAATCCAAAGGACAGAACTTTCCGCAGACCACTAATACCTACCGCAATACAGACACA



GCAGAACATCTGATCATGTGGGGCATTCATCACCCCAGCTCTACTCAAGAAAAGAATGACC



TGTACGGGACTCAAAGTCTGTCCATTTCTGTTGGGTCTAGTACCTACCGGAATAACTTTGT



CCCCGTTGTTGGAGCACGCCCTCAGGTTAACGGTCAGAGTGGAAGGATCGACTTTCACTGG



ACCCTCGTCCAGCCTGGCGACAATATCACATTTAGTCACAACGGGGGCCTAATCGCTCCCT



CTCGGGTGAGCAAGCTGATAGGTCGGGGCTTGGGTATACAGTCTGACGCCCCAATCGATAA



CAACTGTGAAAGCAAGTGCTTCTGGCGGGGTGGCTCTATCAACACCCGACTGCCATTTCAA



AATCTCAGTCCAAGGACAGTGGGGCAATGCCCAAAATACGTCAACAAAAGGTCACTCATGC



TCGCCACAGGAATGCGCAATGTGCCTGAACTGATTCAAGGACGAGGACTGTTTGGCGCTAT



TGCCGGGTTTTTAGAGAATGGCTGGGAAGGCATGGTAGACGGGTGGTACGGGTTCCGGCAT



CAGAATGCCCAAGGGACGGGTCAGGCCGCTGACTATAAGTCCACTCAGGCCGCAATAGATC



AGATCACCGGAAAGTTGAACAGACTAGTGGAGAAGACAAACACTGAGTTCGAGTCCATTGA



GAGCGAATTCAGCGAGATAGAACACCAAATCGGCAATGTGATTAACTGGACCAAAGACAGT



ATTACTGATATCTGGACTTATCAAGCCGAACTGTTGGTGGCAATGGAGAACCAACACACGA



TCGACATGGCAGACAGTGAGATGCTCAATCTGTACGAGAGGGTGCGTAAACAGCTGAGGCA



GAACGCCGAAGAAGACGGAAAGGGGTGTTTCGAGATATACCACGCCTGTGATGACTCCTGT



ATGGAAAGCATCAGGAACAACACTTATGACCATAGTCAATATAGGGAAGAAGCACTGCTCA



ACCGCCTGAACATCAATCCTGTAACACTTTCATCAGGATATAAGGACATCATCCTCTGGTT



TAGTTTCGGAGCTTCATGCTTTGTGCTGCTCGCGGTAGTCATGGGGCTGGTCTTCTTTTGT



TTGAAGAACGGTAACATGAGATGCACCATTTGTATC





821
ATGTACAAAATCGTCGTCATCATCGCCTTACTGGGAGCCGTCAAAGGACTTGATAAAATTT



GTCTTGGTCACCACGCTGTTGCCAATGGAACAATCGTGAAGACACTTACCAATGAGCAGGA



GGAGGTGACTAATGCAACAGAGACAGTGGAGTCCACTGGAATAAATCGGCTGTGCATGAAG



GGCAGAAAACACAAGGATTTGGGCAACTGCCACCCTATTGGAATGCTCATAGGCACCCCTG



CGTGTGACCTTCATCTGACTGGCACTTGGGACACTCTCATCGAACGCGAGAACGCCATCGC



CTACTGCTATCCTGGAGCCACCGCCAACGTGGAGGCTCTACGGCAGAAGATTATGGAGAGC



GGAGGGATTGACAAGATCTCCACGGGTTTCACTTACGGCAGCTCCATCAACAGTGCCGGTA



CAACTCGGGCGTGCATGAGAAACGGGGGCAACAGCTTTTATGCCGAGCTGAAGTGGCTGGT



GAGTAAGTCAAAAGGGCAGAACTTTCCACAGACAACAAATACGTACAGAAATACAGATACA



GCCGAGCACCTGATCATGTGGGGGATTCATCATCCAAGTTCTATCCAGGAGAAAAACGACT



TGTATGGGACTCAGAGTCTCAGTATCAGCGTAGGTTCCTCTACCTACAGGAACAACTTCGT



GCCCGTCGTCGGGGCCCGTCCCCAAGTCAACGGCCAGAGTGGACGGATTGATTTTCACTGG



ACTCTTGTGCAGCCCGGCGACAACATTACCTTCAGTCACAACGGAGGGCTGATTGCACCTT



CCAGAGTCTCGAAGCTGATCGGACGTGGATTGGGGATTCAGTCGGACGCTCCTATCGACAA



TAATTGCGAGAGCAAATGTTTCTGGCGCGGGGGTTCTATTAACACCAGGCTCCCCTTTCAA



AATTTGAGCCCGCGAACCGTCGGCCAATGTCCCAAGTATGTCAACCGGAGAAGCCTGATGT



TGGCTACAGGAATGCGCAATGTGCCGGAGCTCATCCAGGGCCGTGGCTTGTTCGGTGCAAT



TGCCGGATTCCTAGAAAATGGATGGGAGGGAATGGTTGATGGGTGGTACGGCTTCCGCCAC



CAAAACGCTCAGGGCACTGGACAGGCCGCGGACTATAAGTCTACTCAGGCGGCTATCGATC



AGATCACTGGGAAACTGAATAGGCTTGTGGAAAAAACCAATACGGAGTTCGAAAGTATCGA



GTCAGAGTTTAGCGAAATCGAGCATCAGATTGGTAACGTGATCAACTGGACCATGGATAGC



ATTACCGACATCTGGACCTACCAGGCCGAATTGCTGGTGGCCATGGAGAATCAGCACACAA



TTGACATGGCAGACTCTGAAATGCTTAACCTATATGAGCGCGTACGGAAACAGCTCAGACA



GAACGCGGAGGAAGATGGAAAGGGCTGCTTCGAAATTTATCACGCTTGCGACGACTCCTGT



ATGGAGTCTATCAGAAACAATACGTATGATCATTCGCAATACCGGGAGGAAGCACTCCTGA



ATAGACTCAACATCAACCCCGTTACACTGAGCTCAGGGTACAAAGACATTATTCTCTGGTT



TTCCTTCGGAGCTTCTTGCTTCGTACTGTTAGCTGTCGTCATGGGGCTAGTTTTTTTTTGT



CTTAAAAACGGCAACATGAGATGCACCATCTGTATA





822
ATGTATAAAATCGTGGTAATCATTGCACTGCTGGGAGCAGTCAAAGGGCTCGATAAAATAT



GCCTTGGCCACCACGCCGTAGCAAATGGTACAATCGTGAAGACCCTCACGAACGAACAGGA



GGAAGTCACCAACGCTACAGAAACTGTCGAAAGTACCGGGATCAACCGGCTCTGTATGAAG



GGCAGGAAGCATAAAGACTTAGGTAACTGCCATCCTATCGGCATGCTGATTGGCACACCTG



CCTGCGACTTGCACTTAACGGGAATGTGGGACACATTGATTGAGAGAGAGAATGCTATTGC



TTACTGTTACCCAGGAGCGACTGTGAACGTGGAGGCACTACGGCAAAAAATAATGGAGTCC



GGGGGAATCAATAAGATCTCGACAGGATTTACCTATGGGAGCTCAATCAATTCTGCGGGAA



CAACCCGGGCCTGCATGCGCAATGGGGGGAATAGCTTCTATGCCGAACTCAAGTGGCTCGT



TAGCAAGAGCAAAGGGCAGAATTTCCCGCAAACTACTAACACATACAGGAACACAGACACA



GCAGAGCATTTGATTATGTGGGGGATTCACCACCCCTCTAGTACGCAGGAAAAGAACGATC



TTTACGGGACCCAGTCCCTTTCTATCAGCGTAGGAAGCAGCACTTACAGGAATAATTTTGT



CCCTGTGGTTGGCGCGGGCCCTCAGGTTAATGGGCAATCTGGCCGCATTGATTTTCATTGG



ACCCTCGTACAGCCTGGCGACAATATAACATTCTCACATAATGGCGGCCTGATCGCACCTT



CCCGGGTATCTAAATTGATAGGTAGAGGCCTGGGGATTCAAAGCGATGCTCCAATAGATAA



TAACTGTGAATCAAAGTGCTTTTGGGGGGGAGGGTCAATTAATACGCGGCTACCCTTTCAG



AATCTTAGCCCACGCACCGTTGGCCAATGTCCAAAGTACGTGAATCGTAGATCACTGATGC



TGGCTACAGGGATGCGGAATGTGCCAGAACTCATTCAGGGCCGTGGGCTATTCGGCGCTAT



CGCCGGGTTTCTGGAAAACGGCTGGGAGGGGATGGTCGATGGCTGGTACGGCTTCCGGCAC



CAGAACGCTCAGGGTACAGGGCAGGCGGCTGATTATAAAAGCACACAGGCTGCAATCGACC



AAATTACTGGAAAACTAAATAGGCTAGTGGAAAAAACCAACACCGAATTCGAAAGTATTGA



AAGTGAGTTCAGTGAAATTGAGCACCAGATTGGAAACGTGATCAACTGGACTAAGGACAGT



ATCACCGATATTTGGACATATCAGGCAGAACTTCTCGTGGCCATGGAAAACCAGCATACTA



TTGACATGGCTGACAGTGAAATGTTAAATCTCTATGAGCGCGTACGCAAACAATTGCGGCA



GAATGCCGAGGAAGATGGGAAGGGCTGCTTCGAAATCTATCACGCTTGCGACGATTCCTGC



ATGGAGTCCATCAGGAACAATACATACGATCACAGCCAGTATCGCGAAGAAGCCCTGCTTA



ATAGACTAAATATTAATCCCGTCACCCTGTCCTCAGGCTATAAGGACATCATCCTTTGGTT



TTCATTTGGCGCAAGTTGCTTCGTCTTGCTCGCAGTCGTCATGGGGCTGTTTTTTTTCTGT



CTCAAAAACGGAAACATGAGGTGTACCATTTGCATT





823
ATGTACAAAATTGTGGTTATCATCGCTTTGCTTGGCGCTGTGAAGGGGCTGGATAAGATCT



GTCTCGGGCATCACGCTGTCGCCAATGGCACAATTGTCAAGACATTGACGAACGAGCAGGA



GGAAGTGACAAATGCCACTGAAACAGTGGAATCCACTGGGATCAACCGATTGTGCATGAAA



GGTAGGAAGCATAAGGATCTCGGTAACTGTCATCCAATCGGCATGTTGATTGGAACCCCGG



CCTGTGATCTTCACCTCACTGGTATGTGGGACACACTGATTGAAAGAGAAAACGCTATTGC



CTACTGTTACCCAGGTGCAACGGTTAATGTCGAGGCACTGAGACAGAAAATTATGGAAAGC



GGAGGCATCAACAAGATATCAACCGGGTTTACCTATGGCTCATCGATTAATAGCGCAGGCA



CCACTCGCGCGTGTATGCGAAATGGAGGAAATTCATTTTATGCCGAGTTAAAATGGCTGGT



TAGTAAGAGCAAGGGTCAGAACTTCCCTCAGACCACAAATACGTATCGCAATACGGACACT



GCAGAACACCTTATCATGTGGGGTATTCACCACCCTAGCAGTACTCAAGAAAAAAATGACC



TGTATGGTACCCAGAGTCTGAGTATAAGCGTGGGTTCCAGTACTTACCGGAACAACTTCGT



TCCAGTTGTGGGGGCCCGCCCACAGGTTAACGGGCAATCGGGGCGCATCGATTTTCACTGG



ACCTTGGTGCAACCTGGAGACAATATTACTTTCAGTCACAACGGCGGATTGATAGCTCCAT



CCCGTGTCAGTAAATTGATTGGGCGCGGACTGGGAATCCAGTCTGACGCACCCATAGATAA



CAACTGTGAGTCTAAGTGTTTCTGGAGGGGCGGTTCCATTAATACTCGGCTGCCATTTCAG



AATCTTAGCCCGCGCACTGTGGGTCAATGTCCCAAGTACGTGAACAGGCGTTCTCTAATGC



TTGCCACCGGGATGAGAAACGTTCCTGAACTGATACAAGGTAGGGGACTGTTCGGTGCAAT



CGCTGGCTTTTTGGAGAATGGCTGGGAGGGAATGGTGGACGGCTGGTATGGATTCCGCCAT



CAGAACGCCCAGGGAACCGGACAGGCTGCCGACTATAAGTCCACGCAGGCCGCGATTGACC



AAATTACCGGAAAACTCAATCGCCTAGTCGAGAAAACAAACACCGAATTCGAGAGTATCGA



GTCCGAATTTTCTGAGATCGAGCACCAAATCGGCAACGTAATCAATTGGACGAAGGATTCC



ATTACTGACATCTGGACCTACCAAGCCGAATTGTTGGTCGCAATGGAGAACCAGCACACCA



TAGACATGGCTGACAGCGAAATGCTGAACCTGTACGAGCGGGTTCGGAAACAGCTGCGCCA



GAACGCAGAGGAGGATGGCAAAGGCTGCTTCGAAATCTATCACGCCTGCGACGATAGCTGC



ATGGAATCAATAAGGAATAACACTTATGATCACAGCCAGTATCGGGAAGAGGCCCTGCTGA



ATCGGCTCAACATCAATCCCGTGACTCTCTCTTCCGGCTATAAAGACATTATCTTGTGGTT



CTCTTTCGGCGCGTCATGCTTCGTGCTGCTGGCAGTGGTAATGGGACTCTTCTTTTTTTGC



CTGAAAAACGGGAACATGCGCTGCACAATCTGCATC





824
ATGTATAAGATTGTGGTGATTATTGCCCTGCTCGGCGCCGTGAAGGGGTTGGACAAGATTT



GTCTTGGTCACCACGCCGTGGCTAACGGGACCATAGTCAAGACTCTGACCAATGAACAGGA



AGAGGTAACAAACGCAACCGAAACAGTCGAGTCTACAGGAATCAATCGGTTATGTATGAAA



GGCCGAAAACATAAAGACCTCGGCAATTGTCACCCCATAGGGATGCTGATCGGGACTCCAG



CTTGCGACCTGCATTTAACAGGCATGTGGGACACTCTCATCGAGAGAGAGAACGCGATCGC



ATACTGCTACCCAGGAGCTACCGTGAATGTAGAGGCATTGAGACAGAAAATCATGGAAAGT



GGCGGAATAAATAAGATTTCTACAGGGTTTACGTACGGCAGCTCCATTAACAGTGCCGGAA



CAACCCGAGCATGTATGAGAAATGGAGGTAATAGCTTTTACGCCGAACTGAAGTGGCTTGT



GTCCAAAAGTAAGGGGCAAAATTTTCCTCAGACAACGAACACCTACCGGAACACCGACACA



GCTGAGCACCTGATTATGTGGGGGATACATCATCCTAGCAGCACGCAGGAGAAGAATGATC



TATACGGGACCCAATCTCTCAGCATCTCAGTGGGCTCCTCAACTTACCGCAACAACTTCGT



GCCTGTCGTCGGCGCCCGCCCTCAGGTCAACGGTCAGTCTGGCCGAATCGACTTTCACTGG



ACACTGGTGCAGCCTGGAGACAACATCACTTTCTCCCATAACGGGGGACTTATCGCACCGA



GCAGAGTGAGCAAGCTGATTGGAAGAGGACTCGGAATACAATCCGATGCCCCGATAGATAA



TAATTGTGAGAGCAAGTGTTTCTGGCGCGGCGGATCCATCAATACACGCTTACCGTTTCAG



AACTTGAGCCCACGGACTGTTGGGCAGTGCCCAAAGTACGTGAACCGCCGCAGTTTAATGC



TTGCTACCGGTATGAGAAATGTACCTGAACTCATTCAAGGCAGGGGCCTGTTTGGCGCAAT



CGCTGGCTTTCTCGAAAATGGATGGGAAGGCATGGTAGACGGTTGGTACGGATTCAGACAC



CAGAATGCCCAGGGCACGGGTCAAGCAGCCGATTATAAAAGCACACAAGCAGCAATTGATC



AGATTACAGGTAAGCTCAACCGTCTCGTGGAAAAAACTAACACCGAGTTCGAATCCATTGA



GAGTGAGTTCAGTGAGATAGAGCACCAGATCGGAAATGTGATTAACTGGACAAAAGATAGC



ATTACAGATATCTGGACGTACCAGGCTGAGCTCTTGGTGGCGATGGAAAATCAGCATACCA



TTGACATGGCCGACTCAGAGATGCTTAACCTGTATGAGAGAGTGCGCAAACAGCTTAGACA



GAACGCCGAAGAGGATGGCAAGGGATGTTTCGAGATCTACCACGCTTGTGATGACAGCTGT



ATGGAGAGTATTAGAAACAACACGTATGACCATTCCCAGTACCGAGAGGAGGCTTTGCTTA



ATCGTTTGAATATTAACCCCGTCACGCTCAGCAGCGGGTACAAAGATATCATACTCTGGTT



CTCTTTCGGAGCATCATGCTTCGTACTTTTGGCTGTGGTGATGGGGCTGTTTTTCTTCTGC



TTGAAAAACGGCAACATGAGGTGCACTATCTGTATC





825
ATGTACAAAATCGTTGTGATCATTGCTCTGTTGGGCGCGGTAAAGGGCCTAGATAAGATTT



GTCTGGGCCATCACGCCGTTGCCAACGGCACTATAGTTAAAACGCTGACAAATGAACAGGA



AAAGGTAACTAACGCCACCGAGACTGTGGAGTCCACTGGTCTGAACCGACTCTGCATGAAA



GGGCGAAAACATAAAGACCTGGGCAACTGTCACCCAATTGGGATGCTGATCGGGACACCTG



CCTGCGATCTCCACCTGACCGGTACATGGGACACAATCATTGAAAGGGAAAACGCCATCGC



CTACTGTTATCCAGGCGCTACAGTCAACGAGGAAGCATTGCGGCAGAAAATTATGGAGTCT



GGCGGAATCGATAAGATATCCACTGGCTTCACCTACGGATCGTCTATTAACTCTGCGGGTA



CGACACGCGCCTGTATGAGGAACGGCGGAAATAGCTTTTACGCTGAACTAAAGTGGTTAGT



TTCTAAGAGCAAGGGCCAGAATTTCCCACAGACCACAAATACATACAGGAATACAGATACC



GCTGAGCATCTAATCATGTGGGGAATACACCACCCCTCGTCAACTCAGGAGAAGAATGATC



TGTATGGCACACAGTCTCTGTCAATTTCCGTGGGCTCAAGCACATATAGGAACAACTTCGT



GCCTGTTGTTGGCGCCAGACCCCAAGTCAATGGCCAGTCTGGAAGGATTGACTTCCATTGG



ACCCTGGTCCAACCCGGGGATAATATCACCTTTTCCCATAATGGAGGGCTGATCGCGCCTA



GTCGCGTCAGTAAACTCATCGGGAGAGGGCTGGGAATTCAATCAGATGCCCCCATTGATAA



CAACTGTGAAAGTAAATGCTTTTGGCGGGGGGGTTCCATCAATACACGCCTGCCATTTCAG



AATCTGAGCCCCAGGACGGTTGGTCAGTGCCCCAAGTACGTGAACAAGAGAAGCCTGATGC



TGGCAACTGGGATGCGCAATGTTCCTGAACTGATTCAGGGACGCGGGTTATTTGGAGCTAT



TGCCGGTTTTCTCGAGAATGGCTGGGAGGGAATGGTCGATGGGTGGTACGGATTTAGACAC



CAAAACGCTCAGGGAACAGGCCAGGCGGCTGATTACAAAAGCACCCAGGCCGCTATTGATC



AGATCACTGGAAAACTGAACCGCCTTGTCGAGAAAACAAACACCGAATTTGAGAGCATAGA



GTCCGAATTCTCAGAGATTGAACATCAAATTGGCAACGTGATAAATTGGACTAAAGACTCC



ATTACCGACATCTGGACCTACCAGGCCGAGCTCTTGGTTGCTATGGAAAATCAGCATACTA



TCGACATGGCCGACTCTGAAATGCTTAATCTGTACGAACGCGTGAGAAAACAGTTACGCCA



GAACGCGGAGGAAGATGGCAAAGGGTGCTTCGAGATCTACCATGCATGCGATGACAGCTGT



ATGGAAAGCATCCGTAATAATACCTATGATCACTCTCAGTATAGGGAAGAGGCCCTGTTGA



ATAGATTAAACATTAACCCAGTGACACTGAGCAGCGGCTATAAGGACATTATTTTATGGTT



TTCCTTTGGAGCAAGTTGTTTTGTGCTGCTGGCGGTGGTGATGGGGCTCGTGTTCTTTTGC



CTGAAGAATGGTAACATGCGCTGTACTATCTGTATT





826
ATGTACAAGATAGTCGTGATAATTGCACTCCTCGGCGCAGTTAAGGGCTTGGATAAGATCT



GCCTGGGACACCACGCCGTCGCGAACGGCACTATTGTCAAGACTTTAACGAACGAGCAAGA



AGAGGTAACAAATGCAACAGAAACTGTTGAGAGCACGGGCATCAATCGGCTGTGCATGAAG



GGTAGGAAGCATAAGGACCTGGGAAACTGTCACCCCATCGGCATGCTGATCGGGACCCCCG



CATGTGATTTACACCTTACAGGAATGTGGGATACTCTGATCGAAAGAGAGAATGCCATTGC



TTACTGTTACCCTGGGGCCACGGTGAACGTGGAGGCCCTTAGGCAGAAAATCATGGAAAGT



GGAGGGATCAACAAGATTTCCACCGGTTTCACGTATGGCTCTTCTATTAATTCCGCTGGAA



CCACTAGGGCCTGTATGCGAAATGGAGGCAACTCCTTCTACGCTGAATTGAAGTGGCTGGT



AAGCAAGTCCAAAGGGCAGAATTTCCCACAGACAACAAACACGTACAGAAACACGGACACC



GCTGAGCACCTCATCATGTGGGGCATCCACCACCCTAGCTCTACCCAGGAAAAAAATGATT



TATACGGAACGCAGTCTCTTTCAATCTCCGTCGGCTCAAGCACTTATAGAAATAATTTTGT



GCCCGTCGTGGGGGCCCGGCCCCAGGTAAACGGCCAATCAGGGAGGATCGACTTTCATTGG



ACCCTGGTTCAGCCCGGGGATAACATAACCTTTAGCCATAACGGAGGTCTTATAGCGCCGA



GTCGAGTGTCAAAGCTGATCGGGCGCGGTTTGGGCATCCAGTCTGATGCCCCCATCGACAA



CAACTGCGAGAGCAAATGCTTTTGGAGGGGAGGGTCCATTAATACCCGTCTGCCATTCCAG



AATCTCTCTCCCCGGACCGTCGGCCAGTGCCCCAAATACGTGAATCGTCGTTCTCTCATGC



TCGCCACCGGAATGCGCAACGTGCCTGAGTTGATCCAAGGTCGGGGACTGTTCGGGGCCAT



TGCCGGCTTTCTGGAGAACGGGTGGGAGGGGATGGTGGATGGCTGGTACGGCTTTAGGCAC



CAGAACGCTCAGGGAACTGGGCAGGCGGCCGACTACAAGTCAACCCAGGCCGCAATAGATC



AAATTACAGGCAAGCTGAACCGACTGGTCGAAAAAACCAACACAGAATTCGAGTCCATAGA



ATCCGAATTTTCTGAAATAGAACACCAGATTGGGAACGTTATCAATTGGACTAAAGATTCC



ATCACCGATATCTGGACATATCAGGCCGAACTGCTTGTGGCCATGGAAAACCAGCATACCA



TCGATATGGCTGACTCCGAAATGTTGAATTTGTATGAAAGGGTACGCAAGCAGCTGAGGCA



GAACGCTGAGGAGGACGGTAAGGGATGTTTTGAGATCTACCATGCATGCGATGACAGCTGT



ATGGAGTCAATACGCAACAACACTTATGACCACTCCCAATATCGGGAGGAAGCACTTCTCA



ATCGCTTGAATATTAATCCCGTCACTCTGTCTAGTGGTTATAAGGACATTATTTTGTGGTT



CAGCTTTGGAGCCTCCTGTTTCGTTCTACTGGCCGTTGTGATGGGACTATTCTTTTTCTGC



CTCAAAAACGGCAACATGCGGTGCACCATCTGTATT





827
ATGTACAAAATAATTGTTATCATAGCCCTCCTGGGTGCCGTCAAAGGGCTGGATAAAATAT



GCTTAGGGCACCACGCGGTTGCTAACGGCACCATCGTCAAAACCCTCACAAACGAACAGGA



GGAAGTCACCAACGCAACAGAAACAGTCGAATCAACGGGCATCAATAGACTGTGTATGAAA



GGGCGCAAGCACAAGGACTTGGGAAACTGCCACCCGATTGGTATGCTAATTGGAACCCCAG



CCTGTGACCTACACCTGACCGGGACTTGGGATACTCTTATTGAGCGCGAAAACGCTATTGC



GTATTGTTACCCTGGGGCTACCGTCAACGTTGAGGCACTGAGACAGAAAATAATGGAATCA



GGTGGCATAGACAAAATTTCTACCGGCTTCACCTACGGGAGCAGCATAAACTCCGCTGGCA



CTACACGCGCCTGTATGAGGAATGGCGGCAACTCCTTCTACGCCGAGCTGAAGTGGCTGGT



TAGTAAGTCCAAGGGACAGAACTTCCCACAGACCACCAACACTTACCGCAACACCGATACA



GCCGAGCACCTGATTATGTGGGGAATACACCACCCAAGCTCTACCCAGGAAAAAAACGACT



TGTACGGCACTCAAAGTCTGTCCATCTCCGTTGGGTCGTCCACTTACCGCAATAATTTCGT



CCCCGTGGTTGGAGCCCGCCCTCAGGTGAACGGCCAAAGCGGGCGCATCGATTTCCATTGG



ACCCTCGTTCAGCCTGGCGACAACATTACCTTTAGTCACAATGGCGGTCTGATTGCCCCTT



CACGCGTGTCCAAGTTGATTGGACGGGGATTGGGCATCCAGTCGGACGCACCCATCGATAA



CAATTGTGAGAGTAAATGTTTCTGGCGGGGTGGCTCCATTAATACCCGACTGCCATTCCAA



AACCTCTCTCCTCGTACGGTGGGTCAGTGTCCCAAGTATGTGAACAGAAGATCTCTGATGT



TAGCAACCGGTATGAGAAACGTCCCGGAGCTGATCCAGGGCAGAGGCCTGTTCGGAGCCAT



TGCGGGGTTTCTTGAAAACGGATGGGAGGGCATGGTGGACGGATGGTATGGGTTTCGACAT



CAAAATGCCCAGGGGACCGGGCAGGCAGCTGACTACAAATCTACCCAGGCGGCAATAGATC



AGATCACTGGAAAGTTAAACAGACTCGTGGAGAAAACTAACACTGAGTTCGAATCTATCGA



GTCAGAGTTTTCAGAAATTGAACATCAGATCGGAAACGTTATCAATTGGACGAAAGATAGT



ATCACAGACATTTGGACCTATCAAGCTGAATTGCTTGTGGCCATGGAAAACCAACATACCA



TCGACATGGCTGACTCGGAAATGTTGAATTTGTACGAGCGGGTGAGGAAGCAACTGAGGCA



AAATGCCGAGGAGGACGGCAAAGGCTGCTTTGAGATCTACCACGCATGCGATGACTCTTGT



ATGGAAAGTATTCGGAATAATACTTATGACCATTCCCAGTATCGTGAGGAAGCACTGCTCA



ACCGCCTAAATATTAATCCCGTGACCCTGTCATCAGGGTATAAGGACATTATCCTTTGGTT



TTCCTTCGGCGCTAGCTGTTTCGTGCTGCTAGCGGTAGTGATGGGCCTTTTCTTCTTTTGT



TTGAAGAATGGCAATATGCGATGCACAATCTGCATA





828
ATGTATAAGATCGTGGTCATCATAGCCCTGCTCGGAGCCGTTAAGGGTCTTGACAAGATTT



GTCTTGGTCATCATGCTGTTGCTAACGGAACCATCGTGAAAACTCTGACAAACGAGCAGGA



GGAAGTGACAAACGCCACGGAGACAGTGGAATCTACTGGAATCAACCGCTTATGCATGAAA



GGCAGGAAACACAAAGACCTGGGGAATTGCCACCCAATTGGAATGCTGATCGGCACACCTG



CCTGCGACCTGCATCTCACAGGGATGTGGGATACACTGATCGAAAGAGAGAATGCTATCGC



ATACTGCTACCCAGGGGCTACTGTCAATGTGGAGGCCCTTCGACAGAAGATTATGGAATCC



GGAGGTATCAACAAAATTAGCACTGGCTTCACCTACGGGTCTTCCATCAATTCTGCCGGCA



CGACCAGAGCATGTATGAGAAATGGGGGCAACAGTTTTTACGCCGAGTTGAAGTGGCTGGT



GAGTAAGAGCAAAGGACAGAACTTCCCGCAGACCACCAACACATACAGGAATACGGATACC



GCCGAGCACTTAATCATGTGGGGAATTCACCACCCCAGTTCGACACAGGAGAAGAACGATC



TCTATGGCACTCAGTCTCTGTCTATTTCTGTGGGATCATCAACATATCGCAATAACTTTGT



ACCTGTTGTGGGGGCTAGGCCTCAGGTGAACGGCCAATCCGGACGAATCGACTTCCACTGG



ACTCTGGTTCAACCAGGTGATAATATTACTTTCTCACACAACGGCGGACTGATTGCACCTA



GCCGAGTGAGTAAGCTCATTGGTAGAGGACTGGGGATTCAGTCCGATGCCCCTATAGACAA



TAACTGCGAAAGCAAATGCTTCTGGCGCGGCGGAAGCATAAATACAAGATTGCCATTTCAG



AACCTGAGTCCTCGGACCGTTGGACAGTGTCCTAAATACGTGAACAGAAGAAGCCTGATGC



TTGCCACTGGCATGCGGAATGTGCCCGAGCTCATTCAGGGACGGGGCCTATTCGGCGCAAT



CGCCGGATTTCTGGAGAATGGTTGGGAAGGGATGGTCGATGGCTGGTACGGCTTTAGACAC



CAGAATGCACAGGGGACAGGGCAGGCGGCCGATTACAAATCCACTCAGGCTGCTATCGACC



AGATCACCGGCAAGTTAAATAGGTTGGTCGAGAAGACGAACACCGAATTCGAATCTATCGA



GTCAGAGTTTAGCGAGATTGAGCATCAGATAGGTAATGTGATTAACTGGACTAAGGACAGC



ATCACTGATATCTGGACTTACCAGGCAGAGCTCCTGGTTGCCATGGAGAACCAGCACACAA



TAGACATGGCCGACAGTGAAATGCTAAACCTGTACGAACGCGTGCGCAAGCAGCTCCGGCA



GAACGCAGAAGAAGATGGCAAGGGGTGTTTTGAGATATATCATGCATGCGATGACTCCTGT



ATGGAGAGTATCCGTAACAACACTTACGATCACTCCCAGTACCGTGAGGAGGCTCTGCTGA



ACAGACTGAACATCAACCCCGTAACTTTAAGTAGTGGATATAAGGATATCATTCTTTGGTT



TAGCTTCGGAGCAAGCTGTTTCGTCCTTCTCGCAGTGGTTATGGGCCTGTTCTTTTTTTGC



CTAAAGAATGGGAATATGCGGTGCACAATATGTATT





829
ATGTATAAGATCGTGGTGATTATTGCCCTGCTGGGCGCTGTGAAGGGCTTAGACAAGATTT



GCTTAGGTCACCATGCAGTGGCAAATGGAACAATTGTCAAGACATTGACCAATGAACAGGA



GGAGGTAACCAACGCTACAGAAACCGTTGAGTCCACCGGTATTAACCGGCTTTGCATGAAG



GGTCGCAAGCACAAGGATCTGGGCAATTGCCACCCCATCGGTATGCTCATTGGAACTCCCG



CATGTGATCTGCATCTGACAGGGATGTGGGATACGTTGATAGAGCGTGAGAACGCCATCGC



CTACTGTTACCCAGGTGCCACAGTGAACGTGGAAGCCCTGCGTCAAAAGATCATGGAATCC



GGAGGGATCAATAAAATTAGTACAGGCTTCACGTATGGCTCTTCCATCAACTCTGCTGGGA



CTACTCGTGCGTGCATGCGGAATGGAGGCAATTCATTTTACGCGGAACTAAAATGGCTTGT



GAGCAAAAGCAAAGGACAAAACTTCCCGCAGACGACCAACACGTATCGGAACACCGACACC



GCCGAACATCTAATCATGTGGGGCATCCATCATCCCTCATCCACCCAGGAAAAAAATGACT



TATACGGAACACAGTCATTGAGCATTTCCGTAGGATCAAGTACATACCGAAATAATTTCGT



GCCTGTGGTGGGTGCGGGCCCCCAAGTTAATGGCCAATCAGGCCGTATTGACTTTCATTGG



ACCCTCGTTCAGCCTGGCGACAACATCACCTTCTCCCATAACGGGGGACTCATCGCCCCAT



CAAGAGTGTCGAAGCTGATCGGCCGAGGACTCGGGATACAGTCTGACGCCCCCATCGACAA



TAATTGTGAATCCAAGTGCTTTTGGAGAGGAGGGTCAATCAACACCCGCCTACCTTTTCAG



AATCTTTCACCCAGGACCGTTGGGCAGTGTCCCAAATACGTGAACCGGAGATCTCTCATGC



TTGCAACCGGGATGAGAAACGTGCCAGAGCTCATCCAGGGGCGCGGCCTATTTGGGGCCAT



AGCCGGTTTTCTGGAGAACGGATGGGAGGGAATGGTTGATGGCTGGTACGGCTTCAGGCAC



CAGAACGCACAGGGCACCGGGCAAGCCGCAGACTACAAATCAACTCAGGCGGCTATCGATC



AGATCACAGGTAAATTAAACCGACTCGTCGAAAAGACAAATACCGAGTTTGAGTCTATCGA



ATCCGAGTTTTCTGAAATTGAGCATCAAATCGGCAACGTGATTAACTGGACTAAGGACTCC



ATCACCGATATTTGGACTTATCAAGCAGAACTACTGGTCGCCATGGAAAATCAACATACTA



TCGATATGGCAGATAGCGAAATGCTTAACCTCTACGAAAGAGTGCGAAAGCAGCTACGCCA



AAATGCCGAGGAAGACGGGAAGGGCTGCTTCGAGATTTACCATGCGTGTGATGATTCCTGC



ATGGAAAGTATTAGGAACAATACTTATGATCACAGCCAGTATCGTGAGGAAGCTCTGCTTA



ACAGACTTAACATCAATCCAGTGACACTCAGCAGTGGGTACAAAGACATCATCCTCTGGTT



CAGCTTTGGAGCTTCTTGCTTCGTTTTGCTTGCTGTAGTCATGGGACTGTTTTTTTTTTGT



CTGAAGAACGGTAATATGCGATGCACTATTTGTATA





830
ATGTATAAGATCGTGGTCATCATCGCTTTGCTGGGGGCTGTTAAGGGGCTCGACAAGATTT



GTTTGGGCCACCACGCCGTGGCCAACGGGACCATTGTGAAGACGCTGACAAATGAACAAGA



AGAAGTCACAAATGCCACAGAGACTGTTGAATCCACTGGCATTAATAGACTCTGCATGAAA



GGCAGGAAACACAAAGATCTGGGCAACTGTCACCCTATCGGAATGCTGATTGGCACTCCCG



CTTGTGATCTCCATCTTACAGGTATGTGGGATACCCTTATTGAGCGAGAAAATGCCATCGC



CTACTGTTATCCAGGTGCTACTGTGAACGTGGAGGCCTTGAGGCAGAAGATTATGGAGTCA



GGAGGCATCAATAAGATTTCCACCGGGTTTACATACGGCTCATCCATCAACTCCGCCGGCA



CGACTCGAGCTTGCATGAGAAACGGTGGCAACTCCTTTTATGCGGAGCTAAAGTGGCTGGT



CAGCAAGTCAAAAGGTCAGAACTTCCCCCAGACTACGAACACCTATCGGAATACAGACACC



GCTGAGCATTTGATCATGTGGGGAATCCACCATCCTAGCTCCACCCAGGAGAAGAATGACC



TGTATGGAACACAATCTCTTTCTATCTCCGTGGGCTCTTCTACCTACCGTAACAATTTCGT



TCCCGTTGTGGGGGCTCGGCCTCAGGTGAATGGTCAATCCGGAAGAATCGACTTTCACTGG



ACATTAGTACAGCCCGGCGACAACATTACATTTAGTCATAATGGGGGGCTGATCGCGCCTA



GTCGGGTCTCAAAGTTGATCGGGAGAGGCCTCGGAATCCAGAGCGATGCACCTATCGATAA



CAACTGTGAAAGCAAGTGCTTCTGGCGCGGCGGTTCTATTAATACCAGATTGCCCTTCCAG



AACCTGTCTCCCCGAACAGTCGGGCAGTGCCCCAAATACGTGAACAGGAGATCTCTGATGC



TGGCCACAGGGATGCGCAACGTGCCAGAGCTGATCCAGGGAAGGGGTCTCTTCGGGGCCAT



TGCCGGCTTTCTGGAAAATGGCTGGGAAGGGATGGTGGACGGGTGGTATGGCTTCAGGCAC



CAAAACGCGCAAGGCACTGGCCAGGCGGCGGATTACAAGAGCACGCAAGCTGCTATAGACC



AGATCACGGGGAAGCTGAACAGACTCGTGGAAAAGACTAATACTGAATTTGAATCGATCGA



GTCTGAGTTCTCCGAAATCGAGCATCAGATCGGGAATGTCATAAATTGGACCAAGGATTCC



ATTACAGATATTTGGACCTATCAGGCCGAACTGCTGGTGGCCATGGAGAATCAGCACACTA



TTGATATGGCCGACAGTGAGATGCTGAACCTGTATGAGCGTGTTAGGAAGCAACTTCGACA



GAACGCAGAAGAAGATGGTAAGGGATGTTTCGAGATTTACCATGCCTGTGACGACAGTTGT



ATGGAGAGCATTAGGAATAACACTTATGACCATAGCCAATACCGGGAAGAAGCTTTGTTAA



ATCGCCTGAATATCAATCCCGTCACGTTATCGTCGGGGTATAAGGATATTATTCTGTGGTT



CAGCTTCGGAGCGTCCTGCTTTGTTCTGTTGGCCGTGGTAATGGGGCTGTTTTTCTTTTGT



CTTAAGAACGGGAACATGCGCTGCACAATCTGCATC





831
ATGTACAAGATTGTGGTTATCATCGCACTGTTAGGAGCCGTGAAGGGGTTGGACAAGATCT



GTCTGGGGCATCATGCCGTTGCTAATGGAACAATCGTGAAGACGCTCACCAATGAACAAGA



AGAAGTCACAAACGCCACCGAAACCGTGGAGAGCACCGGAATTAACAGACTTTGTATGAAG



GGACGCAAACACAAGGATCTGGGGAACTGCCACCCAATCGGCATGCTGATAGGAACCCCTG



CCTGTGATCTGCACTTAACTGGCATGTGGGACACACTTATAGAGCGCGAGAACGCGATCGC



GTACTGCTACCCCGGAGCAACCGTTAACGTCGAAGCTTTGAGGCAGAAAATTATGGAAAGC



GGCGGCATAAATAAAATTTCTACTGGCTTTACGTACGGCAGCTCTATAAACAGTGCTGGCA



CCACTCGTGCCTGTATGCGGAACGGCGGCAATTCCTTTTACGCCGAATTAAAATGGCTTGT



TAGCAAGTCAAAGGGCCAGAACTTTCCGCAGACGACTAATACATACCGAAACACCGACACC



GCTGAACATCTGATTATGTGGGGTATACATCATCCAAGTTCCACCCAAGAAAAAAATGACT



TGTATGGGACCCAGAGCCTAAGCATCTCCGTGGGGAGTTCTACTTACCGAAACAACTTCGT



ACCTGTGGTGGGGGCCCGACCACAGGTAAATGGACAGTCGGGCCGGATTGATTTCCACTGG



ACCTTGGTGCAGCCGGGAGATAACATAACATTCTCTCATAACGGAGGTCTCATAGCCCCAA



GTCGTGTGTCAAAGCTCATCGGTAGAGGCCTGGGCATTCAGTCAGACGCACCCATTGATAA



TAACTGTGAGTCTAAATGCTTTTGGCGCGGGGGGAGTATCAATACTAGACTGCCTTTTCAG



AACCTCAGCCCAAGGACCGTGGGGCAGTGTCCCAAGTATGTAAATCGGCGAAGCTTAATGC



TGGCTACTGGTATGCGGAATGTGCCTGAACTCATTCAGGGACGGGGCCTCTTCGGAGCAAT



AGCTGGTTTCCTGGAGAACGGCTGGGAAGGCATGGTGGATGGTTGGTACGGTTTTAGACAC



CAAAATGCCCAGGGAACGGGACAGGCTGCCGACTATAAGTCAACTCAAGCCGCGATCGACC



AGATCACTGGTAAATTAAACCGACTCGTCGAAAAGACAAACACGGAGTTCGAGTCTATCGA



AAGTGAGTTCTCAGAGATTGAACACCAAATCGGGAATGTGATTAACTGGACAAAGGACTCG



ATAACCGATATCTGGACCTACCAGGCAGAACTTCTGGTGGCCATGGAAAACCAGCACACTA



TTGACATGGCCGACTCAGAGATGCTGAATCTGTACGAGAGAGTGAGGAAGCAGCTCCGCCA



GAATGCGGAGGAGGATGGTAAAGGCTGCTTCGAAATCTACCACGCTTGCGATGACTCCTGC



ATGGAATCAATCCGAAATAATACATATGACCACTCACAGTACAGAGAAGAAGCCCTTCTGA



ACCGCCTGAACATCAACCCCGTGACGCTGAGTTCAGGATATAAGGATATCATTCTCTGGTT



CTCCTTTGGGGCGAGTTGCTTCGTGCTGCTTGCGGTAGTCATGGGACTCTTTTTTTTTTGT



CTTAAGAACGGTAATATGCGGTGCACTATTTGTATC





832
ATGTACAAGATCGTGGTAATTATCGCCCTGCTCGGAGCTGTGAAAGGATTAGACAAAATTT



GCCTCGGCCACCATGCTGTAGCTAATGGTACAATAGTCAAAACCCTAACTAATGAACAGGA



AGAGGTGACTAATGCAACGGAAACTGTCGAGAGTACCGGCATTAACCGCCTGTGTATGAAA



GGGAGAAAGCACAAGGACTTAGGCAATTGTCATCCAATCGGGATGCTAATTGGCACTCCAG



CCTGTGATCTGCATCTGACCGGAATGTGGGACACCTTAATTGAGAGGGAAAACGCCATAGC



CTATTGCTATCCTGGGGCAACTGTTAATGTGGAAGCTCTCCGGCAAAAAATCATGGAATCT



GGAGGCATTAATAAGATCTCCACGGGCTTCACATATGGGTCCTCTATCAATTCCGCCGGGA



CCACGCGCGCATGCATGAGAAACGGAGGGAATTCTTTCTACGCGGAACTTAAGTGGCTGGT



CAGTAAGTCTAAAGGGCAGAATTTTCCTCAGACCACTAATACCTACAGAAATACGGATACA



GCTGAGCACCTCATTATGTGGGGAATACACCACCCTTCAAGCACACAGGAAAAAAACGATC



TCTACGGGACCCAGAGCCTGTCCATTAGTGTCGGATCTAGCACATACCGGAACAATTTCGT



ACCCGTTGTGGGAGCACGCCCACAGGTGAATGGGCAGTCAGGCAGAATCGATTTCCATTGG



ACTCTCGTGCAGCCCGGCGATAATATAACCTTCAGTCATAATGGCGGATTGATCGCCCCCT



CGCGTGTTTCAAAATTAATCGGGAGGGGGCTCGGGATACAAAGCGACGCTCCTATCGACAA



CAACTGTGAGTCCAAGTGTTTTTGGCGCGGGGGGAGCATTAATACCCGTCTCCCGTTCCAG



AACCTGTCTCCCCGGACAGTAGGACAGTGTCCGAAGTATGTCAATCGTAGAAGTCTTATGC



TGGCGACGGGAATGCGGAACGTGCCCGAGCTGATTCAAGGCCGGGGTCTGTTCGGAGCAAT



AGCTGGTTTCCTGGAGAATGGTTGGGAGGGCATGGTTGACGGCTGGTATGGGTTCAGACAT



CAGAACGCACAGGGAACCGGCCAGGCTGCTGACTATAAATCCACTCAGGCAGCCATAGATC



AGATCACCGGGAAGCTAAACCGGCTGGTTGAGAAAACTAATACGGAGTTCGAGTCTATCGA



GTCCGAGTTTAGCGAAATAGAGCATCAGATAGGGAACGTGATAAATTGGACGAAAGACTCT



ATTACCGACATCTGGACCTACCAGGCGGAACTGCTGGTGGCTATGGAGAATCAGCACACCA



TCGACATGGCTGATAGCGAAATGTTGAATCTGTACGAGCGGGTCAGAAAACAGTTAAGACA



GAACGCAGAGGAAGATGGAAAGGGCTGCTTCGAAATATATCACGCATGTGATGATTCCTGC



ATGGAGTCTATTAGAAACAACACTTATGACCATTCGCAGTACCGCGAAGAAGCGCTGCTAA



ACAGACTCAACATCAATCCTGTGACCTTGAGTAGCGGATACAAGGACATTATACTGTGGTT



CTCCTTTGGTGCCTCCTGTTTTGTCTTGCTTGCCGTAGTTATGGGCCTGTTCTTTTTCTGC



TTGAAGAACGGGAACATGCGCTGCACAATTTGTATC





833
ATGTATAAAGTGGTGGTGATTATCGCTTTACTGGGAGCTGTAAAGGGGCTGGATAAGATTT



GTCTGGGACATCACGCAGTCGCGAACGGCACCATTGTGAAAACACTTACTAATGAACAGGA



GGAGGTGACCAACGCCACCGAAACCGTCGAGTCAACAGGTATAAACAGATTGTGCATGAAG



GGCCGAAAGCACAAGGACCTGGGAAATTGTCATCCAATTGGAATGTTGATCGGCACTCCAG



CCTGCGATCTTCATCTTACCGGAACATGGGACACGCTTATTGAACGGGAAAATGCGATCGC



ATATTGCTACCCCGGGGCCACAGTGAATGTGGAGGCACTGAGACAGAAAATCATGGAAAGT



GGCGGGATCGACAAGATTAGTACTGGCTTTACATACGGGAGCAGCATCAACTCCGCCGGGA



CCACCCGAGCCTGCATGAGGAACGGGGGCAACAGTTTTTATGCTGAGCTGAAGTGGCTCGT



GTCAAAAAATAAGGGCCAGAATTTCCCTCAAACAACGAATACATATCGCAACACAGATACA



GCGGAACACTTAATCATGTGGGGCATTCACCACCCTAGCTCCATTCAAGAAAAGAACGATC



TCTACGGAACACAATCGTTGAGCATCTCAGTGGGGTCTTCCACCTATAGAAACAACTTTGT



ACCTGTGGTCGGCGCAAGACCTCAAGTCAATGGACAAAGCGGCAGAATCGACTTCCACTGG



ACTCTGGTGCAGCCAGGCGATAATATAACCTTCTCTCACAACGGGGGCTTGATCGCTCCCA



GCCGGGTATCTAAGTTAATCGGCCGTGGTCTCGGAATCCAGAGCGATGCACCGATTGACAA



TAACTGTGAAAGTAAATGTTTCTGGCGTGGGGGCTCTATAAACACTAGACTCCCCTTCCAG



AACTTGAGTCCTAGAACAGTGGGGCAGTGCCCGAAATACGTCAACCGGAGATCGTTGATGC



TCGCAACTGGCATGAGGAACGTCCCCGAGTTAATACAGGGACGGGGACTATTCGGCGCCAT



AGCCGGGTTCCTCGAGAACGGATGGGAGGGTATGGTTGATGGTTGGTACGGCTTTCGACAT



CAAAACGCACAAGGTACAGGGCAGGCTGCCGATTACAAGAGCACTCAGGCCGCCATCGACC



AGATCACTGGGAAACTCAACAGGTTAGTGGAGAAAACCAATACCGAATTTGAATCCATCGA



GAGCGAATTCTCAGAGATTGAGCATCAGATAGGAAATGTGATAAACTGGACCATGGATAGT



ATTACAGACATTTGGACGTACCAAGCAGAGCTGCTTGTCGCGATGGAGAATCAACACACCA



TCGACATGGCGGACTCCGAAATGCTGAATCTGTATGAGAGGGTTCGGAAACAGCTTAGACA



AAATGCAGAGGAGGATGGCAAGGGCTGCTTTGAGATCTACCACGCATGTGATGACTCCTGT



ATGGAATCCATCCGGAACAACACGTATGACCACTCTCAGTACAGAGAAGAGGCTCTCCTGA



ATCGCCTTAATATTAACCCTGTGACACTGTCCTCCGGCTATAAGGATATCATCCTGTGGTT



TAGCTTTGGAGCAAGCTGCTTCGTGTTGCTGGCCGTAGTTATGGGCCTGGTCTTCTTCTGT



CTTAAGAACGGAAACATGCGGTGCACAATCTGTATT





834
ATGTATAAGGTCGTCGTTATTATAGCGCTGCTTGGAGCTGTCAAAGGTTTGGATAAAATCT



GTCTGGGCCATCACGCAGTCGCCAACGGTACCATTGTGAAAACGCTCACAAACGAACAGGA



AGAGGTCACGAACGCCACAGAGACTGTGGAGTCTACAGGGATTAACCGCCTGTGCATGAAA



GGCCGGAAACATAAGGACCTTGGCAACTGCCATCCAATCGGCATGCTGATTGGCACTCCGG



CCTGTGATCTGCATTTGACCGGCACATGGGATACCCTGATCGAAAGGGAGAATGCCATCGC



TTACTGTTATCCCGGCGCAACTGTGAATGTGGAGGCACTGAGACAGAAGATCATGGAGTCT



GGGGGGATCGATAAAATTAGTACCGGGTTTACTTACGGCAGTTCGATTAATAGCGCGGGAA



CAACGAGGGCGTGTATGAGGAATGGAGGAAACTCCTTCTATGCCGAGCTCAAGTGGCTGGT



GAGCAAGAACAAGGGGCAAAACTTTCCCCAAACAACTAACACATACCGGAATACAGATACT



GCTGAACATCTGATAATGTGGGGAATCCACCATCCTTCTTCAATTCAGGAGAAAAACGATC



TTTACGGAACTCAAAGTTTAAGCATAAGTGTGGGGTCATCTACGTATAGAAACAACTTTGT



GCCCGTGGTTGGCGCAAGGCCGCAGGTGAATGGTCAATCTGGGAGGATAGATTTCCACTGG



ACATTGGTGCAGCCGGGTGATAATATCACCTTTTCCCATAATGGGGGATTGATTGCCCCCT



CCCGGGTGTCGAAACTTATTGGCCGCGGGCTAGGTATTCAGAGTGACGCCCCCATTGATAA



TAATTGTGAGTCTAAATGTTTTTGGGGGGGTGGCAGCATTAATACACGTCTGCCATTCCAG



AACCTGTCCCCCAGGACTGTCGGGCAATGCCCCAAATACGTGAATAGACGGTCTCTGATGC



TGGCCACTGGGATGCGCAATGTACCCGAGCTTATCCAGGGACGGGGCCTTTTTGGGGCCAT



CGCCGGTTTCCTGGAGAACGGGTGGGAAGGCATGGTTGATGGCTGGTATGGGTTTAGACAC



CAGAATGCTCAAGGGACTGGGCAGGCGGCCGATTATAAGAGTACACAGGCGGCCATCGACC



AGATCACAGGCAAGCTCAACCGTCTGGTGGAGAAAACAAATACAGAATTCGAAAGCATAGA



GAGTGAATTTTCTGAGATTGAGCACCAGATTGGTAATGTCATCAATTGGACAATGGATTCC



ATCACTGACATCTGGACATACCAAGCCGAGCTATTGGTGGCGATGGAGAATCAGCATACAA



TAGATATGGCCGACTCTGAAATGCTGAACTTATATGAGAGAGTGCGTAAACAGTTGAGGCA



GAATGCTGAAGAAGACGGTAAGGGATGTTTTGAGATATATCATGCCTGTGATGACAGTTGC



ATGGAATCCATCAGAAATAACACTTACGACCACAGCCAGTACAGAGAGGAAGCCCTACTGA



ACAGGCTCAATATCAATCCAGTGACTCTATCCAGCGGCTACAAGGACATTATCTTATGGTT



TTCTTTTGGTGCTTCATGTTTTGTGCTCCTCGCCGTGGTCATGGGGCTCGTCTTCTTCTGT



TTAAAGAATGGGAATATGCGGTGCACAATATGTATC





835
ATGTACAAAATAGTAGTAATCATTGCTTTGCTTGGCGCGGTGAAAGGCTTGGATAAGATTT



GCCTGGGACACCATGCTGTCGCGAATGGAACCATAGTTAAGACTTTGACTAATGAGCAAGA



GGAGGTGACCAACGCCACCGAAACGGTGGAGTCCACAGGCATCAACAGGCTCTGTATGAAA



GGACGGAAGCATAAGGACCTGGGGAACTGTCATCCAATTGGAATGCTGATCGGGACGCCCG



CGTGTGACCTCCATCTGACAGGGATGTGGGATACTCTTATTGAGAGAGAGAACGCTATCGC



CTACTGTTATCCTGGTGCTACAGTGAACGTGGAAGCCCTCAGGCAGAAGATTATGGAGAGC



GGTGGGATCAACAAGATTAGTACAGGGTTTACCTATGGGTCATCCATAAACAGTGCGGGCA



CTACCCGAGCGTGCATGCGCAATGGGGGCAATTCGTTCTATGCCGAACTGAAGTGGTTAGT



CTCTAAGTCTAAAGGTCAGAATTTTCCTCAGACAACTAACACATACCGGAATACCGATACC



GCTGAACACCTGATCATGTGGGGAATACATCACCCTAGTAGTACACAAGAGAAAAATGACC



TATATGGGACACAGAGCCTGTCAATTAGCGTGGGTAGTTCCACATATAGAAACAACTTTGT



TCCTGTCGTGGGTGCCCGGCCTCAGGTAAATGGGCAGAGCGGACGGATAGATTTTCATTGG



ACTTTGGTCCAGCCCGGGGATAACATTACCTTCTCTCATAACGGGGGGCTGATCGCTCCAA



GCCGGGTGTCTAAGCTCATAGGCAGAGGCCTGGGTATCCAATCGGACGCCCCCATCGATAA



CAACTGTGAAAGTAAATGCTTTTGGAGGGGCGGCAGTATTAATACGCGGCTACCGTTTCAG



AATCTGTCTCCACGCACAGTAGGGCAGTGTCCAAAGTACGTCAACCGCAGATCCCTCATGC



TGGCCACGGGGATGAGGAACGTGCCCGAGCTGATCCAGGGGAGGGGCCTATTTGGGGCTAT



CGCCGGCTTCCTGGAGAATGGTTGGGAGGGAATGGTCGATGGCTGGTACGGCTTTCGCCAT



CAGAACGCCCAAGGAACTGGACAAGCTGCCGACTACAAAAGCACGCAAGCCGCCATCGATC



AAATTACCGGAAAGCTGAATCGGCTAGTGGAGAAGACCAACACCGAATTTGAGTCTATAGA



GTCAGAGTTTAGCGAAATCGAGCATCAGATTGGCAACGTCATTAATTGGACCAAGGACAGC



ATAACCGACATATGGACATACCAAGCCGAACTCCTGGTAGCTATGGAAAATCAGCATACCA



TCGATATGGCAGATTCCGAAATGCTGAACCTGTATGAAAGAGTGAGGAAGCAACTGCGTCA



GAATGCCGAGGAAGACGGCAAGGGGTGCTTTGAGATCTACCACGCATGTGATGATTCTTGC



ATGGAGAGCATCAGGAATAATACATACGACCACAGCCAGTACCGGGAAGAAGCCCTATTGA



ACAGGCTTAACATCAATCCCGTCACTCTATCCAGCGGCTATAAAGATATAATCTTATGGTT



TTCCTTTGGCGCGTCTTGCTTTGTGCTCCTGGCGGTGGTGATGGGCTTATTCTTCTTTTGT



CTCAAGAATGGCAACATGAGGTGCACAATCTGCATT





836
ATGTACAAGATAGTGGTCATCATCGCACTCCTGGGCGCCGTGAAGGGCCTGGATAAAATTT



GCCTGGGGCACCATGCCGTCGTGAACGGCACGATCGTCAAGACTCTCACTAATGAGCAGGA



GGAAGTCACTAATGCTACGGAGACAGTTGAGTCGACCGGATTGAATAGATTGTGCATGAAG



GGACGTAACCACAAGGACCTCGGGAACTGCCACCCAATTGGCATGTTGATCGGAACACCCG



CCTGCGATCTCCATCTGACCGGTACGTGGGATACACTTATCGAGAGGGAAAACGCAATCGC



CTATTGCTATCCCGGTGCAACCGTTAACGAAGAAGCTCTGAGGCAGAAAATCATGGAGTCT



GGTGGGATTAACAAGATTAGTACAGGGTTTACATACGGAAGCTCCATCAACAGTGCAGGCA



CTACCCGTGCCTGCATGAGAAACGGAGGCAACTCTTTTTACGCTGAACTTAAATGGTTAGT



AAGCAAGAGTAAAGGCCAGAATTTTCCACAGACGACAAACACATACAGAAACACCGACACA



GCCGAACACCTGATCATGTGGGGCATCCACCACCCATCCAGCACCCAGGAGAAGAACGATC



TATATGGAACTCAGAGCCTGTCTATTAGCGTAGGCAGTTCAACCTACCAGAATAACTTCGT



GCCAGTGGTGGGAGCTCGGCCTCAGGTTAATGGACAGAGCGGCAGAATCGACTTCCACTGG



ACTCTCGTGCAACCCGGCGATAACATCACTTTTTCGCATAATGGAGGCTTAATCGCACCCT



CCCGAGTCAGCAAGCTCATCGGAAGGGGATTAGGCATACAGAGTGATGCACCCATCGATAA



CAACTGCGAAAGTAAGTGCTTCTGGCGAGGGGGTTCCATTAATACTAGATTACCATTTCAA



AATCTGAGTCCAAGAACCGTTGGTCAGTGCCCGAAGTATGTCAATAAGCGTTCTCTGATGT



TGGCAACTGGGATGAGGAATGTGCCAGAACTGATGCAAGGGCGAGGCCTCTTTGGTGCAAT



CGCTGGCTTTATAGAGAACGGGTGGGAAGGGATGGTGGATGGCTGGTATGGGTTCCGCCAT



CAGAATGCACAAGGCACCGGTCAGGCCGCCGACTACAAGTCAACCCAGGCGGCTATCGATC



AAATCACGGGGAAACTGAACAGGTTAATCGAAAAAACAAACACAGAGTTCGAGTCAATCGA



GTCTGAGTTTTCTGAAATTGAGCACCAAATCGGGAATGTGATTAACTGGACAAAAGACTCT



ATCACAGACATCTGGACCTACCAGGCCGAACTCCTGGTGGCCATGGAGAATCAACACACCA



TTGACATGGCGGACTCCGAAATGCTGAATCTGTATGAGAGGGTTAGGAAACAACTTAGGCA



GAATGCTGAGGAAGACGGCAAAGGCTGTTTTGAAATTTACCACGCCTGTGATGATAGTTGT



ATGGAGAGCATTCGGAACAATACCTACGATCACTCTCAATATCGCGAGGAAGCTCTGCTTA



ACAGGCTTAACATTAACCCCGTGACGCTGTCAAGTGGCTACAAAGACATTATTCTCTGGTT



CTCCTTCGGTGCATCATGCTTTGTTCTGCTGGCTGTTGTCATGGGCTTAGTGTTCTTCTGC



CTCAAGAACGGTAATATGAGATGTACCATCTGCATT





837
ATGTATAAGGTGGTGGTGATCATCGCCCTCTTGGGTGCTGTTAGAGGGCTGGATAAAATCT



GTCTAGGACATCATGCCGTGGCAAACGGTACTATCGTAAAAACTCTGACAAATGAGCAGGA



GGAGGTGACCAACGCTACTGAGACCGTCGAGTCAAAGAGCCTGGGAAAGTTGTGCATGAAA



GGGAGGTCATATAATGACCTGGGGAACTGTCACCCTATAGGTATACTTATTGGCACCCCTG



CCTGCGATCTCCATCTCACTGGGACATGGGACACCCTGATTGAACGGGAGAACGCTGTTGC



TTATTGCTACCCCGGTGCTACAGTTAATGAGGAGGCGTTGCGTCAGAAGATAATGGAAAGC



GGGGGAATCTCGAAGATTAGCACTGGCTTTACCTACGGGACCAGTATTAATAGCGCGGGAA



CCACAAAAGCCTGCATGAGAAACGGAGGCAACAGCTTTTACGCCGAATTGAAATGGTTAGT



GTCAAAGAACAAAGGACAGAACTTCCCTCAGACCACAAACACGTACAGAAACACCGATACT



GCTGAGCACTTGATTATCTGGGGCATTCATCACCCATCTAGCACACAAGAGAAAAATGATC



TGTATGGAACCCAGTCACTGAGCATCTCAGTCGGCAGTTCCACTTACCAAAATAATTTTGT



TCCTGTGGTGGGAGCACGCCCACAGGTGAATGGACAGTCTGGAAGGATTGATTTTCACTGG



ACCCTGTTGCAGCCAGGAGACAATATAACCTTCAGTCATAACGGGGGCCTCATCGCGCCGT



CTCGGGTGTCAAAGTTGATTGGAAGAGGACTCGGGATTCAATCCGAAGCCCCCATCGATAA



TGGCTGTGAATCTAAATGCTTTTGGAAAGGTGGTTCGATCAATACAAAGCTGCCCTTCCAA



AACCTTTCCCCGCGGACAGTTGGACAATGCCCCAAGTACGTGAACAAGCGCAGTCTGATGC



TCGCCACCGGGATGAGAAACGTGCCGGAGATTATGCATGGCAGGGGCCTGTTCGGAGCTAT



CGCTGGATTCATTGAAAACGGGTGGGAGGGCATGGTTGACGGCTGGTATGGATTCAGGCAT



CAGAACGCACAGGGGACAGGCCAGGCAGCTGACTATAAGAGTACCCAGGCCGCTATCGACC



AAATAACAGGTAAGCTTAACCGTCTTATCGAAAAAACTAACACAGAGTTCGAATCAATCGA



AAGCGAATTCAGTGAGATTGAACACCAGATTGGTAACATAATTAATTGGACAAAAGACTCT



ATCACAGATATTTGGACCTACCAGGCAGAACTGCTCGTGGCCATGGAAAACCAGCACACTA



TCGATATGGCAGATTCCGAAATGTTAAACCTGTATGAGCGAGTGCGAAAACAACTGCGCCA



AAATGCAGAGGAAGACGGGAAAGGCTGTTTTGAAATTTACCATGCGTGCGACGATTCTTGT



ATGGAATCCATCAGAAACAACACATATGATCACTCTCAGTATAGAGAAGAGGCTCTTCTGA



ATCGCTTGAATATAAACCCTGTGAAGTTAAGTTCAGGGTATAAAGATATCATCCTTTGGTT



CTCTTTCGGGGCTTCTTGTCTGATCTTGCTTGCTGTGGTCATGGGTCTCGTGTTTTTTTGT



CTGAAAAACGGCAACATGCGATGTACAATTTGTATT





838
ATGTACAAGATTGTAGTCATCATCGCCCTACTGGGTGCAGTCAAGGGACTGGACAAAATAT



GCCTGGGCCATCATGCAGTGGCCAACGGGACCATTGTTAAGACACTTACAAATGAGAAAGA



AGAGGTTACTAATGCCACCGAAACTGTGGAGTCCACCGGCCTAAACCGACTCTGCATGAAG



GGAAGGAAACACAAAGATCTGGGAAACTGCCACCCCATAGGGATGCTCATCGGCTCTCCCG



CATGTGACCTGCATCTGACAGGAACCTGGGATACCCTGATCGAGAGAGAAAACGCGATCGC



CTATTGTTACCCCGGCGCGACAGTGAATGGTGAGGCTCTGCGCCAAAAAATAATGGAATCA



GGAGGAATAGACAAAATTTCAACAGGATTTACATACGAATCCTCCATTAATAGCGCCGGCA



CAACTAGAGCTTGTATGCGGAATGGGGGCAATTCCTTTTACGCGGAGCTGAAATGGTTGGT



ATCTAAAAGCAAAGGACAGAACTTCCCTCAGACTACCAACACCTATCGAAATACAGACACA



GCCGAGCACTTAATTATGTGGGGGATACATCACCCCTCTTCTACACAGGAGAAAAATGACT



TATACGGAACCCAATCCTTAAGCATTAGTGTGGGCAGCAGCACATATCGAAACAATTTTGT



ACCAGTGGTAGGAGCTCGCCCTCAGGTGAATGGACAGAGCGGCCGGATTGATTTCCACTGG



ACACTGGTTCAGCCTGGCGACAATATCACATTCAGCCATAACGGTGGTTTGATTGCTCCTT



CCAGAGTCAGTAAATTGATCGGGAGAGGACTGGGGATTCAGTCAGACGCCCCCATTGATAA



TAACTGTGAAAGCAAGTGCTTTTGGAGAGGTGGATCCATCAACACACGTCTGCCCTTCCAG



AACCTGAGTCCCCGGACAGTCGGTCAGTGTCCGAAGTACGTCAACAAACGGAGTTTAATGC



TCGCGACTGGGATGAGGAACGTGCCTGAACTTATGCAAGGCCGGGGCTTATTCGGGGCCAT



TGCGGGCTTTCTGGAAAACGGGTGGGAAGGGATGGTTGATGGGTGGTACGGGTTCAGACAC



CAGAATGCTCAGGGCACCGGACAAGCCGCAGATTATAAGTCAACCCAGGCCGCAATAGATC



AGATTACCGGCAAACTGAACAGGCTCGTCGAGAAAACCAATACTGAGTTTGAATCTATTGA



AAGCGAGTTTTCAGAGATTGAACATCAAATCGGCAATGTGATTAATTGGACCAAAGATTCG



ATTACAGATATATGGACCTACCAGGCTGAACTTCTTGTCGCCATGGAAAACCAGCATACGA



TCGATATGGCCGACAGCGAAATGTTAAACCTATACGAGCGGGTGAGGAAGCAGCTGAGGCA



GAACGCAGAAGAGGACGGGAAAGGCTGTTTTGAAATATACCACGCCTGTGATGATTCTTGC



ATGGAGTCGATCCGTAACAACACATACGACCATTCTCAATATCGAGAGGAAGCATTATTGA



ACAGGTTAAACATCAATCCCGTTACTCTCTCCAGCGGATATAAAGACATTATCCTTTGGTT



TTCATTCGGAGCATCCTGTTTTGTCTTACTAGCCGTCGTAATGGGTTTAGTCTTCTTTTGC



CTTAAGAACGGGAATATGAGGTGTACCATATGTATT





839
ATGTATAAAATCGTGGTGATCATCGCTCTTCTTGGCGCTGTGAAGGGGCTCGACAAGATCT



GCTTAGGTCATCACGCAGTGGCTAATGGTACGATCGTGAAGACACTGACGAATGAACAGGA



AGAAGTCACAAATGCCACGGAGACCGTTGAGAGCACTGGCATCAATAGACTGTGCATGAAA



GGACGCAAGCACAAGGACCTGGGCAATTGCCATCCTATCGGCATGCTGATTGGAACGCCGG



CGTGTGACCTGCATTTGACCGGGATGTGGGATACCCTAATCGAGAGGGAGAACGCAATTGC



CTATTGTTACCCCGGCGCAACCGTGAATGTGGAAGCCCTGCGACAAAAGATCATGGAGAGT



GGTGGCATTAATAAGATTTCTACCGGGTTCACTTATGGCAGTAGCATCAACTCTGCCGGCA



CAACCAGGGCTTGTATGAGGAATGGAGGCAACAGCTTTTATGCTGAACTTAAATGGCTCGT



CAGCAAGTCTAAAGGTCAGAACTTCCCTCAGACCACAAATACATACAGAAATACTGACACA



GCCGAGCACCTCATCATGTGGGGCATCCATCATCCATCTTCCACCCAAGAGAAAAACGACC



TCTACGGGACACAGAGCCTGTCTATAAGCGTGGGCTCTAGCACTTATAGAAATAATTTCGT



TCCAGTGGTGGGCGCACGTCCCCAAGTTAACGGCCAGAGCGGAAGGATCGATTTCCATTGG



ACTCTGGTGCAGCCTGGGGACAACATTACATTTTCCCACAATGGAGGTCTTATTGCACCCT



CACGGGTATCCAAGTTAATCGGCCGCGGACTTGGCATCCAATCAGATGCACCCATCGACAA



CAATTGTGAGAGTAAGTGCTTCTGGCGTGGTGGGAGCATCAACACGAGATTACCTTTCCAG



AATCTGAGCCCGAGAACAGTAGGGCAATGTCCAAAGTATGTGAACAGGCGCAGCCTCATGC



TCGCGACCGGAATGAGAAATGTTCCCGAACTGATACAAGGAAGGGGTTTGTTCGGCGCCAT



CGCAGGATTTCTGGAAAACGGGTGGGAGGGAATGGTGGACGGTTGGTACGGCTTCCGTCAC



CAGAACGCCCAGGGCACGGGTCAGGCCGCAGACTATAAAAGTACCCAGGCGGCCATTGATC



AGATAACAGGCAAGCTCAACCGGCTGGTAGAAAAAACCAATACAGAGTTTGAGAGCATAGA



GTCCGAGTTTAGCGAGATAGAACATCAAATAGGAAATGTCATCAACTGGACCAAGGACAGC



ATCACGGATATTTGGACTTACCAGGCCGAATTACTGGTTGCTATGGAGAACCAGCACACTA



TTGATATGGCAGATTCTGAAATGTTAAACTTATATGAACGCGTGAGAAAGCAGTTGAGGCA



GAATGCTGAGGAGGACGGGAAGGGCTGCTTTGAAATATACCATGCCTGCGACGATAGCTGT



ATGGAGAGCATCAGGAACAATACATACGATCACAGTCAATACCGCGAGGAGGCTTTACTCA



ACCGGCTCAACATAAACCCCGTCACTCTCTCTTCGGGCTACAAGGATATTATTCTGTGGTT



TTCATTCGGCGCTTCCTGCTTCGTTCTCCTAGCCGTAGTAATGGGCCTCTTCTTCTTCTGC



CTGAAAAACGGCAACATGCGGTGTACTATCTGCATT





840
ATGTACAAGATTGTGGTCATCATCGCCCTGCTGGGCGCCGTCAAGGGGCTCGATAAGATTT



GCCTAGGTCACCACGCCGTCGCCAATGGCACGATTGTTAAAACACTGACCAATGAACAGGA



GGAAGTGACTAACGCTACGGAAACAGTGGAATCTACAGGGATTAACAGACTTTGCATGAAG



GGGCGCAAGCATAAGGACCTTGGAAATTGCCACCCAATCGGAATGCTTATCGGAACACCTG



CTTGTGACCTTCATCTGACCGGCATGTGGGACACCCTGATAGAGAGGGAGAACGCCATCGC



CTACTGCTATCCTGGAGCCACCGTCAATGTCGAAGCCTTAAGACAGAAAATAATGGAAAGT



GGGGGTATAAACAAAATCAGCACTGGCTTCACTTATGGTTCTTCTATCAATAGCGCAGGGA



CAACCAGAGCCTGCATGCGCAATGGGGGCAATAGCTTTTATGCCGAACTGAAGTGGCTGGT



CTCTAAATCTAAGGGTCAAAATTTTCCTCAGACAACCAACACATACCGCAATACGGACACC



GCGGAGCATCTCATTATGTGGGGGATTCACCACCCTTCAAGCACCCAGGAGAAGAATGACC



TCTATGGGACACAGAGCCTGTCAATCTCAGTGGGATCTAGCACTTATCGTAACAATTTCGT



TCCAGTAGTTGGTGCACGCCCCCAGGTTAATGGGCAGAGTGGGCGAATTGATTTCCACTGG



ACGCTCGTGCAGCCCGGCGATAATATCACATTCAGTCACAATGGGGGGCTAATCGCCCCGT



CCAGAGTTTCTAAGCTGATCGGCAGAGGATTAGGAATTCAATCCGACGCACCCATTGACAA



CAATTGTGAATCAAAATGCTTCTGGCGCGGAGGGTCGATAAACACACGACTTCCTTTTCAA



AACTTATCCCCAAGAACCGTGGGACAGTGCCCCAAGTACGTCAATAGAAGATCACTGATGC



TGGCCACCGGTATGAGGAATGTGCCCGAACTAATCCAGGGCCGCGGGTTGTTCGGCGCTAT



TGCAGGCTTTTTAGAAAACGGCTGGGAAGGGATGGTCGACGGATGGTACGGGTTCAGGCAT



CAGAATGCGCAGGGCACTGGGCAGGCCGCGGATTATAAGAGTACCCAGGCGGCCATAGATC



AAATAACCGGCAAGCTCAACAGGCTGGTCGAGAAGACAAACACAGAGTTTGAGTCAATAGA



GTCCGAATTCTCCGAAATCGAACACCAAATAGGCAATGTGATAAACTGGACCAAGGACTCC



ATCACCGATATCTGGACTTATCAGGCTGAACTGTTAGTGGCGATGGAAAACCAGCACACAA



TCGATATGGCAGACTCAGAGATGCTTAATCTGTATGAACGAGTTAGAAAGCAGCTCCGGCA



GAATGCCGAGGAAGACGGAAAGGGCTGCTTCGAGATCTACCACGCGTGCGATGATTCCTGT



ATGGAGTCTATTCGCAATAACACGTATGATCATTCACAGTATAGAGAAGAGGCCCTCCTAA



ACAGGCTCAACATCAACCCTGTGACGCTGTCGAGCGGCTATAAGGATATTATACTGTGGTT



TAGTTTCGGCGCCAGTTGCTTTGTCCTTCTTGCCGTGGTAATGGGATTATTCTTCTTCTGT



CTGAAAAACGGAAACATGAGATGCACAATATGTATC





841
ATGTATAAAATTGTAGTCATTATTGCCTTGTTAGGTGCAGTGAAGGGCTTAGACAAAATAT



GCCTAGGTCATCACGCCGTCGCTAATGGTACAATAGTCAAGACCCTCACCAATGAACAGGA



GGAGGTCACGAACGCAACAGAGACCGTGGAGTCCACAGGAATAAACCGACTGTGTATGAAG



GGCAGAAAACATAAAGACTTGGGCAACTGTCACCCTATAGGCATGTTGATTGGCACACCAG



CTTGTGATCTCCACCTAACCGGGATGTGGGACACCCTCATAGAACGCGAGAACGCTATCGC



CTATTGTTATCCCGGGGCCACGGTTAATGTGGAAGCTCTGCGACAGAAGATCATGGAGAGC



GGGGGGATTAATAAGATAAGCACTGGTTTCACCTACGGCTCAAGTATCAATTCAGCTGGCA



CCACCCGAGCATGTATGAGGAATGGCGGAAATAGCTTTTATGCAGAACTGAAGTGGTTAGT



CAGTAAAAGTAAAGGTCAGAACTTTCCACAGACCACCAACACATATCGCAATACTGATACA



GCTGAGCACTTAATCATGTGGGGAATTCACCATCCCAGTTCCACACAAGAAAAAAATGATT



TATACGGCACTCAGTCCCTTTCAATCAGCGTGGGGTCCTCTACCTACAGGAATAACTTTGT



CCCCGTGGTTGGCGCCAGACCCCAGGTAAACGGTCAGTCTGGACGGATCGATTTCCACTGG



ACACTGGTGCAGCCAGGTGACAATATTACCTTCAGCCACAATGGGGGCCTGATCGCCCCCT



CAAGAGTGTCCAAGCTGATCGGAAGAGGGTTGGGGATCCAGTCCGATGCCCCAATCGACAA



TAACTGCGAATCCAAATGTTTCTGGCGCGGAGGCTCAATAAATACCAGACTCCCTTTCCAG



AACCTTTCACCAAGAACAGTCGGACAATGCCCTAAGTATGTCAATCGCCGATCGCTAATGC



TTGCGACAGGGATGAGAAATGTGCCAGAGCTGATTCAAGGGCGCGGGCTGTTCGGCGCTAT



CGCCGGCTTTTTAGAGAATGGTTGGGAAGGGATGGTGGATGGCTGGTATGGATTTAGGCAC



CAGAACGCTCAGGGGACAGGGCAGGCTGCCGACTATAAGAGCACACAGGCAGCCATTGACC



AAATCACTGGGAAATTGAACCGTCTTGTGGAAAAAACTAACACCGAGTTCGAGTCCATTGA



GTCCGAGTTCTCGGAGATAGAACACCAAATCGGGAACGTCATCAATTGGACAAAAGATTCC



ATCACCGATATCTGGACTTACCAGGCTGAGTTGCTGGTCGCTATGGAGAACCAGCACACGA



TCGACATGGCAGACTCTGAGATGTTGAACCTGTATGAGAGAGTGCGAAAACAGCTCAGACA



GAACGCTGAAGAAGACGGAAAGGGGTGCTTCGAGATCTATCATGCCTGTGACGATAGCTGT



ATGGAGAGCATAAGAAACAATACGTATGATCACTCTCAGTACAGAGAAGAGGCCCTGCTAA



ATCGGTTAAACATTAATCCAGTGACCCTGAGCAGCGGCTACAAGGACATCATCCTATGGTT



TTCTTTCGGTGCCTCGTGCTTCGTCTTACTCGCTGTCGTCATGGGTCTGTTCTTCTTTTGC



CTGAAGAACGGCAATATGCGGTGTACAATCTGTATT





842
ATGTATAAAGTGGTCGTGATTATTGCTCTGTTAGGCGCCGTGCGCGGCTTGGATAAGATCT



GCCTAGGCCATCACGCCGTCGCTAACGGCACTACCGTAAAGACCCTGACCAACGAGCAGGA



AGAAGTCACAAATGCTACCGAGACCGTTGAGAGCACTTCGTTGAACAAGTTATGCATGAAG



GGCAGACGCTACAAGGATCTGGGTAATTGCCACCCCATAGGGATGCTCATTGGAACGCCCG



TCTGTGACTTGCATTTGACCGGCACATGGGATACCCTCATCGAGCGGGAAAACGCCACAGC



ATACTGCTATCCTGGGGTGACTATCAACGAGGAAGCATTGAGGCAAAAGATCATGGAATCA



GGCGGGATCAGTAAGATGAGAACCGGGTTCACCTACGGGCCTTCCATCAACTCCGCCGGCA



CCACCCGCAGTTGTATGAGAAACGGCGGCAATTCTTTTTATGCTGAGCTGAAGTGGTTGGT



CTCTGGGACCAAGGGCCAAAATTTTCCTCAAACAACGAATACCTACCGGAATACTGACACG



GCTGAACATCTGATCATCTGGGGGATTCACCACCCCTCATCCACCCAAGAGAAGAATGATC



TGTATGGAACGCAGAGCCTGTCTATTTCGGTTGGAAGCAGTACATACCAGAATAACTTCGT



GCCCGTTATTGGGGCCCGTCCCCAGGTCAACGGTCAGTCGGGCCGGATTGAGTTCCATTGG



ACCCTGGTCCGCCCTGGTGACAACATTACTTTTTCGCATAACGGTGGGCTAATCGCACCTG



ATCGAGTGTCCAAGCTGATCGGCAAAGGAATTGGTATACAGTCTGGTGCGGTAATCGATAA



GGACTGTGAAAGCAAATGCTTCTGGAGAGGCGGCAGTATCATCACCGAACTCCCCTTTCAG



AATCTCTCTCCACGTACAGTGGGCCAGTGTCCAAAGTATGTTAAAAAGCGGTCTCTGTTAC



TAGCCACGGGGATGAGGAATGTTCCCGAGGTGGTACAAGGACGGGGCCTCTTCGGGGCGAT



CGCCGGCTTCATTGAAAACGGCTGGGAGGGTATGGTTGACGGATGGTACGGATTCCGCCAC



CAAAACGCCCAGGGAATCGGCCAGGCTGCCGACTACAAATCCACTCAGACCGCCATCGACC



AAATTACGGGTAAACTGAACCGCCTAATCGAGAAGACAAATACTGAATTTGAGAGCATTGA



GAGTGAGTTCAGCGAAATCGAGCACCAGATCGGAAATGTGATTAATTGGACAAAGGATAGT



ATTACCGACATCTGGACCTACCAGGCGGAGCTCCTTGTGGCTATGGAAAACCAACACACCA



TTGACATGGCCGACAGTGAAATGCTGAATCTCTACGAGCGCGTGAGAAAGCAGCTCCGGCA



GAACGCCGAGGAGGACGGCAAAGGATGCTTCGAAATATATCACACATGTGACAACTCATGC



ATGGAAAGTATTAGGAACAACACCTACGACCATTCCCAATACAGAGAGGAGGCCCTACTTA



ACCGCCTTAACATCAATCCCGTGAAACTCTCCTCCGGTTATAAAGATATCATTTTATGGTT



CAGCTTCGGGGCGAGTTGCTTTGTGCTGCTGGCTGTGATTATGGGCCTGGGATTCTTTTGC



CTAAAAAACGGAAACATGCGATGCACTATCTGTATC





843
ATGTATAAAATTATTGTGATCATTGCACTGCTGGGGGCCGTTAAGGGTCTGGACAAAATTT



GTCTAGGACACCACGCTGTGGCAAACGGTACTATCGTGAAAACATTGACCAACGAACAGGA



GGAGGTTACCAACGCCACCGAGACAGTCGAAAGTACCGGAATTAATCGCCTCTGCATGAAA



GGCCGAAAGCATAAGGACCTGGGGAATTGCCATCCCATCGGAATGCTGATCGGCACCCCAG



CCTGTGACTTGCATCTTACAGGAACCTGGGACACACTAATCGAAAGGGAAAACGCCATTGC



TTACTGTTACCCGGGCGCTACAGTTAACGTGGAGGCCCTTAGGCAGAAAATCATGGAGTCC



GGCGGGATCGACAAGATCAGTACCGGCTTCACCTATGGGTCAAGCATCAATTCTGCGGGCA



CTACGAGGGCATGCATGAGGAACGGAGGCAACTCATTCTATGCGGAATTGAAGTGGCTGGT



CTCCAAGTCCAAAGGGCAGAACTTCCCTCAAACTACTAACACCTACCGGAATACAGACACA



GCGGAACACCTCATTATGTGGGGCATCCACCACCCTTCTAGTACTCAAGAGAAGAATGATC



TCTACGGCACTCAGTCCCTGAGTATTAGTGTCGGCTCAAGCACCTATAGAAACAATTTCGT



GCCCGTTGTGGGGGCCCGCCCTCAGGTTAATGGTCAATCAGGGCGAATTGATTTTCACTGG



ACCCTGGTCCAGCCCGGGGACAACATAACATTCAGCCATAATGGGGGTCTGATTGCCCCCA



GCCGGGTGAGCAAGTTGATAGGGAGGGGACTTGGCATCCAGAGTGACGCCCCTATTGACAA



CAACTGCGAAAGCAAATGCTTTTGGCGGGGTGGCTCAATAAACACAAGGCTACCCTTCCAA



AATTTGAGTCCAAGGACCGTGGGTCAATGCCCTAAATACGTCAATCGCCGCTCCTTGATGC



TCGCCACTGGGATGCGCAACGTGCCTGAGCTTATTCAGGGTCGGGGTCTGTTCGGGGCTAT



CGCCGGGTTCCTTGAAAATGGCTGGGAGGGTATGGTAGACGGCTGGTACGGATTTAGACAC



CAGAACGCCCAGGGAACGGGCCAGGCGGCAGACTACAAGTCTACCCAAGCTGCAATCGATC



AGATCACTGGCAAGTTAAACAGACTGGTGGAAAAGACAAATACCGAATTTGAAAGCATTGA



ATCGGAATTCTCAGAGATCGAGCACCAGATTGGAAATGTGATTAATTGGACGAAAGACAGT



ATTACCGACATCTGGACTTATCAGGCAGAACTGCTGGTTGCCATGGAAAACCAGCATACCA



TAGATATGGCAGATTCTGAAATGCTCAATCTTTACGAGCGCGTACGGAAACAGTTAAGACA



GAACGCAGAGGAGGACGGGAAAGGTTGCTTTGAAATATACCACGCATGTGACGATTCTTGC



ATGGAAAGTATCCGCAATAATACGTATGATCACAGTCAATACCGAGAAGAGGCTCTCTTGA



ATCGTTTGAATATCAATCCAGTGACCCTGTCCTCCGGATATAAGGATATAATTCTGTGGTT



CAGTTTTGGGGCAAGTTGCTTCGTCCTCCTCGCTGTCGTTATGGGACTGTTTTTTTTTTGT



CTAAAGAACGGAAACATGCGCTGCACTATATGCATT





844
ATGTATAAAATAGTTGTCATCATTGCACTCTTGGGCGCCGTGAAAGGACTGGATAAAATAT



GTCTCGGCCACCATGCAGTTGCAAACGGGACAATTGTGAAAACATTGACCAACGAGCAGGA



GGAGGTGACCAATGCTACAGAGACGGTGGAATCTACTGGCATCAACCGATTGTGCATGAAA



GGTAGGAAACACAAGGATTTGGGTAATTGCCATCCGATTGGGATGCTTATCGGAACCCCAG



CTTGCGATCTGCATTTGACCGGAATGTGGGACACCCTGATTGAGAGGGAAAACGCCATCGC



CTACTGCTATCCTGGCGCAACAGTTAACGTGGAGGCACTTCGCCAGAAGATCATGGAAAGC



GGGGGGATAAACAAGATCTCTACAGGTTTCACCTATGGTTCTTCCATTAACAGCGCCGGTA



CCACACGAGCTTGTATGCGAAATGGGGGCAACTCCTTCTACGCTGAATTAAAATGGCTGGT



GTCGAAGTCCAAAGGGCAGAACTTCCCTCAGACAACAAACACCTACCGGAACACAGACACC



GCGGAGCACCTGATCATGTGGGGTATACACCACCCCAGCTCTACCCAGGAAAAGAATGATC



TCTATGGAACCCAGTCATTAAGTATCAGCGTCGGTTCCTCTACATATCGTAATAATTTCGT



GCCTGTGGTTGGCGCCAGGCCACAAGTGAATGGGCAGTCCGGCAGAATTGACTTTCATTGG



ACTCTGGTGCAGCCAGGCGACAATATCACATTCTCTCACAACGGGGGACTTATCGCCCCCT



CCAGGGTGTCAAAACTCATCGGCCGGGGGCTGGGAATCCAAAGCGATGCTCCCATCGACAA



CAATTGCGAATCAAAATGTTTCTGGCGAGGGGGTTCCATAAATACCAGACTGCCATTCCAG



AACCTGTCCCCAAGAACAGTGGGCCAATGTCCCAAGTATGTGAACAGAAGGTCTTTGATGC



TCGCAACTGGGATGCGAAATGTTCCAGAGCTGATTCAGGGTCGAGGACTTTTTGGAGCCAT



CGCTGGCTTCTTAGAGAACGGCTGGGAAGGAATGGTGGACGGCTGGTATGGCTTTAGACAC



CAGAACGCCCAGGGTACGGGACAGGCTGCAGATTACAAATCTACACAGGCCGCAATCGACC



AGATCACAGGCAAGCTCAATCGGCTTGTGGAGAAGACAAACACAGAGTTTGAGAGCATTGA



ATCGGAATTTAGTGAGATTGAGCACCAGATTGGCAATGTGATTAATTGGACTAAAGACTCT



ATTACGGATATCTGGACGTATCAGGCAGAGCTGTTGGTGGCAATGGAAAATCAACACACTA



TCGACATGGCCGATAGTGAGATGCTCAATCTATATGAGAGGGTTCGCAAGCAGCTGCGTCA



AAATGCCGAGGAGGATGGCAAGGGATGTTTCGAGATTTATCACGCCTGCGATGATTCGTGC



ATGGAGAGCATTCGCAATAACACGTACGATCACTCTCAGTACAGGGAGGAGGCACTTTTAA



ACCGTCTCAACATCAACCCTGTGACCCTGAGCTCTGGCTACAAAGACATCATTTTGTGGTT



CTCCTTTGGAGCCAGCTGCTTCGTGCTCCTCGCCGTGGTCATGGGCTTGTTTTTCTTCTGT



CTGAAGAATGGAAATATGCGATGCACCATCTGTATT





845
ATGTACAAGGTGGTAGTTATAATCGCACTTCTGGGAGCAGTGAGAGGTCTCGACAAGATTT



GCCTCGGGCACCACGCTGTGGCTAATGGCACAATTGTGAAGACCTTGACAAATGAGCAGGA



AGAAGTGACAAATGCGACTGAGACTGTCGAGTCCAAGTCTCTGGGCAAGTTGTGCATGAAG



GGCAGATCCTACAACGACTTAGGGAACTGTCATCCGATAGGGATCTTAATCGGGACCCCAG



CCTGCGATCTCCACCTGACTGGCACCTGGGATACCTTAATCGAGAGGGAAAACGCAGTGGC



CTACTGCTATCCCGGTGCTACCGTGAATGAGGAGGCTCTGAGGCAGAAGATCATGGAGTCA



GGGGGAATTTCGAAAATAAGCACCGGGTTCACTTACGGTACCAGCATCAATTCTGCTGGAA



CAACTAAGGCATGTATGCGTAATGGCGGAAACTCATTTTACGCAGAGCTCAAGTGGCTAGT



GAGCAAGAATAAAGGGCAGAACTTTCCGCAGACCACTAACACTTACAGAAACACAGATACC



GCTGAACATTTGATTATCTGGGGCATTCACCACCCGTCGTCAACACAGGAGAAGAATGATC



TGTATGGTACACAGTCACTGTCAATTTCTGTCGGATCTTCCACCTACCAGAATAATTTCGT



TCCAGTGGTTGGTGCTAGGCCCCAGGTTAACGGACAATCCGGTCGCATTGACTTCCATTGG



ACCCTGCTGCAGCCAGGCGATAACATTACGTTCTCGCATAACGGCGGCCTAATCGCACCTA



GCAGAGTGTCAAAGTTGATTGGGAGGGGCCTTGGCATCCAGAGCGAGGCCCCCATCGACAA



TGGCTGCGAGTCCAAATGCTTCTGGAAAGGGGGGTCAATCAACACCAAGCTGCCCTTTCAG



AACCTCAGCCCCCGAACCGTCGGGCAGTGCCCTAAATACGTGAATAAGCGCAGTCTGATGT



TAGCTACAGGGATGCGGAATGTACCCGAAATCATGCACGGGCGAGGTCTGTTCGGGGCAAT



TGCAGGCTTCATTGAAAATGGGTGGGAAGGCATGGTCGATGGGTGGTATGGGTTTAGACAC



CAAAACGCACAAGGAACAGGCCAGGCAGCGGACTATAAGAGCACCCAGGCAGCTATTGACC



AGATTACCGGCAAGCTGAACAGGCTTATAGAGAAGACTAACACAGAATTCGAGTCCATTGA



GTCAGAGTTCAGCGAGATTGAGCACCAGATCGGAAACATCATTAACTGGACTAAGGACTCA



ATTACAGATATATGGACGTATCAGGCCGAACTGTTGGTGGCAATGGAGAATCAGCATACCA



TTGATATGGCAGATAGTGAGATGCTGAATCTTTACGAACGCGTTCGCAAACAGTTGCGGCA



GAATGCCGAAGAAGACGGCAAGGGTTGCTTTGAGATATACCACGCTTGTGACGATTCCTGC



ATGGAGTCTATCAGAAACAACACGTACGATCACAGTCAGTATCGCGAGGAGGCATTACTCA



ATCGACTAAATATCAACCCGGTGAAACTGTCTAGCGGATACAAAGACATCATCCTTTGGTT



TTCCTTTGGCGCAAGTTGTTTGATTCTGTTGGCCGTGGTTATGGGTTTAGTCTTTTTTTGT



CTCAAAAACGGTAATATGCGCTGTACGATCTGCATT





846
ATGTACAAGATCGTGGTCATCATCGCCTTGTTGGGGGCAGTGAAAGGATTGGATAAAATTT



GCCTGGGACACCACGCCGTCGCCAATGGAACCATAGTCAAGACGCTGACAAACGAGCAGGA



GGAAGTAACCAATGCGACTGAAACCGTGGAATCAACCGGAATCAATCGACTGTGTATGAAA



GGCAGGAAGCATAAAGACCTGGGCAACTGTCACCCGATCGGGATGTTAATCGGGACACCCG



CTTGTGACTTGCACCTGACCGGCATGTGGGACACTCTGATTGAGCGAGAGAATGCAATCGC



CTATTGTTACCCCGGAGCCACTGTTAACGTTGAGGCCCTCAGACAGAAGATTATGGAGTCT



GGCGGGATCAACAAGATCTCCACAGGGTTTACTTACGGAAGCAGCATCAACTCTGCCGGCA



CTACTCGCGCTTGCATGCGTAACGGGGGTAACAGCTTCTATGCTGAACTCAAATGGCTGGT



GTCTAAAAGTAAGGGCCAGAACTTTCCGCAGACGACTAATACATATAGAAATACCGATACA



GCCGAGCACCTGATTATGTGGGGGATACACCACCCCAGTTCCACCCAGGAAAAGAACGACC



TATATGGAACCCAGTCCCTCTCTATTAGCGTCGGCTCTTCAACTTATCGTAATAATTTTGT



GCCGGTCGTCGGAGCAAGACCTCAGGTCAACGGGCAGTCCGGTCGAATAGATTTTCACTGG



ACCCTAGTTCAGCCAGGAGATAATATCACATTCAGCCACAACGGAGGGTTGATAGCTCCAT



CACGAGTGTCCAAGCTGATCGGCAGGGGGCTCGGCATCCAGTCCGACGCCCCAATTGATAA



CAACTGTGAATCCAAGTGCTTCTGGAGAGGAGGCTCTATCAATACCCGATTGCCGTTCCAA



AATCTATCCCCTAGAACAGTCGGGCAGTGCCCTAAATACGTGAATAGAAGAAGCTTAATGT



TGGCAACAGGAATGAGGAACGTGCCGGAACTCATCCAGGGGCGCGGCTTATTCGGCGCTAT



CGCAGGTTTTCTTGAGAATGGATGGGAGGGCATGGTTGATGGTTGGTACGGATTCAGACAC



CAAAACGCTCAAGGCACCGGCCAAGCTGCCGATTATAAAAGCACTCAAGCTGCTATCGACC



AGATTACCGGAAAACTTAATAGGCTGGTTGAGAAAACGAACACCGAATTCGAGAGCATCGA



GAGCGAATTTAGTGAGATCGAGCATCAAATAGGCAACGTGATCAATTGGACGAAAGATTCT



ATCACCGATATTTGGACTTATCAAGCCGAACTTCTAGTGGCAATGGAGAACCAGCACACAA



TCGACATGGCAGATTCGGAAATGCTGAATTTATACGAGAGGGTGCGTAAACAGTTAAGGCA



AAACGCCGAAGAGGACGGTAAAGGTTGCTTTGAAATTTATCACGCGTGCGATGATTCCTGT



ATGGAGAGTATTCGGAATAATACATATGATCACTCCCAATATCGCGAAGAGGCATTGTTAA



ACCGGCTGAATATAAATCCAGTAACCCTGTCCTCCGGGTACAAAGACATAATCCTGTGGTT



CTCCTTCGGGGCTAGTTGTTTTGTTCTGCTGGCTGTGGTTATGGGATTATTCTTTTTTTGT



CTGAAAAACGGGAATATGCGCTGTACAATATGCATA





847
ATGTACAAAATTGTAGTGATTATCGCTCTTCTAGGCGCCGTAAAGGGGCTTGACAAGATCT



GTCTAGGACACCACGCCGTGGCCAATGGAACCATTGTAAAAACACTGACGAACGAGCAGGA



GGAGGTGACAAACGCCACTGAAACAGTTGAGAGCACCGGGATTAACCGTCTCTGTATGAAG



GGTAGGAAACACAAAGATCTCGGGAATTGTCATCCAATTGGAATGCTGATAGGCACTCCCG



CCTGTGACCTTCACTTAACTGGCATGTGGGACACACTGATCGAGAGGGAGAATGCAATTGC



GTATTGTTACCCGGGCGCCACTGTTAATGTGGAGGCGCTGAGGCAGAAAATAATGGAGTCC



GGCGGAATAAATAAAATCTCTACGGGGTTCACCTACGGATCCTCCATCAACTCTGCAGGCA



CAACAAGAGCCTGCATGAGAAACGGGGGCAACAGTTTTTACGCCGAGCTGAAATGGTTAGT



CAGTAAATCTAAAGGGCAAAATTTCCCTCAGACGACCAACACCTACCGGAACACCGATACC



GCTGAGCATCTCATCATGTGGGGTATCCATCACCCTTCCAGCACTCAGGAGAAAAACGACC



TGTACGGTACTCAATCCCTCTCTATCTCAGTCGGAAGCTCCACATACCGCAATAATTTCGT



GCCTGTGGTCGGGGCCCGCCCGCAGGTTAACGGACAGTCAGGACGGATTGACTTCCACTGG



ACTCTGGTGCAGCCCGGTGACAACATTACGTTTAGCCATAACGGTGGTCTCATTGCCCCGT



CGCGTGTATCCAAGCTGATTGGCCGGGGGTTAGGGATTCAAAGTGACGCACCCATCGACAA



CAATTGCGAATCGAAGTGTTTTTGGAGAGGCGGCAGTATTAATACCCGGTTGCCATTCCAA



AACCTCTCCCCAAGAACAGTTGGCCAGTGTCCAAAATATGTCAACCGGCGGTCCCTTATGC



TCGCCACCGGCATGCGAAACGTACCCGAACTGATCCAAGGCCGCGGTCTGTTTGGAGCTAT



CGCAGGCTTCCTGGAGAACGGGTGGGAGGGCATGGTCGACGGATGGTATGGTTTTAGGCAC



CAGAATGCACAAGGGACGGGTCAAGCCGCCGATTACAAGAGCACACAGGCGGCCATCGACC



AAATCACTGGGAAACTGAATAGACTGGTGGAGAAGACCAACACTGAGTTCGAAAGCATCGA



ATCAGAATTTAGCGAAATAGAACACCAGATCGGCAATGTGATTAACTGGACAAAGGATAGC



ATAACAGACATCTGGACATATCAGGCTGAACTGCTTGTCGCGATGGAGAACCAGCACACCA



TAGATATGGCAGATAGTGAAATGCTCAATTTATACGAGGGGGTGAGAAAACAGCTTAGACA



GAACGCTGAAGAGGACGGCAAGGGGTGCTTTGAGATATACCACGCCTGCGACGACAGCTGC



ATGGAAAGTATCAGGAACAATACATATGACCACTCACAGTATCGCGAAGAGGCACTTCTCA



ATAGACTAAACATCAATCCCGTGACACTGAGTAGTGGATATAAAGATATTATATTATGGTT



CTCTTTTGGGGCGTCATGTTTCGTGCTTCTGGCCGTGGTGATGGGTCTCTTCTTCTTCTGT



CTTAAAAATGGCAATATGCGGTGCACCATTTGCATA





848
ATGTACAAAATCGTACTGGTGCTGGCATTGCTCGGGGCAGTGCACGGCCTGGACAAGATAT



GCCTGGGACACCACGCTGTGCCTAACGGTACCATTGTGAAGACTCTGACGAATGAGAAGGA



AGAGGTGACGAACGCAACGGAGACGGTCGAGTCCAAGAGCCTCGATAAGCTGTGTATGAAG



AACAGGAACTACAAGGACCTCGGGAATTGTCATCCAATTGGCATGGTGGTGGGCACTCCCG



CCTGCGACCTCCATCTGACTGGTACATGGGATACCCTAATAGAGCGGGACAATAGTATCGC



CTACTGTTATCCCGGCGCCACCGTGTCAGAGGAGGCCCTGCGACAGAAAATAATGGAGTCC



GGCGGCATTGATAAGATTTCCACTGGGTTTACATACGGTAGCTCCATTAATTCTGCGGGAA



CTACCAAGGCTTGTATGAGAAATGGCGGTAACTCTTTCTATAGCGAGTTAAAATGGCTGGT



GAGCAAGAATAAGGGCCAAAATTTCCCCCAGACTACGAACACCTACAGAAACACCGACAGT



GTTGAGCACCTGATTATATGGGGGATACATCATCCCAGTTCTACTCAGGAGAAAAACGATT



TATACGGCACTCAAAGTCTGAGTATCTCTGTGGGGTCTAGCACATACCAGAACAACTTCGT



CCCAGTGGTTGGGGCAAGGCCGCAGGTGAATGGACAATCAGGGAGAATCGATTTCCACTGG



ACAATGGTACAGCCTGGGGATAATATCACCTTTTCTCATAACGGCGGACTTATAGCCCCCA



ACCGCGTGAGCAAGCTAAAGGGAAGAGGCCTAGGAATTCAAAGCGGTGCTTCGGTGGACAA



TGACTGCGAGAGCAAGTGCTTCTGGAAAGGTGGCTCCATCAATACTAAGTTGCCTTTTCAG



AACTTGAGCCCGAGAACCGTTGGCCAGTGCCCTAAATATGTGAACAAAAAGTCACTCCTGC



TCGCCACAGGGATGAGGAATGTCCCCGAAGTGGCTCAGGGTCGCGGGCTCTTCGGAGCCAT



CGCCGGATTCATCGAGAACGGCTGGGAAGGGATGGTAGACGGCTGGTATGGCTTTAGGCAT



CAAAACGCCCAGGGGACAGGGCAAGCCGCTGACTATAAGAGTACCCAGGCAGCCATCGACC



AGATCACTGGGAAATTAAATCGGCTGATTGAAAAGACGAACACCGAATTTGAAAGCATCGA



GTCAGAGTTCTCCGAGATAGAGCATCAAATTGGGAACGTGATTAACTGGACGAAGGATAGC



ATCACCGATATTTGGACATACCAGGCGGAGCTGCTGGTGGCCATGGAGAATCAACATACAA



TCGACATGGCCGACTCTGAGATGTTGAATCTCTACGAAAGGGTGAGAAAGCAGTTAAGGCA



GAATGCCGAGGAGGATGGGAAAGGATGCTTCGAGATCTATCACAAATGCGATGACAATTGT



ATGGAATCTATTCGTAACAATACTTACGACCACACTCAGTATCGTGAGGAAGCGCTGTTGA



ATCGGCTCAATATCAATCCAGTGAAGCTGTCATCTGGCTACAAAGATGTGATATTATGGTT



TTCTTTTGGGGCATCTTGCTTCGTGCTGCTGGCTGTCATTATGGGACTTGTATTTTTTTGT



TTGAAGAATGGAAACATGCGCTGCACAATCTGCATC





849
ATGTATAAGATAGTGGTCATAATTGCCCTGCTGGGGGCGGTGAAGGGCCTGGACAAGATTT



GTCTGGGTCATCATGCTGTGGCAAACGGTACGATCGTTAAGACCCTGACGAATGAACAAGA



GGAGGTGACTAACGCTACCGAAACCGTGGAGTCCACCGGCATAAACCGCCTTTGCATGAAG



GGGAGGAAGCACAAGGACCTCGGTAACTGTCACCCAATCGGCATGTTAATTGGCACACCAG



CTTGTGATCTGCACCTGACCGGAATGTGGGATACACTCATTGAAAGAGAAAACGCTATCGC



GTATTGCTACCCTGGAGCAACTGTTAATGTCGAGGCTTTGCGCCAAAAAATAATGGAAAGT



GGCGGTATCAATAAAATCTCAACAGGGTTTACCTACGGGAGCAGTATCAACTCAGCCGGAA



CAACCCGGGCCTGCATGCGCAATGGCGGCAACTCTTTTTACGCTGAACTGAAATGGTTGGT



GTCAAAATCAAAGGGTCAAAACTTTCCTCAAACTACAAATACATATCGGAACACCGATACA



GCTGAGCACTTAATAATGTGGGGGATCCACCACCCTTCTTCAACTCAGGAAAAGAATGATC



TGTATGGCACTCAGTCACTCTCCATTAGCGTAGGGTCATCTACCTATAGAAATAATTTCGT



ACCAGTGGTAGGTGCAAGGCCCCAGGTGAACGGCCAGAGTGGCAGAATAGACTTCCACTGG



ACTCTTGTTCAGCCAGGGGATAACATTACATTCTCGCACAACGGCGGCCTGATAGCCCCAT



CTAGGGTGTCTAAGCTAATTGGCAGAGGTCTGGGCATCCAATCCGACGCACCAATTGACAA



CAATTGCGAAAGTAAGTGTTTCTGGAGAGGAGGGTCAATTAATACAAGATTGCCGTTTCAA



AATCTGTCCCCGAGAACAGTGGGACAGTGCCCAAAATATGTAAATAGACGGTCACTGATGT



TAGCTACCGGCATGCGAAACGTCCCCGAGCTGATTCAGGGTAGAGGCCTGTTCGGAGCTAT



TGCAGGGTTTTTGGAAAATGGGTGGGAGGGCATGGTGGACGGATGGTACGGGTTCCGACAC



CAGAATGCCCAGGGAACCGGCCAGGCGGCTGACTACAAGTCTACACAGGCAGCAATTGACC



AAATCACCGGAAAGTTGAACCGCCTTGTAGAGAAAACAAACACGGAATTTGAATCAATTGA



ATCAGAGTTTTCCGAGATAGAGCACCAGATCGGGAATGTCATAAATTGGACAAAGGATTCT



ATTACGGATATTTGGACCTACCAAGCAGAACTGCTTGTGGCTATGGAAAATCAGCACACCA



TAGATATGGCCGACAGTGAGATGCTGAACCTGTACGAGCGGGTAAGAAAGCAGTTGCGCCA



GAACGCAGAGGAAGACGGGAAAGGCTGCTTCGAAATCTATCACGCCTGTGACGACTCATGC



ATGGAAAGTATCAGGAATAATACATACGATCATTCCCAATACCGTGAGGAAGCACTACTCA



ACCGGCTGAATATCAACCCCGTTACACTCTCCTCAGGTTATAAAGACATAATCCTGTGGTT



CTCCTTCGGCGCTAGCTGCTTTGTCCTGTTGGCCGTAGTAATGGGGCTGTTCTTCTTTTGC



CTTAAAAACGGGAACATGCGATGTACTATCTGCATT





850
ATGTACAAGGTCGTAGTGATTATCGCCCTCCTTGGCGCCGTTAAAGGCCTAGACAAGATCT



GTCTGGGACATCACGCCGTCGCTAATGGCACAATAGTGAAAACGCTCACTAATGAGCAGGA



GGAAGTAACCAACGCCACAGAAACGGTCGAATCCACCGGCATAAATCGGCTTTGCATGAAG



GGGCGTAAACATAAGGACCTGGGGAACTGTCACCCAATAGGGATGCTGATCGGAACACCTG



CTTGTGACCTCCACCTGACAGGCACCTGGGATACGTTGATCGAGCGGGAGAACGCTATCGC



ATACTGCTACCCCGGCGCTACCGTCAATGTGGAAGCACTGCGTCAGAAGATAATGGAATCA



GGAGGCATTGATAAGATCTCAACAGGGTTTACCTACGGCTCTAGTATCAATAGCGCAGGTA



CCACCAGGGCATGCATGCGCAATGGTGGCAACAGTTTCTACGCAGAGCTGAAGTGGCTGGT



GTCTAAAAATAAAGGCCAGAACTTCCCTCAGACCACAAACACTTACCGCAATACAGATACT



GCAGAGCATCTGATTATGTGGGGGATCCACCACCCTTCCTCCATTCAAGAGAAGAACGACC



TGTACGGCACTCAGAGCTTATCAATATCGGTGGGTTCCTCCACTTACCGTAACAATTTCGT



CCCCGTAGTCGGGGCTAGGCCTCAGGTGAATGGTCAGTCAGGGAGGATAGACTTTCACTGG



ACGCTGGTTCAGCCAGGCGACAATATAACCTTCTCACACAACGGGGGTCTGATTGCTCCTT



CTAGGGTGTCAAAGCTGATCGGGAGAGGACTGGGTATACAAAGCGATGCCCCCATCGATAA



TAACTGTGAAAGTAAGTGTTTTTGGCGCGGAGGGAGCATTAACACGCGGCTGCCTTTTCAG



AACCTGTCCCCCCGGACTGTGGGCCAGTGTCCCAAGTACGTGAACCGCAGGTCACTCATGC



TAGCCACGGGTATGAGAAATGTGCCAGAGTTAATTCAGGGCCGCGGTCTGTTTGGGGCTAT



TGCAGGTTTTCTGGAGAACGGGTGGGAGGGCATGGTGGACGGTTGGTACGGCTTTAGGCAT



CAGAACGCACAGGGTACTGGACAGGCAGCCGATTACAAGAGCACTCAGGCAGCGATAGACC



AGATAACTGGCAAGCTCAACCGTTTAGTGGAGAAGACCAACACCGAATTTGAAAGTATTGA



GTCCGAGTTCTCAGAGATTGAGCATCAGATCGGCAATGTCATTAATTGGACAATGGATTCG



ATCACCGATATATGGACCTATCAGGCCGAGTTGCTGGTCGCCATGGAAAATCAACACACTA



TAGATATGGCAGATTCCGAAATGCTGAATCTCTATGAGAGGGTGAGAAAACAACTGAGGCA



AAATGCGGAGGAAGACGGGAAAGGTTGCTTCGAAATTTACCATGCTTGCGATGATAGTTGC



ATGGAGTCCATCCGGAATAACACGTATGATCACAGCCAATACCGGGAAGAAGCCCTGCTTA



ACCGGCTTAACATAAATCCTGTGACTCTCTCATCAGGATATAAGGATATCATCCTCTGGTT



CTCTTTCGGGGCCAGCTGCTTTGTTTTGTTAGCCGTGGTGATGGGACTCGTGTTCTTCTGC



TTAAAAAACGGCAATATGCGTTGCACCATCTGCATC





851
ATGTATAAGATCGTCGTTATTATTGCCCTGCTTGGTGCTGTCAAGGGGTTGGACAAAATTT



GCTTGGGCCACCACGCAGTGGCTAACGGCACTATAGTCAAAACCCTGACGAACGAGCAGGA



GGAGGTGACAAACGCCACTGAGACCGTGGAATCTACGGGAATCAACAGGCTCTGCATGAAG



GGGCGCAAACACAAAGACCTCGGGAACTGCCACCCTATCGGGATGCTCATAGGTACTCCAG



CGTGTGACCTGCACTTAACAGGCACTTGGGATACCCTTATTGAACGGGAAAATGCTATCGC



TTACTGCTACCCGGGCGCGACCGCCAACGTGGAAGCATTACGCCAAAAGATAATGGAATCA



GGCGGCATAGATAAAATCTCCACCGGATTTACATACGGGTCTAGCATAAATTCTGCCGGCA



CCACTAGAGCCTGTATGAGAAACGGCGGAAATTCATTCTACGCTGAGCTGAAATGGCTGGT



CTCAAAGTCTAAGGGGCAGAATTTCCCCCAGACCACGAATACGTACCGGAACACAGATACC



GCCGAGCATCTGATCATGTGGGGAATCCATCACCCCAGTTCAATCCAGGAGAAGAATGACT



TATACGGTACACAATCCCTGTCCATATCAGTAGGTAGCTCTACATATCGGAACAATTTCGT



GCCTGTCGTCGGGGCTAGGCCTCAGGTAAACGGCCAGTCCGGTAGAATCGATTTTCACTGG



ACCCTCGTCCAGCCTGGGGACAATATAACGTTTAGTCACAACGGAGGTCTCATCGCCCCCA



GCCGGGTATCTAAGCTTATTGGCAGGGGCCTGGGTATTCAGAGCGACGCCCCAATTGACAA



TAATTGCGAAAGCAAGTGCTTCTGGAGGGGTGGAAGTATTAACACAAGACTGCCTTTCCAA



AACCTGAGCCCTAGAACTGTGGGACAGTGCCCAAAATACGTCAACAGGAGATCACTTATGC



TGGCGACAGGAATGCGCAATGTACCTGAACTTATTCAAGGGCGAGGACTGTTTGGTGCCAT



AGCTGGGTTCCTGGAAAACGGTTGGGAGGGAATGGTGGACGGCTGGTACGGGTTTAGACAC



CAAAACGCACAAGGAACCGGCCAGGCTGCCGATTATAAGTCCACACAAGCAGCCATCGATC



AAATTACCGGTAAGCTGAATCGGTTAGTTGAAAAAACCAATACCGAGTTTGAATCCATCGA



GAGTGAGTTCTCAGAGATCGAGCACCAGATAGGCAATGTGATCAACTGGACAATGGATTCA



ATTACCGATATCTGGACCTACCAGGCTGAGCTGCTGGTGGCCATGGAAAATCAGCATACAA



TTGATATGGCCGACAGTGAGATGCTGAACTTGTATGAAAGAGTTAGAAAACAGCTGAGGCA



AAATGCCGAAGAGGATGGCAAGGGATGTTTTGAAATCTATCATGCGTGTGATGATAGCTGT



ATGGAATCCATCAGGAACAATACATACGATCACTCACAGTATAGAGAAGAAGCACTCCTGA



ACAGATTAAATATCAATCCAGTGACCTTATCATCTGGCTACAAGGATATAATTCTTTGGTT



TTCGTTTGGGGCTTCCTGCTTCGTGTTGCTGGCCGTGGTCATGGGTCTAGTGTTTTTTTGC



TTGAAAAACGGAAATATGCGGTGTACCATCTGTATC





852
ATGTACAAGATTGTGGTTATAATTGCGCTTCTGGGAGCTGTGAAGGGATTGGACAAGATCT



GCCTTGGGCACCATGCCGTTGCAAATGGTACCATTGTGAAGACGCTGACCAATGAGCAGGA



AGAGGTGACCAATGCTACAGAGACAGTGGAGTCCACTGGCATCAACCGACTCTGTATGAAA



GGTAGAAAACACAAAGATCTCGGCAATTGCCATCCTATAGGTATGCTGATTGGTACGCCTG



CCTGTGACCTCCATCTGACTGGCATGTGGGACACGCTGATCGAAAGGGAGAATGCCATTGC



GTACTGTTATCCTGGCGCTACGGTGAACGTGGAAGCCTTACGGCAGAAGATCATGGAATCC



GGCGGGATCAATAAGATTAGCACCGGATTCACTTACGGATCTTCTATCAACAGCGCTGGCA



CCACTAGGGCATGCATGAGAAACGGGGGGAATAGTTTTTACGCTGAGCTTAAGTGGTTGGT



TTCTAAGAGTAAGGGACAGAACTTCCCTCAGACCACTAATACCTACAGGAACACCGACACC



GCAGAGCATTTAATCATGTGGGGAATCCACCATCCATCCTCCACTCAGGAAAAGAATGACT



TATACGGAACACAGAGCCTTTCCATATCTGTCGGTTCCTCCACATATAGAAATAATTTTGT



GCCCGTGGTCGGTGCACGACCTCAGGTGAATGGCCAGTCAGGAAGAATCGATTTTCACTGG



ACCCTGGTACAGCCTGGCGACAATATCACCTTCAGCCATAACGGCGGTCTGATCGCCCCTA



GTCGGGTGAGTAAATTGATAGGTCGGGGACTGGGAATCCAGAGTGATGCTCCTATTGATAA



TAATTGCGAGTCAAAATGTTTTTGGCGCGGCGGCTCTATTAACACCAGATTACCTTTCCAG



AACCTGAGCCCTCGGACTGTTGGACAGTGTCCTAAATATGTGAATCGCAGGTCTCTGATGC



TGGCTACAGGCATGAGGAACGTGCCTGAGCTCATCCAGGGAAGGGGGCTGTTCGGGGCCAT



CGCTGGATTCCTGGAAAACGGATGGGAGGGAATGGTCGATGGTTGGTACGGTTTTCGGCAT



CAGAATGCTCAAGGGACGGGCCAGGCGGCTGATTATAAGTCAACGCAGGCGGCCATAGACC



AGATCACCGGAAAGCTCAACCGCCTGGTGGAGAAGACAAATACAGAGTTTGAGTCTATAGA



GTCCGAGTTTTCCGAAATCGAACACCAGATCGGGAATGTGATAAACTGGACCAAAGATTCT



ATCACTGACATTTGGACTTACCAGGCAGAACTATTGGTGGCCATGGAAAATCAGCACACCA



TCGACATGGCCGACTCTGAAATGCTGAACTTGTATGAGAGAGTGCGCAAGCAGCTGCGACA



AAATGCCGAAGAAGACGGAAAGGGCTGTTTTGAAATCTATCATGCTTGTGATGACTCTTGC



ATGGAATCTATTAGGAACAATACCTATGATCATTCTCAGTACCGGGAAGAAGCATTGCTGA



ACCGCTTGAATATAAACCCAGTGACGCTGTCATCTGGTTATAAAGACATTATCCTGTGGTT



TAGCTTTGGTGCCTCATGCTTTGTACTCCTAGCCGTAGTCATGGGCCTGTTTTTCTTCTGC



CTGAAGAACGGGAACATGCGATGCACTATTTGCATC





853
ATGTACAAGATCGTGGTGATCATAGCCTTACTGGGGGCCGTAAAAGGTCTGGATAAGATTT



GTCTGGGCCACCACGCTGTCGCCAATGGTACCATTGTGAAGACACTAACCAACGAGCAGGA



GGAGGTCACAAACGCTACCGAGACGGTTGAATCTACTGGTATAAACCGCCTTTGCATGAAG



GGACGCAAACATAAGGATCTGGGGAACTGTCACCCCATTGGTATGCTGATCGGAACCCCTG



CATGTGACCTACACCTGACCGGAATGTGGGATACCTTAATAGAGCGAGAGAACGCGATCGC



CTACTGTTATCCGGGGGCTACGGTGAACGTTGAGGCTCTGAGGCAGAAGATAATGGAAAGT



GGGGGCATCAACAAGATTAGTACCGGATTCACTTATGGTAGTAGCATTAATAGTGCTGGGA



CTACCAGAGCATGTATGAGAAATGGGGGGAACAGCTTCTATGCCGAGCTGAAGTGGCTAGT



GAGCAAGAGCAAGGGCCAAAACTTTCCCCAAACGACCAACACATACCGCAATACCGATACA



GCAGAGCATCTCATAATGTGGGGAATCCACCACCCTAGTTCAACCCAGGAGAAGAACGATC



TTTATGGAACTCAGTCCCTGTCTATCAGCGTGGGGAGTTCTACATATCGCAATAACTTTGT



GCCAGTCGTGGGGGCCCGACCACAGGTAAACGGTCAGTCTGGTCGAATTGACTTTCATTGG



ACCTTGGTCCAGCCGGGCGATAATATCACATTTTCCCATAATGGAGGCCTGATAGCCCCTT



CCAGAGTTAGCAAATTGATAGGCCGAGGACTCGGGATCCAGAGCGATGCACCCATCGACAA



CAACTGCGAGAGCAAATGCTTCTGGCGGGGCGGAAGCATTAACACTAGATTACCCTTCCAG



AACCTTAGTCCTCGCACCGTGGGCCAGTGCCCTAAATATGTGAACCGGCGCTCACTGATGC



TGGCCACAGGCATGAGGAATGTCCCCGAGCTGATCCAGGGCAGAGGACTCTTCGGTGCTAT



CGCAGGATTTCTTGAGAACGGATGGGAAGGAATGGTAGACGGATGGTACGGGTTCCGACAT



CAGAACGCTCAGGGCACTGGCCAAGCAGCCGACTACAAATCCACACAGGCGGCCATCGATC



AGATAACAGGCAAACTGAATCGGCTAGTAGAGAAGACCAACACCGAATTCGAATCAATCGA



GTCTGAATTCAGCGAGATAGAGCACCAAATCGGGAATGTGATTAACTGGACAAAGGATTCC



ATAACCGACATTTGGACCTACCAAGCCGAACTGCTGGTCGCGATGGAAAACCAACATACCA



TCGACATGGCAGACTCCGAAATGCTGAATCTGTACGAACGTGTGCGGAAACAGCTGAGACA



GAATGCTGAAGAAGACGGGAAAGGCTGTTTTGAAATCTACCACGCCTGCGACGACTCATGC



ATGGAAAGCATCAGGAATAACACTTATGACCATTCCCAGTACCGGGAAGAAGCACTCCTGA



ACCGGTTGAACATTAATCCGGTTACCTTGAGCTCTGGATATAAAGACATCATCCTATGGTT



CAGCTTCGGCGCATCCTGCTTTGTTCTGCTTGCAGTGGTCATGGGGCTGTTCTTTTTTTGC



CTGAAGAATGGCAACATGAGATGTACCATTTGCATC





854
ATGTATAAGATAGTAGTCATCATAGCTCTCTTGGGCGCCGTGAAAGGGCTGGACAAGATCT



GTCTGGGTCATCATGCCGTGGCCAACGGAACAATCGTGAAAACCTTGACTAATGAGCAGGA



GGAGGTGACCAATGCGACCGAGACCGTTGAAAGTACGGGCATTAATAGGCTCTGTATGAAG



GGTAGGAAACATAAGGACCTTGGGAACTGTCACCCCATTGGAATGCTGATTGGGACTCCTG



CATGTGACTTACACTTAACAGGCATGTGGGACACTCTGATTGAGAGGGAGAACGCCATTGC



CTATTGTTATCCCGGCGCCACCGTGAACGTGGAGGCACTGCGGCAGAAGATAATGGAAAGC



GGAGGGATTAATAAAATCAGCACCGGATTCACTTATGGTAGTTCTATTAATTCCGCCGGGA



CAACAAGGGCATGTATGAGGAACGGAGGTAATTCCTTCTACGCGGAGCTGAAGTGGCTGGT



CTCTAAGTCCAAGGGGCAGAACTTTCCCCAGACTACAAACACCTACCGAAATACAGATACC



GCTGAGCACCTGATCATGTGGGGAATTCATCACCCTTCATCAACACAAGAGAAGAACGACC



TGTACGGCACACAGTCACTGTCAATCTCAGTAGGGAGCTCGACATATAGAAATAATTTCGT



CCCGGTGGTGGGCGCTCGGCCGCAGGTTAATGGCCAGAGTGGTAGAATCGACTTTCACTGG



ACGCTGGTCCAGCCAGGCGATAATATCACGTTCTCACACAATGGAGGCCTGATAGCCCCAA



GCCGCGTGTCCAAGCTGATAGGGCGAGGACTTGGTATCCAGAGTGATGCCCCCATCGATAA



CAACTGCGAATCCAAGTGTTTCTGGCGTGGCGGCTCAATTAACACCCGGCTTCCATTCCAG



AACCTTAGCCCCCGCACTGTCGGACAATGCCCAAAGTATGTCAACAGGCGGAGCCTGATGC



TGGCCACCGGCATGAGAAATGTGCCTGAGCTCATTCAGGGGCGGGGCCTTTTTGGGGCAAT



CGCTGGCTTTCTCGAGAATGGTTGGGAGGGAATGGTTGACGGCTGGTATGGCTTTAGACAT



CAGAATGCCCAGGGAACGGGCCAGGCTGCTGACTACAAGTCCACCCAGGCCGCCATCGACC



AAATTACCGGGAAGCTGAATAGACTCGTCGAAAAGACCAACACTGAATTTGAGAGTATCGA



GTCTGAGTTTTCCGAGATCGAACATCAAATCGGAAACGTTATCAACTGGACTAAGGACTCA



ATCACCGACATTTGGACATATCAAGCGGAGCTCCTGGTGGCCATGGAAAATCAGCACACGA



TCGACATGGCCGACAGTGAGATGCTGAATCTGTATGAGCGAGTCCGTAAGCAGCTTAGGCA



GAACGCTGAGGAGGATGGAAAAGGATGTTTCGAGATATATCACGCCTGTGATGACTCCTGT



ATGGAATCCATCAGGAACAACACATACGATCATAGTCAGTACAGGGAAGAAGCCTTGCTAA



ATAGGTTGAACATCAACCCTGTCACTCTGAGTTCTGGATACAAGGACATCATATTATGGTT



TTCCTTTGGCGCCTCCTGCTTCGTCCTGCTAGCAGTGGTGATGGGCCTGTTTTTTTTTTGC



CTTAAAAATGGCAATATGCGGTGCACCATTTGCATA





855
ATGTATAAGATCGTTGTCATCATTGCTCTCCTCGGAGCCGTGAAAGGGCTCGATAAGATCT



GTTTAGGACACCATGCCGTGGCAAACGGTACTATAGTCAAGACCCTAACAAATGAGAAAGA



GGAGGTGACGAATGCCACAGAAACAGTAGAATCTACAGGACTGAACCGGCTGTGCATGAAG



GGCCGCAAACACAAGGATTTAGGTAATTGTCACCCAATAGGCATGTTGATTGGAAGTCCGG



CATGTGACCTGCACTTGACGGGCACATGGGATACCCTGATAGAAAGGGAGAACGCTATCGC



CTACTGCTATCCGGGAGCCACGGTCAACGGGGAAGCGCTGCGGCAGAAGATTATGGAGTCG



GGCGGTATAGATAAGATATCCACAGGCTTTACCTATGAATCCTCTATTAACTCAGCTGGTA



CAACTCGCGCTTGCATGAGGAACGGGGGGAACAGTTTCTACGCCGAACTCAAGTGGCTTGT



TTCTAAGTCTAAGGGCCAGAATTTCCCACAGACTACCAATACCTATAGAAACACCGACACG



GCTGAGCACCTTATTATGTGGGGTATTCACCACCCCTCAAGCACTCAGGAGAAGAACGACC



TCTATGGTACCCAGTCCCTTTCCATCTCCGTTGGTAGTTCTACCTACCGCAACAATTTTGT



TCCCGTGGTCGGTGCAAGACCACAGGTTAACGGCCAGAGTGGGCGCATCGATTTCCACTGG



ACGTTGGTCCAGCCTGGGGATAACATCACCTTTTCCCACAACGGGGGATTAATCGCACCCT



CTCGGGTCTCTAAGCTGATCGGACGAGGACTGGGAATCCAAAGTGACGCACCAATAGATAA



TAATTGCGAGAGCAAATGCTTCTGGCGCGGTGGGTCAATCAATACACGGCTGCCGTTTCAG



AATCTATCACCAAGGACTGTGGGACAGTGCCCCAAATATGTAAATAAGCGGTCCCTGATGC



TCGCCACTGGTATGCGGAACGTGCCTGAGCTAATGCAAGGAAGGGGCCTGTTTGGGGCCAT



TGCCGGCTTTCTCGAAAACGGGTGGGAGGGCATGGTGGACGGATGGTACGGTTTCCGGCAC



CAGAATGCTCAAGGCACCGGTCAGGCTGCCGATTATAAAAGCACCCAAGCCGCTATCGATC



AGATCACTGGCAAGTTAAACAGGCTGGTAGAAAAAACTAATACTGAATTCGAGTCCATTGA



GTCCGAGTTCTCTGAGATTGAGCATCAGATCGGGAATGTTATTAACTGGACGAAAGACAGT



ATTACGGATATCTGGACATATCAAGCCGAGCTCCTGGTCGCTATGGAAAACCAACACACTA



TCGACATGGCCGACAGCGAAATGTTGAATCTTTATGAAAGAGTGAGGAAGCAGCTGCGTCA



GAACGCAGAGGAGGATGGGAAAGGATGTTTTGAGATCTACCACGCCTGTGACGATTCCTGC



ATGGAGAGTATTAGAAACAACACATACGACCACAGCCAGTACCGGGAAGAGGCCCTATTGA



ACAGGCTTAATATTAATCCAGTAACCCTGTCGAGTGGGTATAAAGATATTATACTGTGGTT



CTCCTTTGGCGCTTCTTGCTTTGTGCTGCTCGCGGTAGTTATGGGTTTGGTGTTTTTTTGC



CTCAAGAACGGAAATATGCGTTGCACCATCTGTATC





856
ATGTATAAGATCGTGGTCATCATCGCCCTGCTTGGAGCTGTAAAAGGTCTCGACAAGATTT



GTCTTGGACATCATGCTGTGGCAAATGGCACCATTGTAAAGACCCTGACTAATGAGCAAGA



AGAAGTAACCAACGCAACTGAGACCGTAGAGTCAACCGGCATTAATCGGCTCTGCATGAAG



GGAAGGAAGCACAAAGATCTCGGCAATTGTCACCCAATAGGCATGTTGATTGGAACCCCTG



CTTGTGACCTGCATCTCACGGGGATGTGGGATACTTTGATTGAAAGGGAAAACGCAATTGC



GTATTGTTACCCGGGAGCCACCGTGAACGTCGAGGCCCTCCGACAAAAGATCATGGAATCA



GGAGGGATCAACAAAATAAGCACTGGGTTTACCTATGGAAGTTCGATCAACTCAGCCGGGA



CAACGCGCGCTTGCATGAGGAATGGCGGAAATTCCTTCTACGCTGAACTCAAATGGCTCGT



GTCGAAATCAAAGGGTCAGAACTTCCCACAGACTACTAATACCTACAGAAATACTGACACA



GCGGAGCATTTGATCATGTGGGGCATACACCACCCTTCTTCCACACAGGAGAAGAATGACC



TTTACGGCACGCAGAGTCTGTCCATCAGCGTAGGAAGCTCAACCTACAGAAATAATTTCGT



TCCCGTGGTGGGGGCTCGACCACAGGTTAACGGGCAGTCCGGTCGTATTGATTTTCATTGG



ACATTGGTGCAGCCCGGCGATAACATTACTTTTAGCCACAACGGAGGCCTAATTGCCCCTA



GCAGAGTCTCCAAACTGATCGGGAGGGGACTGGGGATACAGTCAGATGCCCCTATCGACAA



CAATTGTGAGAGCAAGTGTTTCTGGCGAGGCGGAAGCATTAACACCCGGTTACCCTTTCAG



AACCTATCTCCAAGAACTGTGGGTCAGTGCCCAAAATACGTGAACAGACGGTCTCTGATGT



TGGCTACTGGTATGCGCAACGTTCCGGAACTAATTCAAGGCAGAGGACTGTTCGGCGCCAT



CGCAGGGTTCCTCGAGAACGGGTGGGAGGGGATGGTCGATGGGTGGTACGGCTTTAGGCAT



CAGAACGCTCAGGGGACTGGTCAGGCCGCCGATTACAAAAGCACGCAAGCTGCTATAGATC



AGATCACAGGGAAACTGAATCGCCTCGTTGAGAAAACTAACACCGAATTTGAATCAATAGA



ATCCGAATTCAGTGAAATCGAGCACCAGATAGGGAACGTAATCAACTGGACCAAAGACAGT



ATTACAGACATCTGGACATACCAGGCGGAACTTTTAGTCGCTATGGAGAATCAGCACACAA



TAGACATGGCCGACAGCGAAATGTTGAACCTGTACGAACGAGTAAGGAAGCAGCTGAGGCA



AAACGCAGAAGAGGACGGAAAGGGCTGCTTTGAGATATACCACGCATGTGATGATAGCTGT



ATGGAGTCAATTCGGAACAATACATATGATCACTCTCAATACCGTGAGGAAGCTCTGCTCA



ATCGTCTGAATATTAACCCAGTGACTCTTTCCAGTGGGTACAAAGACATCATTCTTTGGTT



TTCCTTCGGAGCTTCCTGCTTTGTGCTGCTGGCAGTCGTTATGGGATTGTTCTTTTTCTGC



CTGAAGAACGGGAACATGCGCTGTACTATATGTATC





857
ATGTACAAGGTAGTGGTAATAATTGCTCTGCTGGGAGCCGTGAGAGGTCTGGATAAAATCT



GTTTGGGTCACCACGCCGTCGCCAACGGGACGATCGTCAAAACACTAACAAATGAGCAAGA



AGAAGTGACCAACGCAACAGAGACAGTGGAGAGTAAGAGCCTGGGAAAGCTTTGCATGAAG



GGCCGCTCATATAACGACCTGGGCAACTGTCACCCCATCGGTATTCTGATTGGGACTCCAG



CTTGCGACTTGCATCTGACCGGCACCTGGGACACACTCATCGAGAGAGAAAACGCAGTGGC



TTACTGCTACCCTGGCGCTACCGTCAATGAAGAAGCCCTGCGACAGAAGATTATGGAGAGC



GGTGGGATCAGCAAAATCTCCACCGGTTTCACCTATGGAACCTCCATTAACAGCGCAGGCA



CAACAAAAGCTTGCATGAGGAATGGGGGCAACTCGTTCTATGCTGAACTGAAATGGCTGGT



GTCCAAAAATAAGGGTCAGAATTTCCCTCAGACTACCAACACTTACAGGAACACGGATACA



GCAGAGCACCTGATTATATGGGGGATTCACCACCCTTCGTCTACCCAAGAGAAAAATGACC



TGTACGGAACTCAGAGCCTTTCAATATCCGTGGGGTCCAGTACATATCAAAATAATTTTGT



CCCCGTGGTTGGCGCCCGTCCACAGGTTAACGGTCAGTCAGGGCGGATCGATTTTCATTGG



ACCTTACTTCAGCCCGGAGACAATATCACTTTTTCTCACAACGGAGGACTCATCGCCCCCT



CCCGTGTGTCCAAGCTCATAGGACGGGGCCTGGGTATCCAGAGCGAGGCCCCCATCGATAA



CGGCTGCGAGAGCAAATGTTTTTGGAAGGGAGGGAGTATAAACACTAAGCTCCCATTCCAA



AATTTAAGTCCACGTACTGTGGGCCAGTGTCCCAAGTATGTGAACAAAAGAAGCTTGATGC



TGGCAACTGGGATGCGGAACGTGCCTGAGATCATGCACGGTCGGGGCCTGTTTGGCGCTAT



CGCAGGGTTTATTGAAAATGGCTGGGAGGGCATGGTTGATGGGTGGTACGGGTTTAGGCAT



CAGAATGCCCAGGGCACTGGTCAGGCGGCCGATTACAAGAGTACTCAGGCTGCCATCGACC



AGATCACCGGCAAGCTGAACCGGTTGATCGAAAAGACAAACACTGAATTCGAGAGTATCGA



AAGCGAATTTTCTGAGATCGAGCACCAAATCGGGAATATAATTAATTGGACAAAGGACTCG



ATCACTGACATATGGACATACCAAGCCGAGCTGCTGGTGGCCATGGAAAACCAGCATACCA



TAGACATGGCCGATTCAGAAATGCTTAATCTTTACGAGCGTGTTAGGAAGCAACTGAGGCA



GAATGCCGAAGAGGACGGTAAGGGGTGCTTTGAGATTTATCACGCATGTGACGACAGCTGT



ATGGAGTCCATTAGAAATAATACCTACGATCACAGTCAGTATAGAGAAGAGGCATTGCTTA



ATAGGCTGAACATAAATCCCGTCAAGCTGTCTTCGGGGTACAAGGACATTATCCTGTGGTT



CAGCTTTGGCGCATCGTGTCTGATATTACTGGCCGTCGTGATGGGATTAGTGTTTTTCTGC



TTAAAGAACGGTAACATGCGCTGTACTATCTGTATC





858
ATGTACAAGATCGTGGTCATTATCGCTCTGTTAGGGGCAGTAAAAGGCCTGGACAAAATCT



GCCTTGGCCATCATGCTGTGGCTAATGGTACAATTGTCAAAACCCTCACAAATGAACAGGA



GGAGGTGACAAACGCCACAGAAACTGTGGAGAGTACAGGGATCAACCGTCTCTGCATGAAG



GGAAGAAAGCATAAAGACCTTGGAAACTGTCATCCCATAGGCATGCTGATCGGCACTCCCG



CCTGTGACCTGCACCTGACCGGTATGTGGGACACCCTGATCGAAAGGGAGAATGCCATTGC



CTACTGTTATCCTGGCGCAACAGTGAACGTAGAAGCCTTAAGACAGAAGATCATGGAATCC



GGAGGCATAAACAAAATTAGTACTGGATTCACCTACGGGAGCTCCATTAACTCTGCAGGCA



CCACTCGGGCATGCATGCGCAACGGCGGTAACAGCTTCTATGCCGAGCTGAAGTGGTTAGT



GTCCAAGTCGAAAGGCCAGAACTTTCCCCAGACGACAAACACATATCGGAACACCGATACT



GCAGAACACCTGATCATGTGGGGGATTCACCACCCCAGTTCCACCCAGGAGAAGAACGATC



TGTACGGTACTCAGAGCCTGTCCATAAGTGTTGGATCCTCTACATATCGGAATAATTTCGT



GCCCGTGGTGGGCGCAAGACCACAGGTGAACGGCCAGTCTGGGAGAATTGACTTTCATTGG



ACTCTGGTGCAACCAGGGGACAATATTACCTTCTCACATAATGGCGGCCTGATCGCACCTA



GCAGGGTGTCCAAGCTGATAGGACGCGGACTCGGAATTCAGTCGGATGCACCTATCGATAA



TAACTGCGAGTCTAAGTGTTTTTGGAGAGGCGGTTCAATCAATACTAGGCTTCCTTTTCAG



AACCTGAGCCCCAGAACAGTGGGGCAATGCCCTAAATATGTGAATAGGCGGTCTCTGATGC



TGGCCACTGGGATGAGAAATGTGCCAGAGCTGATTCAGGGTAGAGGCCTGTTCGGCGCAAT



CGCAGGGTTCCTCGAAAACGGCTGGGAAGGTATGGTGGACGGATGGTACGGGTTCCGACAC



CAAAACGCCCAGGGGACGGGCCAGGCCGCCGATTACAAATCAACTCAAGCCGCGATAGATC



AGATAACCGGAAAGCTGAACAGACTCGTCGAGAAGACCAATACCGAGTTTGAGTCCATCGA



AAGCGAGTTCTCAGAGATTGAGCATCAGATAGGGAACGTAATTAACTGGACGAAAGATAGC



ATCACGGACATCTGGACATATCAGGCGGAACTACTGGTGGCAATGGAAAATCAGCATACCA



TCGACATGGCCGACAGTGAGATGTTAAATCTCTATGAGCGGGTGCGGAAACAGCTGAGGCA



AAACGCTGAAGAAGACGGAAAAGGGTGCTTTGAGATCTACCATGCCTGCGACGATAGCTGC



ATGGAGTCAATTCGGAACAATACTTATGACCACTCCCAGTATCGGGAGGAGGCCCTGCTCA



ATCGACTGAACATAAACCCAGTGACTCTGAGTTCCGGATACAAAGATATTATTCTTTGGTT



CAGCTTCGGAGCTTCTTGTTTTGTCCTCCTAGCAGTGGTAATGGGCCTCTTTTTCTTTTGC



CTGAAGAACGGAAACATGAGGTGCACAATTTGTATT





859
ATGTACAAAATAGTGGTGATAATCGCCCTTCTCGGCGCAGTGAAAGGGCTCGACAAGATAT



GTCTGGGACATCACGCTGTGGCTAATGGCACTATCGTGAAGACGCTCACAAATGAACAGGA



GGAGGTTACAAATGCCACTGAGACAGTTGAAAGCACAGGAATCAATAGATTGTGTATGAAA



GGCAGAAAGCATAAGGACTTGGGGAACTGTCACCCTATTGGCATGCTTATCGGCACCCCTG



CTTGTGATCTACATTTGACAGGCATGTGGGACACCCTTATTGAGCGCGAAAACGCAATCGC



GTACTGTTATCCTGGTGCTACTGTGAACGTAGAAGCTCTGAGGCAGAAGATAATGGAATCT



GGCGGGATAAATAAAATCTCAACCGGCTTCACATACGGGAGTAGCATTAATAGCGCCGGTA



CTACCCGGGCCTGTATGAGGAATGGAGGAAACTCTTTTTACGCAGAGCTCAAGTGGCTAGT



ATCTAAGTCCAAGGGACAGAATTTTCCCCAGACTACTAATACTTACCGCAATACGGATACC



GCAGAACACTTAATTATGTGGGGCATACATCACCCATCCTCTACCCAAGAAAAGAACGACC



TTTACGGCACACAGTCCTTGAGTATATCTGTGGGGAGTAGCACCTATAGGAACAATTTCGT



TCCGGTCGTGGGCGCTCGCCCCCAGGTGAACGGCCAATCAGGACGGATCGACTTCCACTGG



ACCCTGGTCCAGCCCGGCGATAACATCACATTTTCCCATAACGGAGGACTTATAGCACCCT



CCCGGGTGTCTAAACTTATTGGACGGGGGCTGGGAATCCAGTCCGACGCCCCCATCGATAA



CAACTGTGAGTCTAAATGTTTTTGGCGCGGCGGATCTATCAACACCAGGCTTCCCTTCCAG



AATCTGTCCCCCCGGACAGTGGGCCAGTGCCCAAAGTACGTTAACAGAAGGTCTTTAATGC



TCGCCACCGGCATGCGAAACGTGCCTGAACTGATCCAGGGAAGAGGACTTTTCGGAGCCAT



CGCCGGCTTTTTAGAGAACGGATGGGAAGGGATGGTAGACGGGTGGTATGGATTCAGGCAC



CAAAACGCTCAGGGGACCGGGCAAGCAGCAGACTACAAAAGTACACAAGCCGCTATCGACC



AAATCACGGGTAAACTGAACCGGCTTGTGGAAAAGACAAACACCGAATTTGAATCGATAGA



GAGCGAATTCAGCGAGATCGAGCACCAAATAGGAAATGTGATCAACTGGACAAAGGATTCG



ATCACAGACATCTGGACGTACCAAGCCGAGCTCCTCGTAGCAATGGAGAACCAGCATACCA



TCGACATGGCCGATTCCGAGATGCTTAATCTTTATGAACGGGTCCGCAAACAGCTGCGCCA



AAATGCCGAAGAAGATGGTAAAGGATGTTTTGAAATCTATCATGCTTGTGATGATTCCTGT



ATGGAGTCAATCCGGAATAATACATACGACCACAGCCAGTACCGGGAAGAAGCCCTGCTGA



ATCGCTTAAATATCAACCCCGTTACCCTTTCCTCTGGATATAAGGATATTATCCTGTGGTT



TTCATTTGGGGCATCCTGTTTCGTCCTTCTGGCAGTGGTCATGGGACTTTTTTTTTTCTGT



CTGAAGAACGGAAACATGCGGTGTACGATCTGTATA





860
ATGTATAAAGTCGTGGTTATCATCGCCCTTCTGGGAGCCGTCAGAGGCCTGGACAAGATAT



GTTTGGGGCATCATGCGGTAGCTAATGGAACCACTGTCAAAACACTTACTAATGAACAGGA



AGAGGTTACGAACGCCACCGAAACAGTGGAATCTACCAGCCTGAATAAATTATGCATGAAG



GGACGACGCTACAAGGATCTGGGGAATTGCCACCCCATCGGAATGCTGATTGGAACACCAG



TCTGTGACCTCCACCTTACAGGGACGTGGGATACCTTGATTGAGCGGGAGAATGCAACAGC



TTACTGTTATCCCGGAGTAACTATTAATGAGGAGGCTCTCCGTCAAAAGATAATGGAGTCA



GGAGGTATTAGTAAAATGCGCACTGGCTTTACATACGGGCCCTCTATAAACAGCGCAGGAA



CCACTCGTTCATGTATGCGCAATGGGGGCAACTCGTTCTACGCCGAGCTGAAGTGGCTGGT



GAGTGGCACCAAAGGTCAGAATTTTCCCCAGACTACAAACACCTACCGGAACACAGACACT



GCCGAGCATCTGATCATCTGGGGGATACATCACCCTTCCTCTACTCAAGAAAAGAACGATC



TGTATGGCACACAAAGCCTGTCTATATCCGTGGGTTCTTCTACCTATCAAAACAACTTTGT



TCCAGTTATAGGCGCCCGGCCCCAGGTGAACGGGCAGTCAGGCCGCATCGAGTTTCACTGG



ACTCTGGTCCGGCCCGGAGATAATATTACATTCAGTCATAACGGCGGTTTGATCGCCCCAG



ACCGAGTGAGCAAGCTCATCGGGAAGGGGATTGGCATACAATCCGGTGCTGTGATTGACAA



GGATTGCGAGAGTAAGTGCTTTTGGCGAGGCGGATCTATTATTACCGAGCTGCCATTTCAG



AACCTTTCTCCTCGAACCGTTGGGCAGTGCCCCAAATATGTGAAAAAGAGGTCACTGCTCC



TCGCCACTGGCATGCGAAATGTTCCTGAGGTGGTGCAGGGCCGTGGGTTGTTCGGTGCCAT



CGCAGGGTTCATCGAGAATGGATGGGAAGGTATGGTCGACGGATGGTACGGATTCCGCCAT



CAGAATGCACAGGGTATCGGACAGGCCGCCGATTATAAGAGCACCCAGACGGCTATAGACC



AAATCACCGGCAAGCTTAACCGGCTCATAGAAAAGACCAACACAGAATTTGAGTCCATCGA



GTCAGAATTCAGCGAAATTGAACATCAGATTGGCAACGTCATCAATTGGACCAAGGACTCC



ATCACTGATATCTGGACATACCAGGCAGAACTTTTGGTTGCTATGGAGAACCAACACACCA



TAGATATGGCCGATTCCGAGATGTTGAATCTGTACGAGAGGGTCCGTAAGCAGCTGAGGCA



GAACGCTGAGGAGGACGGGAAGGGGTGCTTTGAGATCTACCACACCTGTGACAATAGCTGC



ATGGAGTCGATCCGGAATAACACTTATGACCATAGTCAATACAGAGAGGAAGCCCTGCTCA



ATCGTTTAAATATTAATCCAGTAAAGTTATCTTCAGGGTACAAGGATATTATTCTCTGGTT



CTCTTTTGGGGCTAGCTGTTTTGTGCTCCTGGCCGTTATAATGGGACTCGGGTTCTTCTGC



CTAAAAAATGGCAACATGCGCTGTACCATTTGCATT





861
ATGTACAAGATTATCGTGATCATCGCACTGCTGGGCGCCGTTAAAGGGCTGGACAAAATAT



GCTTGGGACACCACGCCGTAGCTAATGGAACAATCGTCAAAACCCTGACTAATGAGCAAGA



GGAGGTCACAAATGCAACGGAAACAGTCGAATCCACTGGCATTAATAGGTTGTGCATGAAG



GGCCGAAAGCACAAAGATCTCGGAAATTGTCATCCCATCGGGATGCTGATTGGCACCCCTG



CCTGTGATTTGCACTTAACAGGGACTTGGGACACTCTGATAGAGCGTGAAAACGCAATTGC



ATATTGCTACCCAGGGGCAACGGTCAACGTGGAGGCTCTCCGACAGAAAATTATGGAAAGC



GGAGGGATCGATAAGATTTCGACAGGCTTCACGTACGGCTCCTCAATCAACTCTGCCGGTA



CGACGCGCGCGTGTATGCGGAATGGAGGGAACAGCTTTTACGCAGAACTGAAGTGGCTCGT



AAGCAAAAGTAAAGGGCAAAATTTCCCTCAGACTACAAATACCTACCGCAACACAGACACA



GCGGAGCACCTGATTATGTGGGGAATTCACCATCCCTCAAGTACCCAGGAGAAGAACGACT



TATATGGCACGCAGAGTCTTTCCATTTCTGTGGGGTCTAGCACCTATAGGAACAATTTCGT



CCCAGTTGTCGGCGCTAGGCCTCAGGTGAATGGACAAAGCGGCCGCATAGATTTCCACTGG



ACCCTGGTCCAGCCCGGCGATAATATCACATTTTCTCACAACGGAGGACTGATTGCTCCTA



GCAGAGTATCAAAACTGATTGGGAGAGGCCTTGGCATTCAGTCTGACGCCCCCATTGACAA



TAATTGTGAGTCTAAGTGTTTTTGGGGGGGAGGAAGCATCAATACCAGACTTCCCTTTCAA



AACCTGAGTCCGCGAACTGTCGGACAGTGCCCCAAATACGTTAATAGGCGCTCCCTAATGC



TTGCTACAGGTATGAGGAATGTACCAGAGTTAATTCAGGGGCGCGGCCTTTTTGGCGCCAT



CGCCGGCTTCCTGGAGAACGGCTGGGAGGGCATGGTGGATGGGTGGTATGGCTTCCGCCAT



CAGAACGCACAGGGGACGGGCCAGGCTGCAGATTATAAGTCAACCCAGGCTGCAATAGACC



AAATTACTGGGAAGCTGAATAGGCTAGTGGAGAAGACCAACACTGAGTTTGAATCAATTGA



GAGCGAATTTAGTGAGATCGAGCACCAGATCGGTAACGTGATTAACTGGACGAAAGATTCA



ATTACTGACATTTGGACATATCAGGCTGAGTTGCTGGTGGCGATGGAGAACCAGCACACCA



TAGATATGGCGGATAGCGAGATGCTTAATCTGTACGAACGGGTGCGCAAGCAGCTCCGCCA



GAACGCTGAAGAAGATGGCAAGGGGTGCTTTGAGATTTACCACGCTTGCGATGATTCATGC



ATGGAGTCCATTCGGAATAATACATACGACCACAGTCAGTACAGGGAAGAAGCCCTACTGA



ACCGGTTGAACATTAACCCTGTGACCCTCAGTTCAGGGTACAAAGACATAATACTTTGGTT



CTCCTTCGGGGCCTCATGTTTCGTGCTGCTGGCAGTCGTTATGGGCCTATTCTTCTTCTGC



TTGAAGAATGGAAATATGCGTTGCACCATCTGCATC





862
ATGTACAAAATCGTCGTCATCATTGCACTTCTGGGAGCCGTGAAGGGGCTGGATAAGATCT



GCCTCGGCCATCATGCCGTCGTGAACGGTACCATAGTGAAGACATTGACGAACGAGCAAGA



GGAAGTCACGAACGCCACCGAGACGGTGGAATCCACGGGACTGAATCGTTTGTGCATGAAA



GGCAGGAACCATAAGGATCTGGGAAATTGCCATCCCATAGGCATGCTTATTGGCACGCCAG



CCTGTGACCTACACTTAACCGGCACTTGGGACACTTTGATCGAGCGCGAGAATGCCATCGC



CTACTGTTATCCAGGAGCCACCGTAAACGAAGAGGCTCTGAGACAGAAGATCATGGAGAGT



GGCGGTATAAACAAAATCAGCACCGGCTTCACCTACGGGAGCTCTATCAACTCAGCCGGTA



CTACTAGAGCTTGCATGCGCAACGGCGGAAACTCCTTCTACGCAGAACTTAAGTGGCTCGT



CAGCAAGAGCAAGGGCCAGAACTTTCCTCAGACAACCAACACCTACCGGAATACCGATACT



GCCGAGCACTTGATAATGTGGGGCATCCACCACCCTTCCTCTACTCAGGAAAAGAACGATC



TGTATGGTACCCAGTCTCTGTCCATATCAGTGGGTTCTTCAACATACCAGAACAATTTCGT



CCCTGTGGTAGGAGCAAGGCCCCAGGTAAATGGCCAGAGCGGCCGCATCGACTTTCATTGG



ACTCTGGTGCAGCCAGGGGACAATATTACCTTCAGTCACAACGGCGGCCTGATCGCACCAT



CCAGAGTGTCTAAACTGATAGGCCGAGGATTGGGAATTCAGTCAGACGCACCCATAGATAA



CAATTGCGAATCGAAGTGTTTCTGGCGCGGCGGCTCAATAAACACCCGACTTCCATTCCAA



AACCTCTCTCCCAGAACTGTGGGGCAGTGCCCCAAATACGTGAATAAGAGGTCGCTCATGT



TAGCCACTGGTATGCGAAACGTCCCGGAACTGATGCAGGGACGAGGCCTTTTTGGGGCTAT



AGCAGGCTTCATCGAGAATGGATGGGAAGGCATGGTTGATGGGTGGTATGGCTTCCGCCAT



CAGAATGCTCAGGGGACAGGGCAAGCGGCCGATTACAAATCAACCCAGGCCGCTATAGATC



AAATCACTGGCAAGCTGAATCGCCTCATCGAAAAAACAAATACGGAGTTCGAGTCCATTGA



AAGCGAGTTTTCCGAGATTGAACACCAAATTGGCAACGTCATAAACTGGACTAAGGACTCT



ATTACCGACATATGGACTTACCAGGCAGAGCTTCTGGTCGCTATGGAGAACCAGCACACCA



TCGATATGGCCGATTCCGAAATGTTAAACCTCTACGAAAGAGTGCGCAAGCAGCTCAGACA



GAACGCCGAAGAAGATGGCAAAGGGTGCTTTGAAATCTACCATGCCTGCGACGATAGTTGT



ATGGAGTCGATCCGCAATAACACTTACGATCACAGTCAATATCGGGAGGAGGCACTGTTAA



ACAGGCTGAACATTAACCCGGTAACCCTCTCTAGTGGTTACAAAGACATCATACTTTGGTT



TTCGTTTGGGGCATCTTGTTTTGTGCTCTTGGCCGTAGTGATGGGACTTGTTTTCTTTTGT



CTCAAGAACGGCAATATGCGGTGTACTATTTGCATC





863
ATGTATAAAATCGTCGTGATCATCGCCCTGETAGGTGCGGTCAAGGGCTTGGACAAGATTT



GTCTGGGACATCACGCAGTCGCCAACGGAACCATCGTTAAAACGCTGACTAACGAGCAGGA



AAAAGTTACTAATGCCACAGAGACCGTTGAGTCAACCGGCCTCAATAGGCTTTGCATGAAA



GGACGGAAGCATAAAGACCTGGGCAACTGCCATCCTATTGGGATGTTAATCGGTACCCCCG



CATGCGACCTGCATCTGACTGGAACCTGGGACACCATTATTGAGCGCGAAAATGCCATCGC



ATATTGTTACCCCGGAGCTACTGTGAATGAAGAGGCCCTGAGGCAGAAGATCATGGAGTCC



GGTGGAATTGACAAGATCTCCACTGGATTTACCTACGGGAGTTCTATCAATAGTGCAGGTA



CCACAAGAGCCTGTATGAGAAATGGGGGCAACAGCTTTTACGCCGAATTAAAATGGCTGGT



GAGCAAGAGTAAGGGACAAAATTTTCCTCAGACTACAAACACCTACAGAAATACAGATACG



GCTGAGCACCTTATCATGTGGGGCATCCACCATCCGTCATCCACCCAAGAGAAGAATGATC



TTTACGGAACCCAGAGCTTGAGCATCTCCGTGGGTTCATCCACCTACCGGAACAACTTCGT



GCCAGTGGTGGGGGCTAGGCCACAGGTGAACGGCCAGTCAGGCCGCATCGACTTCCACTGG



ACACTCGTGCAGCCTGGAGATAACATCACTTTCTCCCACAATGGAGGACTGATAGCCCCAT



CTCGCGTTAGCAAGCTGATTGGCCGGGGTCTCGGAATTCAATCTGACGCCCCCATAGACAA



TAACTGTGAAAGCAAGTGCTTCTGGCGTGGGGGGTCCATTAATACCCGTCTACCTTTTCAG



AATCTGTCCCCCCGCACCGTCGGACAATGCCCTAAGTACGTGAATAAAAGGTCCCTTATGC



TAGCTACGGGGATGCGGAATGTTCCGGAGCTAATCCAGGGGCGCGGGCTGTTCGGAGCCAT



CGCAGGTTTTCTCGAGAATGGCTGGGAGGGAATGGTGGACGGTTGGTACGGATTCCGCCAC



CAGAATGCCCAAGGCACAGGACAGGCAGCTGACTACAAATCAACGCAAGCTGCCATCGACC



AGATAACAGGAAAACTGAACAGACTCGTCGAGAAGACCAATACAGAGTTCGAATCCATCGA



GTCTGAATTTAGCGAAATCGAGCACCAGATCGGAAACGTTATCAACTGGACAAAAGACTCC



ATCACCGATATCTGGACTTACCAGGCTGAACTTCTTGTTGCCATGGAGAATCAGCATACTA



TTGATATGGCCGACTCAGAGATGCTCAACCTCTATGAACGGGTCCGGAAACAATTACGACA



GAACGCGGAGGAGGACGGCAAAGGTTGCTTTGAGATATATCACGCGTGCGACGATTCGTGC



ATGGAATCTATCCGCAATAATACTTACGACCACTCTCAGTACCGGGAGGAAGCACTCCTGA



ATCGGTTGAACATCAACCCCGTGACACTTTCTTCCGGCTATAAGGATATAATCCTGTGGTT



TTCCTTTGGAGCATCCTGTTTTGTACTCCTCGCCGTAGTGATGGGGCTGGTCTTTTTCTGC



CTTAAGAACGGGAACATGAGGTGTACTATATGTATT





864
ATGTACAAGGTGGTGGTCATAATCGCCTTGCTAGGCGCCGTGAGAGGGCTCGACAAAATTT



GCTTGGGGCATCATGCAGTCGCTAATGGAACCATCGTGAAAACACTCACCAACGAGCAAGA



AGAGGTTACTAACGCCACCGAGACCGTAGAGAGTAAATCCCTGGGGAAGCTGTGTATGAAG



GGCCGGTCTTATAATGATCTGGGCAATTGCCATCCCATCGGAATTCTGATCGGGACCCCTG



CATGTGATCTGCATCTAACTGGGACGTGGGATACTCTGATCGAGCGCGAGAACGCAGTTGC



TTACTGTTATCCGGGCGCCACCGTGAACGAGGAGGCACTCCGACAGAAAATTATGGAATCG



GGTGGAATTAGCAAGATATCTACTGGGTTCACCTATGGCACTAGCATCAACTCCGCTGGGA



CAACCAAAGCGTGTATGAGAAACGGGGGGAATTCTTTCTACGCCGAACTGAAATGGCTGGT



GTCCAAAAATAAAGGGCAGAATTTTCCTCAGACCACCAACACATACCGGAACACCGACACC



GCCGAGCACCTGATCATCTGGGGCATTCATCACCCGAGCTCGACTCAAGAGAAGAACGATC



TCTACGGGACTCAGTCGCTGAGTATCAGCGTGGGAAGCAGTACTTACCAGAACAATTTTGT



ACCCGTGGTGGGAGCCCGGCCTCAAGTCAACGGCCAGTCCGGCAGGATTGACTTCCACTGG



ACCTTACTGCAGCCAGGGGACAACATCACCTTTTCACACAATGGTGGACTCATCGCACCCT



CCAGAGTTAGCAAACTGATTGGAAGAGGGCTTGGTATTCAGTCGGAAGCCCCTATTGATAA



TGGTTGTGAGAGTAAGTGCTTCTGGAAAGGAGGCAGCATAAATACCAAACTCCCCTTCCAG



AACCTCTCTCCCAGAACCGTCGGCCAGTGCCCTAAGTACGTGAATAAACGCTCGTTGATGC



TCGCGACAGGAATGAGGAACGTGCCTGAAATTATGCATGGTCGCGGACTGTTCGGAGCTAT



CGCCGGGTTCATCGAGAATGGCTGGGAAGGGATGGTGGACGGTTGGTACGGGTTTCGACAC



CAGAACGCACAGGGCACTGGCCAGGCAGCAGATTATAAGTCCACTCAGGCCGCAATCGACC



AGATTACCGGCAAATTAAATAGATTGATCGAGAAAACGAATACTGAGTTCGAGAGCATCGA



ATCGGAGTTCTCTGAAATCGAGCATCAGATTGGAAACATTATAAATTGGACCAAGGACAGC



ATTACAGATATTTGGACGTATCAGGCAGAGCTGCTGGTGGCCATGGAAAACCAGCATACGA



TCGACATGGCCGATTCCGAAATGCTCAACCTGTATGAAAGGGTGAGGAAACAGCTGAGACA



AAACGCAGAAGAAGACGGCAAAGGTTGCTTCGAAATTTACCACGCTTGCGACGATTCATGC



ATGGAGAGCATTCGGAATAATACCTATGATCATAGCCAGTACAGAGAGGAGGCCCTGCTAA



ATAGACTGAATATAAATCCCGTAAAACTGAGCTCTGGCTATAAGGACATTATTCTGTGGTT



TAGTTTCGGAGCATCCTGCCTCATCCTCCTGGCAGTGGTCATGGGCCTCGTGTTCTTTTGT



CTGAAGAACGGAAATATGCGATGTACTATTTGTATC





865
ATGTACAAAATAGTCGTGATCATCGCACTGCTGGGGGCCGTGAAAGGTCTCGATAAGATTT



GCCTTGGACACCATGCCGTGGCTAACGGGACTATTGTGAAGACACTTACCAATGAGCAGGA



GGAAGTTACCAACGCTACAGAAACTGTCGAGTCGACTGGTATTAATAGGCTGTGTATGAAG



GGACGTAAGCATAAAGACCTCGGGAATTGCCACCCTATAGGCATGCTGATAGGCACCCCAG



CATGTGACCTGCACCTCACAGGCATGTGGGACACATTAATCGAAAGGGAGAATGCCATAGC



CTATTGCTACCCAGGTGCAACAGTTAATGTTGAAGCATTGCGGCAGAAAATCATGGAGTCC



GGCGGCATTAACAAGATCTCTACGGGATTTACGTACGGCTCAAGCATTAATAGTGCCGGGA



CTACTCGAGCATGCATGAGGAATGGAGGGAACAGTTTCTACGCCGAGCTGAAGTGGCTCGT



GTCTAAAAGTAAAGGGCAGAACTTCCCTCAGACCACTAATACCTACAGAAACACAGACACC



GCAGAACACTTAATAATGTGGGGCATACATCACCCCAGCAGCACTCAGGAGAAAAACGACC



TGTACGGTACCCAGTCCCTGTCCATTTCCGTGGGAAGTTCTACGTATCGGAATAACTTCGT



CCCGGTGGTGGGAGCCAGGCCGCAGGTTAACGGACAAAGCGGGCGAATTGATTTCCACTGG



ACACTGGTGCAGCCTGGCGACAATATAACTTTCTCCCATAATGGCGGACTGATCGCTCCAT



CCCGGGTCAGCAAGCTAATCGGTAGAGGGCTGGGGATCCAATCAGACGCACCTATTGATAA



CAACTGCGAGAGTAAGTGCTTCTGGCGAGGCGGTAGCATAAACACACGTTTGCCATTTCAG



AATCTTAGTCCTCGTACTGTGGGCCAATGTCCAAAGTATGTCAACAGGCGCAGTTTAATGT



TAGCTACTGGAATGCGCAACGTACCTGAGCTCATTCAAGGTCGAGGCCTGTTCGGAGCCAT



TGCTGGGTTCCTTGAGAATGGGTGGGAGGGCATGGTCGACGGATGGTACGGATTCCGCCAC



CAGAACGCCCAGGGCACAGGCCAGGCAGCCGATTATAAAAGTACCCAGGCTGCCATCGACC



AGATCACTGGGAAACTCAACCGTCTGGTCGAAAAGACTAACACCGAATTTGAGTCTATTGA



ATCAGAATTCAGCGAAATTGAGCACCAGATCGGCAATGTGATCAATTGGACGAAAGACTCT



ATTACCGACATTTGGACCTACCAGGCCGAGTTACTGGTGGCCATGGAGAACCAGCACACCA



TCGACATGGCCGATAGTGAAATGCTTAACCTCTACGAAAGAGTCCGAAAACAACTCCGCCA



GAACGCGGAGGAGGATGGAAAGGGCTGCTTCGAAATCTATCATGCCTGCGACGACTCCTGT



ATGGAAAGCATTCGCAACAACACCTACGACCACAGTCAGTACAGGGAGGAGGCGCTGCTTA



ATAGGCTGAACATCAATCCGGTAACACTGTCATCGGGATACAAGGACATCATACTCTGGTT



CTCATTCGGCGCGTCCTGTTTCGTACTGCTCGCAGTCGTAATGGGGCTCTTCTTCTTCTGC



TTAAAGAACGGCAACATGCGCTGCACTATCTGCATT





866
ATGTATAAAATTGTGGTCATAATTGCACTGCTCGGCGCAGTCAAGGGTCTGGATAAGATTT



GCCTTGGTCACCATGCCGTAGCCAACGGAACCATTGTGAAGACCCTTACAAATGAACAAGA



AGAAGTGACTAATGCAACTGAGACCGTGGAATCTACAGGTATCAATCGCCTGTGTATGAAG



GGGCGAAAACATAAAGATCTCGGCAATTGTCACCCCATTGGGATGCTGATTGGCACCCCGG



CATGTGACCTACATTTGACCGGAATGTGGGATACACTAATCGAACGGGAGAATGCTATTGC



GTACTGTTACCCTGGCGCTACCGTCAATGTGGAGGCCCTGCGCCAAAAAATCATGGAATCT



GGGGGAATCAATAAGATCTCCACTGGCTTCACTTATGGATCCAGCATTAACAGCGCTGGCA



CAACTCGCGCCTGTATGCGCAATGGGGGCAATTCCTTCTATGCAGAGCTTAAGTGGTTAGT



GAGCAAGTCGAAAGGCCAAAACTTCCCTCAAACAACCAATACATATAGGAACACCGATACC



GCTGAACATCTCATTATGTGGGGAATACATCATCCCAGCTCCACACAAGAGAAGAATGATT



TGTACGGGACCCAATCCTTGTCTATTAGCGTAGGCTCCTCCACATACCGGAACAACTTCGT



CCCAGTCGTGGGGGCACGGCCTCAGGTTAACGGACAGTCCGGCCGTATTGACTTCCACTGG



ACTCTGGTGCAACCAGGGGACAACATCACTTTCTCTCATAACGGGGGTCTGATCGCACCTA



GTAGGGTGTCCAAACTTATAGGAAGGGGTCTCGGCATCCAAAGCGACGCCCCCATCGATAA



TAATTGCGAAAGCAAGTGTTTTTGGAGGGGAGGGAGCATCAATACTCGGTTACCATTTCAG



AATTTAAGTCCAAGAACAGTAGGACAATGCCCTAAGTATGTTAATAGACGTTCCCTCATGT



TAGCAACTGGAATGAGGAACGTTCCGGAGCTGATTCAGGGAAGAGGACTCTTCGGGGCAAT



CGCCGGTTTTTTGGAGAACGGATGGGAGGGCATGGTGGATGGTTGGTACGGATTCCGCCAT



CAGAACGCCCAGGGCACCGGGCAAGCTGCAGACTATAAATCAACACAAGCAGCAATTGATC



AAATCACCGGCAAGTTGAACAGGCTGGTCGAGAAAACCAACACTGAATTCGAGTCCATCGA



GAGCGAGTTCTCTGAAATAGAGCATCAGATTGGAAACGTTATCAACTGGACCAAGGATAGT



ATCACGGACATTTGGACTTATCAAGCCGAGCTGCTGGTCGCCATGGAGAATCAACATACTA



TCGACATGGCGGATAGTGAAATGCTCAACCTGTACGAGCGCGTGCGCAAGCAACTGCGCCA



GAACGCTGAAGAGGACGGTAAAGGTTGCTTTGAAATTTATCACGCTTGTGATGACTCCTGC



ATGGAGTCGATCCGCAATAATACGTACGATCACAGCCAGTACCGGGAGGAGGCTTTGCTGA



ACCGGCTGAACATCAACCCTGTAACCTTGTCTTCTGGCTACAAGGATATTATACTCTGGTT



CAGCTTCGGCGCCAGCTGCTTCGTCCTGCTGGCCGTGGTTATGGGACTCTTCTTTTTCTGT



CTGAAAAATGGTAATATGCGGTGCACAATTTGTATC





867
ATGTACAAGATTGTGGTAATCATCGCTTTACTTGGGGCAGTGAAAGGATTGGACAAGATTT



GTTTGGGGCACCATGCAGTGGCCAACGGCACCATTGTTAAAACACTGACAAATGAGCAGGA



AGAGGTTACCAATGCAACGGAAACCGTGGAATCTACTGGAATCAACAGACTGTGCATGAAG



GGCCGCAAGCATAAAGACTTGGGGAATTGCCACCCAATTGGAATGCTTATTGGAACACCAG



CTTGCGATTTACATCTGACTGGCATGTGGGACACCCTCATCGAGCGGGAAAATGCTATCGC



TTATTGCTACCCGGGGGCCACAGTGAATGTGGAAGCACTACGGCAAAAAATCATGGAATCA



GGCGGAATCAACAAAATCTCAACCGGCTTCACCTATGGGTCATCCATCAATAGTGCTGGCA



CCACACGCGCCTGCATGCGAAATGGTGGAAACTCATTCTATGCGGAACTGAAATGGCTAGT



GTCAAAAAGCAAAGGGCAGAATTTTCCACAGACTACGAACACTTATAGAAATACTGACACA



GCTGAGCATCTTATTATGTGGGGCATCCATCATCCAAGCAGTACACAGGAAAAGAATGACC



TATACGGTACACAGTCCCTGTCTATTTCCGTGGGATCCTCCACATACAGAAACAACTTTGT



CCCTGTGGTGGGAGCAAGGCCTCAGGTCAACGGACAGTCTGGCCGCATCGATTTCCATTGG



ACCCTGGTTCAACCGGGCGATAACATCACCTTCAGCCACAATGGAGGCCTGATCGCCCCTA



GCAGGGTGTCAAAGCTTATAGGCAGGGGTCTTGGGATCCAATCCGACGCCCCCATAGACAA



TAACTGCGAGTCGAAATGTTTCTGGCGGGGTGGTTCCATTAATACTCGTCTCCCCTTCCAG



AATCTTTCTCCCAGAACTGTTGGGCAATGCCCCAAGTACGTAAATCGTAGAAGTCTTATGC



TCGCAACCGGTATGCGCAACGTGCCTGAGCTCATTCAGGGCCGGGGCCTCTTTGGGGCTAT



TGCCGGCTTCCTTGAAAACGGCTGGGAGGGTATGGTGGATGGCTGGTACGGATTCCGCCAC



CAGAATGCCCAAGGCACAGGTCAGGCTGCCGACTATAAGTCAACGCAGGCTGCCATCGATC



AGATCACAGGCAAGTTGAACAGGCTAGTGGAGAAGACCAACACAGAGTTTGAGAGTATTGA



GAGCGAGTTTTCCGAAATCGAACACCAGATAGGCAACGTTATCAACTGGACAAAGGACAGT



ATTACAGACATTTGGACATATCAGGCTGAACTGTTGGTGGCCATGGAGAACCAGCACACTA



TCGATATGGCAGACTCCGAGATGCTGAATTTGTACGAAAGGGTCCGGAAGCAGCTCCGCCA



GAACGCCGAAGAGGATGGGAAAGGCTGCTTTGAAATTTACCACGCTTGCGACGACTCCTGT



ATGGAATCCATTCGAAATAATACATATGATCACAGCCAGTACCGGGAAGAAGCTTTACTTA



ATCGATTGAATATCAATCCAGTTACCCTTTCCTCCGGCTACAAGGACATCATTCTGTGGTT



CTCCTTCGGTGCCTCGTGCTTCGTCCTGCTTGCAGTTGTTATGGGGCTGTTTTTTTTCTGT



CTGAAGAACGGGAATATGCGGTGCACTATTTGCATC





868
ATGTATAAAATCGTGGTTATCATCGCCCTGTTGGGCGCAGTCAAAGGCTTAGACAAAATTT



GCCTGGGCCACCATGCCGTGGCCAATGGCACAATTGTAAAAACTTTGACTAATGAGCAGGA



GGAAGTCACTAACGCCACGGAAACCGTGGAGTCCACTGGAATCAACCGCCTGTGCATGAAG



GGACGGAAGCATAAGGACCTCGGTAATTGTCATCCGATAGGTATGCTCATCGGCACCCCCG



CTTGCGACTTACATTTGACAGGAATGTGGGACACTCTGATTGAGAGGGAGAACGCCATTGC



CTACTGTTACCCCGGCGCAACAGTCAATGTGGAGGCGCTGCGTCAAAAGATAATGGAGAGT



GGAGGCATCAACAAAATTTCAACAGGGTTCACATACGGGAGCTCAATTAACTCTGCGGGCA



CGACCAGGGCTTGCATGAGAAACGGCGGTAATTCCTTTTATGCGGAGTTGAAATGGCTGGT



CTCCAAGTCCAAGGGTCAGAATTTCCCACAAACCACAAATACTTACCGAAATACGGACACT



GCCGAGCATCTGATAATGTGGGGAATACACCATCCTAGTTCTACGCAAGAGAAAAATGACC



TCTATGGGACGCAATCCTTGAGTATCAGCGTTGGCTCCTCAACCTACCGGAACAACTTCGT



CCCAGTTGTAGGAGCTCGACCTCAGGTGAATGGACAGTCAGGTCGTATCGATTTTCATTGG



ACCCTCGTGCAACCTGGGGACAACATAACCTTCTCCCACAACGGGGGGCTGATAGCACCCA



GTCGTGTCTCCAAATTGATCGGGAGGGGGCTGGGCATCCAATCAGATGCACCAATTGATAA



TAATTGTGAGAGCAAGTGCTTCTGGCGTGGGGGTAGCATCAACACTCGCCTCCCCTTTCAG



AACTTGTCACCCCGGACCGTCGGTCAGTGTCCCAAGTATGTTAATCGGCGTTCATTAATGC



TGGCAACCGGTATGCGCAACGTCCCCGAGCTAATCCAAGGAAGAGGGCTTTTTGGGGCTAT



AGCAGGATTTTTAGAGAACGGTTGGGAGGGCATGGTGGACGGATGGTACGGCTTTCGGCAC



CAGAATGCGCAGGGGACAGGGCAAGCTGCCGATTATAAGTCCACTCAAGCTGCTATTGATC



AGATTACAGGCAAGCTTAATCGCCTGGTCGAGAAGACTAACACAGAGTTCGAGAGCATTGA



GTCAGAATTCTCTGAAATTGAGCACCAAATCGGGAATGTAATAAATTGGACAAAGGACAGT



ATTACCGACATCTGGACTTATCAAGCCGAGCTCCTGGTTGCTATGGAGAATCAGCACACAA



TCGACATGGCCGATAGCGAGATGCTAAACCTGTACGAAAGGGTGCGCAAGCAGCTGAGGCA



AAACGCTGAGGAAGATGGCAAGGGCTGTTTCGAGATTTATCACGCGTGTGATGATTCATGC



ATGGAATCAATTAGGAACAACACTTACGATCATTCTCAGTACCGGGAGGAGGCACTCCTGA



ACAGGCTCAACATAAACCCTGTCACCCTGTCTTCAGGCTATAAGGACATTATACTATGGTT



TTCTTTTGGCGCCTCCTGTTTTGTGCTCCTCGCCGTTGTAATGGGCCTTTTTTTTTTTTGC



CTGAAGAACGGTAATATGCGGTGTACTATTTGCATT





869
ATGTACAAGATTGTAGTGATTATCGCACTGCTAGGCGCGGTGAAGGGTCTCGACAAGATTT



GCCTGGGCCATCACGCGGTGGCCAACGGGACTATCGTGAAGACTCTGACCAATGAACAAGA



GGAAGTTACTAACGCCACCGAAACTGTGGAGTCCACAGGCATCAATCGCTTGTGTATGAAG



GGAAGGAAGCATAAAGACCTGGGTAATTGTCACCCCATAGGGATGCTTATCGGTACACCAG



CTTGTGATCTGCATTTAACGGGGATGTGGGACACACTTATAGAACGTGAGAATGCCATTGC



CTATTGTTACCCCGGAGCTACCGTAAACGTGGAGGCCCTGCGCCAGAAGATCATGGAGTCA



GGGGGCATCAATAAGATCAGTACCGGCTTTACCTATGGTAGCTCTATCAACTCCGCCGGCA



CTACCAGGGCCTGTATGAGGAATGGGGGAAACAGCTTCTATGCTGAGCTGAAGTGGCTAGT



TAGCAAGAGCAAGGGCCAGAACTTCCCTCAAACTACAAATACGTATCGGAACACCGACACA



GCGGAGCACCTGATAATGTGGGGAATCCACCACCCATCGTCCACCCAAGAAAAGAACGATC



TGTACGGTACTCAGTCCCTGAGTATTTCCGTGGGCTCCAGTACGTACCGAAATAATTTCGT



CCCAGTGGTCGGGGCAAGGCCGCAAGTGAATGGCCAGTCAGGACGGATAGACTTTCATTGG



ACACTGGTGCAACCCGGCGATAACATCACCTTCAGCCATAACGGGGGGCTGATCGCCCCGA



GCCGAGTTAGCAAACTTATCGGCCGGGGCCTGGGCATCCAGAGTGATGCACCCATCGACAA



TAATTGCGAGAGCAAATGTTTTTGGAGGGGTGGATCGATAAACACACGCCTCCCGTTCCAA



AATCTCAGTCCTAGAACAGTGGGGCAGTGTCCTAAGTATGTGAATCGCCGGAGCCTTATGT



TGGCCACTGGGATGCGAAATGTGCCCGAACTAATTCAAGGGCGAGGACTGTTCGGCGCCAT



TGCCGGCTTCCTGGAGAATGGCTGGGAAGGCATGGTTGATGGTTGGTATGGCTTTCGCCAT



CAGAATGCACAGGGGACAGGCCAGGCCGCGGATTACAAATCGACCCAAGCTGCAATTGATC



AGATCACAGGGAAACTGAATCGACTTGTGGAGAAAACTAATACCGAATTTGAATCTATCGA



GTCCGAATTTAGCGAAATCGAGCACCAGATCGGTAACGTGATCAATTGGACTAAGGACTCC



ATTACAGACATATGGACATATCAGGCCGAGTTGTTGGTGGCAATGGAGAACCAGCATACTA



TCGACATGGCCGATTCTGAGATGCTAAATCTGTATGAACGCGTCCGGAAACAGCTCAGACA



GAATGCTGAGGAAGATGGGAAGGGATGCTTCGAAATATACCACGCCTGCGACGACAGCTGT



ATGGAGTCAATTCGCAACAACACTTACGATCACTCCCAATACCGGGAGGAGGCCCTTCTTA



ACAGACTCAACATTAATCCTGTGACTCTGTCATCCGGATACAAAGACATAATACTCTGGTT



TAGCTTTGGCGCAAGTTGTTTTGTGCTGCTCGCAGTGGTGATGGGGTTGTTTTTTTTCTGC



CTGAAAAATGGTAATATGCGATGCACTATCTGCATC





870
ATGTACAAAATTGTGGTGATAATTGCATTGCTCGGAGCAGTCAAAGGGCTGGACAAAATAT



GTTTGGGGCACCACGCCGTGGTTAATGGTACCATCGTTAAGACTCTGACCAACGAACAGGA



AGAGGTGACCAATGCTACCGAGACCGTGGAAAGCACTGGGTTGAACAGGCTGTGCATGAAA



GGAAGGAATCACAAGGACCTGGGAAACTGTCATCCAATCGGAATGCTCATTGGGACTCCCG



CATGTGATCTGCATCTGACGGGCACCTGGGATACCTTGATAGAGAGGGAGAACGCCATAGC



ATACTGTTATCCCGGAGCCACCGTGAACGAGGAGGCACTGAGGCAGAAAATTATGGAATCT



GGAGGGATCAATAAAATTAGCACAGGGTTTACCTATGGCTCAAGTATCAATAGCGCCGGGA



CTACACGGGCCTGCATGCGAAATGGAGGGAACTCCTTCTACGCTGAACTAAAGTGGCTGGT



CAGTAAGTCCAAAGGGCAGAATTTCCCGCAGACAACCAACACTTACCGCAATACCGATACG



GCTGAACACTTAATCATGTGGGGCATCCATCATCCCTCTAGCACACAAGAGAAAAACGACC



TGTATGGAACACAAAGCCTCAGCATCTCCGTGGGTTCATCTACATATCAGAACAACTTCGT



GCCCGTCGTTGGCGCCCGACCTCAGGTGAATGGTCAATCGGGCCGGATTGACTTTCACTGG



ACCCTCGTCCAGCCAGGTGATAACATCACCTTCAGCCACAACGGCGGACTCATCGCCCCAT



CTCGTGTGTCCAAGCTCATTGGCAGAGGGCTTGGCATCCAGTCTGATGCACCCATCGATAA



CAATTGCGAGAGCAAGTGTTTCTGGCGCGGTGGATCAATAAATACGCGGCTCCCCTTTCAG



AATCTTTCTCCCAGAACCGTAGGCCAGTGTCCAAAGTATGTAAACAAAAGATCATTGATGC



TGGCCACAGGAATGAGGAATGTGCCTGAGCTGATGCAGGGCAGAGGCCTGTTCGGTGCGAT



CGCCGGCTTCATCGAAAATGGCTGGGAGGGGATGGTGGACGGATGGTATGGCTTCCGCCAC



CAGAACGCTCAGGGGACCGGACAAGCTGCGGATTATAAGAGCACTCAGGCGGCAATCGACC



AGATCACCGGAAAACTCAACCGTCTCATCGAGAAGACAAACACCGAATTTGAGTCTATAGA



ATCTGAGTTCAGTGAAATCGAACACCAAATCGGCAACGTCATAAATTGGACTAAGGACTCC



ATCACCGATATCTGGACCTATCAAGCCGAGCTGCTGGTTGCCATGGAGAATCAGCACACGA



TCGACATGGCTGATTCTGAAATGCTGAACCTCTATGAAAGAGTTCGGAAACAGCTCAGACA



AAACGCCGAAGAGGACGGCAAAGGATGTTTTGAGATCTATCATGCCTGCGATGATAGTTGT



ATGGAGAGCATCAGGAATAATACATACGACCACTCCCAGTATCGCGAGGAAGCACTGCTCA



ATCGGTTAAATATAAATCCAGTGACGCTTAGTAGTGGGTATAAGGACATAATCCTCTGGTT



CTCTTTCGGCGCCAGCTGTTTCGTTCTGCTGGCCGTGGTCATGGGACTTGTGTTCTTTTGT



CTTAAAAATGGGAACATGAGATGCACAATATGTATT





871
ATGTATAAAATAGTGGTGATAATCGCGCTACTGGGCGCAGTGAAGGGGCTCGATAAGATTT



GCTTGGGTCATCATGCTGTTGCAAACGGCACCATCGTTAAAACACTGACCAACGAGCAGGA



GGAGGTAACGAACGCCACGGAGACGGTGGAGTCTACCGGGATCAACCGTCTGTGTATGAAG



GGTCGCAAGCATAAGGATTTAGGAAATTGTCATCCTATCGGAATGCTTATAGGTACCCCGG



CCTGCGATCTCCATCTGACAGGCATGTGGGATACTCTCATCGAAAGAGAGAATGCCATCGC



GTATTGTTACCCTGGGGCCACAGTAAATGTCGAAGCATTGAGACAGAAAATCATGGAGTCC



GGAGGCATTAATAAGATTTCCACCGGCTTCACCTACGGATCTTCCATCAATTCCGCAGGCA



CAACCAGAGCCTGCATGCGGAATGGAGGGAATTCCTTTTACGCCGAATTGAAATGGCTTGT



GTCAAAGTCAAAGGGACAGAACTTTCCCCAAACTACGAACACATATAGAAATACAGATACC



GCAGAACACTTAATTATGTGGGGCATCCACCACCCGTCAAGTACTCAGGAGAAGAATGACC



TTTACGGCACCCAGTCTCTTTCAATCTCAGTCGGGAGCTCCACATATAGAAACAACTTTGT



ACCTGTGGTCGGTGCAGGACCGCAGGTGAATGGCCAATCAGGAAGGATCGATTTTCACTGG



ACACTGGTCCAGCCTGGTGACAACATCACGTTCTCACACAATGGGGGCCTAATAGCCCCCT



CCCGCGTGAGCAAGCTAATTGGCCGCGGATTGGGTATCCAGAGCGACGCCCCTATAGACAA



TAACTGTGAGAGCAAGTGCTTCTGGCGCGGAGGGTCAATTAACACCCGGCTCCCCTTCCAG



AACCTGTCCCCCCGGACGGTGGGCCAGTGCCCAAAATACGTCAATCGGCGCTCCCTGATGT



TGGCCACAGGCATGCGGAATGTTCCTGAACTGATACAGGGTCGGGGGTTGTTCGGAGCAAT



TGCCGGGTTTCTTGAAAACGGCTGGGAAGGTATGGTGGATGGTTGGTACGGGTTCAGGCAC



CAGAACGCTCAGGGTACCGGCCAGGCGGCTGACTACAAATCAACCCAGGCAGCAATCGACC



AGATTACAGGAAAGCTGAATCGCCTTGTGGAGAAAACCAATACCGAATTTGAGTCCATCGA



GTCTGAGTTCAGCGAGATAGAGCATCAGATTGGCAACGTCATCAACTGGACGAAGGACTCC



ATTACTGATATATGGACTTATCAGGCTGAACTGCTGGTAGCCATGGAGAACCAGCACACAA



TTGACATGGCTGACTCCGAGATGCTGAATCTATACGAGCGCGTGAGGAAGCAGCTCAGACA



GAACGCTGAGGAGGACGGTAAGGGTTGCTTCGAGATTTACCACGCCTGTGATGACTCCTGT



ATGGAGTCAATCAGGAACAATACCTATGACCACTCTCAATATCGGGAGGAAGCGCTTCTCA



ACCGTCTTAACATTAATCCCGTGACACTGTCTTCAGGTTACAAGGATATCATCCTGTGGTT



CAGCTTTGGCGCCAGCTGTTTCGTGCTACTAGCAGTGGTGATGGGCCTGTTTTTTTTCTGC



CTGAAAAATGGGAACATGAGGTGCACGATTTGCATC





872
ATGTATAAAATCGTTGTAATTATTGCACTGCTTGGCGCCGTGAAGGGACTCGACAAGATCT



GCCTGGGCCACCACGCTGTAGCCAACGGCACCATTGTGAAGACCCTGACAAATGAGCAGGA



GGAGGTTACCAATGCCACTGAGACCGTGGAATCCACAGGCATTAACCGCCTGTGTATGAAG



GGAAGGAAGCACAAGGACCTTGGCAATTGTCACCCAATCGGCATGCTCATCGGCACACCAG



CATGCGACTTGCACCTGACCGGAATGTGGGACACGCTCATAGAAAGAGAGAATGCCATTGC



CTATTGCTACCCAGGAGCCACCGTTAACGTGGAGGCACTGAGGCAGAAGATCATGGAGAGC



GGAGGCATCAATAAAATTAGTACGGGGTTTACATATGGCTCCTCTATAAATTCCGCCGGCA



CCACCCGGGCCTGCATGCGGAATGGCGGAAATAGTTTCTACGCTGAGTTGAAATGGCTGGT



GAGCAAGAGTAAGGGGCAGAACTTTCCGCAAACTACCAATACGTATAGGAACACTGACACC



GCCGAGCACCTAATCATGTGGGGCATACATCATCCCAGCTCCACGCAGGAGAAGAACGACC



TGTATGGAACTCAAAGCCTATCTATCTCCGTGGGATCCAGTACATACCGGAATAACTTTGT



GCCAGTAGTGGGCGCCAGACCGCAGGTGAACGGGCAATCCGGCAGGATCGACTTCCACTGG



ACACTGGTGCAACCAGGCGACAACATTACTTTCAGCCACAATGGTGGTTTAATAGCCCCCT



CAAGGGTTTCCAAATTGATTGGGCGGGGGCTTGGTATTCAATCTGACGCTCCAATAGATAA



CAATTGTGAAAGTAAGTGTTTCTGGCGCGGCGGCTCTATTAATACTCGCCTTCCATTCCAA



AATCTCTCACCACGTACCGTTGGCCAATGTCCCAAATATGTGAACCGTAGGTCCTTGATGC



TCGCAACGGGAATGAGGAACGTTCCGGAGCTGATCCAGGGCCGAGGACTCTTTGGTGCTAT



TGCCGGATTTCTGGAGAACGGGTGGGAGGGCATGGTGGATGGATGGTACGGCTTCCGACAT



CAGAATGCACAAGGCACCGGGCAGGCCGCCGATTACAAGTCCACGCAAGCTGCCATTGACC



AGATTACGGGGAAGTTGAACCGGCTCGTCGAGAAGACCAATACTGAATTCGAATCCATTGA



GAGCGAATTTTCTGAAATTGAACATCAGATTGGTAACGTCATCAATTGGACTAAGGACTCA



ATAACAGACATCTGGACTTATCAGGCTGAACTCCTCGTCGCGATGGAAAATCAGCACACCA



TCGATATGGCCGACTCTGAGATGCTGAACTTGTACGAGCGGGTGAGAAAACAGCTTCGACA



GAATGCCGAGGAAGATGGCAAGGGCTGCTTCGAGATCTATCACGCTTGCGATGACTCATGC



ATGGAGTCTATCCGGAACAACACTTATGACCACTCCCAATACCGCGAGGAGGCCCTGCTGA



ATAGGCTGAACATCAACCCAGTGACCTTGAGCTCAGGCTATAAGGACATAATCCTGTGGTT



TAGCTTTGGGGCCTCGTGCTTTGTCCTGCTGGCCGTAGTTATGGGGCTTTTCTTCTTTTGT



CTTAAGAATGGGAATATGAGGTGTACAATCTGTATC





873
ATGTACAAGATCGTGGTTATCATCGCACTCCTCGGGGCTGTGAAGGGTCTCGACAAAATCT



GCCTTGGTCATCACGCAGTTGCCAACGGAACTATTGTTAAGACCTTGACTAATGAGCAGGA



GGAGGTGACAAACGCCACAGAAACCGTGGAAAGTACGGGGATCAACCGTTTATGCATGAAG



GGAAGGAAACACAAAGATCTCGGTAACTGCCATCCGATCGGTATGCTCATTGGCACTCCAG



CTTGCGACTTGCACTTGACCGGTATGTGGGACACATTAATTGAACGCGAGAACGCCATCGC



CTATTGCTACCCCGGAGCCACTGTGAACGTGGAAGCACTCCGACAGAAAATAATGGAAAGT



GGGGGGATAAATAAGATCTCAACCGGATTTACATACGGTTCCTCAATTAATAGCGCCGGGA



CCACTAGAGCATGCATGCGAAATGGAGGTAATTCTTTTTACGCTGAGCTTAAATGGCTGGT



GTCTAAAAGCAAGGGCCAGAATTTTCCACAGACGACGAACACTTATAGGAATACAGACACA



GCCGAACACCTGATCATGTGGGGAATCCACCACCCATCTAGCACACAGGAGAAAAACGACC



TATATGGTACCCAAAGCCTGTCAATTAGCGTCGGCAGTAGTACATACCGCAATAATTTCGT



TCCCGTTGTCGGAGCCAGGCCGCAAGTGAACGGGCAAAGTGGCAGAATTGATTTCCACTGG



ACACTGGTCCAGCCCGGGGATAACATTACATTCAGCCACAACGGGGGGCTTATCGCCCCCT



CCCGTGTGAGTAAGCTGATCGGCCGGGGCTTAGGTATCCAGTCCGATGCTCCCATCGACAA



CAATTGTGAATCGAAGTGCTTTTGGCGGGGGGGCTCCATCAATACCCGGCTGCCTTTCCAG



AACCTGAGCCCCAGGACCGTTGGACAGTGTCCCAAATACGTTAACCGGCGGAGTCTGATGC



TTGCAACCGGGATGCGCAATGTGCCCGAACTGATCCAGGGGCGAGGACTGTTCGGGGCCAT



CGCCGGATTCCTGGAGAATGGCTGGGAGGGTATGGTGGACGGCTGGTACGGCTTTAGGCAC



CAAAATGCTCAAGGAACAGGGCAGGCTGCTGACTACAAATCAACCCAGGCCGCTATTGATC



AAATTACTGGAAAGCTGAATAGATTGGTGGAGAAAACTAATACTGAATTCGAGTCCATCGA



AAGTGAGTTCAGCGAGATCGAGCACCAGATTGGTAACGTTATTAACTGGACCAAAGACAGC



ATCACCGACATTTGGACCTACCAGGCCGAGCTTCTAGTAGCCATGGAAAATCAACACACGA



TCGATATGGCTGATTCAGAGATGCTGAATCTGTATGAGCGGGTCCGGAAACAGCTGAGACA



GAATGCAGAGGAAGACGGTAAGGGGTGTTTTGAGATTTACCATGCCTGCGATGATTCTTGC



ATGGAATCTATCAGGAACAACACCTATGACCACTCCCAATATCGCGAGGAGGCCCTGCTGA



ACAGGTTAAACATCAACCCCGTCACCCTGTCTTCAGGATATAAAGACATCATCTTATGGTT



CTCCTTCGGAGCGTCCTGTTTTGTGCTGTTGGCAGTGGTCATGGGGCTTTTCTTTTTCTGT



CTAAAAAACGGTAACATGCGGTGCACCATATGCATC





874
ATGTATAAAATTGTAGTTATTATCGCCCTGTTGGGCGCTGTGAAGGGCTTGGACAAGATCT



GCCTGGGACACCATGCAGTCGCAAATGGAACAATTGTCAAGACACTGACTAATGAGCAGGA



AGAGGTTACCAACGCCACAGAGACCGTAGAGTCCACCGGGATTAATCGGCTATGCATGAAA



GGAAGAAAGCACAAAGATCTCGGGAACTGTCATCCAATTGGTATGCTGATCGGAACCCCCG



CCTGTGATCTCCATCTTACTGGCACTTGGGACACCTTGATTGAGAGGGAAAACGCCATTGC



TTATTGTTACCCAGGAGCTACCGCCAACGTCGAGGCCCTAAGGCAGAAGATCATGGAGTCT



GGAGGAATTGATAAGATCTCAACGGGGTTTACATACGGGTCTAGTATCAATAGCGCAGGCA



CTACCCGCGCTTGTATGAGGAACGGCGGCAACTCGTTTTACGCCGAGTTGAAATGGCTGGT



CAGTAAATCAAAGGGGCAGAATTTTCCACAGACCACAAACACTTATAGGAATACCGATACA



GCTGAACACCTCATCATGTGGGGCATCCATCACCCCAGCTCCATTCAAGAGAAGAACGACT



TGTATGGCACACAGTCATTGAGCATCAGTGTGGGCAGCAGCACATACAGAAACAACTTCGT



GCCCGTGGTTGGGGCAAGACCTCAGGTAAACGGCCAGTCCGGTAGGATTGACTTCCATTGG



ACGCTCGTGCAACCGGGAGATAACATCACCTTCAGCCACAATGGGGGACTCATCGCACCCT



CTCGAGTTAGCAAACTGATCGGGCGAGGCTTAGGCATACAATCCGACGCGCCTATCGATAA



CAATTGCGAATCCAAATGTTTCTGGCGCGGCGGTAGCATTAATACTCGTCTGCCATTCCAG



AACCTTAGCCCCAGGACAGTGGGACAGTGTCCAAAATACGTGAATCGCAGAAGTCTCATGC



TGGCTACCGGCATGAGGAACGTGCCAGAGCTTATACAGGGGGGGGGCTTGTTCGGAGCGAT



CGCTGGCTTCTTGGAGAATGGCTGGGAGGGCATGGTCGACGGATGGTATGGTTTTCGACAT



CAAAACGCCCAGGGCACGGGGCAGGCCGCCGATTACAAGTCCACTCAGGCAGCAATCGACC



AGATCACCGGTAAGCTTAATAGACTGGTCGAGAAGACAAATACCGAGTTCGAATCTATTGA



ATCCGAGTTCAGCGAAATCGAACACCAAATAGGGAACGTCATCAACTGGACCATGGACAGC



ATCACCGATATATGGACATATCAGGCTGAGTTGCTTGTGGCCATGGAAAATCAGCACACAA



TCGATATGGCTGATTCCGAAATGCTGAACCTGTACGAACGGGTAAGGAAGCAGCTGCGGCA



GAACGCAGAAGAGGATGGGAAGGGCTGCTTCGAAATTTACCACGCTTGTGATGACTCTTGT



ATGGAGTCTATTCGCAACAACACCTACGACCATTCTCAGTATCGTGAGGAGGCCCTTCTCA



ATCGTCTGAACATCAATCCGGTGACCCTATCTTCAGGATATAAGGATATTATACTCTGGTT



CTCCTTCGGGGCAAGCTGCTTCGTCTTGCTGGCCGTCGTCATGGGGCTGGTTTTCTTCTGT



TTAAAAAATGGAAATATGAGGTGCACCATTTGTATC





875
ATGTACAAGATTGTAGTTATTATCGCTTTACTGGGAGCGGTCAAAGGTCTGGACAAGATAT



GCCTTGGACACCACGCAGTGGCTAACGGCACAATCGTCAAAACTCTGACAAACGAGCAGGA



GGAGGTCACTAATGCGACCGAAACGGTGGAGAGCACCGGAATTAATCGACTATGTATGAAG



GGCAGGAAGCACAAGGATCTCGGGAACTGCCATCCCATCGGCATGCTGATAGGCACGCCAG



CCTGCGATCTTCATCTGACCGGAATGTGGGATACCCTGATCGAGAGAGAAAACGCCATTGC



ATACTGTTACCCGGGAGCAACCGTCAATGTGGAGGCGCTGAGACAGAAAATTATGGAAAGC



GGAGGGATCAATAAAATCAGTACCGGGTTTACTTATGGCTCATCAATCAATTCAGCAGGCA



CTACTAGAGCTTGCATGAGGAATGGAGGGAATAGTTTCTACGCGGAGTTGAAATGGCTCGT



GAGTAAATCTAAGGGGCAGAATTTTCCCCAGACTACAAATACGTATAGAAACACCGATACT



GCCGAGCACTTAATCATGTGGGGCATCCATCATCCAAGCAGTACCCAGGAGAAAAACGACC



TCTATGGGACTCAGTCCTTGAGCATTAGCGTCGGATCTTCCACATACAGAAACAATTTCGT



TCCAGTCGTCGGAGCTCGACCTCAGGTTAACGGGCAATCCGGGCGAATAGACTTTCATTGG



ACTCTGGTGCAGCCCGGGGACAACATAACCTTCAGTCACAATGGAGGGCTGATAGCCCCCA



GTCGCGTGAGTAAATTGATTGGCAGGGGCCTAGGAATCCAATCTGACGCACCCATCGACAA



CAACTGCGAGAGCAAATGCTTTTGGCGCGGTGGGTCAATAAACACTCGCCTCCCTTTTCAG



AATTTGTCACCTCGGACAGTGGGACAGTGCCCTAAGTATGTGAATCGCCGATCCCTGATGC



TAGCCACCGGCATGCGCAATGTGCCCGAGCTGATTCAGGGAAGGGGCCTGTTCGGCGCCAT



CGCCGGCTTCTTGGAAAATGGCTGGGAGGGGATGGTTGACGGCTGGTATGGCTTCCGGCAT



CAGAACGCACAGGGCACCGGCCAGGCGGCCGACTATAAGTCCACACAAGCAGCCATCGATC



AAATCACGGGAAAGCTCAATAGGCTGGTCGAGAAAACAAACACAGAATTCGAAAGTATCGA



ATCAGAGTTCTCCGAGATAGAGCACCAGATCGGAAATGTGATCAATTGGACAAAGGACAGC



ATCACTGACATATGGACGTACCAGGCAGAGCTGCTTGTCGCCATGGAGAACCAGCATACGA



TTGATATGGCAGACTCTGAAATGCTGAACCTCTACGAGAGAGTACGGAAGCAACTACGTCA



GAATGCAGAGGAGGATGGGAAAGGATGCTTTGAAATCTATCATGCATGTGACGATTCTTGC



ATGGAGTCAATACGCAACAATACGTACGACCACAGCCAGTATCGGGAGGAAGCGCTGCTTA



ACAGACTGAATATAAATCCGGTGACACTGTCATCTGGCTACAAGGACATCATCTTATGGTT



TTCGTTTGGTGCGAGTTGTTTTGTCTTACTAGCCGTCGTTATGGGTTTATTCTTTTTTTGT



TTGAAGAATGGGAACATGAGGTGTACAATTTGCATT





876
ATGTACAAGATCGTGGTCATAATCGCCCTTCTCGGTGCTGTTAAGGGACTAGATAAGATAT



GCCTGGGCCACCATGCCGTAGCTAACGGTACAATAGTGAAGACATTAACTAATGAGCAAGA



AGAGGTGACGAACGCTACTGAGACTGTTGAGAGCACAGGCATTAACCGGCTGTGTATGAAG



GGCCGCAAGCACAAGGATCTGGGAAATTGCCACCCAATTGGCATGCTGATCGGAACACCAG



CGTGCGATTTGCACCTAACCGGTATGTGGGATACTCTGATTGAGCGTGAAAATGCTATTGC



CTACTGTTATCCCGGCGCTACAGTCAACGTGGAAGCGCTGCGCCAGAAGATCATGGAATCT



GGAGGAATTAATAAGATCTCAACTGGTTTCACCTACGGTAGCTCGATTAACAGCGCAGGAA



CAACTCGTGCCTGCATGAGAAATGGAGGCAATAGCTTTTATGCTGAACTGAAATGGCTCGT



GTCTAAGTCAAAGGGCCAGAATTTCCCTCAAACAACTAACACCTACAGGAATACTGACACT



GCGGAACATCTGATCATGTGGGGCATTCACCACCCCTCTTCAACACAGGAGAAAAACGATC



TCTACGGCACTCAGTCGCTGTCCATCTCTGTGGGGAGCTCTACCTATCGTAACAATTTCGT



CCCGGTTGTTGGCGCCCGGCCACAAGTGAACGGGCAGAGCGGCCGGATCGACTTCCACTGG



ACCCTCGTACAGCCTGGGGACAACATCACCTTCTCACACAACGGAGGGCTAATCGCCCCCT



CAAGGGTCAGCAAGTTGATAGGCAGGGGCTTGGGAATTCAGTCGGATGCCCCAATTGATAA



CAACTGCGAGAGCAAATGCTTTTGGCGCGGAGGATCCATCAATACAAGGCTCCCCTTCCAA



AACCTCAGCCCCAGAACCGTTGGGCAGTGTCCTAAATATGTGAACAGGAGATCTCTGATGC



TGGCCACTGGAATGAGAAATGTGCCTGAGCTGATCCAGGGCCGAGGACTGTTTGGAGCGAT



CGCCGGATTTCTTGAAAACGGCTGGGAAGGCATGGTGGATGGCTGGTACGGATTTAGACAT



CAGAATGCCCAAGGGACCGGCCAAGCTGCAGACTACAAAAGTACCCAGGCCGCGATAGATC



AGATTACGGGAAAGCTGAACCGTCTGGTGGAAAAAACTAATACGGAGTTTGAGTCCATAGA



GAGTGAGTTTTCTGAAATTGAACACCAGATTGGGAACGTGATCAACTGGACCAAGGACTCA



ATCACTGATATATGGACCTACCAGGCCGAGCTCCTAGTGGCAATGGAAAACCAGCACACAA



TAGACATGGCCGACAGCGAAATGTTGAATCTCTACGAAAGAGTGAGGAAGCAGCTTCGGCA



GAATGCTGAGGAGGACGGAAAGGGATGTTTCGAGATCTACCACGCCTGTGACGATAGTTGC



ATGGAAAGCATCCGTAACAATACCTACGATCACAGTCAATATAGGGAAGAAGCATTGCTGA



ATAGGTTGAATATAAATCCCGTTACTCTTTCCTCGGGGTATAAGGATATTATCCTTTGGTT



TTCATTTGGTGCCTCGTGTTTCGTCCTGCTGGCAGTGGTGATGGGCCTCTTTTTCTTCTGT



TTGAAGAACGGGAATATGCGCTGTACCATCTGCATA





877
ATGTACAAAGTAGTCGTAATCATCGCCCTTTTGGGAGCCGTCAAGGGCCTGGACAAGATAT



GCCTGGGACATCACGCTGTCGCCAACGGGACGATTGTCAAAACACTGACAAACGAGCAGGA



AGAGGTTACCAACGCGACTGAGACTGTTGAGTCAACAGGTATAAACCGACTGTGTATGAAA



GGACGGAAACACAAAGATCTGGGGAATTGCCACCCCATCGGGATGCTGATCGGTACCCCTG



CATGCGACCTGCACCTCACTGGTACTTGGGATACTCTCATAGAACGGGAGAACGCAATCGC



ATACTGCTATCCTGGAGCCACCGTTAATGTTGAGGCCTTGAGACAAAAAATTATGGAGAGT



GGGGGAATCGACAAAATCTCCACCGGCTTTACCTATGGCAGCTCCATCAATTCAGCCGGTA



CCACGCGTGCCTGTATGCGCAACGGAGGTAATTCATTCTACGCCGAGCTAAAATGGCTGGT



GTCCAAAAATAAAGGGCAAAACTTCCCGCAAACAACAAACACTTACAGAAACACAGACACT



GCAGAACATCTGATAATGTGGGGAATCCACCATCCGTCATCTATACAGGAGAAAAACGATC



TGTATGGCACTCAGTCACTCAGTATCTCCGTCGGCTCATCAACGTACAGGAATAATTTTGT



GCCCGTCGTCGGCGCACGTCCACAAGTCAACGGTCAGTCCGGGAGAATCGACTTTCATTGG



ACGCTTGTTCAACCGGGCGATAACATTACATTTTCACATAACGGAGGGCTCATCGCTCCAA



GTAGAGTCTCTAAACTGATCGGACGTGGCCTGGGAATTCAGTCAGATGCGCCCATCGACAA



CAATTGCGAGTCGAAGTGCTTCTGGCGGGGGGGGTCCATAAATACCCGCCTCCCCTTTCAA



AACCTCTCACCCCGTACCGTGGGCCAGTGCCCTAAATATGTGAATCGGCGATCCCTGATGC



TGGCAACTGGAATGCGCAACGTACCAGAGCTGATTCAGGGCAGAGGACTCTTCGGGGCCAT



TGCAGGGTTCCTGGAAAATGGTTGGGAAGGAATGGTTGACGGATGGTATGGCTTCCGCCAC



CAGAATGCACAAGGGACAGGTCAGGCTGCAGATTATAAGTCCACGCAGGCCGCTATTGATC



AGATTACGGGAAAACTCAACAGACTGGTGGAAAAAACCAACACTGAGTTTGAGAGCATTGA



GTCCGAGTTTTCCGAGATTGAACATCAAATCGGTAATGTTATCAATTGGACTATGGATAGT



ATTACGGATATTTGGACTTACCAGGCCGAATTGTTAGTGGCTATGGAAAACCAACACACTA



TTGACATGGCAGACTCAGAGATGCTCAATCTTTATGAGCGCGTGAGGAAGCAGCTCAGACA



GAACGCGGAAGAAGACGGCAAGGGGTGCTTTGAGATTTACCACGCCTGCGACGACTCCTGC



ATGGAAAGCATCCGCAACAACACCTACGACCACAGCCAATATCGCGAGGAGGCCCTCCTTA



ATCGGTTGAACATCAATCCCGTAACACTGTCCTCCGGGTACAAAGACATCATCCTGTGGTT



CAGTTTTGGCGCGAGCTGTTTCGTCTTGTTGGCTGTGGTGATGGGCCTCGTATTTTTTTGC



CTTAAAAACGGGAACATGCGGTGTACAATCTGTATT





878
ATGTACAAAATAATTGTGATCATTGCCCTCCTGGGGGCTGTGAAGGGCCTTGACAAGATCT



GCCTAGGACACCATGCAGTTGCAAACGGAACAATTGTGAAGACCCTAACCAACGAACAAGA



GGAGGTGACAAACGCAACTGAGACCGTGGAGTCAACCGGCATAAATAGGCTTTGCATGAAG



GGAAGGAAACACAAAGATCTCGGCAACTGTCATCCAATCGGCATGCTTATCGGGACGCCTG



CATGTGATCTGCACCTAACTGGCACCTGGGACACACTGATTGAAAGGGAGAATGCTATCGC



TTACTGTTACCCTGGTGCTACTGTGAACGTTGAGGCTTTGCGGCAGAAAATCATGGAGTCA



GGGGGCATTGACAAAATCTCGACAGGCTTTACCTACGGCTCAAGCATTAACTCCGCTGGGA



CCACTAGAGCATGTATGAGAAATGGAGGTAACTCATTCTATGCCGAGCTCAAATGGCTCGT



GTCAAAAAGCAAGGGGCAGAACTTCCCGCAGACGACCAATACTTATCGGAATACAGACACT



GCCGAACATCTTATTATGTGGGGAATTCATCATCCATCCTCAACTCAGGAAAAAAACGACT



TGTACGGGACTCAATCCCTCTCCATTTCCGTGGGCAGTAGCACATATAGGAATAATTTCGT



TCCTGTCGTTGGGGCGAGGCCACAAGTGAATGGCCAGAGCGGCCGAATCGATTTTCATTGG



ACCCTTGTACAACCAGGGGACAATATCACTTTCTCACACAACGGAGGGTTGATTGCCCCAT



CCCGCGTTAGTAAGCTTATCGGCCGCGGCCTGGGTATACAGTCCGATGCACCCATCGATAA



TAATTGTGAGTCTAAGTGTTTTTGGCGAGGTGGCTCCATCAATACGCGGCTACCTTTTCAG



AACCTGTCGCCTCGCACCGTAGGGCAGTGTCCAAAGTATGTCAATAGACGGTCTTTGATGT



TGGCCACCGGAATGAGAAACGTTCCAGAGCTGATTCAGGGGCGCGGGCTGTTCGGCGCCAT



CGCCGGCTTCCTTGAGAATGGGTGGGAGGGCATGGTTGATGGATGGTACGGGTTTCGGCAC



CAGAACGCCCAGGGGACCGGCCAAGCCGCAGATTACAAGAGCACCCAGGCTGCCATCGACC



AGATTACCGGCAAGCTCAATAGGCTCGTGGAAAAAACTAACACCGAGTTTGAGTCTATCGA



ATCGGAGTTTAGCGAGATAGAGCATCAGATTGGAAATGTCATAAATTGGACAAAAGACAGT



ATCACAGATATCTGGACATACCAGGCTGAGCTGCTGGTCGCTATGGAAAATCAGCACACTA



TTGATATGGCCGATTCAGAAATGTTGAACCTGTATGAGCGGGTGCGTAAGCAGCTCCGACA



GAATGCTGAGGAAGATGGGAAGGGCTGCTTCGAGATATACCACGCTTGTGATGACTCTTGC



ATGGAGAGCATCCGGAACAACACGTATGACCATAGTCAGTATCGGGAAGAGGCACTGCTCA



ACAGGCTGAATATCAATCCCGTGACGCTCTCATCTGGATACAAGGACATCATCCTGTGGTT



CAGCTTTGGGGCATCTTGTTTCGTACTTCTGGCTGTCGTCATGGGCCTGTTTTTCTTCTGC



TTAAAGAACGGAAATATGAGATGTACCATATGCATA





879
ATGTATAAAGTGGTAGTCATCATCGCGTTACTGGGGGCAGTGCGAGGCCTTGATAAAATTT



GTCTGGGACATCATGCCGTCGCCAACGGCACCATCGTCAAGACACTAACTAACGAGCAGGA



GGAGGTCACCAATGCCACCGAGACCGTCGAAAGTAAATCGTTGGGAAAGCTATGCATGAAG



GGGAGGTCCTACAACGACCTGGGTAATTGCCATCCTATTGGGATCCTCATCGGTACCCCCG



CATGTGACCTGCACCTGACAGGCACATGGGATACTCTGATTGAAAGAGAGAACGCTGTAGC



GTACTGCTACCCCGGCGCAACTGTCAACGAAGAAGCGCTGAGACAGAAGATCATGGAATCC



GGGGGCATTTCAAAGATCTCTACCGGTTTCACGTATGGAACCAGTATCAACAGCGCAGGCA



CAACAAAGGCCTGCATGCGCAATGGCGGCAATTCCTTCTACGCCGAGCTTAAATGGCTCGT



CAGTAAGAATAAAGGCCAGAATTTTCCCCAGACCACCAACACTTACCGGAACACTGACACG



GCCGAGCATCTCATTATTTGGGGGATTCATCATCCAAGCTCGACTCAAGAAAAGAATGATC



TGTATGGCACTCAGTCTCTGTCTATCTCAGTTGGCAGCTCCACGTACCAGAATAATTTCGT



GCCTGTCGTTGGGGCTAGACCCCAAGTGAATGGACAATCAGGTAGGATAGATTTTCACTGG



ACCTTATTACAGCCTGGAGATAACATAACATTCAGTCACAATGGAGGATTAATAGCTCCAT



CCCGCGTGTCTAAACTGATCGGCAGAGGCTTGGGCATCCAGTCTGAAGCCCCTATTGACAA



TGGTTGCGAGAGCAAATGCTTTTGGAAAGGCGGAAGCATTAACACAAAGTTGCCTTTCCAG



AACCTGTCTCCCCGCACTGTGGGCCAGTGTCCCAAGTACGTCAATAAACGATCTCTGATGC



TGGCTACCGGTATGCGCAATGTTCCCGAAATCATGCATGGGAGAGGGCTGTTCGGGGCTAT



AGCAGGATTTATCGAAAATGGATGGGAAGGGATGGTGGATGGATGGTACGGTTTCAGACAC



CAAAATGCCCAGGGGACGGGGCAGGCTGCTGATTACAAAAGTACGCAGGCCGCCATTGATC



AGATTACCGGCAAGCTTAATCGGCTGATTGAAAAAACGAACACCGAGTTTGAGAGCATCGA



GTCCGAGTTTAGCGAGATTGAGCATCAAATTGGCAACATCATCAACTGGACAAAAGACAGC



ATCACTGATATCTGGACTTACCAAGCTGAACTGCTCGTGGCCATGGAGAATCAGCACACCA



TTGACATGGCAGATTCCGAGATGCTAAACCTGTACGAACGCGTCCGCAAGCAGCTCCGGCA



GAACGCAGAGGAAGATGGAAAGGGGTGCTTCGAGATTTACCACGCTTGCGATGACAGCTGT



ATGGAATCCATTCGAAACAATACATACGATCACTCACAGTATCGCGAGGAGGCTCTGCTCA



ACCGTTTGAATATTAATCCAGTGAAGCTATCTAGCGGCTATAAGGACATAATCCTGTGGTT



CAGCTTCGGCGCCTCTTGCCTAATCTTACTCGCCGTCGTGATGGGACTGGTGTTTTTTTGT



CTCAAGAACGGCAACATGAGGTGCACCATATGCATC





880
ATGTATAAGATCGTGGTCATAATCGCCCTGCTGGGCGCCGTCAAAGGGCTGGACAAAATAT



GCCTCGGACACCATGCTGTCGCCAATGGGACGATTGTCAAAACGCTCACCAACGAACAGGA



GGAAGTTACTAACGCCACAGAAACGGTAGAATCCACAGGGATCAATCGATTGTGTATGAAG



GGTCGTAAGCACAAAGACTTGGGAAACTGTCACCCCATCGGCATGCTGATCGGCACGCCTG



CCTGCGATCTACATCTGACAGGCATGTGGGACACACTAATAGAGAGGGAAAACGCAATCGC



CTACTGTTACCCCGGTGCCACAGTAAACGTGGAAGCTCTGCGGCAGAAGATAATGGAGTCT



GGAGGAATCAATAAAATCAGCACCGGTTTCACATATGGCTCCAGTATCAACTCCGCAGGCA



CTACCAGGGCTTGCATGCGCAATGGGGGAAATTCTTTCTACGCGGAGCTAAAATGGTTAGT



CTCTAAGTCCAAAGGACAGAACTTTCCACAGACAACAAACACCTACAGGAATACAGATACC



GCTGAGCACCTGATCATGTGGGGTATTCATCATCCCAGTTCTACTCAGGAAAAGAACGATC



TGTATGGGACACAGTCGCTGAGTATATCTGTCGGTAGTAGTACATACCGTAATAATTTCGT



GCCCGTTGTAGGCGCTAGACCTCAGGTGAATGGGCAATCCGGCCGGATTGATTTCCACTGG



ACTCTCGTGCAGCCTGGGGATAATATCACGTTTAGCCACAATGGAGGTCTAATCGCCCCCT



CCCGGGTTTCTAAACTGATTGGCCGGGGACTGGGAATCCAATCTGACGCCCCAATAGACAA



CAACTGCGAATCCAAGTGTTTCTGGCGGGGCGGCTCCATAAATACGCGACTTCCCTTCCAG



AACTTAAGTCCCCGGACTGTGGGTCAGTGTCCAAAATACGTGAATCGCCGGAGTCTTATGC



TCGCCACAGGCATGCGTAACGTCCCGGAACTTATACAGGGCCGGGGACTGTTTGGAGCTAT



CGCAGGATTCCTGGAGAACGGATGGGAGGGAATGGTGGACGGATGGTATGGTTTCCGGCAC



CAAAACGCTCAAGGAACGGGCCAGGCAGCAGATTATAAGTCAACACAGGCCGCGATCGACC



AAATTACTGGCAAACTCAATAGGCTGGTCGAGAAAACCAACACTGAGTTTGAGAGCATTGA



ATCCGAATTCAGCGAAATCGAACACCAGATCGGCAACGTGATAAATTGGACGAAAGATTCC



ATTACCGACATTTGGACATACCAGGCCGAGTTGCTGGTCGCTATGGAAAATCAGCATACGA



TTGATATGGCCGATAGTGAGATGCTTAACCTGTATGAACGCGTACGCAAACAGCTGCGCCA



AAATGCTGAAGAGGACGGTAAAGGCTGCTTTGAGATTTATCACGCTTGCGACGATTCATGC



ATGGAAAGTATCAGAAACAATACATATGACCACAGCCAGTACAGGGAGGAAGCGCTGCTCA



ATCGACTAAACATCAATCCTGTGACCCTGTCGAGTGGCTATAAAGACATAATTCTATGGTT



TTCATTCGGAGCATCTTGCTTCGTCCTGCTCGCAGTTGTGATGGGACTCTTCTTCTTTTGT



CTGAAAAATGGTAATATGCGGTGTACCATCTGCATT





881
ATGTACAAGATCGTGGTGATCATTGCTCTGCTTGGAGCCGTCAAGGGCCTGGATAAGATTT



GCCTGGGACATCACGCTGTCGCAAATGGCACCATCGTCAAGACTTTAACAAACGAGCAGGA



AGAGGTGACTAATGCCACTGAGACAGTAGAGAGCACTGGGATAAATAGGTTGTGCATGAAG



GGGAGAAAGCACAAGGACCTCGGAAACTGCCACCCAATTGGTATGCTAATCGGCACTCCAG



CTTGCGACTTGCATCTGACTGGCATGTGGGATACGCTGATAGAACGTGAGAATGCCATCGC



CTACTGTTATCCTGGGGCTACTGTGAACGTCGAGGCTTTAAGACAAAAGATCATGGAAAGT



GGCGGCATCAACAAGATAAGTACCGGGTTTACCTATGGGAGTAGTATTAATTCAGCAGGCA



CAACTCGGGCCTGCATGCGGAATGGGGGGAACAGCTTCTACGCCGAGCTAAAGTGGCTTGT



GAGCAAGTCCAAAGGGCAGAATTTCCCGCAGACCACCAATACTTACCGCAACACCGATACT



GCAGAACACTTAATAATGTGGGGCATCCACCATCCTAGTAGCACGCAAGAGAAGAATGACT



TGTACGGTACCCAGTCGCTAAGTATCAGCGTGGGCAGTTCGACATATAGAAATAACTTTGT



CCCTGTTGTGGGCGCGCGCCCTCAGGTAAATGGACAGTCTGGTCGGATCGACTTTCATTGG



ACCCTGGTGCAGCCAGGGGACAACATTACCTTTTCACATAATGGCGGTCTCATCGCACCCA



GTCGGGTCTCAAAGCTGATCGGGGGGGGGCTGGGCATTCAGTCAGACGCTCCCATAGATAA



TAATTGCGAGTCCAAGTGTTTCTGGAGAGGGGGCTCCATCAATACTAGGCTGCCTTTTCAG



AACCTCTCGCCCCGGACTGTGGGGCAGTGCCCCAAATACGTAAACCGAAGATCCCTAATGC



TGGCTACTGGGATGCGGAACGTACCTGAACTGATCCAGGGACGTGGGCTATTCGGAGCCAT



AGCTGGATTTCTGGAAAATGGCTGGGAGGGAATGGTTGATGGGTGGTACGGGTTTCGGCAC



CAGAATGCCCAGGGCACTGGGCAGGCTGCCGACTACAAATCAACTCAGGCCGCTATTGATC



AAATTACAGGTAAGCTCAACCGTCTAGTTGAGAAAACAAATACTGAGTTCGAAAGCATTGA



GTCTGAGTTTTCCGAGATTGAGCATCAGATCGGCAACGTTATTAATTGGACAAAGGACAGC



ATCACTGACATTTGGACATACCAGGCTGAACTTCTGGTTGCAATGGAAAATCAGCACACTA



TCGACATGGCTGATTCCGAGATGCTAAATCTCTACGAACGGGTCAGAAAGCAACTGCGGCA



GAATGCCGAGGAAGATGGAAAAGGCTGTTTCGAAATTTACCATGCTTGCGACGACTCCTGT



ATGGAGTCGATCAGGAACAACACCTACGATCACAGTCAGTATCGTGAGGAGGCACTTTTGA



ACCGTCTGAACATCAACCCCGTGACCCTTTCCTCCGGGTATAAAGATATCATCCTCTGGTT



CTCCTTCGGAGCATCTTGCTTCGTTCTCCTGGCCGTAGTGATGGGCCTGTTTTTTTTCTGC



CTGAAGAATGGGAACATGAGATGCACCATCTGCATT





882
ATGTATAAAATCGTTGTTATTATCGCCTTATTGGGCGCTGTGAAAGGGCTGGATAAAATCT



GCTTAGGGCATCATGCCGTTGCTAATGGAACGATTGTCAAAACCCTGACAAATGAGCAGGA



AGAGGTTACAAACGCTACTGAGACAGTGGAAAGCACCGGGATAAACCGGTTATGTATGAAA



GGTCGGAAGCACAAAGACCTAGGAAACTGCCACCCAATCGGCATGCTGATTGGTACCCCAG



CATGTGATCTGCACCTAACAGGAACCTGGGACACACTCATCGAGCGGGAAAACGCCATTGC



CTATTGTTATCCTGGCGCCACGGCAAACGTGGAGGCGCTGCGCCAGAAGATTATGGAGTCC



GGAGGTATCGACAAAATCTCTACCGGCTTTACGTACGGGAGTTCAATTAATTCAGCCGGAA



CAACCAGGGCCTGTATGCGCAATGGGGGGAATTCATTTTATGCCGAATTGAAGTGGCTCGT



CTCCAAGAGCAAAGGACAGAACTTTCCTCAGACAACGAATACTTACAGAAACACCGATACC



GCTGAGCACTTAATTATGTGGGGAATCCACCATCCTAGTTCAATCCAGGAAAAAAACGATC



TGTACGGGACACAGAGTCTCTCTATATCTGTTGGATCTTCCACCTATAGGAACAATTTTGT



TCCCGTGGTGGGCGCCAGGCCACAGGTGAATGGCCAGTCCGGGAGAATAGATTTTCACTGG



ACCCTTGTCCAGCCTGGGGATAACATTACTTTCAGCCACAACGGAGGCCTCATCGCGCCAA



GTAGGGTTTCCAAATTGATAGGGAGAGGCCTGGGGATTCAGTCCGACGCCCCCATAGATAA



TAATTGCGAATCAAAGTGTTTTTGGAGGGGGGGGTCCATCAACACAAGACTCCCCTTTCAG



AATCTGTCACCCCGAACCGTTGGCCAGTGTCCGAAATATGTGAACCGGAGGTCCTTAATGC



TGGCCACTGGAATGCGGAATGTGCCAGAGCTTATCCAAGGAAGGGGACTGTTTGGAGCAAT



CGCCGGCTTCCTAGAAAATGGCTGGGAGGGTATGGTGGACGGCTGGTATGGGTTTAGACAT



CAGAATGCCCAAGGAACCGGTCAGGCTGCGGACTATAAGTCCACCCAGGCCGCTATCGACC



AGATCACAGGTAAGCTCAACAGGCTGGTCGAGAAAACAAATACAGAGTTCGAGTCCATAGA



GTCCGAGTTCAGCGAAATAGAACACCAGATTGGAAATGTGATTAACTGGACGATGGATTCC



ATCACAGACATCTGGACCTACCAGGCAGAGTTACTGGTAGCTATGGAAAATCAGCATACAA



TCGACATGGCCGACTCTGAAATGCTAAATCTTTACGAGAGAGTTCGTAAACAGCTTCGCCA



GAACGCCGAGGAAGATGGGAAAGGGTGCTTTGAAATATATCACGCCTGTGATGATAGCTGT



ATGGAATCAATTAGAAATAACACATATGACCATTCTCAGTACAGAGAAGAGGCTCTGCTCA



ATAGGCTCAATATCAATCCAGTGACCCTATCCTCAGGATACAAGGACATCATACTCTGGTT



CAGTTTTGGCGCCTCTTGTTTCGTTCTGTTGGCCGTCGTCATGGGCCTCGTGTTTTTTTGT



TTAAAGAACGGCAATATGCGATGCACTATTTGCATC





883
ATGTATAAGATTGTAGTGATCATTGCTCTGCTCGGGGCCGTGAAGGGCCTGGATAAGATCT



GCCTGGGTCACCATGCCGTCGCAAACGGCACGATTGTGAAAACACTGACGAATGAGCAGGA



GGAGGTTACTAACGCTACAGAGACGGTCGAGTCAACTGGAATTAACCGGCTTTGCATGAAA



GGACGAAAACACAAAGATCTTGGGAACTGCCACCCAATTGGGATGCTGATTGGAACCCCAG



CCTGTGATCTGCACTTGACAGGCATGTGGGACACTCTGATCGAGAGGGAGAACGCAATAGC



CTATTGCTACCCTGGCGCAACCGTGAACGTGGAGGCCTTGCGCCAGAAGATAATGGAGTCT



GGGGGTATCAACAAGATCAGTACAGGTTTCACTTACGGCAGTTCTATTAACTCTGCCGGAA



CCACAAGAGCATGCATGCGTAACGGAGGCAATTCCTTCTATGCCGAACTTAAATGGCTTGT



CTCCAAGTCTAAGGGGCAGAACTTCCCCCAGACAACGAACACTTACCGCAATACGGACACA



GCAGAACACTTAATCATGTGGGGGATCCATCATCCCAGCAGTACACAGGAGAAAAATGACT



TATACGGAACTCAGAGCTTAAGTATCTCCGTGGGCAGTAGTACTTACAGAAACAATTTCGT



CCCTGTCGTAGGCGCTAGGCCTCAGGTGAATGGCCAGTCTGGACGCATCGACTTCCACTGG



ACTCTGGTTCAACCAGGGGACAACATCACTTTCTCGCACAACGGAGGGTTGATCGCACCCA



GTCGGGTGAGTAAACTTATCGGGAGAGGCCTCGGAATACAATCCGATGCTCCCATCGATAA



TAATTGCGAGAGCAAATGTTTTTGGCGCGGAGGGAGCATTAATACACGCCTGCCTTTTCAG



AACTTGTCACCACGAACCGTGGGCCAATGCCCCAAGTACGTCAACAGAAGATCATTGATGC



TGGCTACTGGCATGAGGAATGTGCCTGAATTAATTCAAGGAAGAGGACTGTTCGGCGCCAT



CGCAGGTTTTCTTGAGAATGGGTGGGAGGGGATGGTGGATGGTTGGTATGGCTTTCGCCAC



CAGAATGCGCAGGGCACAGGGCAGGCTGCTGATTACAAGTCAACCCAGGCAGCCATCGACC



AGATTACTGGCAAGCTGAATAGGCTCGTTGAAAAAACCAACACAGAGTTCGAGTCAATTGA



GAGCGAGTTTTCTGAAATAGAGCATCAGATAGGCAACGTGATAAATTGGACCAAAGACAGT



ATCACAGACATTTGGACTTATCAAGCAGAGTTGTTGGTAGCCATGGAGAATCAACACACGA



TCGACATGGCCGATAGCGAAATGCTAAACCTGTATGAGCGCGTTCGGAAGCAGCTGCGCCA



GAACGCAGAGGAGGACGGGAAGGGCTGTTTCGAAATTTATCACGCTTGTGACGACAGTTGC



ATGGAATCCATCCGCAACAATACGTATGATCACTCCCAGTATAGAGAAGAGGCCCTCTTGA



ATAGACTGAACATCAACCCAGTGACTCTGAGCTCAGGTTACAAGGACATTATTCTCTGGTT



TTCTTTCGGAGCTTCCTGCTTTGTCCTCCTCGCTGTCGTAATGGGACTCTTTTTCTTTTGC



CTGAAGAACGGGAATATGAGATGCACCATTTGCATC





884
ATGTATAAGATTGTCGTTATCATTGCACTGCTTGGTGCAGTTAAAGGGCTGGATAAGATTT



GTCTAGGGCACCATGCCGTGGCCAACGGGACCATAGTGAAAACACTGACCAATGAACAGGA



GGAAGTCACCAATGCTACTGAAACTGTTGAATCCACCGGCATTAACCGGCTGTGTATGAAG



GGCCGCAAACACAAGGACCTGGGCAATTGTCACCCCATCGGCATGTTGATTGGCACCCCTG



CATGTGACTTGCACCTCACTGGCATGTGGGACACACTGATCGAACGAGAGAATGCAATTGC



CTACTGCTACCCTGGTGCCACAGTGAACGTGGAGGCTCTTCGACAAAAGATCATGGAAAGC



GGGGGCATCAATAAGATTTCTACAGGGTTCACATACGGTTCATCTATTAACAGTGCAGGAA



CGACCCGGGCCTGCATGCGGAACGGCGGCAATTCATTCTACGCCGAATTGAAGTGGTTGGT



GTCGAAGAGTAAGGGCCAGAATTTCCCGCAGACAACAAACACATATCGCAATACGGATACG



GCCGAACACTTAATCATGTGGGGAATCCATCACCCTTCTTCTACCCAAGAAAAGAACGATC



TATACGGCACCCAGTCCCTGTCAATTTCAGTGGGTTCTTCGACATACAGGAACAATTTCGT



CCCTGTTGTCGGCGCACGGCCCCAGGTAAATGGGCAGAGTGGGAGAATCGACTTCCACTGG



ACTCTGGTGCAGCCTGGGGATAACATTACGTTCAGTCACAATGGCGGCCTCATAGCCCCAT



CACGGGTGAGCAAACTAATAGGACGAGGCCTGGGAATACAGTCCGACGCCCCAATCGATAA



CAACTGCGAGTCAAAATGTTTCTGGCGAGGAGGCAGCATCAATACAAGACTCCCTTTTCAG



AATCTTAGTCCAAGGACAGTCGGACAGTGCCCAAAATACGTGAATAGACGCAGCTTGATGT



TGGCAACGGGGATGCGCAATGTTCCTGAGCTCATACAGGGTAGAGGCCTATTTGGGGCCAT



CGCAGGCTTCCTGGAAAACGGATGGGAGGGCATGGTGGACGGATGGTACGGATTTCGTCAC



CAGAATGCTCAAGGCACAGGTCAGGCTGCCGACTACAAATCTACCCAGGCCGCCATCGACC



AGATTACCGGAAAACTGAACAGGTTGGTGGAAAAAACGAATACAGAATTCGAGAGTATTGA



GAGTGAGTTCTCCGAGATCGAGCACCAAATCGGCAATGTGATTAATTGGACAAAAGACTCC



ATTACCGACATCTGGACTTACCAGGCTGAGTTGCTCGTGGCGATGGAAAACCAGCATACCA



TTGATATGGCCGATAGTGAAATGCTGAATCTGTACGAACGCGTCAGAAAACAGCTACGACA



GAACGCGGAGGAGGATGGGAAGGGCTGCTTCGAAATCTACCACGCTTGCGATGATTCCTGC



ATGGAGTCCATTCGGAATAACACGTACGACCATAGCCAATACAGGGAGGAGGCGCTCCTAA



ATAGGTTGAACATAAATCCAGTTACCCTTTCTTCCGGTTACAAGGATATTATCCTGTGGTT



CTCCTTTGGCGCCTCTTGTTTCGTCCTTCTCGCCGTGGTGATGGGATTATTTTTCTTCTGC



CTCAAGAATGGAAATATGCGGTGTACGATCTGTATT





885
ATGTACAAAGTGGTGGTGATAATTGCTCTCCTCGGCGCCGTGAAAGGCCTCGACAAGATAT



GTCTGGGCCATCATGCAGTCGCCAACGGGACCATCGTCAAGACCCTCACCAATGAACAGGA



GGAGGTTACCAACGCCACTGAAACAGTTGAGTCTACTGGAATCAATCGACTGTGTATGAAG



GGGAGAAAACACAAGGACCTCGGTAACTGTCATCCTATTGGGATGCTTATTGGAACACCAG



CCTGTGATTTACATCTGACGGGCACCTGGGACACCCTGATCGAAAGAGAGAACGCAATTGC



ATATTGCTACCCTGGCGCTACAGTTAATGTTGAAGCTCTGAGGCAAAAAATCATGGAGTCC



GGGGGAATCGACAAGATTTCAACCGGCTTCACGTACGGCAGTTCTATCAACAGCGCAGGTA



CCACAAGGGCCTGTATGAGGAACGGCGGAAATAGCTTTTACGCCGAACTGAAATGGCTGGT



GTCAAAGAACAAAGGACAGAACTTCCCTCAGACCACAAACACATACCGGAATACAGACACC



GCAGAGCACCTTATAATGTGGGGCATCCATCATCCCTCCTCTATTCAGGAGAAGAATGATC



TGTACGGTACACAGTCACTCTCCATCTCTGTAGGCAGCTCCACATATCGTAATAACTTTGT



CCCAGTTGTGGGAGCCCGACCACAGGTGAACGGCCAATCAGGACGAATTGATTTTCACTGG



ACCCTCGTGCAGCCTGGCGACAACATAACATTCAGCCATAATGGAGGACTCATCGCCCCGT



CCCGCGTGTCTAAATTAATCGGTCGGGGGCTGGGGATCCAGTCCGATGCGCCCATAGATAA



CAACTGCGAGTCTAAATGCTTCTGGCGGGGGGGGTCCATTAACACTCGACTGCCCTTCCAA



AATCTCAGCCCACGCACAGTAGGCCAGTGTCCAAAATATGTCAATAGACGTTCTCTAATGC



TCGCCACCGGAATGAGAAATGTGCCTGAGCTGATTCAGGGAAGGGGATTGTTTGGAGCTAT



AGCCGGATTCTTGGAGAATGGTTGGGAAGGCATGGTCGACGGATGGTATGGATTCAGACAC



CAGAACGCTCAAGGCACGGGCCAAGCAGCCGACTACAAATCCACCCAAGCAGCCATTGATC



AGATTACAGGGAAGCTGAACAGGCTGGTGGAGAAGACAAACACAGAATTCGAAAGTATTGA



GAGCGAATTTTCCGAGATCGAGCACCAGATCGGTAATGTGATCAATTGGACCATGGACAGC



ATAACGGACATCTGGACCTATCAGGCCGAACTCCTGGTCGCAATGGAAAATCAGCATACTA



TCGACATGGCCGATAGTGAGATGTTGAACCTGTATGAGAGGGTTCGTAAGCAGCTCCGTCA



GAACGCAGAGGAGGATGGTAAAGGATGTTTTGAGATCTATCACGCATGCGATGACAGTTGC



ATGGAATCTATTCGTAACAATACGTACGATCATAGCCAATACCGCGAAGAAGCATTGCTGA



ACCGGCTGAATATTAACCCCGTGACATTATCCTCCGGGTACAAGGACATAATTCTGTGGTT



CTCCTTCGGGGCCAGCTGCTTCGTGCTGCTCGCTGTGGTCATGGGCCTGGTCTTCTTCTGC



CTGAAAAATGGCAACATGCGATGCACAATATGCATC





886
ATGTACAAAATCGTCGTGATCATAGCACTGCTGGGAGCCGTAAAGGGTCTCGATAAGATCT



GCCTAGGGCACCACGCAGTAGCCAATGGAACCATAGTAAAAACACTCACGAATGAGCAGGA



GGAAGTTACCAACGCCACTGAAACCGTCGAATCTACCGGGATCAACAGATTGTGCATGAAA



GGGCGCAAACACAAGGATCTGGGGAACTGTCACCCAATCGGAATGCTAATTGGAACACCAG



CCTGTGATCTCCATTTGACAGGAATGTGGGATACACTGATAGAGCGTGAAAACGCCATAGC



GTACTGTTACCCCGGCGCCACAGTGAACGTGGAAGCGTTACGACAAAAGATAATGGAATCA



GGAGGCATTAATAAGATAAGTACTGGCTTTACCTACGGGTCTTCAATCAACTCTGCCGGGA



CAACTAGAGCCTGTATGAGAAACGGTGGTAATTCGTTCTACGCTGAGCTGAAGTGGCTGGT



GTCCAAGAGCAAAGGGCAGAATTTCCCACAGACTACAAACACCTACAGAAACACCGATACA



GCCGAACACCTCATCATGTGGGGAATTCATCACCCAAGCAGCACGCAGGAGAAGAACGATT



TATATGGGACACAAAGCTTGTCAATTTCCGTGGGCAGTAGCACATACAGAAATAACTTCGT



GCCAGTGGTAGGGGGGGGTCCCCAGGTGAATGGACAGTCCGGCCGCATTGATTTCCATTGG



ACCCTCGTGCAGCCGGGAGACAACATCACATTCAGCCACAATGGTGGACTAATCGCCCCAT



CCCGCGTCTCCAAACTGATCGGGAGAGGACTGGGTATTCAGTCTGACGCGCCCATTGATAA



TAACTGCGAGTCAAAATGTTTCTGGCGAGGGGGGAGCATCAATACACGATTGCCTTTTCAG



AACTTGTCCCCTCGGACTGTCGGCCAGTGCCCTAAGTATGTGAATAGGAGATCCCTGATGC



TTGCCACCGGAATGAGAAACGTTCCTGAGCTGATTCAGGGTCGCGGTCTATTTGGCGCAAT



CGCCGGCTTTCTCGAAAACGGCTGGGAGGGCATGGTAGATGGTTGGTACGGTTTCCGGCAT



CAGAACGCCCAGGGAACTGGACAAGCCGCTGATTACAAGTCAACACAGGCAGCAATCGACC



AAATTACTGGCAAACTGAACCGGCTTGTCGAGAAAACCAATACTGAATTTGAGTCAATTGA



ATCCGAATTTAGTGAAATTGAACACCAGATCGGCAATGTGATTAATTGGACTAAGGACTCT



ATTACCGATATTTGGACTTATCAGGCTGAGCTACTTGTGGCCATGGAGAACCAGCACACAA



TCGACATGGCTGATAGTGAGATGCTGAACCTTTACGAGCGAGTCAGGAAACAGCTGAGACA



GAACGCCGAGGAGGATGGAAAAGGCTGTTTCGAAATCTATCATGCTTGCGACGATTCATGC



ATGGAGTCAATCAGAAATAACACCTACGACCACAGTCAGTATCGCGAGGAAGCTTTACTCA



ACAGACTCAATATCAATCCTGTAACATTGTCTTCCGGCTACAAAGACATCATCCTGTGGTT



CTCATTTGGAGCCAGCTGCTTTGTCTTGTTGGCTGTGGTGATGGGACTGTTCTTTTTTTGC



CTCAAAAATGGCAATATGAGATGTACCATTTGTATC





887
ATGTATAAGATCGTGGTGATCATTGCTCTCCTGGGCGCAGTAAAGGGTCTTGACAAGATAT



GTCTTGGACACCATGCAGTGGCAAACGGCACAATTGTTAAAACACTCACCAACGAGCAGGA



GGAAGTGACCAATGCCACTGAAACAGTAGAGTCCACGGGGATCAATAGGCTCTGCATGAAA



GGGAGGAAGCACAAAGATCTGGGTAATTGCCATCCAATCGGAATGCTCATAGGAACACCAG



CCTGCGACCTTCATCTGACCGGTATGTGGGATACATTGATCGAACGCGAGAACGCGATAGC



TTACTGCTATCCCGGCGCCACAGTGAATGTGGAGGCCCTCCGACAGAAGATTATGGAGTCG



GGCGGTATTAACAAAATATCCACTGGTTTTACTTACGGATCTTCGATCAATTCCGCAGGAA



CAACACGAGCCTGTATGAGGAATGGCGGGAACTCTTTCTATGCTGAGCTTAAGTGGCTCGT



TTCTAAGTCTAAGGGCCAGAATTTCCCTCAGACGACTAATACCTACAGGAACACGGATACA



GCAGAGCACCTGATTATGTGGGGTATCCATCATCCATCTAGCACCCAAGAGAAAAATGATC



TGTATGGGACCCAGTCACTTTCCATTAGCGTGGGCTCTAGTACATACAGGAATAACTTTGT



ACCTGTGGTGGGGGCTAGACCGCAAGTGAATGGCCAGAGCGGCCGGATTGACTTCCACTGG



ACTTTAGTCCAGCCTGGAGATAACATTACATTTTCACACAACGGCGGGCTGATTGCGCCTA



GTAGGGTGAGCAAACTTATTGGACGAGGATTAGGAATCCAGAGCGATGCCCCCATCGACAA



CAACTGCGAAAGCAAATGCTTTTGGAGGGGCGGTTCAATCAACACCCGTCTCCCTTTCCAG



AATCTGTCCCCCCGTACCGTGGGGCAGTGTCCAAAGTATGTTAATAGAAGGTCACTGATGC



TAGCCACTGGCATGCGGAATGTGCCCGAGCTGATCCAGGGCCGTGGGCTGTTCGGTGCTAT



TGCAGGATTTCTGGAAAATGGCTGGGAAGGCATGGTAGATGGTTGGTACGGTTTTCGGCAC



CAGAACGCCCAGGGGACCGGACAGGCGGCCGACTACAAATCCACTCAAGCCGCTATCGATC



AGATTACGGGAAAGCTAAATAGACTGGTCGAAAAAACCAACACAGAGTTCGAATCCATAGA



GTCCGAGTTCTCTGAGATCGAGCACCAGATCGGGAATGTGATCAACTGGACTAAGGATAGC



ATTACTGATATTTGGACCTACCAGGCAGAGCTGCTGGTCGCCATGGAAAACCAACACACAA



TCGATATGGCGGATAGTGAGATGCTGAACCTGTATGAAAGAGTGAGGAAACAGCTGAGACA



GAACGCAGAGGAGGACGGAAAAGGGTGCTTCGAGATTTACCACGCTTGCGATGACAGTTGC



ATGGAAAGCATACGCAATAACACTTACGACCATAGTCAATACCGGGAGGAGGCTCTCCTGA



ATAGGCTCAACATCAATCCTGTGACCCTGAGTTCAGGTTACAAAGATATCATCTTGTGGTT



TTCATTTGGGGCGAGCTGCTTTGTGCTGCTGGCCGTCGTGATGGGCCTGTTCTTTTTTTGC



CTGAAGAATGGCAATATGCGATGTACCATATGCATC





888
ATGTATAAAATAGTGGTGATCATAGCACTCTTGGGAGCCGTAAAGGGACTGGATAAGATCT



GCCTGGGGCATCATGCCGTTGCCAACGGCACAATCGTGAAGACCCTTACTAATGAACAAGA



AGAAGTGACCAACGCTACTGAGACCGTTGAATCCACCGGCATTAACCGCCTCTGCATGAAG



GGGCGGAAGCACAAAGATCTCGGCAACTGCCACCCAATCGGGATGCTGATTGGGACCCCCG



CGTGCGATTTACATCTGACAGGTATGTGGGATACATTAATTGAAAGGGAGAACGCGATTGC



GTACTGCTACCCTGGGGCTACCGTGAATGTCGAAGCACTCCGACAGAAGATCATGGAATCT



GGGGGGATCAACAAGATCTCGACCGGTTTTACCTATGGGAGTTCTATTAACTCTGCTGGCA



CAACACGGGCATGTATGCGCAATGGGGGGAATAGTTTCTATGCTGAGCTCAAATGGCTTGT



ATCCAAATCCAAAGGGCAGAATTTCCCCCAGACTACAAATACCTACAGAAACACGGATACC



GCTGAGCACCTAATAATGTGGGGAATTCACCATCCTTCCTCAACCCAAGAGAAGAATGATC



TTTACGGGACCCAGAGTCTCAGCATTAGCGTCGGATCGTCGACTTACCGCAACAATTTCGT



CCCAGTGGTCGGAGCCAGGCCACAGGTCAACGGCCAGTCTGGCAGGATAGACTTCCACTGG



ACCCTGGTTCAGCCTGGAGATAACATTACATTTAGTCATAACGGCGGCCTGATTGCTCCCA



GTCGCGTGTCTAAACTAATCGGACGTGGTCTGGGCATCCAATCCGATGCGCCGATCGACAA



TAACTGCGAAAGCAAGTGCTTTTGGAGGGGAGGATCCATCAATACACGACTTCCCTTCCAG



AACCTATCACCAAGAACCGTAGGCCAGTGCCCGAAATACGTGAATCGACGGAGTCTGATGC



TGGCCACCGGCATGAGAAATGTGCCTGAGCTGATTCAGGGACGAGGACTGTTTGGCGCAAT



CGCTGGCTTCCTGGAAAACGGGTGGGAAGGAATGGTCGATGGCTGGTACGGATTTCGGCAT



CAGAACGCCCAAGGCACTGGCCAAGCCGCCGACTACAAGAGTACACAGGCCGCAATCGACC



AGATCACAGGTAAGTTGAATCGATTGGTGGAGAAGACCAACACTGAGTTCGAATCTATTGA



GAGCGAATTCAGTGAAATCGAGCATCAGATCGGAAATGTGATAAATTGGACCAAGGACTCA



ATTACCGACATCTGGACATACCAAGCAGAGCTTCTGGTTGCGATGGAAAACCAACACACAA



TTGATATGGCAGATTCCGAGATGCTGAACCTCTATGAGCGCGTCAGGAAGCAATTGAGGCA



GAATGCAGAGGAAGATGGAAAAGGGTGTTTCGAAATCTATCACGCCTGCGACGACAGTTGC



ATGGAATCGATCCGCAACAATACTTATGACCACTCACAGTATAGAGAGGAGGCTTTGCTGA



ACCGGTTAAATATCAATCCTGTCACGTTGAGTAGCGGCTACAAGGATATCATCCTATGGTT



TTCCTTCGGGGCGTCTTGTTTTGTGCTGTTAGCAGTGGTGATGGGACTTTTCTTCTTCTGT



CTTAAAAACGGAAACATGAGATGTACCATCTGCATA





889
ATGTATAAGATCGTGGTTATCATTGCCCTCCTGGGCGCAGTCAAAGGCTTGGACAAAATCT



GTCTCGGACATCACGCCGTTGCTAACGGCACCATTGTTAAGACCCTTACCAACGAGCAGGA



AGAAGTGACAAATGCAACAGAAACGGTCGAGTCCACAGGCATCAACCGGCTCTGTATGAAA



GGTCGGAAGCACAAGGATCTTGGGAATTGTCACCCAATAGGTATGCTGATTGGCACTCCTG



CCTGCGATCTTCATCTAACTGGGATGTGGGACACCCTTATCGAACGAGAAAATGCCATTGC



ATACTGTTACCCTGGTGCTACTGTCAACGTGGAAGCCCTCAGGCAGAAAATAATGGAGTCG



GGTGGGATAAATAAGATAAGCACCGGGTTCACTTACGGCAGCTCCATTAATTCCGCCGGAA



CTACGCGCGCCTGTATGAGAAATGGCGGTAACTCCTTCTACGCGGAGCTGAAGTGGCTGGT



CTCGAAGTCTAAAGGCCAGAACTTCCCCCAAACAACAAACACCTACAGGAACACTGACACC



GCTGAACACCTCATCATGTGGGGCATTCACCACCCCTCCAGCACCCAGGAAAAAAACGACT



TATACGGCACACAGAGCCTTAGTATAAGCGTGGGAAGCTCAACTTATCGCAACAATTTTGT



TCCAGTGGTGGGCGCAAGACCGCAGGTGAACGGGCAAAGTGGTCGAATTGACTTTCACTGG



ACACTCGTGCAACCAGGCGACAATATCACCTTTTCACATAACGGAGGACTCATTGCCCCGT



CCCGCGTCAGTAAGTTAATTGGGGGGGGCCTCGGCATTCAGTCAGACGCCCCTATCGATAA



CAACTGTGAATCTAAGTGCTTTTGGAGAGGAGGGTCTATAAACACGAGACTCCCCTTCCAG



AACTTATCGCCTCGCACTGTGGGTCAGTGTCCTAAGTACGTTAACAGACGTTCCCTGATGC



TGGCAACGGGAATGAGAAACGTTCCAGAACTGATCCAGGGGCGCGGGTTATTTGGGGCTAT



CGCTGGTTTCCTGGAGAATGGCTGGGAGGGAATGGTTGACGGGTGGTATGGGTTTCGTCAC



CAAAACGCCCAGGGGACGGGGCAGGCCGCAGATTACAAGTCTACTCAGGCGGCCATAGACC



AGATTACAGGCAAGCTGAATAGACTGGTCGAGAAGACGAACACGGAGTTTGAGTCTATTGA



GTCCGAGTTCAGCGAGATTGAACATCAGATAGGTAATGTTATCAATTGGACAAAGGATAGC



ATAACCGATATTTGGACATACCAGGCAGAGTTACTGGTTGCAATGGAAAATCAACACACTA



TTGACATGGCTGACTCAGAGATGCTCAACTTATACGAACGAGTGAGGAAGCAACTACGACA



GAACGCCGAAGAGGACGGAAAGGGTTGCTTTGAGATCTACCACGCCTGCGACGATAGCTGC



ATGGAGAGCATCAGGAATAATACTTACGATCACTCACAGTACAGGGAGGAAGCCCTCTTGA



ACCGTCTGAACATAAATCCTGTCACACTTAGCTCCGGCTACAAAGATATCATCTTGTGGTT



TTCATTTGGCGCGTCATGTTTTGTGCTCCTAGCTGTGGTCATGGGCTTATTCTTTTTCTGC



CTGAAAAATGGCAATATGAGGTGCACAATTTGTATC





890
ATGTACAAGATAGTGGTAATTATCGCGCTGTTGGGCGCAGTGAAAGGACTGGACAAGATCT



GCCTGGGTCACCACGCCGTGGCCAATGGAACGATTGTGAAAACCTTGACAAACGAACAGGA



GGAAGTGACCAACGCAACGGAGACTGTGGAATCAACTGGTATCAATCGGCTATGCATGAAA



GGCAGAAAACACAAAGATTTGGGCAATTGCCATCCCATCGGTATGCTCATTGGAACACCCG



CTTGCGACCTCCACCTGACTGGGACGTGGGATACTTTGATCGAGAGGGAGAATGCTATTGC



CTACTGTTACCCTGGCGCAACAGCTAATGTGGAGGCCCTCCGGCAGAAGATCATGGAGAGC



GGTGGAATCGATAAGATTTCAACTGGCTTCACATACGGCTCCTCGATCAATTCTGCCGGCA



CTACTCGGGCTTGCATGAGAAACGGAGGAAATAGTTTCTATGCTGAGCTGAAGTGGCTTGT



GAGTAAATCTAAAGGCCAGAACTTTCCCCAGACAACCAACACATACCGGAATACCGACACC



GCAGAACATCTGATTATGTGGGGGATACATCACCCATCTAGCATTCAGGAGAAAAACGACC



TGTATGGCACTCAGTCCCTGAGCATTTCCGTAGGCTCTAGTACCTACCGGAACAATTTCGT



ACCCGTCGTAGGCGCCCGCCCCCAAGTGAACGGCCAGTCCGGTCGAATTGACTTCCACTGG



ACACTAGTGCAGCCTGGGGACAATATCACATTTAGTCATAACGGCGGACTGATCGCCCCAT



CGAGAGTGTCTAAACTGATCGGACGCGGGCTGGGTATTCAATCAGATGCCCCCATCGACAA



CAACTGCGAAAGCAAATGCTTCTGGCGCGGCGGGAGTATAAACACCCGGCTTCCATTTCAG



AACCTCTCTCCTCGGACCGTCGGACAGTGCCCGAAATATGTGAACCGCAGGTCACTGATGT



TGGCAACTGGAATGAGGAATGTCCCCGAATTAATACAGGGCCGGGGCTTATTCGGAGCCAT



CGCAGGCTTCCTGGAGAACGGTTGGGAAGGCATGGTGGATGGATGGTATGGATTTAGACAT



CAAAATGCACAGGGAACAGGCCAGGCTGCCGACTACAAATCTACCCAGGCCGCGATAGATC



AAATTACAGGAAAGTTGAACAGGCTGGTGGAAAAGACTAATACCGAATTTGAATCAATCGA



GTCCGAATTCTCCGAAATCGAACACCAGATCGGGAATGTCATTAACTGGACTATGGATTCT



ATAACCGATATCTGGACATACCAGGCAGAACTGCTAGTAGCCATGGAAAATCAACACACGA



TCGACATGGCTGACTCAGAGATGCTGAACCTCTACGAGCGGGTCAGAAAACAGCTCCGACA



GAATGCAGAGGAAGACGGAAAAGGCTGTTTTGAGATTTACCACGCTTGCGACGACTCTTGT



ATGGAGTCCATACGGAATAATACGTACGATCACTCACAGTATAGGGAGGAGGCCCTACTGA



ATAGACTGAACATCAACCCCGTCACGCTGTCTAGTGGCTATAAAGACATCATTTTGTGGTT



TTCTTTCGGAGCAAGTTGCTTCGTGCTCCTCGCCGTGGTGATGGGACTCGTGTTCTTCTGC



TTGAAAAATGGGAATATGCGATGTACCATTTGCATC





891
ATGTATAAAATTGTCGTGATAATCGCTCTGCTTGGCGCTGTGAAGGGCTTAGATAAGATAT



GCCTCGGACACCATGCAGTTGCCAATGGCACGATAGTGAAAACATTGACCAACGAGAAAGA



AGAGGTGACCAACGCTACCGAGACTGTGGAATCCACCGGTCTGAATAGACTCTGCATGAAG



GGGCGGAAGCATAAGGACTTGGGCAATTGTCACCCAATTGGGATGCTCATCGGATCGCCCG



CATGTGACCTGCATCTCACTGGGACCTGGGACACATTGATTGAACGAGAGAACGCTATTGC



GTACTGCTACCCGGGAGCCACTGTTAATGGTGAAGCACTTCGCCAGAAGATCATGGAGTCC



GGAGGCATCGACAAGATCAGCACTGGATTCACCTATGAAAGTTCCATAAACTCCGCAGGCA



CTACAAGAGCTTGCATGAGGAACGGCGGGAATTCATTCTACGCTGAGCTCAAGTGGCTGGT



GAGCAAATCTAAGGGACAGAATTTTCCACAGACAACCAACACGTATCGAAACACCGATACT



GCAGAGCACCTTATTATGTGGGGCATTCACCATCCATCCAGCACGCAGGAGAAAAACGATC



TGTACGGTACCCAGTCTCTGTCTATCTCCGTGGGATCTTCCACCTATAGAAACAATTTCGT



ACCCGTAGTGGGGGCCAGGCCGCAAGTCAATGGCCAATCTGGCCGCATCGACTTCCACTGG



ACCTTGGTACAGCCTGGCGACAATATCACATTCTCACACAACGGCGGCTTGATTGCTCCGA



GCCGGGTGTCTAAGTTGATCGGAAGAGGGCTCGGCATCCAGTCTGATGCCCCTATCGATAA



CAACTGTGAAAGTAAGTGCTTCTGGCGGGGCGGAAGTATTAATACCAGGCTGCCATTCCAG



AATCTTTCCCCCCGCACCGTCGGTCAATGTCCCAAATACGTGAACAAGCGAAGCCTGATGT



TGGCCACTGGGATGCGAAATGTTCCTGAGCTGATGCAGGGACGAGGACTGTTCGGAGCCAT



TGCTGGGTTCCTCGAGAACGGCTGGGAGGGCATGGTTGACGGTTGGTACGGATTCAGACAC



CAAAACGCGCAGGGCACGGGTCAAGCCGCCGATTACAAATCTACACAGGCGGCGATTGACC



AGATTACAGGTAAGCTGAATAGACTCGTGGAGAAAACAAACACCGAATTCGAGTCAATAGA



GTCCGAGTTCTCTGAGATAGAACACCAGATCGGCAATGTAATCAACTGGACGAAAGACTCT



ATTACAGACATTTGGACCTACCAGGCGGAACTCCTGGTGGCTATGGAGAACCAGCATACTA



TTGATATGGCTGACTCTGAGATGCTGAATCTGTACGAGCGCGTCCGGAAGCAACTGCGTCA



GAATGCAGAGGAAGACGGAAAGGGGTGCTTTGAGATTTATCACGCCTGCGATGATAGCTGT



ATGGAGTCAATCCGAAACAACACTTATGATCATAGCCAGTACCGTGAGGAGGCACTACTGA



ACAGGCTGAACATTAATCCCGTCACCCTGAGCAGTGGCTACAAAGACATCATCTTGTGGTT



CTCTTTCGGCGCCTCATGCTTTGTCTTGCTTGCCGTAGTCATGGGTTTAGTGTTTTTTTGT



CTCAAAAACGGTAATATGCGGTGTACAATTTGCATC





892
ATGTACAAAATCGTGGTAATAATCGCGCTTCTGGGCGCAGTGAAGGGCCTGGACAAAATCT



GCCTGGGACATCACGCTGTGGCAAATGGGACCATCGTGAAAACCCTCACCAATGAGAAAGA



GGAAGTGACCAACGCCACGGAAACAGTAGAAAGCACAGGATTAAACCGGCTTTGCATGAAA



GGCCGCAAGCACAAAGACCTGGGCAATTGCCATCCCATCGGGATGCTGATCGGATCACCCG



CCTGTGATCTCCATCTAACCGGCACCTGGGACACTCTGATCGAAAGGGAGAACGCGATCGC



TTACTGCTACCCAGGCGCTACCGTTAATGGCGAGGCTTTGCGCCAGAAGATCATGGAGTCA



GGAGGGATCGACAAGATTAGTACAGGCTTCACCTATGAGAGCTCGATCAATTCCGCAGGAA



CAACCCGGGCCTGCATGAGAAACGGCGGCAATTCCTTTTACGCCGAACTTAAGTGGCTGGT



GAGTAAAAGCAAGGGACAAAACTTCCCACAGACCACCAACACCTACCGTAATACCGATACC



GCTGAGCATTTGATCATGTGGGGAATTCATCATCCCAGCTCCACACAGGAGAAGAATGATC



TTTACGGGACACAGTCACTCAGCATTTCCGTCGGTTCGAGCACTTACCGGAATAATTTTGT



CCCTGTGGTCGGCGCCCGCCCTCAGGTCAACGGGCAGAGCGGCAGGATCGACTTCCATTGG



ACACTAGTTCAGCCTGGCGACAATATTACCTTTAGCCACAACGGCGGTCTGATCGCTCCTT



CGCGTGTCTCAAAACTGATCGGTCGGGGGTTAGGCATTCAAAGCGATGCCCCCATTGACAA



CAATTGTGAATCAAAATGTTTCTGGCGCGGTGGCTCCATTAACACCAGACTGCCTTTCCAG



AATCTTAGCCCAAGAACAGTCGGCCAGTGCCCCAAGTATGTGAATAAAAGGTCTCTGATGC



TGGCTACCGGCATGCGTAATGTCCCAGAGCTTATGCAAGGCAGAGGACTGTTCGGCGCAAT



CGCGGGTTTTCTTGAGAACGGATGGGAGGGTATGGTTGACGGATGGTACGGTTTCCGGCAC



CAGAACGCCCAGGGAACTGGCCAGGCCGCAGACTACAAGTCCACACAGGCGGCAATTGACC



AGATCACTGGCAAACTTAACCGTCTAGTGGAAAAAACCAACACTGAATTCGAGAGTATCGA



GAGTGAGTTCTCCGAGATTGAGCATCAGATAGGGAACGTGATCAATTGGACAAAGGACTCT



ATTACAGACATTTGGACTTATCAGGCCGAGCTGCTGGTGGCCATGGAGAATCAGCACACAA



TCGACATGGCCGACTCTGAGATGCTCAATCTTTATGAACGGGTGCGCAAACAGCTGCGACA



GAATGCAGAGGAGGATGGGAAGGGGTGCTTCGAAATCTATCACGCATGCGACGATTCATGT



ATGGAGTCCATCCGGAATAATACATACGATCATAGTCAGTATCGCGAGGAAGCCTTATTGA



ACAGGCTGAACATTAATCCAGTCACTCTCAGCTCAGGGTACAAGGACATCATTTTGTGGTT



CTCATTTGGAGCATCGTGCTTCGTGCTCCTTGCGGTTGTCATGGGTCTGGTCTTTTTTTGC



CTGAAGAATGGAAACATGAGATGCACCATATGTATC





893
ATGTACAAGATCGTGGTTATTATCGCCCTCCTGGGTGCTGTGAAAGGACTGGATAAGATCT



GTCTGGGACACCATGCTGTGGCAAACGGCACTATTGTTAAAACTCTGACTAACGAGCAAGA



AGAAGTTACTAATGCTACTGAGACGGTCGAAAGTACTGGAATCAATCGGCTTTGCATGAAG



GGCCGGAAGCACAAAGACCTTGGGAATTGCCATCCTATTGGGATGCTGATCGGTACCCCCG



CATGTGACCTCCATCTGACTGGGATGTGGGACACGCTCATCGAGAGGGAGAATGCCATCGC



TTACTGTTATCCCGGAGCCACAGTTAATGTCGAAGCCTTACGACAAAAAATCATGGAGTCA



GGTGGTATCAACAAGATCAGCACCGGTTTCACATACGGCTCCTCCATCAACTCAGCAGGTA



CTACACGCGCATGCATGCGGAACGGCGGAAACAGTTTCTACGCCGAGCTGAAGTGGCTTGT



TAGCAAATCAAAAGGTCAGAATTTCCCTCAGACTACAAACACATACCGTAACACCGATACC



GCAGAACATCTCATCATGTGGGGTATTCATCACCCAAGTTCCACACAAGAAAAGAACGATC



TCTACGGGACTCAATCACTCTCCATCTCCGTCGGATCCTCTACATACCGTAACAACTTTGT



TCCTGTGGTGGGCGCAAGACCTCAGGTTAATGGGCAGTCAGGTAGAATTGACTTCCATTGG



ACACTGGTGCAACCTGGGGACAACATCACCTTCTCCCACAACGGCGGTCTGATCGCGCCCT



CAAGGGTCTCCAAGCTGATAGGTCGGGGCCTCGGCATCCAGAGCGACGCCCCGATCGATAA



CAATTGTGAAAGCAAATGCTTCTGGAGGGGGGGCTCTATCAACACACGACTGCCTTTCCAG



AATCTCTCTCCCCGAACCGTGGGACAGTGTCCTAAATACGTCAACAGGAGGAGCCTGATGC



TCGCCACAGGTATGCGTAATGTCCCAGAGCTGATTCAAGGCCGCGGGTTATTTGGCGCGAT



AGCCGGTTTTCTGGAGAACGGCTGGGAGGGAATGGTGGATGGCTGGTATGGATTCCGGCAC



CAAAATGCTCAGGGAACTGGTCAAGCAGCCGACTATAAATCCACGCAGGCCGCCATCGACC



AGATTACTGGCAAATTAAATCGCCTCGTGGAGAAGACTAACACTGAGTTCGAATCCATAGA



GTCAGAGTTTTCCGAGATCGAGCACCAGATCGGTAATGTGATTAATTGGACCAAAGATTCC



ATCACTGATATTTGGACATACCAAGCCGAGCTCTTGGTGGCTATGGAGAACCAACATACTA



TCGATATGGCCGATAGCGAAATGCTCAACCTGTACGAGAGGGTCAGGAAACAGCTTCGCCA



GAACGCAGAGGAAGACGGCAAAGGATGTTTCGAGATTTACCATGCGTGCGACGATTCTTGC



ATGGAGAGCATTCGGAACAACACGTATGATCACAGCCAGTACAGGGAAGAGGCACTTCTGA



ACCGCCTGAACATAAATCCAGTCACATTGAGCAGCGGCTACAAAGACATTATACTCTGGTT



TTCATTTGGGGCCTCTTGCTTCGTCCTGCTGGCAGTGGTGATGGGATTGTTCTTCTTTTGC



CTCAAAAACGGTAATATGCGCTGCACCATTTGCATC





894
ATGTATAAAATAGTGGTCATTATTGCTCTTCTCGGTGCAGTTAAGGGTCTGGATAAGATCT



GCTTGGGCCATCACGCTGTTGCCAATGGGACCATAGTGAAGACCTTGACAAACGAACAGGA



AGAAGTGACAAACGCCACCGAAACCGTCGAATCCACTGGCATTAACCGGCTGTGCATGAAG



GGGCGAAAACACAAAGACCTCGGTAATTGTCATCCCATAGGGATGCTGATTGGTACACCTG



CCTGTGACCTGCACCTGACCGGAATGTGGGATACGCTCATTGAACGAGAGAATGCCATCGC



CTATTGTTATCCGGGTGCAACTGTGAACGTGGAGGCCCTGCGTCAAAAGATCATGGAAAGC



GGGGGGATAAACAAAATCTCGACCGGTTTCACGTATGGTTCAAGCATTAACAGTGCCGGCA



CAACAAGGGCATGCATGCGCAATGGAGGTAACTCATTCTACGCCGAGCTCAAGTGGCTCGT



GAGCAAGTCCAAAGGACAGAACTTCCCTCAGACTACCAATACCTACCGTAATACTGACACA



GCGGAACATCTGATAATGTGGGGCATTCACCATCCTTCCTCGACCCAGGAAAAAAACGACC



TGTACGGAACCCAGTCTCTCAGCATCTCCGTCGGGAGTAGCACTTACCGCAATAACTTTGT



GCCCGTCGTGGGAGCCCGCCCCCAAGTGAATGGACAGAGGGGGAGGATTGATTTCCACTGG



ACCCTCGTGCAACCGGGGGACAATATTACTTTCAGTCATAATGGAGGACTGATCGCCCCCA



GTCGCGTGTCCAAACTGATCGGAAGGGGGCTCGGTATCCAATCCGATGCACCGATAGATAA



CAATTGCGAGTCTAAGTGTTTCTGGCGTGGAGGCAGTATTAACACTCGGTTACCTTTTCAA



AATCTTTCGCCGCGGACCGTTGGCCAGTGCCCTAAGTACGTCAATCGTAGGTCCCTCATGC



TAGCCACTGGAATGCGCAACGTCCCGGAGCTCATCCAGGGGCGTGGATTGTTTGGAGCTAT



TGCTGGCTTCCTGGAGAATGGCTGGGAGGGAATGGTCGATGGCTGGTACGGGTTTCGGCAT



CAGAACGCACAGGGCACAGGCCAGGCCGCCGACTACAAGTCTACACAGGCCGCCATTGATC



AGATCACCGGGAAGCTGAACCGGCTGGTTGAGAAGACCAATACCGAATTTGAGAGCATCGA



ATCGGAATTCTCGGAAATCGAGCACCAGATTGGTAACGTAATAAACTGGACAAAGGATTCC



ATTACGGACATTTGGACGTATCAAGCAGAACTGCTCGTGGCCATGGAGAACCAACACACGA



TTGATATGGCAGATTCAGAAATGCTAAACTTGTACGAACGGGTCAGAAAGCAGCTGCGTCA



GAATGCTGAGGAGGACGGCAAGGGATGTTTTGAGATCTACCATGCTTGCGATGATTCTTGT



ATGGAGTCCATTCGGAATAACACGTACGACCATTCACAATATCGGGAGGAAGCACTTTTAA



ACCGGCTGAATATCAATCCAGTCACACTGAGTTCAGGCTACAAGGATATCATATTATGGTT



CTCATTCGGTGCCTCATGCTTCGTCCTTTTGGCAGTGGTGATGGGTTTGTTCTTTTTTTGT



CTGAAGAATGGCAACATGAGATGTACAATATGCATC





895
ATGTACAAGATTGTGGTGATCATCGCACTCCTTGGAGCTGTGAAAGGACTGGACAAAATTT



GTCTGGGACATCACGCTGTGGCTAACGGGACCATCGTGAAAACCCTAACGAATGAGCAGGA



AGAAGTCACAAATGCGACAGAGACAGTGGAATCCACTGGTATCAATCGACTGTGTATGAAG



GGCAGAAAACACAAGGACCTGGGCAATTGTCATCCGATAGGCATGTTAATCGGGACACCAG



CCTGTGACCTGCATCTGACCGGCATGTGGGATACTCTTATTGAGCGGGAGAACGCAATAGC



TTACTGCTACCCAGGCGCTACTGTGAATGTGGAAGCTCTGCGTCAGAAAATTATGGAGAGC



GGAGGGATTAACAAAATCTCTACTGGTTTCACATACGGCAGCAGTATTAACTCAGCCGGCA



CCACCAGGGCGTGTATGCGGAATGGTGGAAACTCATTTTATGCTGAGCTTAAATGGCTTGT



CTCAAAGTCGAAAGGCCAGAACTTCCCCCAGACTACAAACACCTACAGGAATACGGATACA



GCCGAGCATCTCATTATGTGGGGAATACATCATCCCAGCAGTACCCAGGAGAAAAACGATC



TGTACGGAACCCAGAGTCTCTCAATCTCAGTGGGATCAAGCACGTACAGAAATAATTTCGT



CCCTGTGGTGGGAGCCAGACCCCAGGTAAATGGACAGTCAGGGCGCATTGACTTTCACTGG



ACTCTCGTCCAGCCAGGAGACAATATCACATTTAGTCACAATGGCGGCCTGATAGCTCCTT



CTCGAGTGAGCAAACTGATCGGACGGGGTCTCGGTATCCAGTCCGACGCCCCCATCGATAA



CAACTGCGAGTCGAAGTGCTTCTGGCGTGGCGGGTCAATTAACACAAGACTACCATTTCAG



AACCTTTCACCTAGAACCGTGGGACAGTGCCCAAAGTACGTCAATAGACGGAGCCTGATGC



TGGCCACAGGGATGAGGAACGTTCCTGAACTGATACAAGGTCGGGGGCTTTTCGGTGCCAT



CGCAGGTTTTCTCGAGAACGGCTGGGAGGGCATGGTGGATGGGTGGTATGGGTTTAGGCAC



CAAAATGCACAAGGGACCGGCCAGGCCGCCGATTATAAGTCTACGCAAGCCGCCATTGACC



AGATCACTGGGAAGCTTAATAGGTTAGTAGAGAAGACAAATACCGAATTCGAGAGTATTGA



GTCAGAATTCTCCGAGATCGAGCACCAGATAGGCAACGTCATTAATTGGACAAAGGACTCT



ATTACCGACATTTGGACGTATCAAGCCGAACTTCTGGTGGCAATGGAAAATCAGCACACAA



TCGACATGGCCGACTCGGAGATGTTGAACTTATATGAAAGGGTGCGCAAACAGCTGCGCCA



GAACGCTGAAGAAGACGGTAAGGGATGCTTTGAGATCTATCATGCCTGCGATGATTCCTGT



ATGGAGTCGATAAGAAACAATACCTATGACCATAGCCAGTACCGGGAAGAAGCCCTCCTGA



ACAGACTGAATATTAACCCCGTTACCTTGTCCTCAGGATACAAGGACATTATCCTGTGGTT



TTCTTTCGGTGCTAGCTGTTTCGTGCTGCTCGCCGTCGTAATGGGGTTGTTTTTCTTCTGC



CTCAAAAACGGTAACATGCGATGCACCATTTGCATT





896
ATGTATAAGATCGTCGTCATTATCGCTCTCCTCGGAGCCGTGAAAGGTCTTGACAAAATTT



GTCTGGGCCATCACGCAGTGGCCAATGGGACCATCGTGAAGACGCTGACGAACGAGAAAGA



AGAGGTGACAAACGCTACTGAGACGGTCGAGAGCACCGGACTCAATAGGTTGTGCATGAAA



GGACGAAAGCATAAAGATCTGGGCAACTGTCACCCCATCGGGATGCTGATTGGCTCCCCAG



CCTGCGACTTACACCTGACTGGCACCTGGGATACACTGATCGAGCGCGAGAACGCCATTGC



CTACTGTTACCCCGGCGCTACAGTGAATGGTGAGGCCCTTCGCCAAAAGATTATGGAGTCA



GGCGGAATAGATAAGATCTCTACAGGCTTCACTTATGAGAGTTCGATTAACTCGGCCGGGA



CAACTAGGGCGTGTATGCGGAATGGCGGGAATTCCTTCTATGCTGAGCTTAAGTGGTTGGT



TTCCAAGAGCAAGGGGCAGAATTTTCCTCAGACCACCAACACCTATCGAAACACAGACACC



GCTGAACACCTCATCATGTGGGGCATTCACCACCCATCTTCAACCCAGGAGAAGAACGACC



TCTACGGTACTCAAAGCCTTAGTATCAGCGTGGGGTCATCTACCTACCGGAACAATTTTGT



GCCCGTGGTGGGAGCGCGCCCTCAAGTGAACGGACAAAGTGGCAGGATCGATTTCCATTGG



ACTTTGGTCCAGCCTGGTGACAACATCACATTCAGTCACAACGGTGGCCTGATCGCACCGT



CCAGAGTTTCCAAACTGATCGGCCGGGGTCTAGGGATTCAGAGCGACGCCCCTATTGATAA



CAACTGCGAGTCAAAATGCTTCTGGAGGGGGGGCTCCATTAACACTCGACTGCCCTTTCAG



AATCTGTCACCCCGAACCGTGGGTCAGTGTCCTAAGTACGTGAACAAGAGATCACTCATGC



TTGCCACTGGGATGCGCAATGTGCCCGAGCTCATGCAGGGAAGAGGACTGTTCGGAGCGAT



TGCTGGGTTTCTGGAAAATGGGTGGGAAGGGATGGTAGATGGATGGTACGGATTTCGTCAT



CAAAACGCACAGGGCACTGGACAAGCGGCGGACTATAAGTCAACTCAGGCTGCCATAGACC



AAATAACCGGGAAACTAAACCGGCTCGTCGAGAAGACCAACACCGAATTTGAATCTATCGA



GTCGGAATTTAGCGAGATTGAGCACCAGATAGGAAATGTTATCAATTGGACCAAGGACTCC



ATTACGGATATTTGGACTTACCAGGCGGAGCTGCTGGTTGCCATGGAGAATCAGCACACTA



TTGACATGGCCGATAGTGAGATGTTGAATTTGTACGAAAGAGTGCGCAAGCAGCTGAGGCA



GAACGCTGAAGAGGACGGTAAGGGATGCTTCGAAATTTATCACGCATGCGATGATTCCTGC



ATGGAATCGATCAGAAACAATACATATGATCATTCTCAATACCGGGAGGAGGCTTTGCTCA



ACCGCCTGAATATAAATCCTGTGACTCTCAGTTCGGGCTATAAAGACATCATCCTGTGGTT



CTCTTTTGGCGCCTCCTGCTTTGTCCTGCTGGCGGTGGTGATGGGACTCGTCTTCTTCTGC



CTAAAGAATGGCAACATGCGGTGTACAATCTGTATT









An alignment of amino acid sequences of hemagglutinin proteins from influenza A H7N9 strains are shown relative to a consensus sequence in FIG. 22. An alignment of amino acid sequences of hemagglutinin proteins from influenza A H10N8 strains are shown relative to a consensus sequence in FIG. 23.


Aspects of the present disclosure provide RNA polynucleotides encoding an influenza hemagglutinin protein or a fragment thereof. The terms “hemagglutinin,” “hemagglutinin protein,” and “HA” may be used interchangeably throughout and refer to a hemagglutinin protein that may be present on the surface of an influenza virus. On the viral surface, the hemagglutinin protein is present in homotrimers, each monomer of which is comprised of two subunits, HA1 and HA2, linked by a disulfide bond. Structurally, hemagglutinin proteins are comprised of several domains: a globular head domain, a stalk domain (also referred to as a stem domain), a transmembrane domain, and a cytoplasmic domain. It is generally though that during infection of a host cell (e.g., a eukaryotic cell such as a human cell) with an influenza virus, the hemagglutinin protein recognizes and binds to sialic acid of a receptor on the surface of a host cell facilitating attachment of the virus to the host cell (Gamblin et al., 2004; Ha et al., 2000). Following endocytosis of the virus and acidification of the endosome, the hemagglutinin protein undergoes a pH-dependent conformational change that allows for the hemagglutinin protein to facilitate fusion of the viral envelope with the endosome membrane of host cell and entry of the viral nucleic acid into the host cell.


In general, influenza viruses are classified based on the amino acid sequence of the viral hemagglutinin protein and/or the amino acid sequence of the viral neuraminidase (NA). In some embodiments, the hemagglutinin is of the subtype H1, H2, H3, H4, H5, H6, H7, H8, H9, H10, H11, H12, H13, H14, H15, H16, H17, or H18. The differences in amino acid sequences between hemagglutinin proteins of different subtypes are largely found within the sequence of the head domain of the protein. The amino acid sequence of the stalk domain is considered to be more conserved between hemagglutinin subtypes compared to sequence of the head domain. Domains of the hemagglutinin protein may be predicted using conventional methods known in the art.


Many naturally occurring and experimentally derived antibodies that bind and neutralize the hemagglutinin protein are thought to bind epitopes within the head domain of hemagglutinin and prevent or reduce interaction of hemagglutinin with sialic acid on receptors of host cells, thereby preventing or reducing infection of the cell. Alternatively or in addition, neutralizing antibodies may prevent or reduce fusion of the virus membrane with the membrane of the endosome. Such antibodies may bind epitopes within the stalk domain, thereby inhibiting the conformations change of the protein.


In some embodiments, the RNA polynucleotides described herein encode a fragment of a hemagglutinin protein, such as a truncated hemagglutinin protein. In some embodiments, the fragment is a headless hemagglutinin, meaning the fragment does not comprise the head domain In some embodiments, the fragment comprises a portion of the head domain. In some embodiments, the fragment is a stalk fragment (see, e.g., Mallajosyula et al. PNAS (2014) E2514-E2523). In some embodiments, fragment does not comprise the cytoplasmic domain. In some embodiments, the fragment does not comprise the transmembrane domain. In such embodiments, the fragment may be referred to as a soluble or secreted hemagglutinin protein or fragment.


In some embodiments, the RNA polypeptide encodes a hemagglutinin protein or fragment thereof that is at least 90% (e.g., 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) identical to a hemagglutinin protein provided by an amino acid sequence in Table 14-16. The terms “identical” or percent “identity” in the context of two or more polypeptide sequences refer to two or more sequences that are the same. The percent identity between polypeptide sequences may be performed using algorithms known in the art, such as BLAST and CLUSTAL.


The sequence of the hemagglutinin protein or fragment thereof may be obtained from any source. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from an avian influenza strain. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from an avian influenza strain that is capable of or at risk of infecting human subjects. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from a porcine influenza strain. In some embodiments, the sequence of the hemagglutinin protein or fragment thereof is from a porcine influenza strain that is capable of or at risk of infecting human subjects.


In any of the embodiments described herein, the sequence of the hemagglutinin or fragment thereof may be modified or optimized (such as codon optimized) for expression in a particular cell or host organism.


Methicillin-Resistant Staphylococcus aureus (MRSA)


MRSA is the most common invasive bacterial infection with an incidence of 20-100 per 100,000 persons. It is responsible for ˜20,000 deaths in US alone


Risk factors for MRSA include healthcare exposure, antibiotic use, and HIV. It is a common complication of joint replacement surgery which then requires removal and replacement of the joint. Symptoms include pneumonia, skin and soft-tissue infections, osteomyelitis (e.g., prostheses), endocarditis, bacteremia and sepsis.


Current treatment includes intravenous anti-staphylococal antibiotics (e.g., Vancomycin, Zyvox, Cubicin), contact precautions, and managment of sepsis (Goal-directed therapy+/−ICU admission).


The MRSA HA pathogens have multiple antigens so a combinatorial approach is an important principle to combat multi-drug resistance. Cell culture limits number of antigens in traditionally-produced vaccines making the present NAV approach superior.


MRSA antigens may include but not limited to NDM1, mecA, all b-lactamases (antibiotic resistance); Protein A mutant (immune escape); SDRD/SDRE (adherence); IsdA or IsdB (Lactoferrin excape, Fe transport); TSST, a-HL, and PVL(toxins).


In one embodiment, the NAVs of the present invention may comprise a multivalent vaccine, e.g., comprising a polynucleotide which encodes at least two MRSA antigens, including but not limited to NDM-1 and SpAmut.


In one embodiment, the SpA antigen or loss of function mutant SpAKKAA of MRSA is encoded by a polynucleotide of a NAV. Kim et al. (J. Exp. Med. Vol. 207 No. 9; 1863-1870; the contents of which are herein incorporated by reference in its entirety) describes that the mutation of the staphylococcal protein A (SpA) at five Ig-binding domains resulted in variant SpAKKAA which cannot bind to Fcγ or Fab VH3 and promote cell apoptosis. Immunization of mice with SpAKKAA raised antibodies was found to protect mice against challenge with highly virulent MRSA strains and even enabled MRSA-challenged mice to mount antibody responses to different staphylococcal antigens. Falugi et al. (mBio 4(5):e00575-13. doi:10.1128/mBio.00575-13; the contents of which are herein incorporated by reference in its entirety) found that the SpAKKAA mutant elicited B cell responses to key virulence antigens that protected animals against a lethal S. aureus challenge and the SpAKKAA mutant was able to elicit an adaptive response that protected against recurrent infection. Schineewind et al. describes a SpA antigen or loss of function mutant of SpA in International Patent Publication Nos. WO2011127032, WO2011005341, WO2012003474, WO2012034067 and WO2013025834 and US Patent Publication Nos. US20130136746, US20120114686, US20130171183 and US20130230550, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, the SpA mutant may comprise at least one substitution in the amino acid sequence that disrupts the Fc binding and at least one substitution in the amino acid sequence that disrupts the VH3 binding (see e.g., International Publication No. WO2011005341 and US Patent publication No. US20120114686, the contents of each of which are herein incorporated by reference in its entirety). As another non-limiting example, the SpA mutant may comprise a substitution in the D domain of a SpA sequence at positions 9, 10, 36 and 37 of the SpA sequence (see e.g., International Patent Publication Nos. WO2011127032, WO2012003474 and WO2012034067 and US Patent Publication Nos. US20130136746, US20130171183 and US20130230550, the contents of each of which are herein incorporated by reference in their entirety). The amino acids at positions 9 and 10 may be substituted for glycine and the amino acids at positions 36 and 37 may be substituted for serine (see e.g., International Patent Publication Nos. WO2011127032 and WO2012003474 and US Patent Publication Nos. US20130136746 and US20130171183, the contents of each of which are herein incorporated by reference in their entirety). As yet another non-limiting example, the SpA mutant may comprise a substitution at position 9, 10, 36 and 37 of SEQ ID NO: 2 described in International Patent Publication Nos. WO2011127032 and WO2012003474 and US Patent Publication Nos. US20130136746 and US20130171183, the contents of each of which are herein incorporated by reference in their entirety.


SpA-binding to B-cell surface V(H)3 leads to B-cell receptor crosslinking followed by B-cell apoptosis, clonal B-cell deletion and block of affinity maturation and B-cell memory. SpA-binding to Fcg at the FcR-binding site of secreted antibodies inhibits activation of effector cells critical for bacterial clearance and adaptive immunity.


SpAKKAA is a loss-of-function mutant of SpA without a functional Fcg and V(H)3 binding site.


Vaccination with SpAKKAA allows clonal B-cell expansion and sufficient time for antibody affinity maturation leading to B-cell clones with higher affinity to SpA epitopes than Fcg or V(H)3 binding of SpA. This enables antibody binding to SpA through affinity-matured CDRs with Fc portions freely available for effector cell activation and B-cell memory creation.


Thus, SpAKKAA immunization enable MRSA-challenged subjects to mount antibody responses to many different staphylococcal antigens.


In one embodiment, the NAV is a multi-valent vaccine with SpAKKAA as the center antigen. This provides a key advantage over inactivated, whole MRSA vaccines currently in clinical development.


In one embodiment, the MRSA NAVs are used to target at risk populations such as those having linezolid-resistant joint/bone infections; chronic disease; healthcare workers and to prevent outbreak of resistant strains.


MRSA toxins such as PVL, a-HL, TSST-1 may be encoded by the NAVs of the invention. Alternatively, any of the beta-lactamase genes may be targeted in a manner which reduces their ability to protect the bacteria thereby rendering it more susceptible to traditional antibiotic attack. Such targeting of the lactamase enzymes may be personalized to a particular subject where a sample is obtained and the unique lactamase sequence is determined through standard techniques in the art. Inhibitors of the unique lactamase sequence can then be designed creating a personalized medicine or vaccine.


Dengue

Dengue fever is a mosquito-borne virus and is epidemic (SE Asia) and endemic (Sub-Saharan Africa. India). As much as 40% of world's population is at risk with over 100 million infections per year according to the World Health Organization. There have been about 1-2 million clinically documented cases. The mortality rate depends on access to healthcare and can reach as high as 20%.


Symptoms include acute onset fevers with terrible joint and muscle pain for 5-7 days, followed by weeks of lethargy and fatigue. Dehydration and hemorrhage are the main drivers of mortality, hence need for access to IV fluids to avoid shock. Supportive care includes fluid resuscitation but prevention is the primary means of limiting the impact of virus (e.g., mosquito control, personal protection).


For Dengue fever, disease characteristics requires a neutralizing—but not enhancing—antibody response to the four most critical Dengue serotypes (DENV1-4). Therefore a multivalent antigen targeting key proteins/protein domains of four serotypes of Dengue virus (DENV 1-4) would have value as a vaccine.


In one embodiment, NAVs of the invention comprise one or more polynucleotides which encode the E protein domain III (DENV1-4 tandem mRNA), the E protein domain I/II hinge region (DENV1-4 individual mRNAs), the prM protein (DENV1-4 tandem or individual mRNAs) and the C protein (DENV1-4 tandem or single mRNAs).


In one embodiment, the most potent NAV vaccine is selected by measuring the antibody titer in Balb/c mice followed by tests of selected vaccines in Dengue disease models. Upon rescue in disease model, crossreactivity analysis in in-vitro viral assays to ensure activity of multi-valent vaccine against all serotypes is performed.


In some embodiments cross-neutralizing Ab-titers agains each of the four Dengue strains (DENV1-4) in a virus neutralization assay are tested either in vitro or in vivo as in (BMC Microbiol. 2014; 14: 44; and Immunology. 2012 July; 136 (3):334-43), the contents of which are incorporated herein by reference.


In some embodiments, neutralizing vs enhancing Ab-titers is evaluated and in another embodiment the RNAV are tested in humanized mouse model for Dengue disease (J Virol. 2014 February; 88(4):2205-18, then contents of which are incorporated herein by reference in their entirety).


The NAV targeting Dengue is referred to as a multi-genotype antigen NAV.


Enterotoxic E. Coli (ETEC)

ETEC is the most common cause of diarrhea in the developing world with between 300k-500k deaths per year. Transmission is via fecal-oral transmission (water, food). Symptoms include secretory diarrhea (mediated by two toxins: heat-stable and heat-labile), abdominal pain and cramping, nausea and vomiting. Generally symptoms last less than 1 week, and rarely greater than 2 weeks. The resultant dehydration is the primary cause of more serious sequelae. Currently supportive care and fluid resuscitation are the treatment where generally an uncomplicated infection resolves on its own.


Previous ETEC vaccines were based on a single antigen or had a sole focus on toxin neutralization that was not effective in providing long-lasting immunity.


According to the present invention three pathways are addressed by the selected antigens in a multivalent approach: (1) Toxins: Sta3 and eltA/eltB; (2) Adhesion proteins critical for delivery of toxins to the endothelium: EatA, etpA, and etpB; and (3) Proteins enabling colonialization: cssA.


The ETEC NAV of the present invention is designed to enable long-term protection against ETEC. And even to provide prophylactic treatment such as for travelers.



Clostridium difficile



C. difficile causes an increasingly common diarrheal illness associated with key risk factors including exposure to a healthcare setting (e.g., hospitalization, nursing home residence), and antibiotics (esp. amoxicillin, clindamycin).


Symptoms include recurrent diarrhea and Pseudomembranous colitis. Current treatment includes diagnostics with toxin and reflex antigen and/or treatment with metronidazole and vanocmycin.


The present invention provides a trivalent antigen approach to the treatment of C. difficile infection. The antigens encoded include toxin A (enterotoxin; CD Toxin A 136754); toxin b (cytotoxin; CD Toxin B 136755), and binary toxin (cdtB; CD cdtB 136757).


In some embodiments, the multivalent NAV prevents C. Difficile infection among patients: (1) receiving certain medications (antibiotics, PPIs) or (2) with healthcare exposure (hospitalized, nursing home etc) in a manner which blocks the effects of the organisms' toxin and key virulence factors.


Tuberculosis

Tuberculosis is an infectious disease caused by various strains of mycobacteria, usually Mycobacterium tuberculosis. Symptoms include a chronic cough with blood-tinged sputum, fever, night sweats, and weight loss.


The current challenges for the development of a vaccine against TB are (i) three different disease states requiring a different set of antigens: pre-infection (prophylactic vaccine), latent infection (therapeutic vaccine) and active infection (therapeutic vaccine); and (ii) different set of adjuvants critical to induce a protective while not overshooting immune response; and (iii) an unclear understanding on the necessary immune response to clear the infection.


Therefore it will be required to combine different sets of cytokines as an adjuvant with a different set of antigens dependent on the disease state. The following cytokines provide a potential adjuvant arm of the vaccine: GM-CSF, IL-17, IFNg, IL-15, IL-2, IL-21, Anti-PD1/2, lactoferrin. The following antigens represent a non-exhaustive list: Ag85A (Rv3804c). Ag85B (Rv 1886c), TB10.4 (Rv0288), ESAT6(Rv3785), Rv2660L, Rv3619, Rv1813c, Rv3620c, Rv2608, Rv1196, Rv0125, and MT401.


Middle-East Respiratory Syndrome Coronavirus (MERS-CoV)

MERS-CoV, previously known as the Novel Coronavirus or SARS-like virus, is a member of the coronavirus family. Symptoms are similar to SARS infections and include coughing, production of mucous, shortness of breath, malaise—a general feeling of being unwell, chest pain, fever, diarrhea (in some cases) and renal (kidney) failure. Human enterovirus 71 and Human enterovirus 68


Enterovirus 71 (EV-71) is one of the major causative agents for hand, foot and mouth disease (HFMD), and is sometimes associated with severe central nervous system diseases. The Enterovirus 71 (EV71) infection may be asymptomatic.


Enterovirus 68 (EV68, EV-D68) is a member of the Picornaviridae family, an enterovirus (a group of ssRNA viruses containing the polioviruses, coxsackievirus, and echoviruses). First isolated in 1962, it has been on a worldwide upswing in the last few years. It may be involved in cases of a recent outbreak of polio-like disease in California.


Antigens

Antigens of the present invention include polypeptides, peptides and/or polypeptides of interest and are encoded by the polynucleotides of the invention. Polynucleotides encoding such antigens of the invention are described in more detail below under “Design, Synthesis and Quantitation of NAV Polynucleotides”.


III. Design, Synthesis and Quantification of NAV Polynucleotides

According to the present invention, the polynucleotides encode at least one polypeptide of interest, e.g., an antigen. Antigens of the present invention may be wild type (i.e., derived from the infectious agent) or modified (e.g., engineered, designed or artificial). They may have any combination of the features described herein.


The present invention provides nucleic acid molecules, specifically polynucleotides which, in some embodiments, encode one or more peptides or polypeptides of interest. Such peptides or polypeptides, according to the invention may serve as an antigen or antigenic molecule. The term “nucleic acid,” in its broadest sense, includes any compound and/or substance that comprise a polymer of nucleotides. These polymers are often referred to as polynucleotides.


Exemplary nucleic acids or polynucleotides of the invention include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a β-D-ribo configuration, α-LNA having an α-L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino-α-LNA having a 2′-amino functionalization), ethylene nucleic acids (ENA), cyclohexenyl nucleic acids (CeNA) or hybrids or combinations thereof.


In one embodiment, linear polynucleotides encoding one or more antigens of the NAVs of the present invention which are made using only in vitro transcription (IVT) enzymatic synthesis methods are referred to as “IVT polynucleotides.”


In another embodiment, the polynucleotides of the present invention which have portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing are known as “chimeric polynucleotides.” A “chimera” according to the present invention is an entity having two or more incongruous or heterogeneous parts or regions. As used herein a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.


In yet another embodiment, the polynucleotides of the present invention that are circular are known as “circular polynucleotides” or “circP.” As used herein, “circular polynucleotides” or “circP” means a single stranded circular polynucleotide which acts substantially like, and has the properties of, an RNA. The term “circular” is also meant to encompass any secondary or tertiary configuration of the circP.


In some embodiments, the polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1.000 to 3,000, from 1,000 to 5,000, from 1.000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).


In one embodiment, the polynucleotides of the present invention may encode at least one peptide or polypeptide of interest. In another embodiment, the polynucleotides of the present invention may be non-coding.


In one embodiment, the length of a region encoding at least one peptide polypeptide of interest of the polynucleotides present invention is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). As used herein, such a region may be referred to as a “coding region” or “region encoding.”


In one embodiment, the polynucleotides of the present invention is or functions as a messenger RNA (mRNA). As used herein, the term “messenger RNA” (mRNA) refers to any polynucleotide which encodes at least one peptide or polypeptide of interest and which is capable of being translated to produce the encoded peptide polypeptide of interest in vitro, in vivo, in situ or ex vivo.


In one embodiment, the polynucleotides of the present invention may be structurally modified or chemically modified. As used herein, a “structural” modification is one in which two or more linked nucleosides are inserted, deleted, duplicated, inverted or randomized in a polynucleotide without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to effect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide “ATCG” may be chemically modified to “AT-5meC-G”. The same polynucleotide may be structurally modified from “ATCG” to “ATCCCG”. Here, the dinucleotide “CC” has been inserted, resulting in a structural modification to the polynucleotide.


In one embodiment, the polynucleotides of the present invention, such as IVT polynucleotides or circular polynucleotides, may have a uniform chemical modification of all or any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all or any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine. In another embodiment, the polynucleotides may have a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way).


When the polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified polynucleotides.”


In one embodiment, the polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide. The self-cleaving peptide may be, but is not limited to, a 2A peptide. As a non-limiting example, the 2A peptide may have the protein sequence: GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 963), fragments or variants thereof. In one embodiment, the 2A peptide cleaves between the last glycine and last proline. As another non-limiting example, the polynucleotides of the present invention may include a polynucleotide sequence encoding the 2A peptide having the protein sequence GSGATNFSLLKQAGDVEENPGP (SEQ ID NO: 963) fragments or variants thereof.


One such polynucleotide sequence encoding the 2A peptide is GGAAGCGGAGCTACTAACTTCAGCCTGCTGAAGCAGGCTGGAGACGTGGA GGAGAACCCTGGACCT (SEQ ID NO: 964). The polynucleotide sequence of the 2A peptide may be modified or codon optimized by the methods described herein and/or are known in the art.


In one embodiment, this sequence may be used to separate the coding region of two or more polypeptides of interest. As a non-limiting example, the sequence encoding the 2A peptide may be between a first coding region A and a second coding region B (A-2Apep-B). The presence of the 2A peptide would result in the cleavage of one long protein into protein A, protein B and the 2A peptide. Protein A and protein B may be the same or different peptides or polypeptides of interest. In another embodiment, the 2A peptide may be used in the polynucleotides of the present invention to produce two, three, four, five, six, seven, eight, nine, ten or more proteins.


Polynucleotide Architecture

Traditionally, the basic components of an mRNA molecule include at least a coding region, a 5′UTR, a 3′UTR, a 5′ cap and a poly-A tail. The IVT polynucleotides of the present invention may function as mRNA but are distinguished from wild-type mRNA in their functional and/or structural design features which serve to overcome existing problems of effective polypeptide production using nucleic-acid based therapeutics. It is to be understood that the antigens of the NAVs of the present invention may be encoded by IVT polynucleotides, as described herein.



FIG. 1 shows a primary construct 100 of an IVT polynucleotide of the present invention. Such polynucleotides are useful in NAV compositions, RNAV compositions or mRNA vaccines. As used herein, “primary construct” refers to a polynucleotide of the present invention which encodes one or more polypeptides of interest and which retains sufficient structural and/or chemical features to allow the polypeptide of interest encoded therein to be translated.


According to FIGS. 1A and 1B, the polynucleotide 100 here contains a first region of linked nucleotides 102 that is flanked by a first flanking region 104 and a second flaking region 106. The polypeptide of interest may comprise at its 5′ terminus one or more signal sequences encoded by a signal sequence region 103. The flanking region 104 may comprise a region of linked nucleotides comprising one or more complete or incomplete 5′ UTRs sequences which may be completely codon optimized or partially codon optimized. The flanking region 104 may include at least one nucleic acid sequence including, but not limited to, miR sequences, TERZAK™ sequences and translation control sequences. The flanking region 104 may also comprise a 5′ terminal cap 108. The 5′ terminal capping region 108 may include a naturally occurring cap, a synthetic cap or an optimized cap. Non-limiting examples of optimized caps include the caps taught by Rhoads in U.S. Pat. No. 7,074,596 and International Patent Publication No. WO2008157668, WO2009149253 and WO2013103659, the contents of each of which are herein incorporated by reference in its entirety. The second flanking region 106 may comprise a region of linked nucleotides comprising one or more complete or incomplete 3′ UTRs. The second flanking region 106 may be completely codon optimized or partially codon optimized. The flanking region 106 may include at least one nucleic acid sequence including, but not limited to, miR sequences and translation control sequences. The flanking region 106 may also comprise a 3′ tailing sequence 110. The 3′ tailing sequence 110 may include a synthetic tailing region 112 and/or a chain terminating nucleoside 114. Non-liming examples of a synthetic tailing region include a polyA sequence, a polyC sequence, and/or a polyA-G quartet. Non-limiting examples of chain terminating nucleosides include 2′-O methyl, F and locked nucleic acids (LNA).


Bridging the 5′ terminus of the first region 102 and the first flanking region 104 is a first operational region 105. Traditionally this operational region comprises a Start codon. The operational region may alternatively comprise any translation initiation sequence or signal including a Start codon.


Bridging the 3′ terminus of the first region 102 and the second flanking region 106 is a second operational region 107. Traditionally this operational region comprises a Stop codon. The operational region may alternatively comprise any translation initiation sequence or signal including a Stop codon. Multiple serial stop codons may also be used in the IVT polynucleotide. In one embodiment, the operation region of the present invention may comprise two stop codons. The first stop codon may be “TGA” or “UGA” and the second stop codon may be selected from the group consisting of “TAA,” “TGA,” “TAG,” “UAA,” “UGA” or “UAG.”


The shortest length of the first region of the primary construct of the IVT polynucleotide of the present invention can be the length of a nucleic acid sequence that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide. In another embodiment, the length may be sufficient to encode a peptide of 2-30 amino acids, e.g. 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids. The length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g. no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids. Examples of dipeptides that the polynucleotide sequences can encode or include, but are not limited to, carnosine and anserine. It is understood that the NAV, RNAV or mRNA vaccines of the invention may be translatable and include such first region of a primary construct.


The length of the first region of the primary construct of the IVT polynucleotide encoding the polypeptide of interest of the present invention is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides).


In some embodiments, the IVT polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).


According to the present invention, the first and second flanking regions of the IVT polynucleotide may range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, and 900 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1,000 nucleotides).


According to the present invention, the tailing sequence of the IVT polynucleotide may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, or 500 nucleotides). Where the tailing region is a polyA tail, the length may be determined in units of or as a function of polyA Binding Protein binding. In this embodiment, the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein. PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides and 160 nucleotides are functional.


According to the present invention, the capping region of the IVT polynucleotide may comprise a single cap or a series of nucleotides forming the cap. In this embodiment the capping region may be from 1 to 10. e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length. In some embodiments, the cap is absent.


According to the present invention, the first and second operational regions of the IT polynucleotide may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length and may comprise, in addition to a Start and/or Stop codon, one or more signal and/or restriction sequences.


In one embodiment, the IVT polynucleotides of the present invention may be structurally modified or chemically modified. When the IVT polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified IVT polynucleotides.”


In one embodiment, if the IVT polynucleotides of the present invention are chemically modified they may have a uniform chemical modification of all or any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all or any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine. In another embodiment, the IVT polynucleotides may have a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way).


In one embodiment, the IVT polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide, described herein, such as but not limited to the 2A peptide. The polynucleotide sequence of the 2A peptide in the IVT polynucleotide may be modified or codon optimized by the methods described herein and/or are known in the art.


In one embodiment, this sequence may be used to separate the coding region of two or more polypeptides of interest in the IVT polynucleotide.


In one embodiment, the IVT polynucleotide of the present invention may be structurally and/or chemically modified. When chemically modified and/or structurally modified the IVT polynucleotide may be referred to as a “modified IVT polynucleotide.”


In one embodiment, the IVT polynucleotide may encode at least one peptide or polypeptide of interest. In another embodiment, the IVT polynucleotide may encode two or more peptides or polypeptides of interest. Non-limiting examples of peptides or polypeptides of intest include heavy and light chains of antibodies, an enzyme and its substrate, a label and its binding molecule, a second messenger and its enzyme or the components of multimeric proteins or complexes.


Chimeric Polynucleotide Architecture

The chimeric polynucleotides or RNA constructs of the present invention maintain a modular organization similar to IVT polynucleotides, but the chimeric polynucleotides comprise one or more structural and/or chemical modifications or alterations which impart useful properties to the polynucleotide. As such, the chimeric polynucleotides which are modified mRNA molecules of the present invention are termed “chimeric modified mRNA” or “chimeric mRNA.”


It is to be understood that the antigens of the NAVs of the present invention may be encoded by a chimeric polynucleotide, RNA construct, chimeric modified mRNA or chimeric mRNA.


Chimeric polynucleotides have portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing.


Examples of parts or regions, where the chimeric polynucleotide functions as an mRNA and encodes a polypeptide of interest include, but are not limited to, untranslated regions (UTRs, such as the 5′ UTR or 3′ UTR), coding regions, cap regions, polyA tail regions, start regions, stop regions, signal sequence regions, and combinations thereof. FIG. 2 illustrates certain embodiments of the chimeric polynucleotides of the invention which may be used as mRNA. FIG. 3 illustrates a schematic of a series of chimeric polynucleotides identifying various patterns of positional modifications and showing regions analogous to those regions of an mRNA polynucleotide. Regions or parts that join or lie between other regions may also be designed to have subregions. These are shown in the figure.


In some embodiments, the chimeric polynucleotides of the invention have a structure comprising Formula I.





5′[An]x-L1-[Bo]y-L2-[Cp]z-L3 3′  Formula I

    • wherein:
    • each of A and B independently comprise a region of linked nucleosides;
    • C is an optional region of linked nucleosides;
    • at least one of regions A, B, or C is positionally modified, wherein said positionally modified region comprises at least two chemically modified nucleosides of one or more of the same nucleoside type of adenosine, thymidine, guanosine, cytidine, or uridine, and wherein at least two of the chemical modifications of nucleosides of the same type are different chemical modifications;
    • n, o and p are independent an integer between 15-1000;
    • x and y are independently 1-20:
    • z is 0-5;
    • L1 and L2 are independently optional linker moieties, said linker moieties being either nucleic acid based or non-nucleic acid based; and
    • L3 is an optional conjugate or an optional linker moiety, said linker moiety being either nucleic acid based or non-nucleic acid based.


In some embodiments the chimeric polynucleotide of Formula I encodes one or more peptides or polypeptides of interest. Such encoded molecules may be encoded across two or more regions.


In another aspect, the invention features a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II:





[An]-L1-[Bo]  Formula II

    • wherein each A and B is independently any nucleoside;
    • n and o are, independently 15 to 1000; and
    • L1 has the structure of Formula III:




embedded image




    • wherein a, b, c, d, e, and f are each, independently, 0 or 1;

    • each of R1, R3, R5, and R7, is, independently, selected from optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, O, S, and NR8.

    • R2 and R6 are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

    • R4 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C6-C12 arylene, optionally substituted C2-C100 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a bond linking (R1)n—(R2)b—(R3)c to (R5)d—(R6)e—(R7)f, wherein if c, d, e, f, g, and h are 0. R4 is not a bond; and

    • R8 is hydrogen, optionally substituted C1-C41 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C1-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl, or optionally substituted C1-C2 heteroalkyl;

    • wherein L1 is attached to [An] and [Bo] at the sugar of one of the nucleosides (e.g., at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [An] and the 5′ position of a five-membered sugar ring or 6′ position of a six membered sugar ring of a nucleoside of [Bo] or at the 5′ position of a five-membered sugar ring or 6′ position of a six membered sugar ring of a nucleoside of [An] and the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [Bo]).





In some embodiments, at least one of [An] and [Bo] includes the structure of Formula IV:




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    • wherein each of N1 and N2 is independently a nucleobase;

    • each of R9, R10, R11, R12, R13, R14, R15, and R16 is, independently, H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, or optionally substituted C6-C10 aryl;

    • each of g and h is, independently, 0 or 1;

    • each X1 and X4 is, independently, O, NH, or S;

    • each X2 is independently O or S; and

    • each X3 is OH or SH, or a salt thereof.





In another aspect, the invention features a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II:





[An]-L1-[Bo]  Formula II

    • wherein each A and B is independently any nucleoside;
    • n and o are, independently 15 to 1000; and
    • L1 is a bond or has the structure of Formula III:




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    • wherein a, b, c, d, e, and f are each, independently, 0 or 1;

    • each of R1, R3, R5, and R7, is, independently, selected from optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, O, S, and NR8.

    • R2 and R6 are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

    • R4 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 alkynylene, optionally substituted C2-C9 heterocyclylene, optionally substituted C6-C12 arylene, optionally substituted C2-C100 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a bond linking (R1)a—(R2)b—(R3)c to (R5)d—(R6)e—(R7)f, and

    • R8 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl, or optionally substituted C1-C7 heteroalkyl;

    • wherein L1 is attached to [An] and [Bo] at the sugar of one of the nucleosides (e.g., at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [An] and the 5′ position of a five-membered sugar ring or 6′ position of a six membered sugar ring of a nucleoside of [B,] or at the 5′ position of a five-membered sugar ring or 6′ position of a six membered sugar ring of a nucleoside of [An] and the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of a nucleoside of [Bo]).

    • wherein at least one of [An] or [Bo] includes the structure of Formula IV:







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    • wherein each of N1 and N2 is independently a nucleobase;

    • each of R9, R10, R11, R12, R13, R14, R15, and R16 is, independently, H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, or optionally substituted C6-C10 aryl;

    • each of g and h is, independently, 0 or 1;

    • each X1 and X4 is, independently, O, NH, or S; and

    • each X2 is independently O or S; and

    • each X3 is OH or SH, or a salt thereof;

    • wherein at least one of X1, X2, or X4 is NH or S.





In some embodiments, X1 is NH. In other embodiments, X4 is NH. In certain embodiments, X2 is S.


In some embodiments, the polynucleotide includes: (a) a coding region; (b) a 5′ UTR including at least one Kozak sequence; (c) a 3′ UTR; and (d) at least one 5′ cap stucture. In other embodiments, the polynucleotide further includes (e) a poly-A tail.


In some embodiments, one of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [An]-L1-[Bo].


In other embodiments, one of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [An] and another of the coding region, the 5′ UTR including at least one Kozak sequence, the 3′ UTR, the 5′ cap structure, or the poly-A tail includes [Bo].


In certain embodiments, the polynucleotide includes at least one modified nucleoside (e.g., a nucleoside of Table 2).


In some embodiments, R4 is optionally substituted C2-9 heterocyclylene, for example, the heterocycle may have the structure:




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In certain embodiments, L1 is attached to [An] at the 3′ position of a five-membered sugar ring or 4′ position of a six membered sugar ring of one of the nucleosides and to [Bo] at the 5′ position of a five-membered sugar ring or 6′ position of a six membered sugar ring of one of the nucleosides.


In some embodiments, the polynucleotide is circular.


In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide includes the structure of Formula V:




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This method includes reacting a compound having the structure of Formula VI:




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with a compound having the structure of Formula VII:




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    • wherein each of N1 and N2 is, independently, a nucleobase; each of R9, R10, R11, R12, R13, R14, R15, and R16 is, independently, H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, or optionally substituted C6-C10 aryl;

    • each of g and h is, independently, 0 or 1;

    • each X1 and X4 is, independently, O, NH, or S; and

    • each X3 is independently OH or SH, or a salt thereof;

    • each of R17 and R19 is, independently, a region of linked nucleosides; and

    • R18 is a halogen.





In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide includes the structure of Formula VIII:




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This method includes reacting a compound having the structure of Formula IX:




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with a compound having the structure of Formula X:




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    • wherein each of N1 and N2 is, independently, a nucleobase;

    • each of R9, R10, R11, R12, R13, R14, R15, and R16 is, independently. H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, or optionally substituted C6-C10 aryl;

    • each of g and h is, independently, 0 or 1;

    • each X4 is, independently, O, NH, or S; and

    • each X2 is independently O or S;

    • each X3 is independently OH, SH, or a salt thereof;

    • each of R20 and R23 is, independently, a region of linked nucleosides; and

    • each of R21 and R22 is, independently, optionally substituted C1-C6 alkoxy.





In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide includes the structure of Formula XI:




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This method includes reacting a compound having the structure of Formula XII:




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with a compound having the structure of Formula XIII:




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    • wherein each of N1 and N2 is, independently, a nucleobase;

    • each of R9, R10, R11, R12, R13, R4, R15, and R16 is, independently, H, halo, hydroxy, thiol, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C2-C6 heteroalkenyl, optionally substituted C2-C6 heteroalkynyl, optionally substituted amino, azido, or optionally substituted C6-C10 aryl;

    • each of g and h is, independently, 0 or 1;

    • each X4 is, independently, O, NH, or S; and

    • each X2 is independently O or S;

    • each X3 is independently OH, SH, or a salt thereof;

    • each of R24 and R21 is, independently, a region of linked nucleosides; and

    • R25 is optionally substituted C1-C6 alkylene or optionally substituted C1-C6 heteroalkylene or R2 and the alkynyl group together form optionally substituted cycloalkynyl.





In another aspect, the invention features a method of producing a composition including a chimeric polynucleotide encoding a polypeptide, wherein the polynucleotide has a sequence including Formula II:





[An]-L1-[Bo],  Formula II


This method includes reacting a compound having the structure of Formula XIV





[An]—(R1)a—(R2)b—(R3)c—N3  Formula XIV


with a compound having the structure of Formula XV:





R27—(R5)d—(R6)e—(R7)f—[Bo]  Formula XV

    • wherein each A and B is independently any nucleoside;
    • n and o are, independently 15 to 1000; and
    • L1 has the structure of Formula III:




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    • wherein a, b, c, d, e, and f are each, independently, 0 or 1;

    • wherein each A and B is independently any nucleoside;

    • n and o are, independently 15 to 1000;

    • R1, R3, R5, and R7 each, independently, is selected from optionally substituted C1-C6 alkylene, optionally substituted C1-C6 heteroalkylene, O, S, and NR8;

    • R2 and R6 are each, independently, selected from carbonyl, thiocarbonyl, sulfonyl, or phosphoryl;

    • R4 is an optionally substituted triazolene; and

    • R8 is hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C3-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted C2-C6 heterocyclyl, optionally substituted C6-C12 aryl, or optionally substituted C1-C7 heteroalkyl; and

    • R27 is an optionally substituted C2-C3 alkynyl or an optionally substituted C8-C12 cycloalkynyl,

    • wherein L1 is attached to [An] and [Bo] at the sugar of one of the nucleosides.





In some embodiments, the optionally substituted triazolene has the structure:




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In one embodiment, at least one of the regions of linked nucleosides of A may comprise a sequence of linked nucleosides which can function as a 5′ untranslated region (UTR). The sequence of linked nucleosides may be a natural or synthetic 5′ UTR. As a non-limiting example, the chimeric polynucleotide may encode a polypeptide of interest and the sequence of linked nucleosides of A may encode the native 5′ UTR of a polypeptide encoded by the chimeric polynucleotide or the sequence of linked nucleosides may be a non-heterologous 5′ UTR such as, but not limited to a synthetic UTR.


In another embodiment, at least one of the regions of linked nucleosides of A may be a cap region. The cap region may be located 5′ to a region of linked nucleosides of A functioning as a 5′UTR. The cap region may comprise at least one cap such as, but not limited to, Cap0, Cap1, ARCA, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, 2-azido-guanosine, Cap2 and Cap4.


In one embodiment, at least one of the regions of linked nucleosides of B may comprise at least one open reading frame of a nucleic acid sequence. The nucleic acid sequence may be codon optimized and/or comprise at least one modification.


In one embodiment, at least one of the regions of linked nucleosides of C may comprise a sequence of linked nucleosides which can function as a 3′ UTR. The sequence of linked nucleosides may be a natural or synthetic 3′ UTR. As a non-limiting example, the chimeric polynucleotide may encode a polypeptide of interest and the sequence of linked nucleosides of C may encode the native 3′ UTR of a polypeptide encoded by the chimeric polynucleotide or the sequence of linked nucleosides may be a non-heterologous 3′ UTR such as, but not limited to a synthetic UTR.


In one embodiment, at least one of the regions of linked nucleosides of A comprises a sequence of linked nucleosides which functions as a 5′ UTR and at least one of the regions of linked nucleosides of C comprises a sequence of linked nucleosides which functions as a 3′ UTR. In one embodiment, the 5′ UTR and the 3′ UTR may be from the same or different species. In another embodiment, the 5′ UTR and the 3′ UTR may encode the native untranslated regions from different proteins from the same or different species.



FIGS. 4 and 5 provide schematics of a series of chimeric polynucleotides illustrating various patterns of positional modifications based on Formula I as well as those having a blocked or structured 3′ terminus.


Chimeric polynucleotides, including the parts or regions thereof, of the present invention may be classified as hemimers, gapmers, wingmers, or blockmers.


As used herein, a “hemimer” is chimeric polynucleotide comprising a region or part which comprises half of one pattern, percent, position or population of a chemical modification(s) and half of a second pattern, percent, position or population of a chemical modification(s). Chimeric polynucleotides of the present invention may also comprise hemimer subregions. In one embodiment, a part or region is 50% of one and 50% of another.


In one embodiment the entire chimeric polynucleotide can be 50% of one and 50% of the other. Any region or part of any chimeric polynucleotide of the invention may be a hemimer. Types of hemimers include pattern hemimers, population hemimers or position hemimers. By definition, hemimers are 50:50 percent hemimers.


As used herein, a “gapmer” is a chimeric polynucleotide having at least three parts or regions with a gap between the parts or regions. The “gap” can comprise a region of linked nucleosides or a single nucleoside which differs from the chimeric nature of the two parts or regions flanking it. The two parts or regions of a gapmer may be the same or different from each other.


As used herein, a “wingmer” is a chimeric polynucleotide having at least three parts or regions with a gap between the parts or regions. Unlike a gapmer, the two flanking parts or regions surrounding the gap in a wingmer are the same in degree or kind. Such similarity may be in the length of number of units of different modifications or in the number of modifications. The wings of a wingmer may be longer or shorter than the gap. The wing parts or regions may be 20, 30, 40, 50, 60 70, 80, 90 or 95% greater or shorter in length than the region which comprises the gap.


As used herein, a “blockmer” is a patterned polynucleotide where parts or regions are of equivalent size or number and type of modifications. Regions or subregions in a blockmer may be 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 299, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490 or 500, nucleosides long.


Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification pattern are referred to as “pattern chimeras.” Pattern chimeras may also be referred to as blockmers. Pattern chimeras are those polynucleotides having a pattern of modifications within, across or among regions or parts.


Patterns of modifications within a part or region are those which start and stop within a defined region. Patterns of modifications across a part or region are those patterns which start in on part or region and end in another adjacent part or region. Patterns of modifications among parts or regions are those which begin and end in one part or region and are repeated in a different part or region, which is not necessarily adjacent to the first region or part.


The regions or subregions of pattern chimeras or blockmers may have simple alternating patterns such as ABAB[AB]n where each “A” and each “B” represent different chemical modifications (at at least one of the base, sugar or backbone linker), different types of chemical modifications (e.g., naturally occurring and non-naturally occurring), different percentages of modifications or different populations of modifications. The pattern may repeat n number of times where n=3-300. Further, each A or B can represent from 1-2500 units (e.g., nucleosides) in the pattern. Patterns may also be alternating multiples such as AABBAABB[AABB]n (an alternating double multiple) or AAABBBAAABBB[AAABBB]n (an alternating triple multiple) pattern. The pattern may repeat n number of times where n=3-300.


Different patterns may also be mixed together to form a second order pattern. For example, a single alternating pattern may be combined with a triple alternating pattern to form a second order alternating pattern A‘B’. One example would be [ABABAB][AAABBBAAABBB][ABABAB][AAABBBAAABBB][ABABAB][AAABBBAAABBB], where [ABABAB] is A′ and [AAABBBAAABBB] is B′. In like fashion, these patterns may be repeated n number of times, where n=3-300.


Patterns may include three or more different modifications to form an ABCABC[ABC]n pattern. These three component patterns may also be multiples, such as AABBCCAABBCC[AABBCC]n and may be designed as combinations with other patterns such as ABCABCAABBCCABCABCAABBCC, and may be higher order patterns.


Regions or subregions of position, percent, and population modifications need not reflect an equal contribution from each modification type. They may form series such as “1-2-3-4”, “1-2-4-8”, where each integer represents the number of units of a particular modification type. Alternatively, they may be odd only, such as ‘1-3-3-1-3-1-5” or even only “2-4-2-4-6-4-8” or a mixuture of both odd and even number of units such as “1-3-4-2-5-7-3-3-4”.


Pattern chimeras may vary in their chemical modification by degree (such as those described above) or by kind (e.g., different modifications).


Chimeric polynucleotides, including the parts or regions thereof, of the present invention having at least one region with two or more different chemical modifications of two or more nucleoside members of the same nucleoside type (A, C, G, T, or U) are referred to as “positionally modified” chimeras. Positionally modified chimeras are also referred to herein as “selective placement” chimeras or “selective placement polynucleotides”. As the name implies, selective placement refers to the design of polynucleotides which, unlike polynucleotides in the art where the modification to any A, C, G, T or U is the same by virtue of the method of synthesis, can have different modifications to the individual As, Cs, Gs, Ts or Us in a polynucleotide or region thereof. For example, in a positionally modified chimeric polynucleotide, there may be two or more different chemical modifications to any of the nucleoside types of As, Cs, Gs, Ts, or Us. There may also be combinations of two or more to any two or more of the same nucleoside type. For example, a positionally modified or selective placement chimeric polynucleotide may comprise 3 different modifications to the population of adenines in the molecule and also have 3 different modifications to the population of cytosines in the construct-all of which may have a unique, non-random, placement.


Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification percent are referred to as “percent chimeras.” Percent chimeras may have regions or parts which comprise at least 1%, at least 2%, at least 5%, at least 8%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or at least 99% positional, pattern or population of modifications. Alternatively, the percent chimera may be completely modified as to modification position, pattern, or population. The percent of modification of a percent chimera may be split between naturally occurring and non-naturally occurring modifications.


Chimeric polynucleotides, including the parts or regions thereof, of the present invention having a chemical modification population are referred to as “population chimeras.” A population chimera may comprise a region or part where nucleosides (their base, sugar or backbone linkage, or combination thereof) have a select population of modifications. Such modifications may be selected from functional populations such as modifications which induce, alter or modulate a phenotypic outcome. For example, a functional population may be a population or selection of chemical modifications which increase the level of a cytokine. Other functional populations may individually or collectively function to decrease the level of one or more cytokines. Use of a selection of these like-function modifications in a chimeric polynucleotide would therefore constitute a “functional population chimera.” As used herein, a “functional population chimera” may be one whose unique functional feature is defined by the population of modifications as described above or the term may apply to the overall function of the chimeric polynucleotide itself. For example, as a whole the chimeric polynucleotide may function in a different or superior way as compared to an unmodified or non-chimeric polynucleotide.


It should be noted that polynucleotides which have a uniform chemical modification of all of any of the same nucleoside type or a population of modifications produced by mere downward titration of the same starting modification in all of any of the same nucleoside type, or a measured percent of a chemical modification of all any of the same nucleoside type but with random incorporation, such as where all uridines are replaced by a uridine analog, e.g., pseudouridine, are not considered chimeric. Likewise, polynucleotides having a uniform chemical modification of two, three, or four of the same nucleoside type throughout the entire polynucleotide (such as all uridines and all cytosines, etc. are modified in the same way) are not considered chimeric polynucleotides. One example of a polynucleotide which is not chimeric is the canonical pseudouridine/5-methyl cytosine modified polynucleotide of the prior art. These uniform polynucleotides are arrived at entirely via in vitro transcription (IVT) enzymatic synthesis; and due to the limitations of the synthesizing enzymes, they contain only one kind of modification at the occurrence of each of the same nucleoside type, i.e., adenosine (A), thymidine (T), guanosine (G), cytidine (C) or uradine (U), found in the polynucleotide. Such polynucleotides may be characterized as IVT polynucleotides.


The chimeric polynucleotides of the present invention may be structurally modified or chemically modified. When the chimeric polynucleotides of the present invention are chemically and/or structurally modified the polynucleotides may be referred to as “modified chimeric polynucleotides.”


In some embodiments of the invention, the chimeric polynucleotides may encode two or more peptides or polypeptides of interest. Such peptides or polypeptides of interest include the heavy and light chains of antibodies, an enzyme and its substrate, a label and its binding molecule, a second messenger and its enzyme or the components of multimeric proteins or complexes.


The regions or parts of the chimeric polynucleotides of the present invention may be separated by a linker or spacer moiety. Such linkers or spaces may be nucleic acid based or non-nucleosidic.


In one embodiment, the chimeric polynucleotides of the present invention may include a sequence encoding a self-cleaving peptide described herein, such as, but not limited to, a 2A peptide. The polynucleotide sequence of the 2A peptide in the chimeric polynucleotide may be modified or codon optimized by the methods described herein and/or are known in the art.


Notwithstanding the foregoing, the chimeric polynucleotides of the present invention may comprise a region or part which is not positionally modified or not chimeric as defined herein.


For example, a region or part of a chimeric polynucleotide may be uniformly modified at one ore more A, T, C, G, or U but according to the invention, the polynucleotides will not be uniformly modified throughout the entire region or part.


Regions or parts of chimeric polynucleotides may be from 15-1000 nucleosides in length and a polynucleotide may have from 2-100 different regions or patterns of regions as described herein.


In one embodiment, chimeric polynucleotides encode one or more polypeptides of interest. In another embodiment, the chimeric polynucleotides are substantially non-coding. In another embodiment, the chimeric polynucleotides have both coding and non-coding regions and parts.



FIG. 2 illustrates the design of certain chimeric polynucleotides of the present invention when based on the scaffold of the polynucleotide of FIG. 1. Shown in the figure are the regions or parts of the chimeric polynucleotides where patterned regions represent those regions which are positionally modified and open regions illustrate regions which may or may not be modified but which are, when modified, uniformly modified. Chimeric polynucleotides of the present invention may be completely positionally modified or partially positionally modified. They may also have subregions which may be of any pattern or design. Shown in FIG. 2 are a chimeric subregion and a hemimer subregion.


In one embodiment, the shortest length of a region of the chimeric polynucleotide of the present invention encoding a peptide can be the length that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide. In another embodiment, the length may be sufficient to encode a peptide of 2-30 amino acids, e.g. 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids. The length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g. no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids. Examples of dipeptides that the polynucleotide sequences can encode or include, but are not limited to, carnosine and anserine.


In one embodiment, the length of a region of the chimeric polynucleotide of the present invention encoding the peptide or polypeptide of interest is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 0.200, 1,300, 1,400, 1,500, 1,600, 1,700, 1.800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides). As used herein, such a region may be referred to as a “coding region” or “region encoding.”


In some embodiments, the chimeric polynucleotide includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1.000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 3,000, from 1,000 to 5,000, from 1,000 to 7,000, from 1,000 to 10,000, from 1,000 to 25,000, from 1,000 to 50,000, from 1,000 to 70,000, from 1,000 to 100,000, from 1,500 to 3,000, from 1,500 to 5,000, from 1,500 to 7,000, from 1,500 to 10,000, from 1,500 to 25,000, from 1,500 to 50,000, from 1,500 to 70,000, from 1,500 to 100,000, from 2,000 to 3,000, from 2,000 to 5,000, from 2,000 to 7,000, from 2,000 to 10,000, from 2,000 to 25,000, from 2,000 to 50,000, from 2,000 to 70,000, and from 2,000 to 100,000).


According to the present invention, regions or subregions of the chimeric polynucleotides may also range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900 and 950 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950 and 1,000 nucleotides).


According to the present invention, regions or subregions of chimeric polynucleotides may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 250, 300, 350, 400, 450, or 500 nucleotides). Where the region is a polyA tail, the length may be determined in units of or as a function of polyA Binding Protein binding. In this embodiment, the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein. PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides to about 160 nucleotides are functional. The chimeric polynucleotides of the present invention which function as an mRNA need not comprise a polyA tail.


According to the present invention, chimeric polynucleotides which function as an mRNA may have a capping region. The capping region may comprise a single cap or a series of nucleotides forming the cap. In this embodiment the capping region may be from 1 to 10, e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length. In some embodiments, the cap is absent.


The present invention contemplates chimeric polynucleotides which are circular or cyclic. As the name implies circular polynucleotides are circular in nature meaning that the termini are joined in some fashion, whether by ligation, covalent bond, common association with the same protein or other molecule or complex or by hybridization. Any of the circular polynucleotides as taught in for example U.S. Provisional Application No. 61/873,010 filed Sep. 3, 2013, (Attorney Docket number M51) the contents of which are incorporated herein by reference in their entirety, may be made chimeric according to the present invention.


Chimeric polynucleotides, formulations and compositions comprising chimeric polynucleotides, and methods of making, using and administering chimeric polynucleotides are also described in co-pending U.S. Provisional Application No. 61/873,034, filed Sep. 3, 2013, entitled Chimeric Polynucleotides, and U.S. Provisional Application No. 61/877,582, filed Sep. 13, 2013, entitled Chimeric Polynucleotides (Attorney Docket Number M57); each of which is incorporated by reference in its entirety.


Circular Polynucleotide Architecture

The present invention contemplates polynucleotides which are circular or cyclic. As the name implies circular polynucleotides are circular in nature meaning that the termini are joined in some fashion, whether by ligation, covalent bond, common association with the same protein or other molecule or complex or by hybridization. Any of the circular polynucleotides as taught in for example U.S. Provisional Application No. 61/873,010 filed Sep. 3, 2013. (Attorney Docket number M51.60) the contents of which are incorporated herein by reference in their entirety.


Circular polynucleotides of the present invention may be designed according to the circular RNA construct scaffolds shown in FIGS. 6-12. Such polynucleotides are circular polynucleotides or circular constructs.


The circular polynucleotides or circPs of the present invention which encode at least one peptide or polypeptide of interest are known as circular RNAs or circRNA. The antigens of the NAVs of the present invention may be encoded by one or more circular RNAs or circRNAs.


As used herein, “circular RNA” or “circRNA” means a circular polynucleotide that can encode at least one peptide or polypeptide of interest. The circPs of the present invention which comprise at least one sensor sequence and do not encode a peptide or polypeptide of interest are known as circular sponges or circSP. As used herein, “circular sponges,” “circular polynucleotide sponges” or “circSP” means a circular polynucleotide which comprises at least one sensor sequence and does not encode a polypeptide of interest. Such noncoding polynucleotides may be useful in the NAVs of the present invention as noncoding nucleic acids may function as an antigenic composition.


As used herein, “sensor sequence” means a receptor or pseudo-receptor for endogenous nucleic acid binding molecules. Non-limiting examples of sensor sequences include, microRNA binding sites, microRNA seed sequences, microRNA binding sites without the seed sequence, transcription factor binding sites and artificial binding sites engineered to act as pseudo-receptors and portions and fragments thereof.


The circPs of the present invention which comprise at least one sensor sequence and encode at least one peptide or polypeptide of interest are known as circular RNA sponges or circRNA-SP. As used herein, “circular RNA sponges” or “circRNA-SP” means a circular polynucleotide which comprises at least one sensor sequence and at least one region encoding at least one peptide or polypeptide of interest.



FIG. 6A shows a representative circular construct 200 of the circular polynucleotides of the present invention. As used herein, the term “circular construct” refers to a circular polynucleotide transcript which may act substantially similar to and have properties of a RNA molecule. In one embodiment the circular construct acts as an mRNA. If the circular construct encodes one or more peptides or polypeptides of interest (e.g., a circRNA or circRNA-SP) then the polynucleotide transcript retains sufficient structural and/or chemical features to allow the polypeptide of interest encoded therein to be translated. Circular constructs may be polynucleotides of the invention. When structurally or chemically modified, the construct may be referred to as a modified circP, modified circSP, modified circRNA or modified circRNA-SP.


Returning to FIG. 6A, the circular construct 200 here contains a first region of linked nucleotides 202 that is flanked by a first flanking region 204 and a second flanking region 206. As used herein, the “first region” may be referred to as a “coding region.” a “non-coding region” or “region encoding” or simply the “first region.” In one embodiment, this first region may comprise nucleotides such as, but is not limited to, encoding at least one peptide or polypeptide of interest and/or nucleotides encoding a sensor region. The peptide or polypeptide of interest may comprise at its 5′ terminus one or more signal peptide sequences encoded by a signal peptide sequence region 203. The first flanking region 204 may comprise a region of linked nucleosides or portion thereof which may act similarly to an untranslated region (UTR) in an mRNA and/or DNA sequence. The first flanking region may also comprise a region of polarity 208. The region of polarity 208 may include an IRES sequence or portion thereof. As a non-limiting example, when linearized this region may be split to have a first portion be on the 5′ terminus of the first region 202 and second portion be on the 3′ terminus of the first region 202. The second flanking region 206 may comprise a tailing sequence region 210 and may comprise a region of linked nucleotides or portion thereof 212 which may act similarly to a UTR in an mRNA and/or DNA.


Bridging the 5′ terminus of the first region 202 and the first flanking region 104 is a first operational region 205. In one embodiment, this operational region may comprise a start codon. The operational region may alternatively comprise any translation initiation sequence or signal including a start codon.


Bridging the 3′ terminus of the first region 202 and the second flanking region 106 is a second operational region 207. Traditionally this operational region comprises a stop codon. The operational region may alternatively comprise any translation initiation sequence or signal including a stop codon. According to the present invention, multiple serial stop codons may also be used. In one embodiment, the operation region of the present invention may comprise two stop codons. The first stop codon may be “TGA” or “UGA” and the second stop codon may be selected from the group consisting of “TAA,” “TGA.” “TAG,” “UAA,” “UGA” or “UAG.”


Turning to FIG. 6B, at least one non-nucleic acid moiety 201 may be used to prepare a circular construct 200 where the non-nucleic acid moiety 201 is used to bring the first flanking region 204 near the second flanking region 206. Non-limiting examples of non-nucleic acid moieties which may be used in the present invention are described herein. The circular construct 200 may comprise more than one non-nucleic acid moiety wherein the additional non-nucleic acid moeities may be heterologous or homologous to the first non-nucleic acid moiety.


Turning to FIG. 7A, the first region of linked nucleosides 202 may comprise a spacer region 214. This spacer region 214 may be used to separate the first region of linked nucleosides 202 so that the circular construct can include more than one open reading frame, non-coding region or an open reading frame and a non-coding region.


Turning to FIG. 7B, the second flanking region 206 may comprise one or more sensor regions 216 in the 3′UTR 212. These sensor sequences as discussed herein operate as pseudo-receptors (or binding sites) for ligands of the local microenvironment of the circular construct. For example, microRNA binding sites or miRNA seeds may be used as sensors such that they function as pseudoreceptors for any microRNAs present in the environment of the circular polynucleotide. As shown in FIG. 9, the one or more sensor regions 216 may be separated by a spacer region 214.


As shown in FIG. 8A, a circular construct 200, which includes one or more sensor regions 216, may also include a spacer region 214 in the first region of linked nucleosides 202. As discussed above for FIG. 7, this spacer region 214 may be used to separate the first region of linked nucleosides 202 so that the circular construct can include more than one open reading frame and/or more than one non-coding region.


Turning to FIG. 8B, a circular construct 200 may be a non-coding construct known as a circSP comprising at least one non-coding region such as, but not limited to, a sensor region 216. Each of the sensor regions 216 may include, but are not limited to, a miR sequence, a miR seed, a miR binding site and/or a miR sequence without the seed.


Turning to FIG. 9, at least one non-nucleic acid moiety 201 may be used to prepare a circular construct 200 which is a non-coding construct. The circular construct 200 which is a non-coding construct may comprise more than one non-nucleic acid moiety wherein the additional non-nucleic acid moeities may be heterologous or homologous to the first non-nucleic acid moiety.


Circular polynucleotides, formulations and compositions comprising circular polynucleotides, and methods of making, using and administering circular polynucleotides are also described in co-pending US Provisional Application No 61/873,010, filed Sep. 3, 2013, entitled Circular Polynucleotides, and U.S. Provisional Application No. 61/877,527, filed Sep. 13, 2013, entitled Circular Polynucleotides; each of which is incorporated by reference in its entirety.


Multimers of Polynucleotides

According to the present invention, multiple distinct chimeric polynucleotides and/or IVT polynucleotides may be linked together through the 3′-end using nucleotides which are modified at the 3′-terminus. Chemical conjugation may be used to control the stoichiometry of delivery into cells. For example, the glyoxylate cycle enzymes, isocitrate lyase and malate synthase, may be supplied into cells at a 1:1 ratio to alter cellular fatty acid metabolism. This ratio may be controlled by chemically linking chimeric polynucleotides and/or IVT polynucleotides using a 3′-azido terminated nucleotide on one polynucleotides species and a C5-ethynyl or alkynyl-containing nucleotide on the opposite polynucleotide species. The modified nucleotide is added post-transcriptionally using terminal transferase (New England Biolabs, Ipswich, MA) according to the manufacturer's protocol. After the addition of the 3′-modified nucleotide, the two polynucleotides species may be combined in an aqueous solution, in the presence or absence of copper, to form a new covalent linkage via a click chemistry mechanism as described in the literature.


In another example, more than two chimeric polynucleotides and/or IVT polynucleotides may be linked together using a functionalized linker molecule. For example, a functionalized saccharide molecule may be chemically modified to contain multiple chemical reactive groups (SH—, NH2—, N3, etc. . . . ) to react with the cognate moiety on a 3′-functionalized mRNA molecule (i.e., a 3′-maleimide ester, 3′-NHS-ester, alkynyl). The number of reactive groups on the modified saccharide can be controlled in a stoichiometric fashion to directly control the stoichiometric ratio of conjugated chimeric polynucleotides and/or IVT polynucleotides.


In one embodiment, the chimeric polynucleotides and/or IVT polynucleotides may be linked together in a pattern. The pattern may be a simple alternating pattern such as CD[CD]A where each “C” and each “D” represent a chimeric polynucleotide, IVT polynucleotide, different chimeric polynucleotides or different IVT polynucleotides. The pattern may repeat x number of times, where x=1-300. It is to be understood that the antigens of the NAVs of the present invention may be encoded by such linked polynucleotides, as described herein. Patterns may also be alternating multiples such as CCDD[CCDD]x (an alternating double multiple) or CCCDDD[CCCDDD]x (an alternating triple multiple) pattern. The alternating double multiple or alternating triple multiple may repeat x number of times, where x=1-300.


Conjugates and Combinations of Polynucleotides

In order to further enhance protein production, polynucleotides of the present invention can be designed to be conjugated to other polynucleotides, dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g. EDTA), alkylating agents, phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG]2, polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g. biotin), transport/absorption facilitators (e.g., aspirin, vitamin E, folic acid), synthetic ribonucleases, proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell, hormones and hormone receptors, non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, or a drug.


In a preferred embodiment, the polynucleotides of the present invention which encode an antigen are conjugated to one or more dendritic cell markers.


Conjugation may result in increased stability and/or half life and may be particularly useful in targeting the polynucleotides to specific sites in the cell, tissue or organism.


According to the present invention, the polynucleotides may be administered with, conjugated to or further encode one or more of RNAi agents, siRNAs, shRNAs, miRNAs, miRNA binding sites, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers or vectors, and the like.


Bifunctional Polynucleotides

In one embodiment of the invention NAVs may comprise bifunctional polynucleotides (e.g., bifunctional IVT polynucleotides, bifunctional chimeric polynucleotides or bifunctional circular polynucleotides). As the name implies, bifunctional polynucleotides are those having or capable of at least two functions. These molecules may also by convention be referred to as multi-functional. It is to be understood that the NAV polynucleotides of the present invention may be conjugated to other molecules or agents, as described supra.


The multiple functionalities of bifunctional polynucleotides may be encoded by the NAV (the function may not manifest until the encoded product is translated) or may be a property of the polynucleotide itself. It may be structural or chemical. Bifunctional modified polynucleotides may comprise a function that is covalently or electrostatically associated with the polynucleotides. Further, the two functions may be provided in the context of a complex of a chimeric polynucleotide and another molecule.


Noncoding Polynucleotides

As described herein, provided are polynucleotides having sequences that are partially or substantially not translatable, e.g., having a noncoding region. As one non-limiting example, the noncoding region may be the first region of the IVT polynucleotide or the circular polynucleotide. Alternatively, the noncoding region may be a region other than the first region. As another non-limiting example, the noncoding region may be the A. B and/or C region of the chimeric polynucleotide.


Such molecules are generally not translated, but can exert an effect on the immune response or protein production by one or more of binding to and sequestering one or more translational machinery components such as a ribosomal protein or a transfer RNA (tRNA), thereby effectively reducing protein expression in the cell or modulating one or more pathways or cascades in a cell which in turn alters protein levels. The polynucleotide may contain or encode one or more long noncoding RNA (OncRNA, or lincRNA) or portion thereof, a small nucleolar RNA (sno-RNA), micro RNA (miRNA), small interfering RNA (siRNA) or Piwi-interacting RNA (piRNA). Examples of such lncRNA molecules and RNAi constructs designed to target such lncRNA any of which may be encoded in the polynucleotides are taught in International Publication, WO2012/018881 A2, the contents of which are incorporated herein by reference in their entirety.


According to the present invention, the polynucleotide may be designed to encode one or more polypeptides of interest or fragments thereof. Such polypeptide of interest may include, but is not limited to, whole polypeptides, a plurality of polypeptides or fragments of polypeptides, which independently may be encoded by one or more regions or parts or the whole of a polynucleotide. As used herein, the term “polypeptides of interest” refer to any polypeptide which is selected to be encoded within, or whose function is affected by, the polynucleotides of the present invention. Any of the peptides or polypeptides of the invention may be antigenic.


As used herein, “polypeptide” means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds. The term, as used herein, refers to proteins, polypeptides, and peptides of any size, structure, or function. In one embodiment, the polypeptides of interest are antigens encoded by the polynucleotides as described herein.


In some instances the polypeptide encoded is smaller than about 50 amino acids and the polypeptide is then termed a peptide. If the polypeptide is a peptide, it will be at least about 2, 3, 4, or at least 5 amino acid residues long. Thus, polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing. A polypeptide may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer. They may also comprise single chain or multichain polypeptides such as antibodies or insulin and may be associated or linked. Most commonly disulfide linkages are found in multichain polypeptides. The term polypeptide may also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid.


The term “polypeptide variant” refers to molecules which differ in their amino acid sequence from a native or reference sequence. The amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence. Ordinarily, variants will possess at least about 50% identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, more preferably at least about 90% identical (homologous) to a native or reference sequence.


In some embodiments “variant mimics” are provided. As used herein, the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence. For example, glutamate may serve as a mimic for phosphoro-threonine and/or phosphoro-serine. Alternatively, variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.


“Homology” as it applies to amino acid sequences is defined as the percentage of residues in the candidate amino acid sequence that are identical with the residues in the amino acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art. It is understood that homology depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation.


By “homologs” as it applies to polypeptide sequences means the corresponding sequence of other species having substantial identity to a second sequence of a second species.


“Analogs” is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting polypeptide.


The present invention contemplates several types of compositions which are polypeptide based including variants and derivatives. These include substitutional, insertional, deletion and covalent variants and derivatives. The term “derivative” is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule.


As such, polynucleotides encoding peptides or polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications with respect to reference sequences, in particular the polypeptide sequences disclosed herein, are included within the scope of this invention. For example, sequence tags or amino acids, such as one or more lysines, can be added to the peptide sequences of the invention (e.g., at the N-terminal or C-terminal ends). Sequence tags can be used for peptide purification or localization. Lysines can be used to increase peptide solubility or to allow for biotinylation. Alternatively, amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences. Certain amino acids (e.g., C-terminal or N-terminal residues) may alternatively be deleted depending on the use of the sequence, as for example, expression of the sequence as part of a larger sequence which is soluble, or linked to a solid support.


“Substitutional variants” when referring to polypeptides are those that have at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule.


As used herein the term “conservative amino acid substitution” refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity. Examples of conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue. Likewise, examples of conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine. Additionally, the substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions. Examples of non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue.


“Insertional variants” when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. “Immediately adjacent” to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.


“Deletional variants” when referring to polypeptides are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.


“Covalent derivatives” when referring to polypeptides include modifications of a native or starting protein with an organic proteinaceous or non-proteinaceous derivatizing agent, and/or post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of the protein with an organic derivatizing agent that is capable of reacting with selected side-chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of anti-protein antibodies for immunoaffinity purification of the recombinant glycoprotein. Such modifications are within the ordinary skill in the art and are performed without undue experimentation.


Certain post-translational modifications are the result of the action of recombinant host cells on the expressed polypeptide. Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues may be present in the polypeptides produced in accordance with the present invention.


Other post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)).


“Features” when referring to polypeptides are defined as distinct amino acid sequence-based components of a molecule. Features of the polypeptides encoded by the polynucleotides of the present invention include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof.


As used herein when referring to polypeptides the term “surface manifestation” refers to a polypeptide based component of a protein appearing on an outermost surface.


As used herein when referring to polypeptides the term “local conformational shape” means a polypeptide based structural manifestation of a protein which is located within a definable space of the protein.


As used herein when referring to polypeptides the term “fold” refers to the resultant conformation of an amino acid sequence upon energy minimization. A fold may occur at the secondary or tertiary level of the folding process. Examples of secondary level folds include beta sheets and alpha helices. Examples of tertiary folds include domains and regions formed due to aggregation or separation of energetic forces. Regions formed in this way include hydrophobic and hydrophilic pockets, and the like.


As used herein the term “turn” as it relates to protein conformation means a bend which alters the direction of the backbone of a peptide or polypeptide and may involve one, two, three or more amino acid residues.


As used herein when referring to polypeptides the term “loop” refers to a structural feature of a polypeptide which may serve to reverse the direction of the backbone of a peptide or polypeptide. Where the loop is found in a polypeptide and only alters the direction of the backbone, it may comprise four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (J. Mol Biol 266 (4): 814-830; 1997). Loops may be open or closed. Closed loops or “cyclic” loops may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids between the bridging moieties. Such bridging moieties may comprise a cysteine-cysteine bridge (Cys-Cys) typical in polypeptides having disulfide bridges or alternatively bridging moieties may be non-protein based such as the dibromozylyl agents used herein.


As used herein when referring to polypeptides the term “half-loop” refers to a portion of an identified loop having at least half the number of amino acid resides as the loop from which it is derived. It is understood that loops may not always contain an even number of amino acid residues. Therefore, in those cases where a loop contains or is identified to comprise an odd number of amino acids, a half-loop of the odd-numbered loop will comprise the whole number portion or next whole number portion of the loop (number of amino acids of the loop/2+/−0.5 amino acids). For example, a loop identified as a 7 amino acid loop could produce half-loops of 3 amino acids or 4 amino acids (7/2=3.5+/−0.5 being 3 or 4).


As used herein when referring to polypeptides the term “domain” refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions).


As used herein when referring to polypeptides the term “half-domain” means a portion of an identified domain having at least half the number of amino acid resides as the domain from which it is derived. It is understood that domains may not always contain an even number of amino acid residues. Therefore, in those cases where a domain contains or is identified to comprise an odd number of amino acids, a half-domain of the odd-numbered domain will comprise the whole number portion or next whole number portion of the domain (number of amino acids of the domain/2+/−0.5 amino acids). For example, a domain identified as a 7 amino acid domain could produce half-domains of 3 amino acids or 4 amino acids (7/2=3.5+/−0.5 being 3 or 4). It is also understood that sub-domains may be identified within domains or half-domains, these subdomains possessing less than all of the structural or functional properties identified in the domains or half domains from which they were derived. It is also understood that the amino acids that comprise any of the domain types herein need not be contiguous along the backbone of the polypeptide (i.e., nonadjacent amino acids may fold structurally to produce a domain, half-domain or subdomain).


As used herein when referring to polypeptides the terms “site” as it pertains to amino acid based embodiments is used synonymously with “amino acid residue” and “amino acid side chain.” A site represents a position within a peptide or polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide based molecules of the present invention.


As used herein the terms “termini” or “terminus” when referring to polypeptides refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions. The polypeptide based molecules of the present invention may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2)) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH)). Proteins of the invention are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These sorts of proteins will have multiple N- and C-termini. Alternatively, the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide based moiety such as an organic conjugate.


Once any of the features have been identified or defined as a desired component of a polypeptide to be encoded by a polynucleotide of the invention, any of several manipulations and/or modifications of these features may be performed by moving, swapping, inverting, deleting, randomizing or duplicating. Furthermore, it is understood that manipulation of features may result in the same outcome as a modification to the molecules of the invention. For example, a manipulation which involved deleting a domain would result in the alteration of the length of a molecule just as modification of a nucleic acid to encode less than a full length molecule would.


Modifications and manipulations can be accomplished by methods known in the art such as, but not limited to, site directed mutagenesis or a priori incorporation during chemical synthesis. The resulting modified molecules may then be tested for activity using in vitro or in vivo assays such as those described herein or any other suitable screening assay known in the art.


According to the present invention, the polypeptides may comprise a consensus sequence which is discovered through rounds of experimentation. As used herein a “consensus” sequence is a single sequence which represents a collective population of sequences allowing for variability at one or more sites.


As recognized by those skilled in the art, protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of polypeptides of interest of this invention. For example, provided herein is any protein fragment (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) of a reference protein 10, 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length. In another example, any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids which are about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% identical to any of the sequences described herein can be utilized in accordance with the invention. In certain embodiments, a polypeptide to be utilized in accordance with the invention includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein.


In one embodiment, at least one polypeptide of interest may be an antigen or fragment thereof, or any component of a ribonucleic acid vaccine.


Reference molecules (polypeptides or polynucleotides) may share a certain identity with the designed molecules (polypeptides or polynucleotides). The term “identity” as known in the art, refers to a relationship between the sequences of two or more peptides, polypeptides or polynucleotides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between them as determined by the number of matches between strings of two or more amino acid residues or nucleosides. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). Identity of related peptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M. Stockton Press, New York, 1991; and Carillo et al., SIAM J. Applied Math. 48, 1073 (1988).


In some embodiments, the encoded polypeptide variant may have the same or a similar activity as the reference polypeptide. Alternatively, the variant may have an altered activity (e.g., increased or decreased) relative to a reference polypeptide. Generally, variants of a particular polynucleotide or polypeptide of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 100% sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art. Such tools for alignment include those of the BLAST suite (Stephen F. Altschul, Thomas L. Madden, Alejandro A. Schaffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25:3389-3402.) Other tools are described herein, specifically in the definition of “Identity.”


Default parameters in the BLAST algorithm include, for example, an expect threshold of 10, Word size of 28, Match/Mismatch Scores 1, −2, Gap costs Linear. Any filter can be applied as well as a selection for species specific repeats, e.g., Homo sapiens.


Cell-Penetrating Polypeptides

The polynucleotides disclosed herein (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention), may also encode one or more cell-penetrating polypeptides. As used herein, “cell-penetrating polypeptide” or CPP refers to a polypeptide which may facilitate the cellular uptake of molecules. A cell-penetrating polypeptide of the present invention may contain one or more detectable labels. The polypeptides may be partially labeled or completely labeled throughout. The polynucleotides may encode the detectable label completely, partially or not at all. The cell-penetrating peptide may also include a signal sequence. As used herein, a “signal sequence” refers to a sequence of amino acid residues bound at the amino terminus of a nascent protein during protein translation. The signal sequence may be used to signal the secretion of the cell-penetrating polypeptide.


In one embodiment, the polynucleotides may also encode a fusion protein. The fusion protein may be created by operably linking a charged protein to a therapeutic protein. As used herein, “operably linked” refers to the therapeutic protein and the charged protein being connected in such a way to permit the expression of the complex when introduced into the cell. As used herein, “charged protein” refers to a protein that carries a positive, negative or overall neutral electrical charge. Preferably, the therapeutic protein may be covalently linked to the charged protein in the formation of the fusion protein. The ratio of surface charge to total or surface amino acids may be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9.


The cell-penetrating polypeptide encoded by the polynucleotides may form a complex after being translated. The complex may comprise a charged protein linked, e.g. covalently linked, to the cell-penetrating polypeptide. “Therapeutic protein” refers to a protein that, when administered to a cell has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.


In one embodiment, the cell-penetrating polypeptide may comprise a first domain and a second domain. The first domain may comprise a supercharged polypeptide. The second domain may comprise a protein-binding partner. As used herein, “protein-binding partner” includes, but is not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides. The cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner. The cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotides may be introduced. The cell-penetrating polypeptide may also be capable of penetrating the first cell.


In a further embodiment, the cell-penetrating polypeptide is capable of penetrating a second cell. The second cell may be from the same area as the first cell, or it may be from a different area. The area may include, but is not limited to, tissues and organs. The second cell may also be proximal or distal to the first cell.


In one embodiment, the polynucleotides may encode a cell-penetrating polypeptide which may comprise a protein-binding partner. The protein binding partner may include, but is not limited to, an antibody, a supercharged antibody or a functional fragment. The polynucleotides may be introduced into the cell where a cell-penetrating polypeptide comprising the protein-binding partner is introduced.


Anti-Microbial and Anti-Viral Polypeptides

The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be designed to encode, or be co-administered with, a polynucleotide encoding one or more antimicrobial peptides (AMP) or antiviral peptides (AVP). AMPs and AVPs have been isolated and described from a wide range of animals such as, but not limited to, microorganisms, invertebrates, plants, amphibians, birds, fish, and mammals (Wang et al., Nucleic Acids Res. 2009; 37 (Database issue):D933-7). For example, anti-microbial polypeptides are described in Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php; Wang et al., Nucleic Acids Res. 2009; 37 (Database issue):D933-7), CAMP: Collection of Anti-Microbial Peptides (http://www.bicnirrh.res.in/antimicrobial/); Thomas et al., Nucleic Acids Res. 2010; 38 (Database issue):D774-80), U.S. Pat. Nos. 5,221,732, 5,447,914, 5,519,115, 5,607,914, 5,714,577, 5,734,015, 5,798,336, 5,821,224, 5,849,490, 5,856,127, 5,905,187, 5,994,308, 5,998,374, 6,107,460, 6,191,254, 6,211,148, 6,300,489, 6,329,504, 6,399,370, 6,476,189, 6,478,825, 6,492,328, 6,514,701, 6,573,361, 6,573,361, 6,576,755, 6,605,698, 6,624,140, 6,638,531, 6,642,203, 6,653,280, 6,696,238, 6,727,066, 6,730,659, 6,743,598, 6,743,769, 6,747,007, 6,790,833, 6,794,490, 6,818,407, 6,835,536, 6,835,713, 6,838,435, 6,872,705, 6,875,907, 6,884,776, 6,887,847, 6,906,035, 6,911,524, 6,936,432, 7,001,924, 7,071,293, 7,078,380, 7,091,185, 7,094,759, 7,166,769, 7,244,710, 7,314,858, and 7,582,301, the contents of which are incorporated by reference in their entirety.


The anti-microbial polypeptides described herein may block cell fusion and/or viral entry by one or more enveloped viruses (e.g., HIV, HCV). For example, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the transmembrane subunit of a viral envelope protein, e.g., HIV-1 gp120 or gp41. The amino acid and nucleotide sequences of HIV-1 gp120 or gp41 are described in, e.g., Kuiken et al., (2008). “HIV Sequence Compendium,” Los Alamos National Laboratory.


In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding viral protein sequence.


In other embodiments, the anti-microbial polypeptide may comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a capsid binding protein. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding sequence of the capsid binding protein.


The anti-microbial polypeptides described herein may block protease dimerization and inhibit cleavage of viral proproteins (e.g., HIV Gag-pol processing) into functional proteins thereby preventing release of one or more enveloped viruses (e.g., HIV, HCV). In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence.


In other embodiments, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a protease binding protein. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding sequence of the protease binding protein.


The anti-microbial polypeptides described herein can include an in vitro-evolved polypeptide directed against a viral pathogen.


Anti-Microbial Polypeptides

Anti-microbial polypeptides (AMPs) are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of microorganisms including, but not limited to, bacteria, viruses, fungi, protozoa, parasites, prions, and tumor/cancer cells. (See, e.g., Zaiou, J Mol Med, 2007; 85:317; herein incorporated by reference in its entirety). It has been shown that AMPs have broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects.


In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or 1 kDa. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may consist of from about 15 to about 45 amino acids. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially cationic.


In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be substantially amphipathic. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be substantially cationic and amphipathic. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide may be cytostatic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In certain embodiments, the anti-microbial polypeptide may be cytostatic and cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell). In some embodiments, the anti-microbial polypeptide may be cytostatic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell). In certain embodiments, the anti-microbial polypeptide may be cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human tumor or cancer cell). In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be a secreted polypeptide.


In some embodiments, the anti-microbial polypeptide comprises or consists of a defensin. Exemplary defensins include, but are not limited to, α-defensins (e.g., neutrophil defensin 1, defensin alpha 1, neutrophil defensin 3, neutrophil defensin 4, defensin 5, defensin 6), β-defensins (e.g., beta-defensin 1, beta-defensin 2, beta-defensin 103, beta-defensin 107, beta-defensin 110, beta-defensin 136), and O-defensins. In other embodiments, the anti-microbial polypeptide comprises or consists of a cathelicidin (e.g., hCAP18).


Anti-Viral Polypeptides

Anti-viral polypeptides (AVPs) are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of viruses. See, e.g., Zaiou, J Mol Med, 2007; 85:317. It has been shown that AVPs have a broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects. In some embodiments, the anti-viral polypeptide is under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or 1 kDa. In some embodiments, the anti-viral polypeptide comprises or consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the anti-viral polypeptide comprises or consists of from about 15 to about 45 amino acids. In some embodiments, the anti-viral polypeptide is substantially cationic. In some embodiments, the anti-viral polypeptide is substantially amphipathic. In certain embodiments, the anti-viral polypeptide is substantially cationic and amphipathic. In some embodiments, the anti-viral polypeptide is cytostatic to a virus. In some embodiments, the anti-viral polypeptide is cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic and cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a bacterium, fungus, protozoan, parasite, prion or a combination thereof. In certain embodiments, the anti-viral polypeptide is cytostatic and cytotoxic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In certain embodiments, the anti-viral polypeptide is cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is a secreted polypeptide.


Cytotoxic Nucleosides

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may incorporate one or more cytotoxic nucleosides. For example, cytotoxic nucleosides may be incorporated into polynucleotides such as bifunctional modified RNAs or mRNAs. Cytotoxic nucleoside anti-cancer agents include, but are not limited to, adenosine arabinoside, cytarabine, cytosine arabinoside, 5-fluorouracil, fludarabine, floxuridine, FTORAFUR® (a combination of tegafur and uracil), tegafur ((RS)-5-fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione), and 6-mercaptopurine.


A number of cytotoxic nucleoside analogues are in clinical use, or have been the subject of clinical trials, as anticancer agents. Examples of such analogues include, but are not limited to, cytarabine, gemcitabine, troxacitabine, decitabine, tezacitabine, 2′-deoxy-2′-methylidenecytidine (DMDC), cladribine, clofarabine, 5-azacytidine, 4′-thio-aracytidine, cyclopentenylcytosine and 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-cytosine. Another example of such a compound is fludarabine phosphate. These compounds may be administered systemically and may have side effects which are typical of cytotoxic agents such as, but not limited to, little or no specificity for tumor cells over proliferating normal cells.


A number of prodrugs of cytotoxic nucleoside analogues are also reported in the art. Examples include, but are not limited to, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, N4-octadecyl-1-beta-D-arabinofuranosylcytosine, N4-palmitoyl-1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine, and P-4055 (cytarabine 5′-elaidic acid ester). In general, these podrugs may be converted into the active drugs mainly in the liver and systemic circulation and display little or no selective release of active drug in the tumor tissue. For example, capecitabine, a prodrug of 5′-deoxy-5-fluorocytidine (and eventually of 5-fluorouracil), is metabolized both in the liver and in the tumor tissue. A series of capecitabine analogues containing “an easily hydrolysable radical under physiological conditions” has been claimed by Fujiu et al. (U.S. Pat. No. 4,966,891) and is herein incorporated by reference. The series described by Fujiu includes N4 alkyl and aralkyl carbamates of 5′-deoxy-5-fluorocytidine and the implication that these compounds will be activated by hydrolysis under normal physiological conditions to provide 5′-deoxy-5-fluorocytidine.


A series of cytarabine N4-carbamates has been by reported by Fadl et al (Pharmazie. 1995, 50, 382-7, herein incorporated by reference in its entirety) in which compounds were designed to convert into cytarabine in the liver and plasma. WO 2004/041203, herein incorporated by reference in its entirety, discloses prodrugs of gemcitabine, where some of the prodrugs are N4-carbamates. These compounds were designed to overcome the gastrointestinal toxicity of gemcitabine and were intended to provide gemcitabine by hydrolytic release in the liver and plasma after absorption of the intact prodrug from the gastrointestinal tract. Nomura et al (Bioorg Med. Chem. 2003, 11, 2453-61, herein incorporated by reference in its entirety) have described acetal derivatives of 1-(3-C-ethynyl-β-D-ribo-pentofaranosyl) cytosine which, on bioreduction, produced an intermediate that required further hydrolysis under acidic conditions to produce a cytotoxic nucleoside compound.


Cytotoxic nucleotides which may be chemotherapeutic also include, but are not limited to, pyrazolo [3,4-D]-pyrimidines, allopurinol, azathioprine, capecitabine, cytosine arabinoside, fluorouracil, mercaptopurine, 6-thioguanine, acyclovir, ara-adenosine, ribavirin, 7-deaza-adenosine, 7-deaza-guanosine, 6-aza-uracil, 6-aza-cytidine, thymidine ribonucleotide, 5-bromodeoxyuridine, 2-chloro-purine, and inosine, or combinations thereof.


Polynucleotides Having Untranslated Regions (UTRs)

The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise one or more regions or parts which act or function as an untranslated region. Where polynucleotides are designed to encode at least one polypeptide of interest, the polynucleotides may comprise one or more of these untranslated regions.


By definition, wild type untranslated regions (UTRs) of a gene are transcribed but not translated. In mRNA, the 5′UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3′UTR starts immediately following the stop codon and continues until the transcriptional termination signal. There is growing body of evidence about the regulatory roles, played by the UTRs in terms of stability of the nucleic acid molecule and translation. The regulatory features of a UTR can be incorporated into the polynucleotides of the present invention to, among other things, enhance the stability of the molecule. The specific features can also be incorporated to ensure controlled down-regulation of the transcript in case they are misdirected to undesired organs sites.


Tables 19 and 20 provide a listing of exemplary UTRs which may be utilized in the polynucleotides of the present invention. Shown in Table 19 is a listing of a 5′-untranslated region of the invention. Variants of 5′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A. T, C or CG.









TABLE 19







5′-Untranslated Regions










5′ UTR
Name/

SEQ ID


Identifier
Description
Sequence
NO.





5UTR-001
Upstream UTR
GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG
897




AAATATAAGAGCCACC






5UTR-002
Upstream UTR
GGGAGATCAGAGAGAAAAGAAGAGTAAGAAG
898




AAATATAAGAGCCACC






5UTR-003
Upstream UTR
GGAATAAAAGTCTCAACACAACATATACAAAA
899




CAAACGAATCTCAAGCAATCAAGCATTCTACT





TCTATTGCAGCAATTTAAATCATTTCTTTTAAA





GCAAAAGCAATTTTCTGAAAATTTTCACCATTT





ACGAACGATAGCAAC






5UTR-004
Upstream UTR
GGGAGACAAGCUUGGCAUUCCGGUACUGUUG
900




GUAAAGCCACC






5UTR-005
Upstream UTR
GGGAGATCAGAGAGAAAAGAAGAGTAAGAAG
901




AAATATAAGAGCCACC






5UTR-006
Upstream UTR
GGAATAAAAGTCTCAACACAACATATACAAAA
902




CAAACGAATCTCAAGCAATCAAGCATTCTACT





TCTATTGCAGCAATTTAAATCATTTCTTTTAAA





GCAAAAGCAATTTTCTGAAAATTTTCACCATTT





ACGAACGATAGCAAC






5UTR-007
Upstream UTR
GGGAGACAAGCUUGGCAUUCCGGUACUGUUG
903




GUAAAGCCACC






5UTR-008
Upstream UTR
GGGAATTAACAGAGAAAAGAAGAGTAAGAAG
904




AAATATAAGAGCCACC






5UTR-009
Upstream UTR
GGGAAATTAGACAGAAAAGAAGAGTAAGAAG
905




AAATATAAGAGCCACC






5UTR-010
Upstream UTR
GGGAAATAAGAGAGTAAAGAACAGTAAGAAG
906




AAATATAAGAGCCACC






5UTR-011
Upstream UTR
GGGAAAAAAGAGAGAAAAGAAGACTAAGAAG
907




AAATATAAGAGCCACC






5UTR-012
Upstream UTR
GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG
908




ATATATAAGAGCCACC






5UTR-013
Upstream UTR
GGGAAATAAGAGACAAAACAAGAGTAAGAAG
909




AAATATAAGAGCCACC






5UTR-014
Upstream UTR
GGGAAATTAGAGAGTAAAGAACAGTAAGTAG
910




AATTAAAAGAGCCACC






5UTR-015
Upstream UTR
GGGAAATAAGAGAGAATAGAAGAGTAAGAAG
911




AAATATAAGAGCCACC






5UTR-016
Upstream UTR
GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG
912




AAAATTAAGAGCCACC






5UTR-017
Upstream UTR
GGGAAATAAGAGAGAAAAGAAGAGTAAGAAG
913




AAATTTAAGAGCCACC









Shown in Table 20 is a listing of 3′-untranslated regions of the invention. Variants of 3′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.









TABLE 20







3′-Untranslated Regions










3′ UTR
Name/

SEQ ID


Identifier
Description
Sequence
NO.





3UTR-001
Creatine
GCGCCTGCCCACCTGCCACCGACTGCTGGAACCCAGC
914



Kinase
CAGTGGGAGGGCCTGGCCCACCAGAGTCCTGCTCCCT





CACTCCTCGCCCCGCCCCCTGTCCCAGAGTCCCACCTG





GGGGCTCTCTCCACCCTTCTCAGAGTTCCAGTTTCAAC





CAGAGTTCCAACCAATGGGCTCCATCCTCTGGATTCTG





GCCAATGAAATATCTCCCTGGCAGGGTCCTCTTCTTTT





CCCAGAGCTCCACCCCAACCAGGAGCTCTAGTTAATG





GAGAGCTCCCAGCACACTCGGAGCTTGTGCTTTGTCTC





CACGCAAAGCGATAAATAAAAGCATTGGTGGCCTTTG





GTCTTTGAATAAAGCCTGAGTAGGAAGTCTAGA






3UTR-002
Myoglobin
GCCCCTGCCGCTCCCACCCCCACCCATCTGGGCCCCGG
915




GTTCAAGAGAGAGCGGGGTCTGATCTCGTGTAGCCAT





ATAGAGTTTGCTTCTGAGTGTCTGCTTTGTTTAGTAGA





GGTGGGCAGGAGGAGCTGAGGGGCTGGGGCTGGGGT





GTTGAAGTTGGCTTTGCATGCCCAGCGATGCGCCTCCC





TGTGGGATGTCATCACCCTGGGAACCGGGAGTGGCCC





TTGGCTCACTGTGTTCTGCATGGTTTGGATCTGAATTA





ATTGTCCTTTCTTCTAAATCCCAACCGAACTTCTTCCA





ACCTCCAAACTGGCTGTAACCCCAAATCCAAGCCATT





AACTACACCTGACAGTAGCAATTGTCTGATTAATCACT





GGCCCCTTGAAGACAGCAGAATGTCCCTTTGCAATGA





GGAGGAGATCTGGGCTGGGCGGGCCAGCTGGGGAAG





CATTTGACTATCTGGAACTTGTGTGTGCCTCCTCAGGT





ATGGCAGTGACTCACCTGGTTTTAATAAAACAACCTG





CAACATCTCATGGTCTTTGAATAAAGCCTGAGTAGGA





AGTCTAGA






3UTR-003
α-actin
ACACACTCCACCTCCAGCACGCGACTTCTCAGGACGA
916




CGAATCTTCTCAATGGGGGGGCGGCTGAGCTCCAGCC





ACCCCGCAGTCACTTTCTTTGTAACAACTTCCGTTGCT





GCCATCGTAAACTGACACAGTGTTTATAACGTGTACAT





ACATTAACTTATTACCTCATTTTGTTATTTTTCGAAACA





AAGCCCTGTGGAAGAAAATGGAAAACTTGAAGAAGC





ATTAAAGTCATTCTGTTAAGCTGCGTAAATGGTCTTTG





AATAAAGCCTGAGTAGGAAGTCTAGA






3UTR-004
Albumin
CATCACATTTAAAAGCATCTCAGCCTACCATGAGAAT
917




AAGAGAAAGAAAATGAAGATCAAAAGCTTATTCATCT





GTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCT





AAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCT





CTGTGCTTCAATTAATAAAAAATGGAAAGAATCTAAT





AGAGTGGTACAGCACTGTTATTTTTCAAAGATGTGTTG





CTATCCTGAAAATTCTGTAGGTTCTGTGGAAGTTCCAG





TGTTCTCTCTTATTCCACTTCGGTAGAGGATTTCTAGTT





TCTTGTGGGCTAATTAAATAAATCATTAATACTCTTCT






3UTR-005
α-globin
AATGGTCTTTGAATAAAGCCTGAGTAGGAAGTCTAGA
918




GCTGCCTTCTGCGGGGCTTGCCTTCTGGCCATGCCCTT





CTTCTCTCCCTTGCACCTGTACCTCTTGGTCTTTGAATA





AAGCCTGAGTAGGAAGGCGGCCGCTCGAGCATGCATC





TAGA






3UTR-006
G-CSF
GCCAAGCCCTCCCCATCCCATGTATTTATCTCTATTTA
919




ATATTTATGTCTATTTAAGCCTCATATTTAAAGACAGG





GAAGAGCAGAACGGAGCCCCAGGCCTCTGTGTCCTTC





CCTGCATTTCTGAGTTTCATTCTCCTGCCTGTAGCAGT





GAGAAAAAGCTCCTGTCCTCCCATCCCCTGGACTGGG





AGGTAGATAGGTAAATACCAAGTATTTATTACTATGA





CTGCTCCCCAGCCCTGGCTCTGCAATGGGCACTGGGAT





GAGCCGCTGTGAGCCCCTGGTCCTGAGGGTCCCCACC





TGGGACCCTTGAGAGTATCAGGTCTCCCACGTGGGAG





ACAAGAAATCCCTGTTTAATATTTAAACAGCAGTGTTC





CCCATCTGGGTCCTTGCACCCCTCACTCTGGCCTCAGC





CGACTGCACAGCGGCCCCTGCATCCCCTTGGCTGTGA





GGCCCCTGGACAAGCAGAGGTGGCCAGAGCTGGGAG





GCATGGCCCTGGGGTCCCACGAATTTGCTGGGGAATC





TCGTTTTTCTTCTTAAGACTTTTGGGACATGGTTTGACT





CCCGAACATCACCGACGCGTCTCCTGTTTTTCTGGGTG





GCCTCGGGACACCTGCCCTGCCCCCACGAGGGTCAGG





ACTGTGACTCTTTTTAGGGCCAGGCAGGTGCCTGGAC





ATTTGCCTTGCTGGACGGGGACTGGGGATGTGGGAGG





GAGCAGACAGGAGGAATCATGTCAGGCCTGTGTGTGA





AAGGAAGCTCCACTGTCACCCTCCACCTCTTCACCCCC





CACTCACCAGTGTCCCCTCCACTGTCACATTGTAACTG





AACTTCAGGATAATAAAGTGTTTGCCTCCATGGTCTTT





GAATAAAGCCTGAGTAGGAAGGCGGCCGCTCGAGCAT





GCATCTAGA






3UTR-007
Col1a2;
ACTCAATCTAAATTAAAAAAGAAAGAAATTTGAAAAA
920



collagen,
ACTTTCTCTTTGCCATTTCTTCTTCTTCTTTTTTAACTGA




type I, alpha
AAGCTGAATCCTTCCATTTCTTCTGCACATCTACTTGC




2
TTAAATTGTGGGCAAAAGAGAAAAAGAAGGATTGATC





AGAGCATTGTGCAATACAGTTTCATTAACTCCTTCCCC





CGCTCCCCCAAAAATTTGAATTTTTTTTTCAACACTCTT





ACACCTGTTATGGAAAATGTCAACCTTTGTAAGAAAA





CCAAAATAAAAATTGAAAAATAAAAACCATAAACATT





TGCACCACTTGTGGCTTTTGAATATCTTCCACAGAGGG





AAGTTTAAAACCCAAACTTCCAAAGGTTTAAACTACC





TCAAAACACTTTCCCATGAGTGTGATCCACATTGTTAG





GTGCTGACCTAGACAGAGATGAACTGAGGTCCTTGTT





TTGTTTTGTTCATAATACAAAGGTGCTAATTAATAGTA





TTTCAGATACTTGAAGAATGTTGATGGTGCTAGAAGA





ATTTGAGAAGAAATACTCCTGTATTGAGTTGTATCGTG





TGGTGTATTTTTTAAAAAATTTGATTTAGCATTCATAT





TTTCCATCTTATTCCCAATTAAAAGTATGCAGATTATT





TGCCCAAATCTTCTTCAGATTCAGCATTTGTTCTTTGCC





AGTCTCATTTTCATCTTCTTCCATGGTTCCACAGAAGC





TTTGTTTCTTGGGCAAGCAGAAAAATTAAATTGTACCT





ATTTTGTATATGTGAGATGTTTAAATAAATTGTGAAAA





AAATGAAATAAAGCATGTTTGGTTTTCCAAAAGAACA





TAT






3UTR-008
Col6a2;
CGCCGCCGCCCGGGCCCCGCAGTCGAGGGTCGTGAGC
921



collagen,
CCACCCCGTCCATGGTGCTAAGCGGGCCCGGGTCCCA




type VI,
CACGGCCAGCACCGCTGCTCACTCGGACGACGCCCTG




alpha 2
GGCCTGCACCTCTCCAGCTCCTCCCACGGGGTCCCCGT





AGCCCCGGCCCCCGCCCAGCCCCAGGTCTCCCCAGGC





CCTCCGCAGGCTGCCCGGCCTCCCTCCCCCTGCAGCCA





TCCCAAGGCTCCTGACCTACCTGGCCCCTGAGCTCTGG





AGCAAGCCCTGACCCAATAAAGGCTTTGAACCCAT






3UTR-009
RPN1;
GGGGCTAGAGCCCTCTCCGCACAGCGTGGAGACGGGG
922



riophorin I
CAAGGAGGGGGGTTATTAGGATTGGTGGTTTTGTTTTG





CTTTGTTTAAAGCCGTGGGAAAATGGCACAACTTTACC





TCTGTGGGAGATGCAACACTGAGAGCCAAGGGGTGGG





AGTTGGGATAATTTTTATATAAAAGAAGTTTTTCCACT





TTGAATTGCTAAAAGTGGCATTTTTCCTATGTGCAGTC





ACTCCTCTCATTTCTAAAATAGGGACGTGGCCAGGCA





CGGTGGCTCATGCCTGTAATCCCAGCACTTTGGGAGG





CCGAGGCAGGCGGCTCACGAGGTCAGGAGATCGAGA





CTATCCTGGCTAACACGGTAAAACCCTGTCTCTACTAA





AAGTACAAAAAATTAGCTGGGCGTGGTGGTGGGCACC





TGTAGTCCCAGCTACTCGGGAGGCTGAGGCAGGAGAA





AGGCATGAATCCAAGAGGCAGAGCTTGCAGTGAGCTG





AGATCACGCCATTGCACTCCAGCCTGGGCAACAGTGT





TAAGACTCTGTCTCAAATATAAATAAATAAATAAATA





AATAAATAAATAAATAAAAATAAAGCGAGATGTTGCC





CTCAAA






3UTR-010
LRP1; low
GGCCCTGCCCCGTCGGACTGCCCCCAGAAAGCCTCCT
923



density
GCCCCCTGCCAGTGAAGTCCTTCAGTGAGCCCCTCCCC




lipoprotein
AGCCAGCCCTTCCCTGGCCCCGCCGGATGTATAAATGT




receptor-
AAAAATGAAGGAATTACATTTTATATGTGAGCGAGCA




related
AGCCGGCAAGCGAGCACAGTATTATTTCTCCATCCCCT




protein 1
CCCTGCCTGCTCCTTGGCACCCCCATGCTGCCTTCAGG





GAGACAGGCAGGGAGGGCTTGGGGCTGCACCTCCTAC





CCTCCCACCAGAACGCACCCCACTGGGAGAGCTGGTG





GTGCAGCCTTCCCCTCCCTGTATAAGACACTTTGCCAA





GGCTCTCCCCTCTCGCCCCATCCCTGCTTGCCCGCTCC





CACAGCTTCCTGAGGGCTAATTCTGGGAAGGGAGAGT





TCTTTGCTGCCCCTGTCTGGAAGACGTGGCTCTGGGTG





AGGTAGGCGGGAAAGGATGGAGTGTTTTAGTTCTTGG





GGGAGGCCACCCCAAACCCCAGCCCCAACTCCAGGGG





CACCTATGAGATGGCCATGCTCAACCCCCCTCCCAGA





CAGGCCCTCCCTGTCTCCAGGGCCCCCACCGAGGTTCC





CAGGGCTGGAGACTTCCTCTGGTAAACATTCCTCCAGC





CTCCCCTCCCCTGGGGACGCCAAGGAGGTGGGCCACA





CCCAGGAAGGGAAAGCGGGCAGCCCCGTTTTGGGGAC





GTGAACGTTTTAATAATTTTTGCTGAATTCCTTTACAA





CTAAATAACACAGATATTGTTATAAATAAAATTGT






3UTR-011
Nnt1;
ATATTAAGGATCAAGCTGTTAGCTAATAATGCCACCTC
924



cardio-
TGCAGTTTTGGGAACAGGCAAATAAAGTATCAGTATA




trophin-
CATGGTGATGTACATCTGTAGCAAAGCTCTTGGAGAA




like
AATGAAGACTGAAGAAAGCAAAGCAAAAACTGTATA




cytokine
GAGAGATTTTTCAAAAGCAGTAATCCCTCAATTTTAAA




factor 1
AAAGGATTGAAAATTCTAAATGTCTTTCTGTGCATATT





TTTTGTGTTAGGAATCAAAAGTATTTTATAAAAGGAG





AAAGAACAGCCTCATTTTAGATGTAGTCCTGTTGGATT





TTTTATGCCTCCTCAGTAACCAGAAATGTTTTAAAAAA





CTAAGTGTTTAGGATTTCAAGACAACATTATACATGGC





TCTGAAATATCTGACACAATGTAAACATTGCAGGCAC





CTGCATTTTATGTTTTTTTTTTCAACAAATGTGACTAAT





TTGAAACTTTTATGAACTTCTGAGCTGTCCCCTTGCAA





TTCAACCGCAGTTTGAATTAATCATATCAAATCAGTTT





TAATTTTTTAAATTGTACTTCAGAGTCTATATTTCAAG





GGCACATTTTCTCACTACTATTTTAATACATTAAAGGA





CTAAATAATCTTTCAGAGATGCTGGAAACAAATCATTT





GCTTTATATGTTTCATTAGAATACCAATGAAACATACA





ACTTGAAAATTAGTAATAGTATTTTTGAAGATCCCATT





TCTAATTGGAGATCTCTTTAATTTCGATCAACTTATAA





TGTGTAGTACTATATTAAGTGCACTTGAGTGGAATTCA





ACATTTGACTAATAAAATGAGTTCATCATGTTGGCAA





GTGATGTGGCAATTATCTCTGGTGACAAAAGAGTAAA





ATCAAATATTTCTGCCTGTTACAAATATCAAGGAAGA





CCTGCTACTATGAAATAGATGACATTAATCTGTCTTCA





CTGTTTATAATACGGATGGATTTTTTTTCAAATCAGTG





TGTGTTTTGAGGTCTTATGTAATTGATGACATTTGAGA





GAAATGGTGGCTTTTTTTAGCTACCTCTTTGTTCATTTA





AGCACCAGTAAAGATCATGTCTTTTTATAGAAGTGTA





GATTTTCTTTGTGACTTTGCTATCGTGCCTAAAGCTCT





AAATATAGGTGAATGTGTGATGAATACTCAGATTATTT





GTCTCTCTATATAATTAGTTTGGTACTAAGTTTCTCAA





AAAATTATTAACACATGAAAGACAATCTCTAAACCAG





AAAAAGAAGTAGTACAAATTTTGTTACTGTAATGCTC





GCGTTTAGTGAGTTTAAAACACACAGTATCTTTTGGTT





TTATAATCAGTTTCTATTTTGCTGTGCCTGAGATTAAG





ATCTGTGTATGTGTGTGTGTGTGTGTGTGCGTTTGTGT





GTTAAAGCAGAAAAGACTTTTTTAAAAGTTTTAAGTG





ATAAATGCAATTTGTTAATTGATCTTAGATCACTAGTA





AACTCAGGGCTGAATTATACCATGTATATTCTATTAGA





AGAAAGTAAACACCATCTTTATTCCTGCCCTTTTTCTT





CTCTCAAAGTAGTTGTAGTTATATCTAGAAAGAAGCA





ATTTTGATTTCTTGAAAAGGTAGTTCCTGCACTCAGTT





TAAACTAAAAATAATCATACTTGGATTTTATTTATTTT





TGTCATAGTAAAAATTTTAATTTATATATATTTTTATTT





AGTATTATCTTATTCTTTGCTATTTGCCAATCCTTTGTC





ATCAATTGTGTTAAATGAATTGAAAATTCATGCCCTGT





TCATTTTATTTTACTTTATTGGTTAGGATATTTAAAGG





ATTTTTGTATATATAATTTCTTAAATTAATATTCCAAA





AGGTTAGTGGACTTAGATTATAAATTATGGCAAAAAT





CTAAAAACAACAAAAATGATTTTTATACATTCTATTTC





ATTATTCCTCTTTTTCCAATAAGTCATACAATTGGTAG





ATATGACTTATTTTATTTTTGTATTATTCACTATATCTT





TATGATATTTAAGTATAAATAATTAAAAAAATTTATTG





TACCTTATAGTCTGTCACCAAAAAAAAAAAATTATCT





GTAGGTAGTGAAATGCTAATGTTGATTTGTCTTTAAGG





GCTTGTTAACTATCCTTTATTTTCTCATTTGTCTTAAAT





TAGGAGTTTGTGTTTAAATTACTCATCTAAGCAAAAAA





TGTATATAAATCCCATTACTGGGTATATACCCAAAGG





ATTATAAATCATGCTGCTATAAAGACACATGCACACG





TATGTTTATTGCAGCACTATTCACAATAGCAAAGACTT





GGAACCAACCCAAATGTCCATCAATGATAGACTTGAT





TAAGAAAATGTGCACATATACACCATGGAATACTATG





CAGCCATAAAAAAGGATGAGTTCATGTCCTTTGTAGG





GACATGGATAAAGCTGGAAACCATCATTCTGAGCAAA





CTATTGCAAGGACAGAAAACCAAACACTGCATGTTCT





CACTCATAGGTGGGAATTGAACAATGAGAACACTTGG





ACACAAGGTGGGGAACACCACACACCAGGGCCTGTCA





TGGGGTGGGGGGAGTGGGGAGGGATAGCATTAGGAG





ATATACCTAATGTAAATGATGAGTTAATGGGTGCAGC





ACACCAACATGGCACATGTATACATATGTAGCAAACC





TGCACGTTGTGCACATGTACCCTAGAACTTAAAGTATA





ATTAAAAAAAAAAAGAAAACAGAAGCTATTTATAAA





GAAGTTATTTGCTGAAATAAATGTGATCTTTCCCATTA





AAAAAATAAAGAAATTTTGGGGTAAAAAAACACAAT





ATATTGTATTCTTGAAAAATTCTAAGAGAGTGGATGTG





AAGTGTTCTCACCACAAAAGTGATAACTAATTGAGGT





AATGCACATATTAATTAGAAAGATTTTGTCATTCCACA





ATGTATATATACTTAAAAATATGTTATACACAATAAAT





ACATACATTAAAAAATAAGTAAATGTA






3UTR-012
Col6a1;
CCCACCCTGCACGCCGGCACCAAACCCTGTCCTCCCAC
925



collagen,
CCCTCCCCACTCATCACTAAACAGAGTAAAATGTGAT




type VI,
GCGAATTTTCCCGACCAACCTGATTCGCTAGATTTTTT




alpha 1
TTAAGGAAAAGCTTGGAAAGCCAGGACACAACGCTGC





TGCCTGCTTTGTGCAGGGTCCTCCGGGGCTCAGCCCTG





AGTTGGCATCACCTGCGCAGGGCCCTCTGGGGCTCAG





CCCTGAGCTAGTGTCACCTGCACAGGGCCCTCTGAGG





CTCAGCCCTGAGCTGGCGTCACCTGTGCAGGGCCCTCT





GGGGCTCAGCCCTGAGCTGGCCTCACCTGGGTTCCCC





ACCCCGGGCTCTCCTGCCCTGCCCTCCTGCCCGCCCTC





CCTCCTGCCTGCGCAGCTCCTTCCCTAGGCACCTCTGT





GCTGCATCCCACCAGCCTGAGCAAGACGCCCTCTCGG





GGCCTGTGCCGCACTAGCCTCCCTCTCCTCTGTCCCCA





TAGCTGGTTTTTCCCACCAATCCTCACCTAACAGTTAC





TTTACAATTAAACTCAAAGCAAGCTCTTCTCCTCAGCT





TGGGGCAGCCATTGGCCTCTGTCTCGTTTTGGGAAACC





AAGGTCAGGAGGCCGTTGCAGACATAAATCTCGGCGA





CTCGGCCCCGTCTCCTGAGGGTCCTGCTGGTGACCGGC





CTGGACCTTGGCCCTACAGCCCTGGAGGCCGCTGCTG





ACCAGCACTGACCCCGACCTCAGAGAGTACTCGCAGG





GGCGCTGGCTGCACTCAAGACCCTCGAGATTAACGGT





GCTAACCCCGTCTGCTCCTCCCTCCCGCAGAGACTGGG





GCCTGGACTGGACATGAGAGCCCCTTGGTGCCACAGA





GGGCTGTGTCTTACTAGAAACAACGCAAACCTCTCCTT





CCTCAGAATAGTGATGTGTTCGACGTTTTATCAAAGGC





CCCCTTTCTATGTTCATGTTAGTTTTGCTCCTTCTGTGT





TTTTTTCTGAACCATATCCATGTTGCTGACTTTTCCAAA





TAAAGGTTTTCACTCCTCTC






3UTR-013
Calr;
AGAGGCCTGCCTCCAGGGCTGGACTGAGGCCTGAGCG
926



calreticulin
CTCCTGCCGCAGAGCTGGCCGCGCCAAATAATGTCTCT





GTGAGACTCGAGAACTTTCATTTTTTTCCAGGCTGGTT





CGGATTTGGGGTGGATTTTGGTTTTGTTCCCCTCCTCC





ACTCTCCCCCACCCCCTCCCCGCCCTTTTTTTTTTTTTT





TTTTAAACTGGTATTTTATCTTTGATTCTCCTTCAGCCC





TCACCCCTGGTTCTCATCTTTCTTGATCAACATCTTTTC





TTGCCTCTGTCCCCTTCTCTCATCTCTTAGCTCCCCTCC





AACCTGGGGGGCAGTGGTGTGGAGAAGCCACAGGCCT





GAGATTTCATCTGCTCTCCTTCCTGGAGCCCAGAGGAG





GGCAGCAGAAGGGGGTGGTGTCTCCAACCCCCCAGCA





CTGAGGAAGAACGGGGCTCTTCTCATTTCACCCCTCCC





TTTCTCCCCTGCCCCCAGGACTGGGCCACTTCTGGGTG





GGGCAGTGGGTCCCAGATTGGCTCACACTGAGAATGT





AAGAACTACAAACAAAATTTCTATTAAATTAAATTTTG





TGTCTCC






3UTR-014
Col1a1;
CTCCCTCCATCCCAACCTGGCTCCCTCCCACCCAACCA
927



collagen,
ACTTTCCCCCCAACCCGGAAACAGACAAGCAACCCAA




type I, alpha
ACTGAACCCCCTCAAAAGCCAAAAAATGGGAGACAAT




1
TTCACATGGACTTTGGAAAATATTTTTTTCCTTTGCATT





CATCTCTCAAACTTAGTTTTTATCTTTGACCAACCGAA





CATGACCAAAAACCAAAAGTGCATTCAACCTTACCAA





AAAAAAAAAAAAAAAAAGAATAAATAAATAACTTTTT





AAAAAAGGAAGCTTGGTCCACTTGCTTGAAGACCCAT





GCGGGGGTAAGTCCCTTTCTGCCCGTTGGGCTTATGAA





ACCCCAATGCTGCCCTTTCTGCTCCTTTCTCCACACCC





CCCTTGGGGCCTCCCCTCCACTCCTTCCCAAATCTGTC





TCCCCAGAAGACACAGGAAACAATGTATTGTCTGCCC





AGCAATCAAAGGCAATGCTCAAACACCCAAGTGGCCC





CCACCCTCAGCCCGCTCCTGCCCGCCCAGCACCCCCAG





GCCCTGGGGGACCTGGGGTTCTCAGACTGCCAAAGAA





GCCTTGCCATCTGGCGCTCCCATGGCTCTTGCAACATC





TCCCCTTCGTTTTTGAGGGGGTCATGCCGGGGGAGCCA





CCAGCCCCTCACTGGGTTCGGAGGAGAGTCAGGAAGG





GCCACGACAAAGCAGAAACATCGGATTTGGGGAACGC





GTGTCAATCCCTTGTGCCGCAGGGCTGGGCGGGAGAG





ACTGTTCTGTTCCTTGTGTAACTGTGTTGCTGAAAGAC





TACCTCGTTCTTGTCTTGATGTGTCACCGGGGCAACTG





CCTGGGGGCGGGGATGGGGGCAGGGTGGAAGCGGCT





CCCCATTTTATACCAAAGGTGCTACATCTATGTGATGG





GTGGGGTGGGGAGGGAATCACTGGTGCTATAGAAATT





GAGATGCCCCCCCAGGCCAGCAAATGTTCCTTTTTGTT





CAAAGTCTATTTTTATTCCTTGATATTTTTCTTTTTTTTT





TTTTTTTTTTGTGGATGGGGACTTGTGAATTTTTCTAAA





GGTGCTATTTAACATGGGAGGAGAGCGTGTGCGGCTC





CAGCCCAGCCCGCTGCTCACTTTCCACCCTCTCTCCAC





CTGCCTCTGGCTTCTCAGGCCTCTGCTCTCCGACCTCT





CTCCTCTGAAACCCTCCTCCACAGCTGCAGCCCATCCT





CCCGGCTCCCTCCTAGTCTGTCCTGCGTCCTCTGTCCC





CGGGTTTCAGAGACAACTTCCCAAAGCACAAAGCAGT





TTTTCCCCCTAGGGGTGGGAGGAAGCAAAAGACTCTG





TACCTATTTTGTATGTGTATAATAATTTGAGATGTTTTT





AATTATTTTGATTGCTGGAATAAAGCATGTGGAAATG





ACCCAAACATAATCCGCAGTGGCCTCCTAATTTCCTTC





TTTGGAGTTGGGGGAGGGGTAGACATGGGGAAGGGG





CTTTGGGGTGATGGGCTTGCCTTCCATTCCTGCCCTTT





CCCTCCCCACTATTCTCTTCTAGATCCCTCCATAACCC





CACTCCCCTTTCTCTCACCCTTCTTATACCGCAAACCTT





TCTACTTCCTCTTTCATTTTCTATTCTTGCAATTTCCTT





GCACCTTTTCCAAATCCTCTTCTCCCCTGCAATACCAT





ACAGGCAATCCACGTGCACAACACACACACACACTCT





TCACATCTGGGGTTGTCCAAACCTCATACCCACTCCCC





TTCAAGCCCATCCACTCTCCACCCCCTGGATGCCCTGC





ACTTGGTGGCGGTGGGATGCTCATGGATACTGGGAGG





GTGAGGGGAGTGGAACCCGTGAGGAGGACCTGGGGG





CCTCTCCTTGAACTGACATGAAGGGTCATCTGGCCTCT





GCTCCCTTCTCACCCACGCTGACCTCCTGCCGAAGGAG





CAACGCAACAGGAGAGGGGTCTGCTGAGCCTGGCGAG





GGTCTGGGAGGGACCAGGAGGAAGGCGTGCTCCCTGC





TCGCTGTCCTGGCCCTGGGGGAGTGAGGGAGACAGAC





ACCTGGGAGAGCTGTGGGGAAGGCACTCGCACCGTGC





TCTTGGGAAGGAAGGAGACCTGGCCCTGCTCACCACG





GACTGGGTGCCTCGACCTCCTGAATCCCCAGAACACA





ACCCCCCTGGGCTGGGGTGGTCTGGGGAACCATCGTG





CCCCCGCCTCCCGCCTACTCCTTTTTAAGCTT






3UTR-015
Pld1;
TTGGCCAGGCCTGACCCTCTTGGACCTTTCTTCTTTGC
928



procollagen-
CGACAACCACTGCCCAGCAGCCTCTGGGACCTCGGGG




lysine, 2-
TCCCAGGGAACCCAGTCCAGCCTCCTGGCTGTTGACTT




oxoglutarate
CCCATTGCTCTTGGAGCCACCAATCAAAGAGATTCAA




5-
AGAGATTCCTGCAGGCCAGAGGCGGAACACACCTTTA




dioxygenase
TGGCTGGGGCTCTCCGTGGTGTTCTGGACCCAGCCCCT




1
GGAGACACCATTCACTTTTACTGCTTTGTAGTGACTCG





TGCTCTCCAACCTGTCTTCCTGAAAAACCAAGGCCCCC





TTCCCCCACCTCTTCCATGGGGTGAGACTTGAGCAGAA





CAGGGGCTTCCCCAAGTTGCCCAGAAAGACTGTCTGG





GTGAGAAGCCATGGCCAGAGCTTCTCCCAGGCACAGG





TGTTGCACCAGGGACTTCTGCTTCAAGTTTTGGGGTAA





AGACACCTGGATCAGACTCCAAGGGCTGCCCTGAGTC





TGGGACTTCTGCCTCCATGGCTGGTCATGAGAGCAAA





CCGTAGTCCCCTGGAGACAGCGACTCCAGAGAACCTC





TTGGGAGACAGAAGAGGCATCTGTGCACAGCTCGATC





TTCTACTTGCCTGTGGGGAGGGGAGTGACAGGTCCAC





ACACCACACTGGGTCACCCTGTCCTGGATGCCTCTGAA





GAGAGGGACAGACCGTCAGAAACTGGAGAGTTTCTAT





TAAAGGTCATTTAAACCA






3UTR-016
Nucb1;
TCCTCCGGGACCCCAGCCCTCAGGATTCCTGATGCTCC
929



nucleobindin
AAGGCGACTGATGGGCGCTGGATGAAGTGGCACAGTC




1
AGCTTCCCTGGGGGCTGGTGTCATGTTGGGCTCCTGGG





GCGGGGGCACGGCCTGGCATTTCACGCATTGCTGCCA





CCCCAGGTCCACCTGTCTCCACTTTCACAGCCTCCAAG





TCTGTGGCTCTTCCCTTCTGTCCTCCGAGGGGCTTGCC





TTCTCTCGTGTCCAGTGAGGTGCTCAGTGATCGGCTTA





ACTTAGAGAAGCCCGCCCCCTCCCCTTCTCCGTCTGTC





CCAAGAGGGTCTGCTCTGAGCCTGCGTTCCTAGGTGG





CTCGGCCTCAGCTGCCTGGGTTGTGGCCGCCCTAGCAT





CCTGTATGCCCACAGCTACTGGAATCCCCGCTGCTGCT





CCGGGCCAAGCTTCTGGTTGATTAATGAGGGCATGGG





GTGGTCCCTCAAGACCTTCCCCTACCTTTTGTGGAACC





AGTGATGCCTCAAAGACAGTGTCCCCTCCACAGCTGG





GTGCCAGGGGCAGGGGATCCTCAGTATAGCCGGTGAA





CCCTGATACCAGGAGCCTGGGCCTCCCTGAACCCCTG





GCTTCCAGCCATCTCATCGCCAGCCTCCTCCTGGACCT





CTTGGCCCCCAGCCCCTTCCCCACACAGCCCCAGAAG





GGTCCCAGAGCTGACCCCACTCCAGGACCTAGGCCCA





GCCCCTCAGCCTCATCTGGAGCCCCTGAAGACCAGTC





CCACCCACCTTTCTGGCCTCATCTGACACTGCTCCGCA





TCCTGCTGTGTGTCCTGTTCCATGTTCCGGTTCCATCCA





AATACACTTTCTGGAACAAA






3UTR-017
α-globin
GCTGGAGCCTCGGTGGCCATGCTTCTTGCCCCTTGGGC
930




CTCCCCCCAGCCCCTCCTCCCCTTCCTGCACCCGTACC





CCCGTGGTCTTTGAATAAAGTCTGAGTGGGCGGC









5′ UTR and Translation Initiation

Natural 5′UTRs bear features which play roles in translation initiation. They harbor signatures like Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG (SEQ ID NO: 965), where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’. 5′UTR also have been known to form secondary structures which are involved in elongation factor binding.


By engineering the features typically found in abundantly expressed genes of specific target organs, one can enhance the stability and protein production of the polynucleotides of the invention. For example, introduction of 5′ UTR of liver-expressed mRNA, such as albumin, serum amyloid A, Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII, could be used to enhance expression of a nucleic acid molecule, such as a polynucleotides, in hepatic cell lines or liver. Likewise, use of 5′ UTR from other tissue-specific mRNA to improve expression in that tissue is possible for muscle (MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (Tie-1, CD36), for myeloid cells (C/EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (CD45, CD18), for adipose tissue (CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (SP-A/B/C/D).


Untranslated regions useful in the design and manufacture of polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) include, but are not limited, to those disclosed in co-pending, co-owned US Provisional Application U.S. Ser. No. 61/829,372 (Attorney Docket Number M42.60), U.S. Provisional Application 61/829,372 (USSN) (Attorney Docket Number M42.61), and international Application, PCT/US14/21522 filed Mar. 7, 2014, the contents of each of which are incorporated herein by reference in its entirety.


Other non-UTR sequences may also be used as regions or subregions within the polynucleotides. For example, introns or portions of introns sequences may be incorporated into regions of the polynucleotides of the invention. Incorporation of intronic sequences may increase protein production as well as polynucleotide levels.


Combinations of features may be included in flanking regions and may be contained within other features. For example, the ORF may be flanked by a 5′ UTR which may contain a strong Kozak translational initiation signal and/or a 3′ UTR which may include an oligo(dT) sequence for templated addition of a poly-A tail. 5′UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes such as the 5′UTRs described in US Patent Application Publication No. 20100293625, herein incorporated by reference in its entirety.


Co-pending, co-owned US Provisional Application U.S. Ser. No. 61/829,372 (Attorney Docket Number M42.60) and U.S. Provisional Application 61/829,372 (USSN) (Attorney Docket Number M42.61) provides a listing of exemplary UTRs which may be utilized in the polynucleotide of the present invention as flanking regions. Variants of 5′ or 3′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.


It should be understood that any UTR from any gene may be incorporated into the regions of the polynucleotide. Furthermore, multiple wild-type UTRs of any known gene may be utilized. It is also within the scope of the present invention to provide artificial UTRs which are not variants of wild type regions. These UTRs or portions thereof may be placed in the same orientation as in the transcript from which they were selected or may be altered in orientation or location. Hence a 5′ or 3′ UTR may be inverted, shortened, lengthened, made with one or more other 5′ UTRs or 3′ UTRs. As used herein, the term “altered” as it relates to a UTR sequence, means that the UTR has been changed in some way in relation to a reference sequence. For example, a 3′ or 5′ UTR may be altered relative to a wild type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. Any of these changes producing an “altered” UTR (whether 3′ or 5′) comprise a variant UTR.


In one embodiment, a double, triple or quadruple UTR such as a 5′ or 3′ UTR may be used. As used herein, a “double” UTR is one in which two copies of the same UTR are encoded either in series or substantially in series. For example, a double beta-globin 3′ UTR may be used as described in US Patent publication 20100129877, the contents of which are incorporated herein by reference in its entirety.


It is also within the scope of the present invention to have patterned UTRs. As used herein “patterned UTRs” are those UTRs which reflect a repeating or alternating pattern, such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than 3 times. In these patterns, each letter, A, B, or C represent a different UTR at the nucleotide level.


In one embodiment, flanking regions are selected from a family of transcripts whose proteins share a common function, structure, feature of property. For example, polypeptides of interest may belong to a family of proteins which are expressed in a particular cell, tissue or at some time during development. The UTRs from any of these genes may be swapped for any other UTR of the same or different family of proteins to create a new polynucleotide. As used herein, a “family of proteins” is used in the broadest sense to refer to a group of two or more polypeptides of interest which share at least one function, structure, feature, localization, origin, or expression pattern.


The untranslated region may also include translation enhancer elements (TEE). As a non-limiting example, the TEE may include those described in US Application No. 20090226470, herein incorporated by reference in its entirety, and those known in the art.


3′ UTR and the AU Rich Elements

Natural or wild type 3′ UTRs are known to have stretches of Adenosines and Uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al, 1995): Class I AREs contain several dispersed copies of an AUUUA motif within U-rich regions. C-Myc and MyoD contain class I AREs. Class II AREs possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Molecules containing this type of AREs include GM-CSF and TNF-α. Class ITT ARES are less well defined. These U rich regions do not contain an AUULUA motif. c-Jun and Myogenin are two well-studied examples of this class. Most proteins binding to the AREs are known to destabilize the messenger, whereas members of the ELAV family, most notably HuR, have been documented to increase the stability of mRNA. HuR binds to AREs of all the three classes. Engineering the HuR specific binding sites into the 3′ UTR of nucleic acid molecules will lead to HuR binding and thus, stabilization of the message in vivo.


Introduction, removal or modification of 3′ UTR AU rich elements (AREs) can be used to modulate the stability of polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention). When engineering specific polynucleotides, one or more copies of an ARE can be introduced to make polynucleotides of the invention less stable and thereby curtail translation and decrease production of the resultant protein. Likewise, AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein. Transfection experiments can be conducted in relevant cell lines, using polynucleotides of the invention and protein production can be assayed at various time points post-transfection. For example, cells can be transfected with different ARE-engineering molecules and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, and 7 days post-transfection.


microRNA Binding Sites


microRNAs (or miRNA) are 19-25 nucleotide long noncoding RNAs that bind to the 3′UTR of nucleic acid molecules and down-regulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation. The polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise one or more microRNA target sequences, microRNA sequences, or microRNA seeds. Such sequences may correspond to any known microRNA such as those taught in US Publication US2005/0261218 and US Publication US2005/0059005, the contents of which are incorporated herein by reference in their entirety.


A microRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 of the mature microRNA, which sequence has perfect Watson-Crick complementarity to the miRNA target sequence. A microRNA seed may comprise positions 2-8 or 2-7 of the mature microRNA. In some embodiments, a microRNA seed may comprise 7 nucleotides (e.g., nucleotides 2-8 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked by an adenine (A) opposed to microRNA position 1. In some embodiments, a microRNA seed may comprise 6 nucleotides (e.g., nucleotides 2-7 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked byan adenine (A) opposed to microRNA position 1. See for example, Grimson A, Farh K K, Johnston W K, Garrett-Engele P, Lim L P, Bartel D P; Mol Cell. 2007 Jul. 6; 27(1):91-105; each of which is herein incorporated by reference in their entirety. The bases of the microRNA seed have complete complementarity with the target sequence. By engineering microRNA target sequences into the polynucleotides (e.g., in a 3′UTR like region or other region) of the invention one can target the molecule for degradation or reduced translation, provided the microRNA in question is available. This process will reduce the hazard of off target effects upon nucleic acid molecule delivery. Identification of microRNA, microRNA target regions, and their expression patterns and role in biology have been reported (Bonauer et al., Curr Drug Targets 2010 11:943-949; Anand and Cheresh Cuff Opin Hematol 2011 18:171-176; Contreras and Rao Leukemia 2012 26:404-413 (2011 Dec. 20. doi: 10.1038/leu.2011.356); Bartel Cell 2009 136:215-233; Landgraf et al, Cell, 2007 129:1401-1414; each of which is herein incorporated by reference in its entirety).


For example, if the nucleic acid molecule is an mRNA and is not intended to be delivered to the liver but ends up there, then miR-122, a microRNA abundant in liver, can inhibit the expression of the gene of interest if one or multiple target sites of miR-122 are engineered into the 3′ UTR region of the polynucleotides. Introduction of one or multiple binding sites for different microRNA can be engineered to further decrease the longevity, stability, and protein translation of polynucleotides.


As used herein, the term “microRNA site” refers to a microRNA target site or a microRNA recognition site, or any nucleotide sequence to which a microRNA binds or associates. It should be understood that “binding” may follow traditional Watson-Crick hybridization rules or may reflect any stable association of the microRNA with the target sequence at or adjacent to the microRNA site.


Conversely, for the purposes of the polynucleotides of the present invention, microRNA binding sites can be engineered out of (i.e. removed from) sequences in which they occur, e.g., in order to increase protein expression in specific tissues. For example, miR-122 binding sites may be removed to improve protein expression in the liver. Regulation of expression in multiple tissues can be accomplished through introduction or removal or one or several microRNA binding sites.


Examples of tissues where microRNA are known to regulate mRNA, and thereby protein expression, include, but are not limited to, liver (miR-122), muscle (miR-133, miR-206, miR-208), endothelial cells (miR-17-92, miR-126), myeloid cells (miR-142-3p, miR-142-5p, miR-16, miR-21, miR-223, miR-24, miR-27), adipose tissue (let-7, miR-30c), heart (miR-1d, miR-149), kidney (miR-192, miR-194, miR-204), and lung epithelial cells (let-7, miR-133, miR-126). MicroRNA can also regulate complex biological processes such as angiogenesis (miR-132) (Anand and Cheresh Curr Opin Hematol 2011 18:171-176; herein incorporated by reference in its entirety).


Expression profiles, microRNA and cell lines useful in the present invention include those taught in for example, U.S. Provisional Application Nos 61/857,436 (Attorney Docket Number M39) and 61/857,304 (Attorney Docket Number M37) each filed Jul. 23, 2013, the contents of which are incorporated by reference in their entirety.


In the polynucleotides of the present invention, binding sites for microRNAs that are involved in such processes may be removed or introduced, in order to tailor the expression of the polynucleotides expression to biologically relevant cell types or to the context of relevant biological processes. A listing of microRNA, miR sequences and miR binding sites is listed in Table 9 of U.S. Provisional Application No. 61/753,661 filed Jan. 17, 2013, in Table 9 of U.S. Provisional Application No. 61/754,159 filed Jan. 18, 2013, and in Table 7 of U.S. Provisional Application No. 61/758,921 filed Jan. 31, 2013, each of which are herein incorporated by reference in their entireties.


Examples of use of microRNA to drive tissue or disease-specific gene expression are listed (Getner and Naldini, Tissue Antigens. 2012, 80:393-403; herein incoroporated by reference in its entirety). In addition, microRNA seed sites can be incorporated into mRNA to decrease expression in certain cells which results in a biological improvement. An example of this is incorporation of miR-142 sites into a UGTI A1-expressing lentiviral vector. The presence of miR-142 seed sites reduced expression in hematopoietic cells, and as a consequence reduced expression in antigen-presentating cells, leading to the absence of an immune response against the virally expressed UGT1 A1 (Schmitt et al., Gastroenterology 2010; 139:999-1007; Gonzalez-Asequinolaza et al. Gastroenterology 2010, 139:726-729; both herein incorporated by reference in its entirety). Incorporation of miR-142 sites into modified mRNA could not only reduce expression of the encoded protein in hematopoietic cells, but could also reduce or abolish immune responses to the mRNA-encoded protein. Incorporation of miR-142 seed sites (one or multiple) into mRNA would be important in the case of treatment of patients with complete protein deficiencies (UGT1 A1 type I, LDLR-deficient patients. CRIM-negative Pompe patients, etc.).


Lastly, through an understanding of the expression patterns of microRNA in different cell types, polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can be engineered for more targeted expression in specific cell types or only under specific biological conditions. Through introduction of tissue-specific microRNA binding sites, polynucleotides could be designed that would be optimal for protein expression in a tissue or in the context of a biological condition.


Transfection experiments can be conducted in relevant cell lines, using engineered polynucleotides and protein production can be assayed at various time points post-transfection. For example, cells can be transfected with different microRNA binding site-engineering polynucleotides and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, 72 hour and 7 days post-transfection. In vivo experiments can also be conducted using microRNA-binding site-engineered molecules to examine changes in tissue-specific expression of formulated polynucleotides.


Regions Having a 5′ Cap

The 5′ cap structure of a natural mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsible for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species. The cap further assists the removal of 5′ proximal introns removal during mRNA splicing.


Endogenous mRNA molecules may be 5′-end capped generating a 5′-ppp-5′-triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule. This 5′-guanylate cap may then be methylated to generate an N7-methyl-guanylate residue. The ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5′ end of the mRNA may optionally also be 2′-O-methylated. 5′-decapping through hydrolysis and cleavage of the guanylate cap structure may target a nucleic acid molecule, such as an mRNA molecule, for degradation.


In some embodiments, polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be designed to incorporate a cap moiety. Modifications to the polynucleotides of the present invention may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides may be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, MA) may be used with α-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides may be used such as α-methyl-phosphonate and seleno-phosphate nucleotides.


Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and/or 5′-anteterminal nucleotides of the polynucleotide (as mentioned above) on the 2′-hydroxyl group of the sugar ring. Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as a polynucleotide which functions as an mRNA molecule.


Cap analogs, which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e. endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs may be chemically (i.e. non-enzymatically) or enzymatically synthesized and/or linked to the polynucleotides of the invention.


For example, the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine (m7G-3′mppp-G; which may equivaliently be designated 3′ O-Me-m7G(5′)ppp(5′)G). The 3′-0 atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped polynucleotide. The N7- and 3′-O-methylated guanine provides the terminal moiety of the capped polynucleotide.


Another exemplary cap is mCAP, which is similar to ARCA but has a 2′-O-methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-uiphosphate-5′-guanosine, m7Gm-ppp-G).


In one embodiment, the cap is a dinucleotide cap analog. As a non-limiting example, the dinucleotide cap analog may be modified at different phosphate positions with a boranophosphate group or a phosphoroselenoate group such as the dinucleotide cap analogs described in U.S. Pat. No. 8,519,110, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the cap is a cap analog is a N7-(4-chlorophenoxyethyl) substituted dicucleotide form of a cap analog known in the art and/or described herein. Non-limiting examples of a N7-(4-chlorophenoxyethyl) substituted dicucleotide form of a cap analog include a N7-(4-chlorophenoxyethyl)-G(5′)ppp(5′)G and a N7-(4-chlorophenoxyethyl)-m3′-O-( )G(5′)ppp(5′)G cap analog (See e.g., the various cap analogs and the methods of synthesizing cap analogs described in Kore et al. Bioorganic & Medicinal Chemistry 2013 21:4570-4574; the contents of which are herein incorporated by reference in its entirety). In another embodiment, a cap analog of the present invention is a 4-chloro/bromophenoxyethyl analog.


While cap analogs allow for the concomitant capping of a polynucleotide or a region thereof, in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped. This, as well as the structural differences of a cap analog from an endogenous 5′-cap structures of nucleic acids produced by the endogenous, cellular transcription machinery, may lead to reduced translational competency and reduced cellular stability.


Polynucleotides of the invention may also be capped post-manufacture (whether IVT or chemical synthesis), using enzymes, in order to generate more authentic 5′-cap structures. As used herein, the phrase “more authentic” refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a “more authentic” feature is better representative of an endogenous, wild-type, natural or physiological cellular function and/or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects. Non-limiting examples of more authentic 5′cap structures of the present invention are those which, among other things, have enhanced binding of cap binding proteins, increased half life, reduced susceptibility to 5′ endonucleases and/or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild-type, natural or physiological 5′cap structure). For example, recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of a polynucleotide and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl. Such a structure is termed the Cap1 structure. This cap results in a higher translational-competency and cellular stability and a reduced activation of cellular pro-inflammatory cytokines, as compared, e.g., to other 5′cap analog structures known in the art. Cap structures include, but are not limited to, 7mG(5′)ppp(5′)N,pN2p (cap 0), 7mG(5′)ppp(5′)NlmpNp (cap 1), and 7mG(5′)-ppp(5′)NlmpN2mp (cap 2).


As a non-limiting example, capping chimeric polynucleotides post-manufacture may be more efficient as nearly 100% of the chimeric polynucleotides may be capped. This is in contrast to ˜80% when a cap analog is linked to a chimeric polynucleotide in the course of an in vitro transcription reaction.


According to the present invention, 5′ terminal caps may include endogenous caps or cap analogs. According to the present invention, a 5′ terminal cap may comprise a guanine analog. Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.


Viral Sequences

Additional viral sequences such as, but not limited to, the translation enhancer sequence of the barley yellow dwarf virus (BYDV-PAV), the Jaagsiekte sheep retrovirus (JSRV) and/or the Enzootic nasal tumor virus (See e.g., International Pub. No. WO2012129648; herein incorporated by reference in its entirety) can be engineered and inserted in the polynucleotides of the invention and can stimulate the translation of the construct in vitro and in vivo. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.


IRES Sequences

Further, provided are polynucleotides (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) which may contain an internal ribosome entry site (IRES). First identified as a feature Picoma virus RNA, IRES plays an important role in initiating protein synthesis in absence of the 5′ cap structure. An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. Polynucleotides containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (“multicistronic nucleic acid molecules”). When polynucleotides are provided with an IRES, further optionally provided is a second translatable region. Examples of IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g. FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV).


Poly-A Tails

During RNA processing, a long chain of adenine nucleotides (poly-A tail) may be added to a polynucleotide such as an mRNA molecule in order to increase stability. Immediately after transcription, the 3′ end of the transcript may be cleaved to free a 3′ hydroxyl. Then poly-A polymerase adds a chain of adenine nucleotides to the RNA. The process, called polyadenylation, adds a poly-A tail that can be between, for example, approximately 80 to approximately 250 residues long, including approximately 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 residues long.


PolyA tails may also be added after the construct is exported from the nucleus.


According to the present invention, terminal groups on the poly A tail may be incorporated for stabilization into polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the RNAVs of the invention). Polynucleotides of the present invention may incude des-3′ hydroxyl tails. They may also include structural moieties or 2′-Omethyl modifications as taught by Junjie Li, et al. (Current Biology, Vol. 15, 1501-1507, Aug. 23, 2005, the contents of which are incorporated herein by reference in its entirety).


The polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be designed to encode transcripts with alternative polyA tail structures including histone mRNA. According to Norbury, “Terminal uridylation has also been detected on human replication-dependent histone mRNAs. The turnover of these mRNAs is thought to be important for the prevention of potentially toxic histone accumulation following the completion or inhibition of chromosomal DNA replication. These mRNAs are distinguished by their lack of a 3′ poly(A) tail, the function of which is instead assumed by a stable stem-loop structure and its cognate stem-loop binding protein (SLBP); the latter carries out the same functions as those of PABP on polyadenylated mRNAs” (Norbury, “Cytoplasmic RNA: a case of the tail wagging the dog,” Nature Reviews Molecular Cell Biology: AOP, published online 29 Aug. 2013; doi:10.1038/nrm3645) the contents of which are incorporated herein by reference in its entirety.


Unique poly-A tail lengths provide certain advantages to the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention).


Generally, the length of a poly-A tail, when present, is greater than 30 nucleotides in length. In another embodiment, the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides). In some embodiments, the polynucleotide or region thereof includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1.500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1.000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 3,000, from 2,000 to 3,000, from 2,000 to 2,500, and from 2,500 to 3,000).


In one embodiment, the poly-A tail is designed relative to the length of the overall polynucleotide or the length of a particular region of the polynucleotide. This design may be based on the length of a coding region, the length of a particular feature or region or based on the length of the ultimate product expressed from the polynucleotides.


In this context the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotide or feature thereof. The poly-A tail may also be designed as a fraction of the polynucleotides to which it belongs. In this context, the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct, a construct region or the total length of the construct minus the poly-A tail. Further, engineered binding sites and conjugation of polynucleotides for Poly-A binding protein may enhance expression.


Additionally, multiple distinct polynucleotides may be linked together via the PABP (Poly-A binding protein) through the Y-end using modified nucleotides at the 3′-terminus of the poly-A tail. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.


In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) are designed to include a polyA-G Quartet region. The G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA. In this embodiment, the G-quartet is incorporated at the end of the poly-A tail. The resultant polynucleotide is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production from an mRNA equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone.


Start Codon Region

In some embodiments, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may have regions that are analogous to or function like a start codon region.


In one embodiment, the translation of a polynucleotide may initiate on a codon which is not the start codon AUG. Translation of the polynucleotide may initiate on an alternative start codon such as, but not limited to, ACG, AGG, AAG, CTG/CUG, GTG/GUG, ATA/AUA, ATT/AUU, TTG/UUG (see Touriol et al. Biology of the Cell 95 (2003) 169-178 and Matsuda and Mauro PLoS ONE, 2010 5:11; the contents of each of which are herein incorporated by reference in its entirety). As a non-limiting example, the translation of a polynucleotide begins on the alternative start codon ACG. As another non-limiting example, polynucleotide translation begins on the alternative start codon CTG or CUG. As yet another non-limiting example, the translation of a polynucleotide begins on the alternative start codon GTG or GUG.


Nucleotides flanking a codon that initiates translation such as, but not limited to, a start codon or an alternative start codon, are known to affect the translation efficiency, the length and/or the structure of the polynucleotide. (See e.g., Matsuda and Mauro PLoS ONE, 2010 5:11; the contents of which are herein incorporated by reference in its entirety). Masking any of the nucleotides flanking a codon that initiates translation may be used to alter the position of translation initiation, translation efficiency, length and/or structure of a polynucleotide.


In one embodiment, a masking agent may be used near the start codon or alternative start codon in order to mask or hide the codon to reduce the probability of translation initiation at the masked start codon or alternative start codon. Non-limiting examples of masking agents include antisense locked nucleic acids (LNA) polynucleotides and exon-junction complexes (EJCs) (See e.g., Matsuda and Mauro describing masking agents LNA polynucleotides and EJCs (PLoS ONE, 2010 5:11); the contents of which are herein incorporated by reference in its entirety).


In another embodiment, a masking agent may be used to mask a start codon of a polynucleotide in order to increase the likelihood that translation will initiate on an alternative start codon.


In one embodiment, a masking agent may be used to mask a first start codon or alternative start codon in order to increase the chance that translation will initiate on a start codon or alternative start codon downstream to the masked start codon or alternative start codon.


In one embodiment, a start codon or alternative start codon may be located within a perfect complement for a miR binding site. The perfect complement of a miR binding site may help control the translation, length and/or structure of the polynucleotide similar to a masking agent. As a non-limiting example, the start codon or alternative start codon may be located in the middle of a perfect complement for a miR-122 binding site. The start codon or alternative start codon may be located after the first nucleotide, second nucleotide, third nucleotide, fourth nucleotide, fifth nucleotide, sixth nucleotide, seventh nucleotide, eighth nucleotide, ninth nucleotide, tenth nucleotide, eleventh nucleotide, twelfth nucleotide, thirteenth nucleotide, fourteenth nucleotide, fifteenth nucleotide, sixteenth nucleotide, seventeenth nucleotide, eighteenth nucleotide, nineteenth nucleotide, twentieth nucleotide or twenty-first nucleotide.


In another embodiment, the start codon of a polynucleotide may be removed from the polynucleotide sequence in order to have the translation of the polynucleotide begin on a codon which is not the start codon. Translation of the polynucleotide may begin on the codon following the removed start codon or on a downstream start codon or an alternative start codon. In a non-limiting example, the start codon ATG or AUG is removed as the first 3 nucleotides of the polynucleotide sequence in order to have translation initiate on a downstream start codon or alternative start codon. The polynucleotide sequence where the start codon was removed may further comprise at least one masking agent for the downstream start codon and/or alternative start codons in order to control or attempt to control the initiation of translation, the length of the polynucleotide and/or the structure of the polynucleotide.


Stop Codon Region

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may include at least two stop codons before the 3′ untranslated region (UTR). The stop codon may be selected from TGA, TAA and TAG. In one embodiment, the polynucleotides of the present invention include the stop codon TGA and one additional stop codon. In a further embodiment the addition stop codon may be TAA. In another embodiment, the polynucleotides of the present invention include three stop codons.


Signal Sequences

The polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may also encode additional features which facilitate trafficking of the polypeptides to therapeutically relevant sites. One such feature which aids in protein trafficking is the signal sequence. As used herein, a “signal sequence” or “signal peptide” is a polynucleotide or polypeptide, respectively, which is from about 9 to 200 nucleotides (3-60 amino acids) in length which is incorporated at the 5′ (or N-terminus) of the coding region or polypeptide encoded, respectively. Addition of these sequences result in trafficking of the encoded polypeptide to the endoplasmic reticulum through one or more secretory pathways. Some signal peptides are cleaved from the protein by signal peptidase after the proteins are transported.


Additional signal sequences which may be utilized in the present invention include those taught in, for example, databases such as those found at http://www.signalpeptide.de/ or http://proline.bic.nus.edu.sg/spdb/. Those described in U.S. Pat. Nos. 8,124,379; 7,413,875 and 7,385,034 are also within the scope of the invention and the contents of each are incorporated herein by reference in their entirety.


Protein Cleavage Signals and Sites

In exemplary embodiments, polypeptides of the invention (e.g., antigen polypeptides) may include various protein cleavage signals and/or sites.


In one embodiment, the polypeptides of the present invention may include at least one protein cleavage signal containing at least one protein cleavage site. The protein cleavage site may be located at the N-terminus, the C-terminus, at any space between the N- and the C-termini such as, but not limited to, half-way between the N- and C-termini, between the N-terminus and the half way point, between the half way point and the C-terminus, and combinations thereof.


In one embodiment, the polynucleotides of the present invention may be engineered such that the polynucleotide contains at least one encoded protein cleavage signal. The encoded protein cleavage signal may be located in any region including but not limited to before the start codon, after the start codon, before the coding region, within the coding region such as, but not limited to, half way in the coding region, between the start codon and the half way point, between the half way point and the stop codon, after the coding region, before the stop codon, between two stop codons, after the stop codon and combinations thereof.


In one embodiment, the polynucleotides of the present invention may include at least one encoded protein cleavage signal containing at least one protein cleavage site. The encoded protein cleavage signal may include, but is not limited to, a proprotein convertase (or prohormone convertase), thrombin and/or Factor Xa protein cleavage signal.


As a non-limiting example, U.S. Pat. No. 7,374,930 and U.S. Pub. No. 20090227660, herein incorporated by reference in their entireties, use a furin cleavage site to cleave the N-terminal methionine of GLP-1 in the expression product from the Golgi apparatus of the cells. In one embodiment, the polypeptides of the present invention include at least one protein cleavage signal and/or site with the proviso that the polypeptide is not GLP-1.


Insertions and Substitutions

In exemplary embodiments, polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can include various substitutions and/or insertions.


In one embodiment, the 5′UTR of the polynucleotide may be replaced by the insertion of at least one region and/or string of nucleosides of the same base. The region and/or string of nucleotides may include, but is not limited to, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 nucleotides and the nucleotides may be natural and/or unnatural. As a non-limiting example, the group of nucleotides may include 5-8 adenine, cytosine, thymine, a string of any of the other nucleotides disclosed herein and/or combinations thereof.


In one embodiment, the 5′UTR of the polynucleotide may be replaced by the insertion of at least two regions and/or strings of nucleotides of two different bases such as, but not limited to, adenine, cytosine, thymine, any of the other nucleotides disclosed herein and/or combinations thereof. For example, the 5′UTR may be replaced by inserting 5-8 adenine bases followed by the insertion of 5-8 cytosine bases. In another example, the 5′UTR may be replaced by inserting 5-8 cytosine bases followed by the insertion of 5-8 adenine bases.


In one embodiment, the polynucleotide may include at least one substitution and/or insertion downstream of the transcription start site which may be recognized by an RNA polymerase. As a non-limiting example, at least one substitution and/or insertion may occur downstream the transcription start site by substituting at least one nucleic acid in the region just downstream of the transcription start site (such as, but not limited to, +1 to +6). Changes to region of nucleotides just downstream of the transcription start site may affect initiation rates, increase apparent nucleotide triphosphate (NTP) reaction constant values, and increase the dissociation of short transcripts from the transcription complex curing initial transcription (Brieba et al, Biochemistry (2002) 41: 5144-5149; herein incorporated by reference in its entirety). The modification, substitution and/or insertion of at least one nucleoside may cause a silent mutation of the sequence or may cause a mutation in the amino acid sequence.


In one embodiment, the polynucleotide may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or at least 13 guanine bases downstream of the transcription start site.


In one embodiment, the polynucleotide may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 guanine bases in the region just downstream of the transcription start site. As a non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 adenine nucleotides. In another non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 cytosine bases. In another non-limiting example, if the nucleotides in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 thymine, and/or any of the nucleotides described herein.


In one embodiment, the polynucleotide may include at least one substitution and/or insertion upstream of the start codon. For the purpose of clarity, one of skill in the art would appreciate that the start codon is the first codon of the protein coding region whereas the transcription start site is the site where transcription begins. The polynucleotide may include, but is not limited to, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 substitutions and/or insertions of nucleotide bases. The nucleotide bases may be inserted or substituted at 1, at least 1, at least 2, at least 3, at least 4 or at least 5 locations upstream of the start codon. The nucleotides inserted and/or substituted may be the same base (e.g., all A or all C or all T or all G), two different bases (e.g., A and C, A and T, or C and T), three different bases (e.g., A, C and T or A, C and T) or at least four different bases. As a non-limiting example, the guanine base upstream of the coding region in the polynucleotide may be substituted with adenine, cytosine, thymine, or any of the nucleotides described herein. In another non-limiting example the substitution of guanine bases in the polynucleotide may be designed so as to leave one guanine base in the region downstream of the transcription start site and before the start codon (see Esvelt et al. Nature (2011) 472(7344):499-503; the contents of which is herein incorporated by reference in its entirety). As a non-limiting example, at least 5 nucleotides may be inserted at 1 location downstream of the transcription start site but upstream of the start codon and the at least 5 nucleotides may be the same base type.


Incorporating Post Transcriptional Control Modulators

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may include at least one post transcriptional control modulator. These post transcriptional control modulators may be, but are not limited to, small molecules, compounds and regulatory sequences. As a non-limiting example, post transcriptional control may be achieved using small molecules identified by PTC Therapeutics Inc. (South Plainfield, NJ) using their GEMS™ (Gene Expression Modulation by Small-Molecules) screening technology.


The post transcriptional control modulator may be a gene expression modulator which is screened by the method detailed in or a gene expression modulator described in International Publication No. WO2006022712, herein incorporated by reference in its entirety. Methods identifying RNA regulatory sequences involved in translational control are described in International Publication No. WO2004067728, herein incorporated by reference in its entirety; methods identifying compounds that modulate untranslated region dependent expression of a gene are described in International Publication No. WO2004065561, herein incorporated by reference in its entirety.


In one embodiment, the polynucleotides of the present invention may include at least one post transcriptional control modulator is located in the 5′ and/or the 3′ untranslated region of the polynucleotides of the present invention.


In another embodiment, the polynucleotides of the present invention may include at least one post transcription control modulator to modulate premature translation termination. The post transcription control modulators may be compounds described in or a compound found by methods outlined in International Publication Nos. WO2004010106, WO2006044456, WO2006044682, WO2006044503 and WO2006044505, each of which is herein incorporated by reference in its entirety. As a non-limiting example, the compound may bind to a region of the 28S ribosomal RNA in order to modulate premature translation termination (See e.g., WO2004010106, herein incorporated by reference in its entirety).


In one embodiment, polynucleotides of the present invention may include at least one post transcription control modulator to alter protein expression. As a non-limiting example, the expression of VEGF may be regulated using the compounds described in or a compound found by the methods described in International Publication Nos. WO2005118857, WO2006065480, WO2006065479 and WO2006058088, each of which is herein incorporated by reference in its entirety.


The polynucleotides of the present invention may include at least one post transcription control modulator to control translation. In one embodiment, the post transcription control modulator may be a RNA regulatory sequence. As a non-limiting example, the RNA regulatory sequence may be identified by the methods described in International Publication No. WO2006071903, herein incorporated by reference in its entirety.


Codon Optimization

The polynucleotides contained in the NAVs of the invention, their regions or parts or subregions may be codon optimized. Codon optimization methods are known in the art and may be useful in efforts to achieve one or more of several goals. These goals include to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that may impair gene construction or expression, customize transcriptional and translational control regions, insert or remove protein trafficking sequences, remove/add post translation modification sites in encoded protein (e.g. glycosylation sites), add, remove or shuffle protein domains, insert or delete restriction sites, modify ribosome binding sites and mRNA degradation sites, to adjust translational rates to allow the various domains of the protein to fold properly, or to reduce or eliminate problem secondary structures within the polynucleotide. Codon optimization tools, algorithms and services are known in the art, non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park CA) and/or proprietary methods. In one embodiment, the ORF sequence is optimized using optimization algorithms. Codon options for each amino acid are given in Table 21.









TABLE 21







Codon Options










Single



Amino Acid
Letter Code
Codon Options





Isoleucine
I
ATT, ATC, ATA


Leucine
L
CTT, CTC, CTA, CTG, TTA, TTG


Valine
V
GTT, GTC, GTA, GTG


Phenylalanine
F
TTT, TTC


Methionine
M
ATG


Cysteine
C
TGT, TGC


Alanine
A
GCT, GCC, GCA, GCG


Glycine
G
GGT, GGC, GGA, GGG


Proline
P
CCT, CCC, CCA, CCG


Threonine
T
ACT, ACC, ACA, ACG


Serine
S
TCT, TCC, TCA, TCG, AGT, AGC


Tyrosine
Y
TAT, TAC


Tryptophan
W
TGG


Glutamine
Q
CAA, CAG


Asparagine
N
AAT, AAC


Histidine
H
CAT, CAC


Glutamic acid
E
GAA, GAG


Aspartic acid
D
GAT, GAC


Lysine
K
AAA, AAG


Arginine
R
CGT, CGC, CGA, CGG, AGA, AGG


Selenocysteine
Sec
UGA in mRNA in presence of




Selenocystein insertion element




(SECIS)


Stop codons
Stop
TAA, TAG, TGA









Features, which may be considered beneficial in some embodiments of the present invention, may be encoded by regions of the polynucleotide and such regions may be upstream (5′) or downstream (3′) to a region which encodes a polypeptide. These regions may be incorporated into the polynucleotide before and/or after codon optimization of the protein encoding region or open reading frame (ORF). It is not required that a polynucleotide contain both a 5′ and 3′ flanking region. Examples of such features include, but are not limited to, untranslated regions (UTRs), Kozak sequences, an oligo(dT) sequence, and detectable tags and may include multiple cloning sites which may have XbaI recognition.


In some embodiments, a 5′ UTR and/or a 3′ UTR region may be provided as flanking regions. Multiple 5′ or 3′ UTRs may be included in the flanking regions and may be the same or of different sequences. Any portion of the flanking regions, including none, may be codon optimized and any may independently contain one or more different structural or chemical modifications, before and/or after codon optimization.


After optimization (if desired), the polynucleotides components are reconstituted and transformed into a vector such as, but not limited to, plasmids, viruses, cosmids, and artificial chromosomes. For example, the optimized polynucleotide may be reconstituted and transformed into chemically competent E. coli, yeast, neurospora, maize, drosophila, etc. where high copy plasmid-like or chromosome structures occur by methods described herein.


Synthetic polynucleotides and their nucleic acid analogs play an important role in the research and studies of biochemical processes. Various enzyme-assisted and chemical-based methods have been developed to synthesize polynucleotides and nucleic acids, in particular, polynucleotides and nucleic acids featured in the NAVs of the invention, as described infra.


Synthesis: Enzymatic Methods
In Vitro Transcription-Enzymatic Synthesis

cDNA encoding the polynucleotides described herein may be transcribed using an in vitro transcription (IVT) system. The system typically comprises a transcription buffer, nucleotide triphosphates (NTPs), an RNase inhibitor and a polymerase. The NTPs may be manufactured in house, may be selected from a supplier, or may be synthesized as described herein. The NTPs may be selected from, but are not limited to, those described herein including natural and unnatural (modified) NTPs. The polymerase may be selected from, but is not limited to, T7 RNA polymerase, T3 RNA polymerase and mutant polymerases such as, but not limited to, polymerases able to incorporate polynucleotides (e.g., modified nucleic acids).


RNA Polymerases Useful for Synthesis

Any number of RNA polymerases or variants may be used in the synthesis of the polynucleotides of the present invention.


RNA polymerases may be modified by inserting or deleting amino acids of the RNA polymerase sequence. As a non-limiting example, the RNA polymerase may be modified to exhibit an increased ability to incorporate a 2′-modified nucleotide triphosphate compared to an unmodified RNA polymerase (see International Publication WO2008078180 and U.S. Pat. No. 8,101,385; herein incorporated by reference in their entireties).


Variants may be obtained by evolving an RNA polymerase, optimizing the RNA polymerase amino acid and/or nucleic acid sequence and/or by using other methods known in the art. As a non-limiting example, T7 RNA polymerase variants may be evolved using the continuous directed evolution system set out by Esvelt et al. (Nature (2011) 472(7344):499-503; herein incorporated by reference in its entirety) where clones of T7 RNA polymerase may encode at least one mutation such as, but not limited to, lysine at position 93 substituted for threonine (K93T), 14M, A7T, E63V, V64D, A65E, D66Y, T76N, C125R, S128R, A136T, N165S, G175R, H176L, Y178H, F182L, L196F, G198V, D208Y, E222K, S228A, Q239R, T243N, G259D, M2671, G280C, H300R, D351A, A354S, E356D, L360P, A383V, Y385C, D388Y, S397R, M40 IT, N410S, K450R, P451T, G452V, E484A, H523L, H524N, G542V. E565K, K577E, K577M, N601 S, S684Y, L6991, K713E, N748D, Q754R, E775K, A827V, D851N or L864F. As another non-limiting example, T7 RNA polymerase variants may encode at least mutation as described in U.S. Pub. Nos. 20100120024 and 20070117112; herein incorporated by reference in their entireties. Variants of RNA polymerase may also include, but are not limited to, substitutional variants, conservative amino acid substitution, insertional variants, deletional variants and/or covalent derivatives.


In one embodiment, the polynucleotide may be designed to be recognized by the wild type or variant RNA polymerases. In doing so, the polynucleotide may be modified to contain sites or regions of sequence changes from the wild type or parent polynucleotide.


Polynucleotide or nucleic acid synthesis reactions may be carried out by enzymatic methods utilizing polymerases. Polymerases catalyze the creation of phosphodiester bonds between nucleotides in a polynucleotide or nucleic acid chain. Currently known DNA polymerases can be divided into different families based on amino acid sequence comparison and crystal structure analysis. DNA polymerase 1 (pol I) or A polymerase family, including the Klenow fragments of E. Coli, Bacillus DNA polymerase I, Thermus aquaticus (Taq) DNA polymerases, and the T7 RNA and DNA polymerases, is among the best studied of these families. Another large family is DNA polymerase a (pol a) or B polymerase family, including all eukaryotic replicating DNA polymerases and polymerases from phages T4 and RB69. Although they employ similar catalytic mechanism, these families of polymerases differ in substrate specificity, substrate analog-incorporating efficiency, degree and rate for primer extension, mode of DNA synthesis, exonuclease activity, and sensitivity against inhibitors.


DNA polymerases are also selected based on the optimum reaction conditions they require, such as reaction temperature, pH, and template and primer concentrations. Sometimes a combination of more than one DNA polymerases is employed to achieve the desired DNA fragment size and synthesis efficiency. For example, Cheng et al. increase pH, add glycerol and dimethyl sulfoxide, decrease denaturation times, increase extension times, and utilize a secondary thermostable DNA polymerase that possesses a 3′ to 5′ exonuclease activity to effectively amplify long targets from cloned inserts and human genomic DNA (Cheng et al., PNAS, Vol. 91, 5695-5699 (1994), the contents of which are incorporated herein by reference in their entirety). RNA polymerases from bacteriophage T3, T7, and SP6 have been widely used to prepare RNAs for biochemical and biophysical studies. RNA polymerases, capping enzymes, and poly-A polymerases are disclosed in the copending application No. PCT/US2013/054635 (M032), the contents of which are incorporated herein by reference in their entirety.


In one embodiment, the RNA polymerase which may be used in the synthesis of the chimeric polynucleotides described herein is a Syn5 RNA polymerase (see Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety). The Syn5 RNA polymerase was recently characterized from marine cyanophage Syn5 by Zhu et al. where they also identified the promoter sequence (see Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety). Zhu et al. found that Syn5 RNA polymerase catalyzed RNA synthesis over a wider range of temperatures and salinity as compared to T7 RNA polymerase. Additionally, the requirement for the initiating nucleotide at the promoter was found to be less stringent for Syn5 RNA polymerase as compared to the T7 RNA polymerase making Syn5 RNA polymerase promising for RNA synthesis.


In one embodiment, a Syn5 RNA polymerase may be used in the synthesis of the chimeric polynucleotides described herein. As a non-limiting example, a Syn5 RNA polymerase may be used in the synthesis of the chimeric polynucleotide requiring a precise 3′-termini.


In one embodiment, a Syn5 promoter may be used in the synthesis of the chimeric polynucleotides. As a non-limiting example, the Syn5 promoter may be 5′-ATTGGGCACCCGTAAGGG-3′ (SEQ ID NO: 966) as described by Zhu et al. (Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, a Syn5 RNA polymerase may be used in the synthesis of chimeric polynucleotides comprising at least one chemical modification described herein and/or known in the art. (see e.g., the incorporation of pseudo-UTP and 5Me-CTP described in Zhu et al. Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the chimeric polynucleotides described herein may be synthesized using a Syn5 RNA polymerase which has been purified using modified and improved purification procedure described by Zhu et al. (Nucleic Acids Research 2013, the contents of which is herein incorporated by reference in its entirety).


Various tools in genetic engineering are based on the enzymatic amplification of a target gene which acts as a template. For the study of sequences of individual genes or specific regions of interest and other research needs, it is necessary to generate multiple copies of a target gene from a small sample of polynucleotides or nucleic acids. Such methods may be applied in the manufacture of the polynucleotides of the invention.


Polymerase chain reaction (PCR) has wide applications in rapid amplification of a target gene, as well as genome mapping and sequencing. The key components for synthesizing DNA comprise target DNA molecules as a template, primers complementary to the ends of target DNA strands, deoxynucleoside triphosphates (dNTPs) as building blocks, and a DNA polymerase. As PCR progresses through denaturation, annealing and extension steps, the newly produced DNA molecules can act as a template for the next circle of replication, achieving exponentially amplification of the target DNA. PCR requires a cycle of heating and cooling for denaturation and annealing. Variations of the basic PCR include, but are not limited to, asymmetric PCR (See e.g., Innis et al., PNAS, vol. 85, 9436-9440 (1988), the contents of which are incorporated herein by reference in their entirety), inverse PCR (see e.g., Ochman et al., Genetics, vol. 120(3), 621-623, (1988), the contents of which are incorporated herein by reference in their entirety), and reverse transcription PCR (RT-PCR) (see e.g., Freeman et al., BioTechniques, vol. 26(1), 112-22, 124-5 (1999), the contents of which are incorporated herein by reference in their entirety). In RT-PCR, a single stranded RNA is the desired target and is converted to a double stranded DNA first by reverse transcriptase.


A variety of isothermal in vitro nucleic acid amplification techniques have been developed as alternatives or complements of PCR. For example, strand displacement amplification (SDA) is based on the ability of a restriction enzyme to form a nick (Walker et al., PNAS, vol. 89, 392-396 (1992), the contents of which are incorporated herein by reference in their entirety). A restriction enzyme recognition sequence is inserted into an annealed primer sequence. Primers are extended by a DNA polymerase and dNTPs to form a duplex. Only one strand of the duplex is cleaved by the restriction enzyme. Each single strand chain is then available as a template for subsequent synthesis. SDA does not require the complicated temperature control cycle of PCR.


Nucleic acid sequence-based amplification (NASBA), also called transcription mediated amplification (TMA), is also an isothermal amplification method that utilizes a combination of DNA polymerase, reverse transcriptase, RNAse H, and T7 RNA polymerase (Compton, Nature, vol. 350, 91-92 (1991), the contents of which are incorporated herein by reference in their entirety). A target RNA is used as a template and a reverse transcriptase synthesizes its complementary DNA strand. RNAse H hydrolyzes the RNA template, making space for a DNA polymerase to synthesize a DNA strand complementary to the first DNA strand which is complementary to the RNA target, forming a DNA duplex. T7 RNA polymerase continuously generates complementary RNA strands of this DNA duplex. These RNA strands act as templates for new cycles of DNA synthesis, resulting in amplification of the target gene.


Rolling-circle amplification (RCA) amplifies a single stranded circular polynucleotide and involves numerous rounds of isothermal enzymatic synthesis where Φ29 DNA polymerase extends a primer by continuously progressing around the polynucleotide circle to replicate its sequence over and over again. Therefore, a linear copy of the circular template is achieved. A primer can then be annealed to this linear copy and its complementary chain can be synthesized (Lizardi et al., Nature Genetics, vol. 19, 225-232 (1998), the contents of which are incorporated herein by reference in their entirety). A single stranded circular DNA can also serve as a template for RNA synthesis in the presence of an RNA polymerase (Daubendiek et al., JACS, vol. 117, 7818-7819 (1995), the contents of which are incorporated herein by reference in their entirety). An inverse rapid amplification of cDNA ends (RACE) RCA is described by Polidoros et al. (BioTechniques, vol. 41, 35-42 (2006), the contents of which are incorporated herein by reference in their entirety). A messenger RNA (mRNA) is reverse transcribed into cDNA, followed by RNAse H treatment to separate the cDNA. The cDNA is then circularized by CircLigase into a circular DNA. The amplification of the resulting circular DNA is achieved with RCA.


Any of the foregoing methods may be utilized in the manufacture of one or more regions of the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention).


Assembling polynucleotides or nucleic acids (e.g., antigen-encoding polynucleotides or nucleic acids) by a ligase is also widely used. DNA or RNA ligases promote intermolecular ligation of the 5′ and 3′ ends of polynucleotide chains through the formation of a phosphodiester bond. Ligase chain reaction (LCR) is a promising diagnosing technique based on the principle that two adjacent polynucleotide probes hybridize to one strand of a target gene and couple to each other by a ligase. If a target gene is not present, or if there is a mismatch at the target gene, such as a single-nucleotide polymorphism (SNP), the probes cannot ligase (Wiedmann et al., PCR Methods and Application, vol. 3 (4), s51-s64 (1994), the contents of which are incorporated herein by reference in their entirety). LCR may be combined with various amplification techniques to increase sensitivity of detection or to increase the amount of products if it is used in synthesizing polynucleotides and nucleic acids.


Several library preparation kits for nucleic acids are now commercially available. They include enzymes and buffers to convert a small amount of nucleic acid samples into an indexed library for downstream applications. For example, DNA fragments may be placed in a NEBNEXT® ULTRA™ DNA Library Prep Kit by NEWENGLAND BIOLABS® for end preparation, ligation, size selection, clean-up, PCR amplification and final clean-up.


Continued development is going on to improvement the amplification techniques. For example, U.S. Pat. No. 8,367,328 to Asada et al. the contents of which are incorporated herein by reference in their entirety, teaches utilizing a reaction enhancer to increase the efficiency of DNA synthesis reactions by DNA polymerases. The reaction enhancer comprises an acidic substance or cationic complexes of an acidic substance. U.S. Pat. No. 7,384,739 to Kitabayashi et al. the contents of which are incorporated herein by reference in their entirety, teaches a carboxylate ion-supplying substance that promotes enzymatic DNA synthesis, wherein the carboxylate ioin-supplying substance is selected from oxalic acid, malonic acid, esters of oxalic acid, esters of malonic acid, salts of malonic acid, and esters of maleic acid. U.S. Pat. No. 7,378,262 to Sobek et al. the contents of which are incorporated herein by reference in their entirety, discloses an enzyme composition to increase fidelity of DNA amplifications. The composition comprises one enzyme with 3′ exonuclease activity but no polymerase activity and another enzyme that is a polymerase. Both of the enzymes are thermostable and are reversibly modified to be inactive at lower temperatures.


U.S. Pat. No. 7,550,264 to Getts et al. teaches multiple round of synthesis of sense RNA molecules are performed by attaching oligodeoxynucleotides tails onto the 3′ end of cDNA molecules and initiating RNA transcription using RNA polymerase, the contents of which are incorporated herein by reference in their entirety. US Pat. Publication No. 2013/0183718 to Rohayem teaches RNA synthesis by RNA-dependent RNA polymerases (RdRp) displaying an RNA polymerase activity on single-stranded DNA templates, the contents of which are incorporated herein by reference in their entirety. Oligonucleotides with non-standard nucleotides may be synthesized with enzymatic polymerization by contacting a template compring non-standard nucleotides with a mixture of nucleotides that are complementary to the nucleotides of the template as disclosed in U.S. Pat. No. 6,617,106 to Benner, the contents of which are incorporated herein by reference in their entirety.


Synthesis: Solid-Phase Chemical Synthesis

Chimeric polynucleotides or circular polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be manufactured in whole or in part using solid phase techniques.


Solid-phase chemical synthesis of polynucleotides or nucleic acids is an automated method wherein molecules are immobilized on a solid support and synthesized step by step in a reactant solution. Impurities and excess reagents are washed away and no purification is required after each step. The automation of the process is amenable on a computer-controlled solid-phase synthesizer. Solid-phase synthesis allows rapid production of polynucleotides or nucleic acids in a relatively large scale that leads to the commercial availability of some polynucleotides or nucleic acids. Furthermore, it is useful in site-specific introduction of chemical modifications in the polynucleotide or nucleic acid sequences. It is an indispensable tool in designing modified derivatives of natural nucleic acids.


In automated solid-phase synthesis, the chain is synthesized in 3′ to 5′ direction. The hydroxyl group in the 3′ end of a nucleoside is tethered to a solid support via a chemically cleavable or light-cleavable linker. Activated nucleoside monomers, such as 2′-deoxynucleosides (dA, dC, dG and T), ribonucleosides (A, C, G, and U), or chemically modified nucleosides, are added to the support-bound nucleoside sequentially. Currently most widely utilized monomers are the 3′-phophoramidite derivatives of nucleoside building blocks. The 3′ phosphorus atom of the activated monomer couples with the 5′ oxygen atom of the support-bound nucleoside to form a phosphite triester. To prevent side reactions, all functional groups not involved in the coupling reaction, such as the 5′ hydroxyl group, the hydroxyl group on the 3′ phosphorus atom, the 2′ hydroxyl group in ribonucleosides monomers, and the amino groups on the purine or pyrimidine bases, are all blocked with protection groups. The next step involves oxidation of the phosphite triester to form a phosphate triester or phosphotriester, where the phosphorus atom is pentavalent. The protection group on the 5′ hydroxyl group at the end of the growing chain is then removed, ready to couple with an incoming activated monomer building block. At the end of the synthesis, a cleaving agent such as ammonia or ammonium hydroxide is added to remove all the protecting groups and release the polynucleotide chains from the solid support. Light may also be applied to cleave the polynucleotide chain. The product can then be further purified with high pressure liquid chromatography (HPLC) or electrophoresis.


In solid-phase synthesis, the polynucleotide chain is covalently bound to the solid support via its 3′ hydroxyl group. The solid supports are insoluble particles also called resins, typically 50-200 μm in diameter. Many different kinds of resins are now available, as reviewed in “Solid-phase supports for polynucleotide synthesis” by Guzaev (Guzaev, Current Protocols in Nucleic Acid Chemistry, 3.1.1-3.1.60 (2013), the contents of which are incorporated herein by reference in their entirety). The most common materials for the resins include highly cross-linked polystyrene beads and controlled pore glass (CPG) beads. The surface of the beads may be treated to have functional groups, such as amino or aminomethyl groups that can be used as anchoring points for linkers to tether nucleosides. They can be implemented in columns, multi-well plates, microarrays or microchips. The column-based format allows relatively large scale synthesis of the polynucleotides or nucleic acids. The resins are held between filters in columns that enable all reagents and solvents to pass through freely. Multi-well plates, microarrays, or microchips are designed specifically for cost-effective small scale synthesis. Up to a million polynucleotides can be produced on a single microarray chip. However, the error rates of microchip-based synthesis are higher than traditional column-based methods (Borovkov et al., Nucleic Acids Research, vol. 38(19), e180 (2010), the contents of which are incorporated herein by reference in their entirety). Multi-well plates allow parallel synthesis of polynucleotides or nucleic acids with different sequences simultaneously (Sindelar, et al., Nucleic Acids Research, vol. 23, 982-987 (1995), the contents of which are incorporated herein by reference in their entirety). The loading on the solid supports is limited. In addition, as the extension progresses, the morphology and bulkiness of the growing chains on the solid supports might hinder the incoming monomers from reacting with the terminal group of the growing chains. Therefore, the number of monomers that can be added to the growing chain is also limited.


Linkers are attached to the solid support for further extension of the chain. They are stable to all the reagents used in the synthesis process, except in the end of the synthesis when the chain is detached from the solid support. Solid supports with a specific nucleoside linker, i.e., A, C, dT, G, or U, can be used to prepare polynucleotides with A, C, T, G, or U as the first nucleotide in the sequence, respectively. Universal solid supports with non-nucleoside linkers can be used for all polynucleotide sequences (U.S. Pat. No. 6,653,468 to Guzaev et al., the contents of which are incorporated herein by reference in their entirety). Various non-nucleoside linkers have been developed for universal supports, a lot of them with two vicinal hydroxyl groups. For example, a succinyl group is a frequently used linker.


As used herein, a linker refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine. The linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety. A linker may be nucleic acid based or non-nucleosidic. The linker may be of sufficient length as to not interfere with incorporation into a nucleic acid sequence. The linker can be used for any useful purpose, such as to form multimers (e.g., through linkage of two or more chimeric polynucleotides molecules) or conjugates, as well as to administer a therapeutic molecule or incorporate a label, as described herein. Examples of chemical groups that can be incorporated into the linker include, but are not limited to, alkyl, alkenyl, alkynyl, amido, amino, ether, thioether, ester, alkylene, heteroalkylene, aryl, or heterocyclyl, each of which can be optionally substituted, as described herein. Examples of linkers include, but are not limited to, unsaturated alkanes, polyethylene glycols (e.g., ethylene or propylene glycol monomeric units, e.g., diethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, tetraethylene glycol, or tetraethylene glycol), and dextran polymers and derivatives thereof. Other examples include, but are not limited to, cleavable moieties within the linker, such as, for example, a disulfide bond (—S—S—) or an azo bond (—N═N—), which can be cleaved using a reducing agent or photolysis. Non-limiting examples of a selectively cleavable bond include an amido bond can be cleaved for example by the use of tris(2-carboxyethyl)phosphine (TCEP), or other reducing agents, and/or photolysis, as well as an ester bond can be cleaved for example by acidic or basic hydrolysis.)


Besides the functional groups on the activated monomer and the growing chain needed for the coupling reaction to extend the chain, all other functional groups need to be protected to avoid side reactions. The conditions for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found and/or described, for example, in Greene, et al. (Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, the contents of which is incorporated herein by reference in its entirety.) For example, the 5′ hydroxyl group on the activated nucleoside phosphoramidite monomers may be protected with 4,4′-dimethoxytrityl (DMT) and the hydroxyl group on the phosphorus atom may be protected with 2-cyanoethyl. The exocyclic amino groups on the A, C, G bases may be protected with acyl groups.


In a solid-phase synthesis system, the reactivity of the activated monomers is important, because of the heterogeneity of the media. A majority of solid-phase synthesis uses phosphoramidite nucleosides, the mechanism of which is discussed above. Another activated monomer example is nucleoside H-phosphonates (Abramova, Molecules, vol. 18, 1063-1075 (2013), the contents of which are incorporated herein by reference in their entirety). A large excess of reagents, such as monomers, oxidizing agents, and deprotection agents, is required in order to ensure high yields in the solid-phase synthesis system.


Scientific studies and research are going on to further improve the solid-phase synthesis method. For example, instead of the well-established 3′-to-5′ synthesis, U.S. Pat. No. 8,309,707 and US Pat. Publication No. 2013/0072670 to Srivastava et al. disclosed a 5′-to-3′ synthesis of RNA utilizing a novel phosphoramidite and a novel nucleoside derivative, thereby allowing easy modifications of the synthetic RNA at the 3′ end. PCT application WO2013123125 to Church et al. the contents of which are incorporated herein by reference in their entirety, describes assembly of a target nucleic acid sequence from a plurality of subsequences, wherein resins with the subsequences are placed in an emulsion droplet. The subsequences are cleaved off the resins and assemble within the emulsion droplet. To reduce the cost of solid supports, a reusable CPG solid support has been developed with a hydroquinone-O, O′-diacetic acid linker (Q-linker) (Pon et al., Nucleic Acid Research, vol. 27, 1531-1538 (1999), the contents of which are incorporated herein by reference in their entirety).


New protecting groups for solid-phase synthesis have also been developed. Nagat et al. has successfully synthesized 110-nt-long RNA with the sequence of a candidate precursor microRNA by using 2-cyanoethoxymethyl (CEM) as the 2′-hydroxy protecting group (Shiba et al., Nucleic Acids Research, vol. 35, 3287-3296 (2007), the contents of which are incorporated herein by reference in their entirety). Also with CEM as 2′-O-protecting group, a 130-nt mRNA has been synthesized encoding a 33-amino acid peptide that includes the sequence of glucagon-like peptide-1 (GLP-1). The biological activity of the artificial 130-nt mRNA is shown by producing GLP-1 in a cell-free protein synthesis system and in Chinese hamster ovary (CHO) cells (Nagata et al., Nucleic Acids Research, vol. 38(21), 7845-7857 (2010), the contents of which are incorporated herein by reference in their entirety). Novel protecting groups for solid-phase synthesis monomers include, but are not limited to, carbonate protecting group disclosed in U.S. Pat. No. 8,309,706 to Dellinger et al., orthoester-type 2′ hydroxyl protecting group and an acyl carbonate-type hydroxyl protecting group disclosed in U.S. Pat. No. 8,242,258 to Dellinger et al., 2′-hydroxyl thiocarbon protecting group disclosed in U.S. Pat. No. 8,202,983 to Dellinger et al., 2′-silyl containing thiocarbonate protecting group disclosed in U.S. Pat. No. 7,999,087 to Dellinger et al., 9-fluorenylmethoxycarbonyl (FMOS) derivatives as an amino protecting group disclosed in U.S. Pat. No. 7,667,033 to Alvarado, fluoride-labile 5′silyl protecting group disclosed in U.S. Pat. No. 5,889,136 to Scaringe et al., and pixyl protecting groups disclosed in US Pat. Publication No. 2008/0119645 to Griffey et al., the contents of which are incorporated herein by reference in their entirety. US Pat. Publication No. 2011/0275793 to Debart et al. teaches RNA synthesis using a protecting group of the hyoxyls in position 2′ of the ribose that can be removed by a base, the contents of which are incorporated herein by reference in their entirety. Novel solid supports include polymers made from monomers comprising protected hydroxypolyC24 alkyleneoxy chain attached to a polymerizable unit taught in U.S. Pat. No. 7,476,709 to Moody et al., the contents of which are incorporated herein by reference in their entirety.


Synthesis: Liquid Phase Chemical Synthesis

The synthesis of chimeric polynucleotides or circular polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) by the sequential addition of monomer building blocks may be carried out in a liquid phase. A covalent bond is formed between the monomers or between a terminal functional group of the growing chain and an incoming monomer. Functional groups not involved in the reaction must be temporarily protected. After the addition of each monomer building block, the reaction mixture has to be purified before adding the next monomer building block. The functional group at one terminal of the chain has to be deprotected to be able to react with the next monomer building blocks. A liquid phase synthesis is labor- and time-consuming and cannot not be automated. Despite the limitations, liquid phase synthesis is still useful in preparing short polynucleotides in a large scale. Because the system is homogenous, it does not require a large excess of reagents and is cost-effective in this respect.


Synthesis: Combination of Synthetic Methods

The synthetic methods discussed above each has its own advantages and limitations. Attempts have been conducted to combine these methods to overcome the limitations. Such combinations of methods are within the scope of the present invention.


Short polynucleotide chains with 2-4 nucleotides may be prepared in liquid phase followed by binding to a solid support for extension reactions by solid phase synthesis. A high efficiency liquid phase (HELP) synthesis is developed that uses monomethyl ether of polyethylene glycol (MPEG) beads as a support for the monomer building blocks. MPEG is soluble in methylene chloride and pyridine solvents but precipitates in a diethyl ether solvent. By choosing an appropriate solvent, the coupling reaction between monomers or between a growing chain and an incoming monomer bound on MPEG can be carried out in a homogenous liquid phase system. The mixture can then be washed with a diethyl ether solvent to easily precipitate and purify the product (Bonora et al., Nucleic Acids Research, vol. 18, 3155-3159 (1990), the contents of which are incorporated herein by reference in their entirety). U.S. Pat. No. 8,304,532 to Adamo et al., the contents of which are incorporated herein in their entirety, teaches a solution phase oligonucleotide synthesis where at least some of the reagents are solid supported.


The use of solid-phase or liquid-phase chemical synthesis in combination with enzymatic ligation provides an efficient way to generate long chain polynucleotides that cannot be obtained by chemical synthesis alone. Moore and Sharp describe preparing RNA fragments 10- to 20-nt long by chemical synthesis, to which site-specific modifications may be introduced, annealing the fragments to a cDNA bridge, and then assemble the fragments with T4 DNA ligase (Moore et al., Science, vol. 256, 992-997 (1992), the contents of which are incorporated herein by reference in their entirety).


A solid-phase synthesizer may produce enough polynucleotides or nucleic acids with good purity to preform PCR and other amplification techniques. Agilent Technologies have developed microarrays that are commercially available. Polynucleotides may be synthesized on a microarray substrate, cleaved by a strong base or light, followed by PCR amplification to generate a library of polynucleotides (Cleary et al., Nature Methods, vol. 1(3), 241-247 (2004), the contents of which are incorporated herein by reference in their entirety).


Synthesis: Small Region Synthesis

Regions or subregions of the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may comprise small RNA molecules such as siRNA, and therefore may be synthesized in the same manner. There are several methods for preparing siRNA, such as chemical synthesis using appropriately protected ribonucleoside phosphoramidites, in vitro transcription, siRNA expression vectors, and PCR expression cassettes. Sigma-Aldrich® is one of the siRNA suppliers and synthesizes their siRNA using ribonucleoside phosphoramidite monomers protected at the 2′ position with a t-butylmethylsilyl (TBDMS) group. The solid-phase chemical synthesis is carried out with SIGMA-ALDRICH®'s Ultra Fast Parallel Synthesis (UFPS) and Ultra Fast Parallel Deprotection (UFPD) to achieve high coupling efficiency and fast deprotection. The final siRNA products may be purified with HPLC or PAGE. Such methods may be used to synthesize regions or subregions of chimeric polynucleotides.


In vitro transcription and expression from a vector or a PCR-generated siRNA cassette require appropriate templates to produce siRNAs. The commercially available AMBION® SILENCER® siRNA construction kit produces siRNA by in vitro transcription of DNA templates and contains the enzymes, buffers, primers needed. Such methods may be used to synthesize regions or subregions of chimeric polynucleotides.


Synthesis: Ligation of Polynucleotide Regions or Subregions

Polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) such as chimeric polynucleotides and/or circular polynucleotides may be prepared by ligation of one or more regions or subregions.


Ligation is an indispensable tool for assembling polynucleotide or nucleic acid fragments into larger constructs. DNA fragments can be joined by a ligase catalyzed reaction to create recombinant DNA with different functions. Two oligodeoxynucleotides, one with a 5′ phosphoryl group and another with a free 3′ hydroxyl group, serve as substrates for a DNA ligase. Oligodexoynucleotides with fluorescent or chemiluminescent labels may also serve as DNA ligase substrates (Martinelli et al., Clinical Chemistry, vol. 42, 14-18 (1996), the contents of which are incorporated herein by reference in their entirety). RNA ligases such as T4 RNA ligase catalyze the formation of a phosphodiester bond between two single stranded oligoribonucleotides or RNA fragments. Copies of large DNA constructs have been synthesized with a combination of polynucleotide fragments, thermostable DNA polymerases, and DNA ligases. US Pat. Publication No. 2009/0170090 to Ignatov et al., the contents of which are incorporated herein by reference in their entirety, discloses improving PCT, especially enhancing yield of a long distance PCR and/or a low copy DNA template PCR amplication, by using a DNA ligase in addition to a DNA polymerase.


Ligases may be used with other enzymes to prepare desired chimeric polynucleotide or nucleic acid molecules and to perform genome analysis. For example, ligation-mediated selective PCR amplification is disclosed in EP Pat. Pub. No. 0735144 to Kato. Complementary DNAs (cDNAs) reverse-transcribed from tissue- or cell-derived RNA or DNA are digested into fragments with type IIS restriction enzymes the contents of which are incorporated herein by reference in their entirety. Biotinylated adapter sequences are attached to the fragments by E. coli DNA ligases. The biotin-labeled DNA fragments are then immobilized onto streptavidin-coated beads for downstream analysis.


A ligation splint or a ligation splint oligo is an oligonucleotide that is used to provide an annealing site or a ligation template for joining two ends of one nucleic acid, i.e., intramolecular joining, or two ends of two nucleic acids, i.e., intermolecular joining, using a ligase or another enzyme with ligase activity. The ligation splint holds the ends adjacent to each other and creates a ligation junction between the 5′-phosphorylated and a 3′-hydroxylated ends that are to be ligated.


In one embodiment, a splint-mediated ligation or splint ligation method may be used to synthesize the chimeric polynucleotides described herein. The chimeric polynucleotide may be assembled using a method that does not rely on the presence of restriction endonuclease cleavage sites such as the method described in international Patent Publication No. WO2012138453, the contents of which are herein incorporated by reference in its entirety. Splint-mediated ligation allows for the rapid synthesis of the construct using controlled concatenation and without the need or with limited need for the introduction of restriction sites at the joining regions. As a non-limiting example, splint ligation may be used to add at least one untranslated region to a coding region of the chimeric polynucleotide. In one embodiment, splint ligation may be used in combination with other synthesis methods in the synthesis of the chimeric polynucleotides described herein.


If the 5′-phosphorylated and the 3′-hydroxyl ends of nucleic acids are ligated when the ends are annealed to a ligation splint so that the ends are adjacent, enzymes such as, but not limited to, T4 DNA ligase, AMPLIGASE® DNA Ligase (EPICENTRE® Technologies), Tth DNA ligase, TJ7 DNA ligase, or Tsc DNA Ligase (Prokaria) can be used. Farugui IN U.S. Pat. No. 6,368,801 (the contents of which is incorporated by reference in its entirety) describes that T4 RNA ligase can efficiently ligate ends of DNA molecules that are adjacent to each other when hybridized to an RNA splint. Thus, T4 RNA ligase is a suitable ligase for joining DNA ends with a ligation splint oligo comprising RNA or modified RNA. Examples of RNA splints include modified RNA containing 2′-fluorine-CTP (2′-F-dCTP) and 2′-fluorine-UTP (2′-F-dUTP) made using the DURASCRIBE® T7 Transcription Kit (EPICENTRE® Technologies) disclosed in U.S. Pat. No. 8,137,911 and US Pat. Publication 2012/0156679 to Dahl et al, the contents of each of which are incorporated herein by reference in their entirety. The modified RNA produced from DURASCRIBE® T7 Transcription kit is completely resistant to RNase A digestion. DNA splint and DNA ligase may be used to generate RNA-protein fusions disclosed in U.S. Pat. No. 6,258,558 to Szostak et al., the contents of which are incorporated herein by reference in their entirety.


For intramolecular ligation of linear ssDNA, U.S. Pat. No. 7,906,490 to Kool et al. teaches constructing a 83-nucleotide circle by making linear oligodeoxynucleotides fragments on a DNA synthesizer followed by ligation with T4 DNA ligase and two 30 nucleotide splint oligonucleotides. Circulation of linear sense promoter-containing cDNA is disclosed in US Pat. Publication No. 2012/0156679 to Dahl et al., the contents of which are incorporated herein by reference in their entirety. THERMOPHAGET ssDNA ligase (Prokazyme), which is derived from phage TS2126 that infects Thermus scotoductus, catalyzes ATP-dependent intra- and inter-molecular ligation of DNA and RNA.


The solid-phase chemical synthesis method that uses phosphoramidite monomers is limited to produce DNA molecules with short strands. The purity of the DNA products and the yield of reactions become poor when the length exceeds 150 bases. For the synthesis of long polynucleotides in high yields, it is more convenient to use enzymatic ligation method in tandem with chemical synthesis. For example, Moore and Sharp describe preparing RNA fragments 10- to 20-nt long by chemical synthesis, to which site-specific modifications may be introduced, annealing the fragments to a cDNAsplint, and then assemble the fragments with T4 DNA ligase (Moore et al., Science, vol. 256, 992-997 (1992), the contents of which are incorporated herein by reference in their entirety). Ligation reactions of oligoribonucleotides with T4 RNA ligase and a DNA splint or a polyribonucleotide to generate large, synthetic RNAs are described in Bain et al., Nucleic Acids Research, vol. 20(16), 4372 (1992), Stark et al., RNA, vol. 12, 2014-2019 (2006), and US Pat. Application No. 2005/0130201 to Deras et al., the contents of each of which are incorporated herein by reference in their entirety. 5′-cap and 3′-polyA tail are often added by enzymatic addition to an oligonucleotide synthesized with solid-phase methods. As a non-limiting example, a synthetic capped 42-mer mRNA has been synthesized in three fragments enzymatically ligated as described by Iwase et al. (Nucleic Acids Research, vol. 20, 1643-1648 (1992), the contents of which are incorporated herein by reference in their entirety). As another example, a 16.3-kilobase mouse mitochondrial genome has been produced from 600 overlapping 60-mer polynucleotides. The method cycles between in vitro recombination and amplification may be repeated until the desired length is reached (Gibson et al., Nature Methods, vol. 7, 901-903 (2010), the contents of which are incorporated herein by reference in their entirety). The assembly of a 1.08 megabase Mycoplasma mycoides JCVI-syn1.0 genome has also been reported. As a non-limiting example, 1080 bp cassettes are produced by assembling polynucleotide fragments chemically generated from a polynucleotide synthesizer. The genome is then assembled in three stages by transformation and homologous recombination in yeast (Gibson, et al., Science, vol. 329, 52-56 (2010), the contents of which are incorporated herein by reference in their entirety).


Studies have been conducted to join short DNA fragments with chemical linkers. ‘Click’ chemistry or ‘click’ ligation, the cycloaddition reaction between azide and alkyne, has gained a lot of interest because of its advantages such as mild reaction condition, high yields, and inoffensive byproducts. ‘Click’ chemistry is reviewed by Nwe et al. in Cancer Biotherapy and Radiopharmaceuticals, vol. 24(3), 289-302 (2009), the contents of which are incorporated here by reference for their entirety. DNA constructs up to 300 bases in length have been produced with click ligation and longer sequences are feasible. Demonstrated with PCR data, various DNA polymerases are able to amplify the synthesized DNA constructs made by click ligation despite the triazole linkers between the fragments resulting from the cycloaddition reaction. In vitro transcription and rolling circle amplification can also be performed on the synthesized DNA constructs. Hairpin ribozymes up to 100 nucleotides in length and cyclic mini-DNA duplexes have also been prepared with click ligation (EI-Sagheer et al., Accounts of Chemical Research, vol. 45(8), 1258-1267 (2012), the contents of which are incorporated herein by reference in their entirety).


Sequential ligation can be performed on a solid substrate. For example, initial linker DNA molecules modified with biotin at the end are attached to streptavidin-coated beads. The 3′-ends of the linker DNA molecules are complimentary with the 5′-ends of the incoming DNA fragments. The beads are washed and collected after each ligation step and the final linear constructs are released by a meganuclease. This method allows rapid and efficient assembly of genes in an optimized order and orientation. (Takita, DNA Research, vol. 20(4), 1-10 (2013), the contents of which are incorporated herein by reference in their entirety). Labeled polynucleotides synthesized on solid-supports are disclosed in US Pat. Pub. No. 2001/0014753 to Soloveichik et al. and US Pat. Pub. No. 2003/0191303 to Vinayak et al., the contents of which are incorporated herein by reference for their entirety.


Quantification

In one embodiment, the polynucleotides of the present invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) may be quantified in exosomes or when derived from one or more bodily fluid. As used herein “bodily fluids” include peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowpers fluid or pre-ejaculatory fluid, sweat, fecal matter, hair, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, and umbilical cord blood. Alternatively, exosomes may be retrieved from an organ selected from the group consisting of lung, heart, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colon, breast, prostate, brain, esophagus, liver, and placenta.


In the exosome quantification method, a sample of not more than 2 mL is obtained from the subject and the exosomes isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof. In the analysis, the level or concentration of a polynucleotide may be an expression level, presence, absence, truncation or alteration of the administered construct. It is advantageous to correlate the level with one or more clinical phenotypes or with an assay for a human disease biomarker. The assay may be performed using construct specific probes, cytometry, qRT-PCR, real-time PCR. PCR, flow cytometry, electrophoresis, mass spectrometry, or combinations thereof while the exosomes may be isolated using immunohistochemical methods such as enzyme linked immunosorbent assay (ELISA) methods. Exosomes may also be isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof.


These methods afford the investigator the ability to monitor, in real time, the level of polynucleotides remaining or delivered. This is possible because the polynucleotides of the present invention differ from the endogenous forms due to the structural or chemical modifications.


In one embodiment, the polynucleotide may be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis). A non-limiting example of a UV/Vis spectrometer is a NANODROP® spectrometer (ThermoFisher, Waltham, MA). The quantified polynucleotide may be analyzed in order to determine if the polynucleotide may be of proper size, check that no degradation of the polynucleotide has occurred. Degradation of the polynucleotide may be checked by methods such as, but not limited to, agarose gel electrophoresis, HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).


Purification

Purification of the polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) described herein may include, but is not limited to, polynucleotide clean-up, quality assurance and quality control. Clean-up may be performed by methods known in the arts such as, but not limited to, AGENCOURT® beads (Beckman Coulter Genomics, Danvers, MA), poly-T beads. LNA™ oligo-T capture probes (EXIQON® Inc, Vedbaek, Denmark) or HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC). The term “purified” when used in relation to a polynucleotide such as a “purified polynucleotide” refers to one that is separated from at least one contaminant. As used herein, a “contaminant” is any substance which makes another unfit, impure or inferior. Thus, a purified polynucleotide (e.g., DNA and RNA) is present in a form or setting different from that in which it is found in nature, or a form or setting different from that which existed prior to subjecting it to a treatment or purification method.


A quality assurance and/or quality control check may be conducted using methods such as, but not limited to, gel electrophoresis. UV absorbance, or analytical HPLC.


In another embodiment, the polynucleotides may be sequenced by methods including, but not limited to reverse-transcriptase-PCR.


IV. Modifications

In exemplary embodiments, polynucleotides of the invention (e.g., antigen-encoding polynucleotides featured in the NAVs of the invention) can include various substitutions and/or insertions.


The data presented in the Examples demonstrate significant enhanced immune responses using the formulations of the invention. The data demonstrated the effectiveness of both chemically modified and unmodified RNA vaccines of the invention. Surprisingly, in contrast to prior art reports that it was preferable to use chemically unmodified mRNA formulated in a carrier for the production of vaccines, it was discovered herein that chemically modified mRNA-LNP vaccines required a much lower effective mRNA dose than unmodified mRNA, i.e., tenfold less than unmodified mRNA.


Additionally, a study described herein involved intravenous (IV), intramuscular (IM), or intradermal (ID) vaccination of mice, followed by challenge with a lethal dose of virus. In addition to all of the vaccinated animals surviving the lethal dose, significantly stronger early immune responses were observed (anti-viral activity via virus neutralization assay and HA inhibition (HAI)) in comparison to protein antigen and other lipid based formulations (lipoplex). The data demonstrated that as early as 1 week after vaccination both groups of animals receiving a chemically modified mRNA-LNP formulation (ID or IM) displayed HAI titers over 40, at 60 and 114, respectively. An HAI titer of greater than 40 is deemed sufficient to protect from a lethal challenge of influenza. The rapid response was unexpected, particularly when compared to the response seen with protein antigen and mRNA vaccines formulated in other lipid carriers (lipoplex), which at one week and even at three weeks following vaccination continued to show ineffective HAI titers of less than 40.


At each of the later time points (3 weeks and 5 weeks), the formulations of the invention continued to provide significantly stronger therapeutic responses than did protein antigen. In fact even chemically unmodified mRNA-LNP formulation administered by TV route had enhanced HAI titers with respect to the protein antigen. By week 3, all of the animals receiving an mRNA-LNP formulation by 1M or ID administration displayed HAI activity over 40, as compared to protein antigen, which at one week and three weeks continued to show HAI titers of less than 40. By week 5 the chemically modified mRNA-LNP formulation administered by ID route had a surprising HAI activity of greater than 10,000, in contrast to the HAI titer of around 400 for protein antigen at that time point.


Both the chemically modified and unmodified RNA vaccines of the invention produced better immune responses than did mRNA vaccines formulated in a different lipid carrier (lipoplex). At week 5 the non-chemically modified mRNA—lipoplex vaccine produced HAI titers of 197, in comparison to those achieved by the mRNA-LNP formulations of the invention (HAI titers of 635-10,152). At all other time points and for all of the chemically modified mRNA-lipoplex vaccines, none of the HAI titers reached the critical level of greater than 40. Additionally, the mRNA—lipoplex vaccine did not result in any detectable neutralizing activity in the microneutralization activity, even as late as five weeks after vaccination.


As used herein in a polynucleotide (such as a chimeric polynucleotide, IVT polynucleotide or a circular polynucleotide), the terms “chemical modification” or, as appropriate, “chemically modified” refer to modification with respect to adenosine (A), guanosine (G), uridine (U), thymidine (T) or cytidine (C) ribo- or deoxyribnucleosides in one or more of their position, pattern, percent or population. Generally, herein, these terms are not intended to refer to the ribonucleotide modifications in naturally occurring 5′-terminal mRNA cap moieties.


In a polypeptide, the term “modification” refers to a modification as compared to the canonical set of 20 amino acids.


The modifications may be various distinct modifications. In some embodiments, the regions may contain one, two, or more (optionally different) nucleoside or nucleotide modifications. In some embodiments, a modified polynucleotide, introduced to a cell may exhibit reduced degradation in the cell, as compared to an unmodified polynucleotide.


Modifications of the polynucleotides of the NAVs which are useful in the present invention include, but are not limited to those in Table 22. Noted in the table are the symbol of the modification, the nucleobase type and whether the modification is naturally occurring or not.









TABLE 22







Modifications













Naturally


Name
Symbol
Base
Occurring





2-methylthio-N6-(cis-
ms2i6A
A
YES


hydroxyisopentenyl)adenosine





2-methylthio-N6-methyladenosine
ms2m6A
A
YES


2-methylthio-N6-threonyl
ms2t6A
A
YES


carbamoyladenosine





N6-glycinylcarbamoyladenosine
g6A
A
YES


N6-isopentenyladenosine
i6A
A
YES


N6-methyladenosine
m6A
A
YES


N6-threonylcarbamoyladenosine
t6A
A
YES


1,2′-O-dimethyladenosine
m1Am
A
YES


1-methyladenosine
m1A
A
YES


2′-O-methyladenosine
Am
A
YES


2′-O-ribosyladenosine (phosphate)
Ar(p)
A
YES


2-methyladenosine
m2A
A
YES


2-methylthio-N6 isopentenyladenosine
ms2i6A
A
YES


2-methylthio-N6-hydroxynorvalyl
ms2hn6A
A
YES


carbamoyladenosine





2′-O-methyladenosine
m6A
A
YES


2′-O-ribosyladenosine (phosphate)
Ar(p)
A
YES


Isopentenyladenosine
Iga
A
YES


N6-(cis-hydroxyisopentenyl)adenosine
io6A
A
YES


N6,2′-O-dimethyladenosine
m6Am
A
YES


N6,2′-O-dimethyladenosine
m6Am
A
YES


N6,N6,2′-O-trimethyladenosine
m62Am
A
YES


N6,N6-dimethyladenosine
m62A
A
YES


N6-acetyladenosine
ac6A
A
YES


N6-hydroxynorvalylcarbamoyladenosine
hn6A
A
YES


N6-methyl-N6-
m6t6A
A
YES


threonylcarbamoyladenosine





2-methyladenosine
m2A
A
YES


2-methylthio-N6-isopentenyladenosine
ms2i6A
A
YES


7-deaza-adenosine

A
NO


N1-methyl-adenosine

A
NO


N6,N6 (dimethyl)adenine

A
NO


N6-cis-hydroxy-isopentenyl-adenosine

A
NO


α-thio-adenosine

A
NO


2 (amino)adenine

A
NO


2 (aminopropyl)adenine

A
NO


2 (methylthio) N6 (isopentenyl)adenine

A
NO


2-(alkyl)adenine

A
NO


2-(aminoalkyl)adenine

A
NO


2-(aminopropyl)adenine

A
NO


2-(halo)adenine

A
NO


2-(halo)adenine

A
NO


2-(propyl)adenine

A
NO


2′-Amino-2′-deoxy-ATP

A
NO


2′-Azido-2′-deoxy-ATP

A
NO


2′-Deoxy-2′-a-aminoadenosine TP

A
NO


2′-Deoxy-2′-a-azidoadenosine TP

A
NO


6 (alkyl)adenine

A
NO


6 (methyl)adenine

A
NO


6-(alkyl)adenine

A
NO


6-(methyl)adenine

A
NO


7 (deaza)adenine

A
NO


8 (alkenyl)adenine

A
NO


8 (alkynyl)adenine

A
NO


8 (amino)adenine

A
NO


8 (thioalkyl)adenine

A
NO


8-(alkenyl)adenine

A
NO


8-(alkyl)adenine

A
NO


8-(alkynyl)adenine

A
NO


8-(amino)adenine

A
NO


8-(halo)adenine

A
NO


8-(hydroxyl)adenine

A
NO


8-(thioalkyl)adenine

A
NO


8-(thiol)adenine

A
NO


8-azido-adenosine

A
NO


aza adenine

A
NO


deaza adenine

A
NO


N6 (methyl)adenine

A
NO


N6-(isopentyl)adenine

A
NO


7-deaza-8-aza-adenosine

A
NO


7-methyladenine

A
NO


1-Deazaadenosine TP

A
NO


2′Fluoro-N6-Bz-deoxyadenosine TP

A
NO


2′-OMe-2-Amino-ATP

A
NO


2′O-methyl-N6-Bz-deoxyadenosine TP

A
NO


2′-a-Ethynyladenosine TP

A
NO


2-aminoadenine

A
NO


2-Aminoadenosine TP

A
NO


2-Amino-ATP

A
NO


2′-a-Trifluoromethyladenosine TP

A
NO


2-Azidoadenosine TP

A
NO


2′-b-Ethynyladenosine TP

A
NO


2-Bromoadenosine TP

A
NO


2′-b-Trifluoromethyladenosine TP

A
NO


2-Chloroadenosine TP

A
NO


2′-Deoxy-2′,2′-difluoroadenosine TP

A
NO


2′-Deoxy-2′-a-mercaptoadenosine TP

A
NO


2′-Deoxy-2′-a-thiomethoxyadenosine TP

A
NO


2′-Deoxy-2′-b-aminoadenosine TP

A
NO


2′-Deoxy-2′-b-azidoadenosine TP

A
NO


2′-Deoxy-2′-b-bromoadenosine TP

A
NO


2′-Deoxy-2′-b-chloroadenosine TP

A
NO


2′-Deoxy-2′-b-fluoroadenosine TP

A
NO


2′-Deoxy-2′-b-iodoadenosine TP

A
NO


2′-Deoxy-2′-b-mercaptoadenosine TP

A
NO


2′-Deoxy-2′-b-thiomethoxyadenosine TP

A
NO


2-Fluoroadenosine TP

A
NO


2-Iodoadenosine TP

A
NO


2-Mercaptoadenosine TP

A
NO


2-methoxy-adenine

A
NO


2-methylthio-adenine

A
NO


2-Trifluoromethyladenosine TP

A
NO


3-Deaza-3-bromoadenosine TP

A
NO


3-Deaza-3-chloroadenosine TP

A
NO


3-Deaza-3-fluoroadenosine TP

A
NO


3-Deaza-3-iodoadenosine TP

A
NO


3-Deazaadenosine TP

A
NO


4′-Azidoadenosine TP

A
NO


4′-Carbocyclic adenosine TP

A
NO


4′-Ethynyladenosine TP

A
NO


5′-Homo-adenosine TP

A
NO


8-Aza-ATP

A
NO


8-bromo-adenosine TP

A
NO


8-Trifluoromethyladenosine TP

A
NO


9-Deazaadenosine TP

A
NO


2-aminopurine

A/G
NO


7-deaza-2,6-diaminopurine

A/G
NO


7-deaza-8-aza-2,6-diaminopurine

A/G
NO


7-deaza-8-aza-2-aminopurine

A/G
NO


2,6-diaminopurine

A/G
NO


7-deaza-8-aza-adenine, 7-deaza-2-

A/G
NO


aminopurine





2-thiocytidine
s2C
C
YES


3-methylcytidine
m3C
C
YES


5-formylcytidine
f5C
C
YES


5-hydroxymethylcytidine
hm5C
C
YES


5-methylcytidine
m5C
C
YES


N4-acetylcytidine
ac4C
C
YES


2′-O-methylcytidine
Cm
C
YES


2′-O-methylcytidine
Cm
C
YES


5,2′-O-dimethylcytidine
m5 Cm
C
YES


5-formyl-2′-O-methylcytidine
f5Cm
C
YES


Lysidine
k2C
C
YES


N4,2′-O-dimethylcytidine
m4Cm
C
YES


N4-acetyl-2′-O-methylcytidine
ac4Cm
C
YES


N4-methylcytidine
m4C
C
YES


N4,N4-Dimethyl-2′-O-OMe-Cytidine TP

C
YES


4-methylcytidine

C
NO


5-aza-cytidine

C
NO


Pseudo-iso-cytidine

C
NO


pyrrolo-cytidine

C
NO


α-thio-cytidine

C
NO


2-(thio)cytosine

C
NO


2′-Amino-2′-deoxy-CTP

C
NO


2′-Azido-2′-deoxy-CTP

C
NO


2′-Deoxy-2′-a-aminocytidine TP

C
NO


2′-Deoxy-2′-a-azidocytidine TP

C
NO


3 (deaza) 5 (aza)cytosine

C
NO


3 (methyl)cytosine

C
NO


3-(alkyl)cytosine

C
NO


3-(deaza) 5 (aza)cytosine

C
NO


3-(methyl)cytidine

C
NO


4,2′-O-dimethylcytidine

C
NO


5 (halo)cytosine

C
NO


5 (methyl)cytosine

C
NO


5 (propynyl)cytosine

C
NO


5 (trifluoromethyl)cytosine

C
NO


5-(alkyl)cytosine

C
NO


5-(alkynyl)cytosine

C
NO


5-(halo)cytosine

C
NO


5-(propynyl)cytosine

C
NO


5-(trifluoromethyl)cytosine

C
NO


5-bromo-cytidine

C
NO


5-iodo-cytidine

C
NO


5-propynyl cytosine

C
NO


6-(azo)cytosine

C
NO


6-aza-cytidine

C
NO


aza cytosine

C
NO


deaza cytosine

C
NO


N4 (acetyl)cytosine

C
NO


1-methyl-1-deaza-pseudoisocytidine

C
NO


1-methyl-pseudoisocytidine

C
NO


2-methoxy-5-methyl-cytidine

C
NO


2-methoxy-cytidine

C
NO


2-thio-5-methyl-cytidine

C
NO


4-methoxy-1-methyl-pseudoisocytidine

C
NO


4-methoxy-pseudoisocytidine

C
NO


4-thio-1-methyl-1-deaza-

C
NO


pseudoisocytidine





4-thio-1-methyl-pseudoisocytidine

C
NO


4-thio-pseudoisocytidine

C
NO


5-aza-zebularine

C
NO


5-methyl-zebularine

C
NO


pyrrolo-pseudoisocytidine

C
NO


Zebularine

C
NO


(E)-5-(2-Bromo-vinyl)cytidine TP

C
NO


2,2′-anhydro-cytidine TP hydrochloride

C
NO


2′Fluor-N4-Bz-cytidine TP

C
NO


2′Fluoro-N4-Acetyl-cytidine TP

C
NO


2′-O-Methyl-N4-Acetyl-cytidine TP

C
NO


2′O-methyl-N4-Bz-cytidine TP

C
NO


2′-a-Ethynylcytidine TP

C
NO


2′-a-Trifluoromethylcytidine TP

C
NO


2′-b-Ethynylcytidine TP

C
NO


2′-b-Trifluoromethylcytidine TP

C
NO


2′-Deoxy-2′,2′-difluorocytidine TP

C
NO


2′-Deoxy-2′-a-mercaptocytidine TP

C
NO


2′-Deoxy-2′-a-thiomethoxycytidine TP

C
NO


2′-Deoxy-2′-b-aminocytidine TP

C
NO


2′-Deoxy-2′-b-azidocytidine TP

C
NO


2′-Deoxy-2′-b-bromocytidine TP

C
NO


2′-Deoxy-2′-b-chlorocytidine TP

C
NO


2′-Deoxy-2′-b-fluorocytidine TP

C
NO


2′-Deoxy-2′-b-iodocytidine TP

C
NO


2′-Deoxy-2′-b-mercaptocytidine TP

C
NO


2′-Deoxy-2′-b-thiomethoxycytidine TP

C
NO


2′-O-Methyl-5-(1-propynyl)cytidine TP

C
NO


3′-Ethynylcytidine TP

C
NO


4′-Azidocytidine TP

C
NO


4′-Carbocyclic cytidine TP

C
NO


4′-Ethynylcytidine TP

C
NO


5-(1-Propynyl)ara-cytidine TP

C
NO


5-(2-Chloro-phenyl)-2-thiocytidine TP

C
NO


5-(4-Amino-phenyl)-2-thiocytidine TP

C
NO


5-Aminoallyl-CTP

C
NO


5-Cyanocytidine TP

C
NO


5-Ethynylara-cytidine TP

C
NO


5-Ethynylcytidine TP

C
NO


5′-Homo-cytidine TP

C
NO


5-Methoxycytidine TP

C
NO


5-Trifluoromethyl-Cytidine TP

C
NO


N4-Amino-cytidine TP

C
NO


N4-Benzoyl-cytidine TP

C
NO


Pseudoisocytidine

C
NO


7-methylguanosine
m7G
G
YES


N2,2′-O-dimethylguanosine
m2Gm
G
YES


N2-methylguanosine
m2G
G
YES


Wyosine
imG
G
YES


1,2′-O-dimethylguanosine
m1Gm
G
YES


1-methylguanosine
m1G
G
YES


2′-O-methylguanosine
Gm
G
YES


2′-O-ribosylguanosine (phosphate)
Gr(p)
G
YES


2′-O-methylguanosine
Gm
G
YES


2′-O-ribosylguanosine (phosphate)
Gr(p)
G
YES


7-aminomethyl-7-deazaguanosine
preQ1
G
YES


7-cyano-7-deazaguanosine
preQ0
G
YES


Archaeosine
G+
G
YES


Methylwyosine
mimG
G
YES


N2,7-dimethylguanosine
m2,7G
G
YES


N2,N2,2′-O-trimethylguanosine
m22Gm
G
YES


N2,N2,7-trimethylguanosine
m2,2,7G
G
YES


N2,N2-dimethylguanosine
m22G
G
YES


N2,7,2′-O-trimethylguanosine
m2,7Gm
G
YES


6-thio-guanosine

G
NO


7-deaza-guanosine

G
NO


8-oxo-guanosine

G
NO


N1-methyl-guanosine

G
NO


α-thio-guanosine

G
NO


2 (propyl)guanine

G
NO


2-(alkyl)guanine

G
NO


2′-Amino-2′-deoxy-GTP

G
NO


2′-Azido-2′-deoxy-GTP

G
NO


2′-Deoxy-2′-a-aminoguanosine TP

G
NO


2′-Deoxy-2′-a-azidoguanosine TP

G
NO


6 (methyl)guanine

G
NO


6-(alkyl)guanine

G
NO


6-(methyl)guanine

G
NO


6-methyl-guanosine

G
NO


7 (alkyl)guanine

G
NO


7 (deaza)guanine

G
NO


7 (methyl)guanine

G
NO


7-(alkyl)guanine

G
NO


7-(deaza)guanine

G
NO


7-(methyl)guanine

G
NO


8 (alkyl)guanine

G
NO


8 (alkynyl)guanine

G
NO


8 (halo)guanine

G
NO


8 (thioalkyl)guanine

G
NO


8-(alkenyl)guanine

G
NO


8-(alkyl)guanine

G
NO


8-(alkynyl)guanine

G
NO


8-(amino)guanine

G
NO


8-(halo)guanine

G
NO


8-(hydroxyl)guanine

G
NO


8-(thioalkyl)guanine

G
NO


8-(thiol)guanine

G
NO


aza guanine

G
NO


deaza guanine

G
NO


N (methyl)guanine

G
NO


N-(methyl)guanine

G
NO


1-methyl-6-thio-guanosine

G
NO


6-methoxy-guanosine

G
NO


6-thio-7-deaza-8-aza-guanosine

G
NO


6-thio-7-deaza-guanosine

G
NO


6-thio-7-methyl-guanosine

G
NO


7-deaza-8-aza-guanosine

G
NO


7-methyl-8-oxo-guanosine

G
NO


N2,N2-dimethyl-6-thio-guanosine

G
NO


N2-methyl-6-thio-guanosine

G
NO


1-Me-GTP

G
NO


2′Fluoro-N2-isobutyl-guanosine TP

G
NO


2′O-methyl-N2-isobutyl-guanosine TP

G
NO


2′-a-Ethynylguanosine TP

G
NO


2′-a-Trifluoromethylguanosine TP

G
NO


2′-b-Ethynylguanosine TP

G
NO


2′-b-Trifluoromethylguanosine TP

G
NO


2′-Deoxy-2′,2′-difluoroguanosine TP

G
NO


2′-Deoxy-2′-a-mercaptoguanosine TP

G
NO


2′-Deoxy-2′-a-thiomethoxyguanosine TP

G
NO


2′-Deoxy-2′-b-aminoguanosine TP

G
NO


2′-Deoxy-2′-b-azidoguanosine TP

G
NO


2′-Deoxy-2′-b-bromoguanosine TP

G
NO


2′-Deoxy-2′-b-chloroguanosine TP

G
NO


2′-Deoxy-2′-b-fluoroguanosine TP

G
NO


2′-Deoxy-2′-b-iodoguanosine TP

G
NO


2′-Deoxy-2′-b-mercaptoguanosine TP

G
NO


2′-Deoxy-2′-b-thiomethoxyguanosine TP

G
NO


4′-Azidoguanosine TP

G
NO


4′-Carbocyclic guanosine TP

G
NO


4′-Ethynylguanosine TP

G
NO


5′-Homo-guanosine TP

G
NO


8-bromo-guanosine TP

G
NO


9-Deazaguanosine TP

G
NO


N2-isobutyl-guanosine TP

G
NO


1-methylinosine
m1I
I
YES


Inosine
I
I
YES


1,2′-O-dimethylinosine
m1Im
I
YES


2′-O-methylinosine
Im
I
YES


7-methylinosine

I
NO


2′-O-methylinosine
Im
I
YES


Epoxyqueuosine
oQ
Q
YES


galactosyl-queuosine
galQ
Q
YES


Mannosylqueuosine
manQ
Q
YES


Queuosine
Q
Q
YES


allyamino-thymidine

T
NO


aza thymidine

T
NO


deaza thymidine

T
NO


deoxy-thymidine

T
NO


2′-O-methyluridine

U
YES


2-thiouridine
s2U
U
YES


3-methyluridine
m3U
U
YES


5-carboxymethyluridine
cm5U
U
YES


5-hydroxyuridine
ho5U
U
YES


5-methyluridine
m5U
U
YES


5-taurinomethyl-2-thiouridine
τm5s2U
U
YES


5-taurinomethyluridine
τm5U
U
YES


Dihydrouridine
D
U
YES


Pseudouridine
Ψ
U
YES


(3-(3-amino-3-carboxypropyl)uridine
acp3U
U
YES


1-methyl-3-(3-amino-5-
m1acp3Ψ
U
YES


carboxypropyl)pseudouridine





1-methylpseduouridine
m1Ψ
U
YES


1-methyl-pseudouridine

U
YES


2′-O-methyluridine
Um
U
YES


2′-O-methylpseudouridine
Ψm
U
YES


2′-O-methyluridine
Um
U
YES


2-thio-2′-O-methyluridine
s2Um
U
YES


3-(3-amino-3-carboxypropyl)uridine
acp3U
U
YES


3,2′-O-dimethyluridine
m3Um
U
YES


3-Methyl-pseudo-Uridine TP

U
YES


4-thiouridine
s4U
U
YES


5-(carboxyhydroxymethyl)uridine
chm5U
U
YES


5-(carboxyhydroxymethyl)uridine methyl
mchm5U
U
YES


ester





5,2′-O-dimethyluridine
m5Um
U
YES


5,6-dihydro-uridine

U
YES


5-aminomethyl-2-thiouridine
nm5s2U
U
YES


5-carbamoylmethyl-2′-O-methyluridine
ncm5Um
U
YES


5-carbamoylmethyluridine
ncm5U
U
YES


5-carboxyhydroxymethyluridine

U
YES


5-carboxyhydroxymethyluridine methyl

U
YES


ester





5-carboxymethylaminomethyl-2′-O-
cmnm5Um
U
YES


methyluridine





5-carboxymethylaminomethyl-2-
cmnm5s2U
U
YES


thiouridine





5-carboxymethylaminomethyl-2-

U
YES


thiouridine





5-carboxymethylaminomethyluridine
cmnm5U
U
YES


5-carboxymethylaminomethyluridine

U
YES


5-Carbamoylmethyluridine TP

U
YES


5-methoxycarbonylmethyl-2′-O-
mcm5Um
U
YES


methyluridine





5-methoxycarbonylmethyl-2-thiouridine
mcm5s2U
U
YES


5-methoxycarbonylmethyluridine
mcm5U
U
YES


5-methoxyuridine
mo5U
U
YES


5-methyl-2-thiouridine
m5s2U
U
YES


5-methylaminomethyl-2-selenouridine
mnm5se2U
U
YES


5-methylaminomethyl-2-thiouridine
mnm5s2U
U
YES


5-methylaminomethyluridine
mnm5U
U
YES


5-Methyldihydrouridine

U
YES


5-Oxyacetic acid-Uridine TP

U
YES


5-Oxyacetic acid-methyl ester-Uridine TP

U
YES


N1-methyl-pseudo-uridine

U
YES


uridine 5-oxyacetic acid
cmo5U
U
YES


uridine 5-oxyacetic acid methyl ester
mcmo5U
U
YES


3-(3-Amino-3-carboxypropyl)-Uridine TP

U
YES


5-(iso-Pentenylaminomethyl)-2-

U
YES


thiouridine TP





5-(iso-Pentenylaminomethyl)-2′-O-

U
YES


methyluridine TP





5-(iso-Pentenylaminomethyl)uridine TP

U
YES


5-propynyl uracil

U
NO


α-thio-uridine

U
NO


1 (aminoalkylamino-carbonylethylenyl)-

U
NO


2(thio)-pseudouracil





1 (aminoalkylaminocarbonylethylenyl)-

U
NO


2,4-(dithio)pseudouracil





1 (aminoalkylaminocarbonylethylenyl)-4

U
NO


(thio)pseudouracil





1 (aminoalkylaminocarbonylethylenyl)-

U
NO


pseudouracil





1 (aminocarbonylethylenyl)-2(thio)-

U
NO


pseudouracil





1 (aminocarbonylethylenyl)-2,4-

U
NO


(dithio)pseudouracil





1 (aminocarbonylethylenyl)-4

U
NO


(thio)pseudouracil





1 (aminocarbonylethylenyl)-pseudouracil

U
NO


1 substituted 2(thio)-pseudouracil

U
NO


1 substituted 2,4-(dithio)pseudouracil

U
NO


1 substituted 4 (thio)pseudouracil

U
NO


1 substituted pseudouracil

U
NO


1-(aminoalkylamino-carbonylethylenyl)-2-

U
NO


(thio)-pseudouracil





1-Methyl-3-(3-amino-3-carboxypropyl)

U
NO


pseudouridine TP





1-Methyl-3-(3-amino-3-

U
NO


carboxypropyl)pseudo-UTP





1-Methyl-pseudo-UTP

U
NO


2 (thio)pseudouracil

U
NO


2′ deoxy uridine

U
NO


2′ fluorouridine

U
NO


2-(thio)uracil

U
NO


2,4-(dithio)psuedouracil

U
NO


2′ methyl, 2′amino, 2′azido, 2′fluro-

U
NO


guanosine





2′-Amino-2′-deoxy-UTP

U
NO


2′-Azido-2′-deoxy-UTP

U
NO


2′-Azido-deoxyuridine TP

U
NO


2′-O-methylpseudouridine

U
NO


2′ deoxy uridine
2′ dU
U
NO


2′ fluorouridine

U
NO


2′-Deoxy-2′-a-aminouridine TP

U
NO


2′-Deoxy-2′-a-azidouridine TP

U
NO


2-methylpseudouridine
m3Ψ
U
NO


3 (3 amino-3 carboxypropyl)uracil

U
NO


4 (thio)pseudouracil

U
NO


4-(thio)pseudouracil

U
NO


4-(thio)uracil

U
NO


4-thiouracil

U
NO


5 (1,3-diazole-1-alkyl)uracil

U
NO


5 (2-aminopropyl)uracil

U
NO


5 (aminoalkyl)uracil

U
NO


5 (dimethylaminoalkyl)uracil

U
NO


5 (guanidiniumalkyl)uracil

U
NO


5 (methoxycarbonylmethyl)-2-(thio)uracil

U
NO


5 (methoxycarbonyl-methyl)uracil

U
NO


5 (methyl) 2 (thio)uracil

U
NO


5 (methyl) 2,4 (dithio)uracil

U
NO


5 (methyl) 4 (thio)uracil

U
NO


5 (methylaminomethyl)-2 (thio)uracil

U
NO


5 (methylaminomethyl)-2,4 (dithio)uracil

U
NO


5 (methylaminomethyl)-4 (thio)uracil

U
NO


5 (propynyl)uracil

U
NO


5 (trifluoromethyl)uracil

U
NO


5-(2-aminopropyl)uracil

U
NO


5-(alkyl)-2-(thio)pseudouracil

U
NO


5-(alkyl)-2,4 (dithio)pseudouracil

U
NO


5-(alkyl)-4 (thio)pseudouracil

U
NO


5-(alkyl)pseudouracil

U
NO


5-(alkyl)uracil

U
NO


5-(alkynyl)uracil

U
NO


5-(allylamino)uracil

U
NO


5-(cyanoalkyl)uracil

U
NO


5-(dialkylaminoalkyl)uracil

U
NO


5-(dimethylaminoalkyl)uracil

U
NO


5-(guanidiniumalkyl)uracil

U
NO


5-(halo)uracil

U
NO


5-(1,3-diazole-1-alkyl)uracil

U
NO


5-(methoxy)uracil

U
NO


5-(methoxycarbonylmethyl)-2-(thio)uracil

U
NO


5-(methoxycarbonyl-methyl)uracil

U
NO


5-(methyl) 2(thio)uracil

U
NO


5-(methyl) 2,4 (dithio)uracil

U
NO


5-(methyl) 4 (thio)uracil

U
NO


5-(methyl)-2-(thio)pseudouracil

U
NO


5-(methyl)-2,4 (dithio)pseudouracil

U
NO


5-(methyl)-4 (thio)pseudouracil

U
NO


5-(methyl)pseudouracil

U
NO


5-(methylaminomethyl)-2 (thio)uracil

U
NO


5-(methylaminomethyl)-2,4(dithio)uracil

U
NO


5-(methylaminomethyl)-4-(thio)uracil

U
NO


5-(propynyl)uracil

U
NO


5-(trifluoromethyl)uracil

U
NO


5-aminoallyl-uridine

U
NO


5-bromo-uridine

U
NO


5-iodo-uridine

U
NO


5-uracil

U
NO


6 (azo)uracil

U
NO


6-(azo)uracil

U
NO


6-aza-uridine

U
NO


allyamino-uracil

U
NO


aza uracil

U
NO


deaza uracil

U
NO


N3 (methyl)uracil

U
NO


Pseudo-UTP-1-2-ethanoic acid

U
NO


Pseudouracil

U
NO


4-Thio-pseudo-UTP

U
NO


1-carboxymethyl-pseudouridine

U
NO


1-methyl-1-deaza-pseudouridine

U
NO


1-propynyl-uridine

U
NO


1-taurinomethyl-1-methyl-uridine

U
NO


1-taurinomethyl-4-thio-uridine

U
NO


1-taurinomethyl-pseudouridine

U
NO


2-methoxy-4-thio-pseudouridine

U
NO


2-thio-1-methyl-1-deaza-pseudouridine

U
NO


2-thio-1-methyl-pseudouridine

U
NO


2-thio-5-aza-uridine

U
NO


2-thio-dihydropseudouridine

U
NO


2-thio-dihydrouridine

U
NO


2-thio-pseudouridine

U
NO


4-methoxy-2-thio-pseudouridine

U
NO


4-methoxy-pseudouridine

U
NO


4-thio-1-methyl-pseudouridine

U
NO


4-thio-pseudouridine

U
NO


5-aza-uridine

U
NO


Dihydropseudouridine

U
NO


(±)1-(2-Hydroxypropyl)pseudouridine TP

U
NO


(2R)-1-(2-Hydroxypropyl)pseudouridine

U
NO


TP





(2S)-1-(2-Hydroxypropyl)pseudouridine

U
NO


TP





(E)-5-(2-Bromo-vinyl)ara-uridine TP

U
NO


(E)-5-(2-Bromo-vinyl)uridine TP

U
NO


(Z)-5-(2-Bromo-vinyl)ara-uridine TP

U
NO


(Z)-5-(2-Bromo-vinyl)uridine TP

U
NO


1-(2,2,2-Trifluoroethyl)-pseudo-UTP

U
NO


1-(2,2,3,3,3-Pentafluoropropyl)

U
NO


pseudouridine TP





1-(2,2-Diethoxyethyl)pseudouridine TP

U
NO


1-(2,4,6-Trimethylbenzyl)pseudouridine

U
NO


TP





1-(2,4,6-Trimethyl-benzyl)pseudo-UTP

U
NO


1-(2,4,6-Trimethyl-phenyl)pseudo-UTP

U
NO


1-(2-Amino-2-carboxyethyl)pseudo-UTP

U
NO


1-(2-Amino-ethyl)pseudo-UTP

U
NO


1-(2-Hydroxyethyl)pseudouridine TP

U
NO


1-(2-Methoxyethyl)pseudouridine TP

U
NO


1-(3,4-Bis-trifluoromethoxybenzyl)

U
NO


pseudouridine TP





1-(3,4-Dimethoxybenzyl)pseudouridine

U
NO


TP





1-(3-Amino-3-carboxypropyl)pseudo-UTP

U
NO


1-(3-Amino-propyl)pseudo-UTP

U
NO


1-(3-Cyclopropyl-prop-2-

U
NO


ynyl)pseudouridine TP





1-(4-Amino-4-carboxybutyl)pseudo-UTP

U
NO


1-(4-Amino-benzyl)pseudo-UTP

U
NO


1-(4-Amino-butyl)pseudo-UTP

U
NO


1-(4-Amino-phenyl)pseudo-UTP

U
NO


1-(4-Azidobenzyl)pseudouridine TP

U
NO


1-(4-Bromobenzyl)pseudouridine TP

U
NO


1-(4-Chlorobenzyl)pseudouridine TP

U
NO


1-(4-Fluorobenzyl)pseudouridine TP

U
NO


1-(4-Iodobenzyl)pseudouridine TP

U
NO


1-(4-Methanesulfonylbenzyl)

U
NO


pseudouridine TP





1-(4-Methoxybenzyl)pseudouridine TP

U
NO


1-(4-Methoxy-benzyl)pseudo-UTP

U
NO


1-(4-Methoxy-phenyl)pseudo-UTP

U
NO


1-(4-Methylbenzyl)pseudouridine TP

U
NO


1-(4-Methyl-benzyl)pseudo-UTP

U
NO


1-(4-Nitrobenzyl)pseudouridine TP

U
NO


1-(4-Nitro-benzyl)pseudo-UTP

U
NO


1 (4-Nitro-phenyl)pseudo-UTP

U
NO


1-(4-Thiomethoxybenzyl)pseudouridine

U
NO


TP





1-(4-Trifluoromethoxybenzyl)

U
NO


pseudouridine TP





1-(4-Trifluoromethylbenzyl)pseudouridine

U
NO


TP





1-(5-Amino-pentyl)pseudo-UTP

U
NO


1-(6-Amino-hexyl)pseudo-UTP

U
NO


1,6-Dimethyl-pseudo-UTP

U
NO


1-[3-(2-{2-[2-(2-Aminoethoxy)-ethoxy]-

U
NO


ethoxy}-ethoxy)-propionyl]pseudouridine





TP





1-{3-[2-(2-Aminoethoxy)-ethoxy]-

U
NO


propionyl} pseudouridine TP





1-Acetylpseudouridine TP

U
NO


1-Alkyl-6-(1-propynyl)-pseudo-UTP

U
NO


1-Alkyl-6-(2-propynyl)-pseudo-UTP

U
NO


1-Alkyl-6-allyl-pseudo-UTP

U
NO


1-Alkyl-6-ethynyl-pseudo-UTP

U
NO


1-Alkyl-6-homoallyl-pseudo-UTP

U
NO


1-Alkyl-6-vinyl-pseudo-UTP

U
NO


1-Allylpseudouridine TP

U
NO


1-Aminomethyl-pseudo-UTP

U
NO


1-Benzoylpseudouridine TP

U
NO


1-Benzyloxymethylpseudouridine TP

U
NO


1-Benzyl-pseudo-UTP

U
NO


1-Biotinyl-PEG2-pseudouridine TP

U
NO


1-Biotinylpseudouridine TP

U
NO


1-Butyl-pseudo-UTP

U
NO


1-Cyanomethylpseudouridine TP

U
NO


1-Cyclobutylmethyl-pseudo-UTP

U
NO


1-Cyclobutyl-pseudo-UTP

U
NO


1-Cycloheptylmethyl-pseudo-UTP

U
NO


1-Cycloheptyl-pseudo-UTP

U
NO


1-Cyclohexylmethyl-pseudo-UTP

U
NO


1-Cyclohexyl-pseudo-UTP

U
NO


1-Cyclooctylmethyl-pseudo-UTP

U
NO


1-Cyclooctyl-pseudo-UTP

U
NO


1-Cyclopentylmethyl-pseudo-UTP

U
NO


1-Cyclopentyl-pseudo-UTP

U
NO


1-Cyclopropylmethyl-pseudo-UTP

U
NO


1-Cyclopropyl-pseudo-UTP

U
NO


1-Ethyl-pseudo-UTP

U
NO


1-Hexyl-pseudo-UTP

U
NO


1-Homoallylpseudouridine TP

U
NO


1-Hydroxymethylpseudouridine TP

U
NO


1-iso-propyl-pseudo-UTP

U
NO


1-Me-2-thio-pseudo-UTP

U
NO


1-Me-4-thio-pseudo-UTP

U
NO


1-Me-alpha-thio-pseudo-UTP

U
NO


1-Methane sulfonylmethylpseudouridine

U
NO


TP





1-Methoxymethylpseudouridine TP

U
NO


1-Methyl-6-(2,2,2-Trifluoroethyl)pseudo-

U
NO


UTP





1-Methyl-6-(4-morpholino)-pseudo-UTP

U
NO


1-Methyl-6-(4-thiomorpholino)-pseudo-

U
NO


UTP





1-Methyl-6-(substituted phenyl)pseudo-

U
NO


UTP





1-Methyl-6-amino-pseudo-UTP

U
NO


1-Methyl-6-azido-pseudo-UTP

U
NO


1-Methyl-6-bromo-pseudo-UTP

U
NO


1-Methyl-6-butyl-pseudo-UTP

U
NO


1-Methyl-6-chloro-pseudo-UTP

U
NO


1-Methyl-6-cyano-pseudo-UTP

U
NO


1-Methyl-6-dimethylamino-pseudo-UTP

U
NO


1-Methyl-6-ethoxy-pseudo-UTP

U
NO


1-Methyl-6-ethylcarboxylate-pseudo-UTP

U
NO


1-Methyl-6-ethyl-pseudo-UTP

U
NO


1-Methyl-6-fluoro-pseudo-UTP

U
NO


1-Methyl-6-formyl-pseudo-UTP

U
NO


1-Methyl-6-hydroxyamino-pseudo-UTP

U
NO


1-Methyl-6-hydroxy-pseudo-UTP

U
NO


1-Methyl-6-iodo-pseudo-UTP

U
NO


1-Methyl-6-iso-propyl-pseudo-UTP

U
NO


1-Methyl-6-methoxy-pseudo-UTP

U
NO


1-Methyl-6-methylamino-pseudo-UTP

U
NO


1-Methyl-6-phenyl-pseudo-UTP

U
NO


1-Methyl-6-propyl-pseudo-UTP

U
NO


1-Methyl-6-tert-butyl-pseudo-UTP

U
NO


1-Methyl-6-trifluoromethoxy-pseudo-UTP

U
NO


1-Methyl-6-trifluoromethyl-pseudo-UTP

U
NO


1-Morpholinomethylpseudouridine TP

U
NO


1-Pentyl-pseudo-UTP

U
NO


1-Phenyl-pseudo-UTP

U
NO


1-Pivaloylpseudouridine TP

U
NO


1-Propargylpseudouridine TP

U
NO


1-Propyl-pseudo-UTP

U
NO


1-propynyl-pseudouridine

U
NO


1-p-tolyl-pseudo-UTP

U
NO


1-tert-Butyl-pseudo-UTP

U
NO


1-Thiomethoxymethylpseudouridine TP

U
NO


1-Thiomorpholinomethylpseudouridine TP

U
NO


1-Trifluoroacetylpseudouridine TP

U
NO


1-Trifluoromethyl-pseudo-UTP

U
NO


1-Vinylpseudouridine TP

U
NO


2,2′-anhydro-uridine TP

U
NO


2′-bromo-deoxyuridine TP

U
NO


2′-F-5-Methyl-2′-deoxy-UTP

U
NO


2′-OMe-5-Me-UTP

U
NO


2′-OMe-pseudo-UTP

U
NO


2′-a-Ethynyluridine TP

U
NO


2′-a-Trifluoromethyluridine TP

U
NO


2′-b-Ethynyluridine TP

U
NO


2′-b-Trifluoromethyluridine TP

U
NO


2′-Deoxy-2′,2′-difluorouridine TP

U
NO


2′-Deoxy-2′-a-mercaptouridine TP

U
NO


2′-Deoxy-2′-a-thiomethoxyuridine TP

U
NO


2′-Deoxy-2′-b-aminouridine TP

U
NO


2′-Deoxy-2′-b-azidouridine TP

U
NO


2′-Deoxy-2′-b-bromouridine TP

U
NO


2′-Deoxy-2′-b-chlorouridine TP

U
NO


2′-Deoxy-2′-b-fluorouridine TP

U
NO


2′-Deoxy-2′-b-iodouridine TP

U
NO


2′-Deoxy-2′-b-mercaptouridine TP

U
NO


2′-Deoxy-2′-b-thiomethoxyuridine TP

U
NO


2-methoxy-4-thio-uridine

U
NO


2-methoxyuridine

U
NO


2′-O-Methyl-5-(1-propynyl)uridine TP

U
NO


3-Alkyl-pseudo-UTP

U
NO


4′-Azidouridine TP

U
NO


4′-Carbocyclic uridine TP

U
NO


4′-Ethynyluridine TP

U
NO


5-(1-Propynyl)ara-uridine TP

U
NO


5-(2-Furanyl)uridine TP

U
NO


5-Cyanouridine TP

U
NO


5-Dimethylaminouridine TP

U
NO


5′-Homo-uridine TP

U
NO


5-iodo-2′-fluoro-deoxyuridine TP

U
NO


5-Phenylethynyluridine TP

U
NO


5-Trideuteromethyl-6-deuterouridine TP

U
NO


5-Trifluoromethyl-Uridine TP

U
NO


5-Vinylarauridine TP

U
NO


6-(2,2,2-Trifluoroethyl)-pseudo-UTP

U
NO


6-(4-Morpholino)-pseudo-UTP

U
NO


6-(4-Thiomorpholino)-pseudo-UTP

U
NO


6-(Substituted-Phenyl)-pseudo-UTP

U
NO


6-Amino-pseudo-UTP

U
NO


6-Azido-pseudo-UTP

U
NO


6-Bromo-pseudo-UTP

U
NO


6-Butyl-pseudo-UTP

U
NO


6-Chloro-pseudo-UTP

U
NO


6-Cyano-pseudo-UTP

U
NO


6-Dimethylamino-pseudo-UTP

U
NO


6-Ethoxy-pseudo-UTP

U
NO


6-Ethylcarboxylate-pseudo-UTP

U
NO


6-Ethyl-pseudo-UTP

U
NO


6-Fluoro-pseudo-UTP

U
NO


6-Formyl-pseudo-UTP

U
NO


6-Hydroxyamino-pseudo-UTP

U
NO


6-Hydroxy-pseudo-UTP

U
NO


6-Iodo-pseudo-UTP

U
NO


6-iso-Propyl-pseudo-UTP

U
NO


6-Methoxy-pseudo-UTP

U
NO


6-Methylamino-pseudo-UTP

U
NO


6-Methyl-pseudo-UTP

U
NO


6-Phenyl-pseudo-UTP

U
NO


6-Phenyl-pseudo-UTP

U
NO


6-Propyl-pseudo-UTP

U
NO


6-tert-Butyl-pseudo-UTP

U
NO


6-Trifluoromethoxy-pseudo-UTP

U
NO


6-Trifluoromethyl-pseudo-UTP

U
NO


Alpha-thio-pseudo-UTP

U
NO


Pseudouridine 1-(4-

U
NO


methylbenzenesulfonic acid) TP





Pseudouridine 1-(4-methylbenzoic acid)

U
NO


TP





Pseudouridine TP 1-[3-(2-

U
NO


ethoxy)]propionic acid





Pseudouridine TP 1-[3-{2-(2-[2-(2-

U
NO


ethoxy)-ethoxy]-ethoxy)-ethoxy}]





propionic acid





Pseudouridine TP 1-[3-{2-(2-[2-{2-(2-

U
NO


ethoxy)-ethoxy}-ethoxy]-ethoxy)-





ethoxyl}]propionic acid





Pseudouridine TP 1-[3-{2-(2-[2-ethoxy]-

U
NO


ethoxy)-ethoxy}]propionic acid





Pseudouridine TP 1-[3-{2-(2-ethoxy)-

U
NO


ethoxy}] propionic acid





Pseudouridine TP 1-methylphosphonic

U
NO


acid





Pseudouridine TP 1-methylphosphonic

U
NO


acid diethyl ester





Pseudo-UTP-N1-3-propionic acid

U
NO


Pseudo-UTP-N1-4-butanoic acid

U
NO


Pseudo-UTP-N1-5-pentanoic acid

U
NO


Pseudo-UTP-N1-6-hexanoic acid

U
NO


Pseudo-UTP-N1-7-heptanoic acid

U
NO


Pseudo-UTP-N1-methyl-p-benzoic acid

U
NO


Pseudo-UTP-N1-p-benzoic acid

U
NO


Wybutosine
yW
W
YES


Hydroxywybutosine
OHyW
W
YES


Isowyosine
imG2
W
YES


Peroxywybutosine
o2yW
W
YES


undermodified hydroxywybutosine
OHyW*
W
YES


4-demethylwyosine
imG-14
W
YES









Other modifications which may be useful in the polynucleotides of the NAVs of the present invention are listed in Table 23.









TABLE 23







Additional Modification types








Name
Type





2,6-(diamino)purine
Other


1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl
Other


1,3-(diaza)-2-(oxo)-phenthiazin-1-yl
Other


1,3-(diaza)-2-(oxo)-phenoxazin-1-yl
Other


1,3,5-(triaza)-2,6-(dioxa)-naphthalene
Other


2 (amino)purine
Other


2,4,5-(trimethyl)phenyl
Other


2′methyl, 2′amino, 2′azido, 2′fluro-cytidine
Other


2′methyl, 2′amino, 2′azido, 2′fluro-adenine
Other


2′methyl, 2′amino, 2′azido, 2′fluro-uridine
Other


2′-amino-2′-deoxyribose
Other


2-amino-6-Chloro-purine
Other


2-aza-inosinyl
Other


2′-azido-2′-deoxyribose
Other


2′fluoro-2′-deoxyribose
Other


2′-fluoro-modified bases
Other


2′-O-methyl-ribose
Other


2-oxo-7-aminopyridopyrimidin-3-yl
Other


2-oxo-pyridopyrimidine-3-yl
Other


2-pyridinone
Other


3 nitropyrrole
Other


3-(methyl)-7-(propynyl)isocarbostyrilyl
Other


3-(methyl)isocarbostyrilyl
Other


4-(fluoro)-6-(methyl)benzimidazole
Other


4-(methyl)benzimidazole
Other


4-(methyl)indolyl
Other


4,6-(dimethyl)indolyl
Other


5 nitroindole
Other


5 substituted pyrimidines
Other


5-(methyl)isocarbostyrilyl
Other


5-nitroindole
Other


6-(aza)pyrimidine
Other


6-(azo)thymine
Other


6-(methyl)-7-(aza)indolyl
Other


6-chloro-purine
Other


6-phenyl-pyrrolo-pyrimidin-2-on-3-yl
Other


7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenthiazin-1-yl
Other


7-(aminoalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl
Other


7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenoxazin-1-yl
Other


7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenthiazin-1-yl
Other


7-(aminoalkylhydroxy)-1,3-(diaza)-2-(oxo)-phenoxazin-1-yl
Other


7-(aza)indolyl
Other


7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-
Other


3-(aza)-phenoxazinl-yl



7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-
Other


3-(aza)-phenthiazin-1-yl



7-(guanidiniumalkylhydroxy)-1-(aza)-2-(thio)-3-(aza)-
Other


phenoxazin-1-yl



7-(guanidiniumalkylhydroxy)-1,3-(diaza)-
Other


2-(oxo)-phenoxazin-1-yl



7-(guanidiniumalkyl-hydroxy)-1,3-(diaza)-
Other


2-(oxo)-phenthiazin-1-yl



7-(guanidiniumalkylhydroxy)-1,3-(diaza)-
Other


2-(oxo)-phenoxazin-1-yl



7-(propynyl)isocarbostyrilyl
Other


7-(propynyl)isocarbostyrilyl, propnyl-7-(aza)indolyl
Other


7-deaza-inosinyl
Other


7-substituted 1-(aza)-2-(thio)-3-(aza)-phenoxazin-1-yl
Other


7-substituted 1,3-(diaza)-2-(oxo)-phenoxazin-1-yl
Other


9-(methyl)-imidizopyridinyl
Other


Aminoindolyl
Other


Anthracenyl
Other


bis-ortho-(aminoalkylhydroxy)-6-phenyl-
Other


pyrrolo-pyrimidin-2-on-3-yl



bis-ortho-substituted-6-phenyl-pyrrolo-
Other


pyrimidin-2-on-3-yl



Difluorotolyl
Other


Hypoxanthine
Other


Imidizopyridinyl
Other


Inosinyl
Other


Isocarbostyrilyl
Other


Isoguanisine
Other


N2-substituted purines
Other


N6-methyl-2-amino-purine
Other


N6-substituted purines
Other


N-alkylated derivative
Other


Napthalenyl
Other


Nitrobenzimidazolyl
Other


Nitroimidazolyl
Other


Nitroindazolyl
Other


Nitropyrazolyl
Other


Nubularine
Other


O6-substituted purines
Other


O-alkylated derivative
Other


ortho-(aminoalkylhydroxy)-6-phenyl-
Other


pyrrolo-pyrimidin-2-on-3-yl



ortho-sub stituted-6-phenyl-
Other


pyrrolo-pyrimidin-2-on-3-yl



Oxoformycin TP
Other


para-(aminoalkylhydroxy)-6-phenyl-
Other


pyrrolo-pyrimidin-2-on-3-yl



para-substituted-6-phenyl-
Other


pyrrolo-pyrimidin-2-on-3-yl



Pentacenyl
Other


Phenanthracenyl
Other


Phenyl
Other


propynyl-7-(aza)indolyl
Other


Pyrenyl
Other


pyridopyrimidin-3-yl
Other


pyridopyrimidin-3-yl, 2-oxo-7-amino-
Other


pyridopyrimidin-3-yl



pyrrolo-pyrimidin-2-on-3-yl
Other


Pyrrolopyrimidinyl
Other


Pyrrolopyrizinyl
Other


Stilbenzyl
Other


substituted 1,2,4-triazoles
Other


Tetracenyl
Other


Tubercidine
Other


Xanthine
Other


Xanthosine-5′-TP
Other


2-thio-zebularine
Other


5-aza-2-thio-zebularine
Other


7-deaza-2-amino-purine
Other


pyridin-4-one ribonucleoside
Other


2-Amino-riboside-TP
Other


Formycin A TP
Other


Formycin B TP
Other


Pyrrolosine TP
Other


2′-OH-ara-adenosine TP
Other


2′-OH-ara-cytidine TP
Other


2′-OH-ara-uridine TP
Other


2′-OH-ara-guanosine TP
Other


5-(2-carbomethoxyvinyl)uridine TP
Other


N6-(19-Amino-pentaox anonadecyl)adenoine TP
Other









The polynucleotides of the NAVs can include any useful linker between the nucleosides. Such linkers, including backbone modifications are given in Table









TABLE 24







Linker modifications










Name
TYPE






3′-alkylene phosphonates
Linker



3′-amino phosphoramidate
Linker



alkene containing backbones
Linker



Aminoalkylphosphoramidates
Linker



Aminoalkylphosphotriesters
Linker



Boranophosphates
Linker



—CH2-0-N(CH3)—CH2—
Linker



—CH2—N(CH3)—N(CH3)—CH2—
Linker



—CH2—NH—CH2—
Linker



chiral phosphonates
Linker



chiral phosphorothioates
Linker



formacetyl and thioformacetyl backbones
Linker



methylene (methylimino)
Linker



methylene formacetyl and
Linker



thioformacetyl backbones




methyleneimino and
Linker



methylenehydrazino backbones




morpholino linkages
Linker



—N(CH3)—CH2—CH2—
Linker



oligonucleosides with heteroatom
Linker



internucleoside linkage




Phosphinates
Linker



phosphoramidates
Linker



Phosphorodithioates
Linker



phosphorothioate internucleoside
Linker



linkages




Phosphorothioates
Linker



Phosphotriesters
Linker



PNA
Linker



siloxane backbones
Linker



sulfamate backbones
Linker



sulfide sulfoxide and sulfone backbones
Linker



sulfonate and sulfonamide backbones
Linker



Thionoalkylphosphonates
Linker



Thionoalkylphosphotriesters
Linker



Thionophosphoramidates
Linker









The polynucleotides of the NAVs of the invention can include any useful modification, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g. to a linking phosphate/to a phosphodiester linkage/to the phosphodiester backbone). One or more atoms of a pyrimidine nucleobase may be replaced or substituted with optionally substituted amino, optionally substituted thiol, optionally substituted alkyl (e.g., methyl or ethyl), or halo (e.g., chloro or fluoro). In certain embodiments, modifications (e.g., one or more modifications) are present in each of the sugar and the internucleoside linkage. Modifications according to the present invention may be modifications of ribonucleic acids (RNAs) to deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs) or hybrids thereof). Additional modifications are described herein.


Non-natural modified nucleotides may be introduced to polynucleotides, e.g., of the NAVs of the invention, or nucleic acids during synthesis or post-synthesis of the chains to achieve desired functions or properties. The modifications may be on internucleotide lineage, the purine or pyrimidine bases, or sugar. The modification may be introduced at the terminal of a chain or anywhere else in the chain; with chemical synthesis or with a polymerase enzyme. For example, hexitol nucleic acids (HNAs) are nuclease resistant and provide strong hybridization to RNA. Short messenger RNAs (mRNAs) with hexitol residues in two codons have been constructed (Lavrik et al., Biochemistry, 40, 11777-11784 (2001), the contents of which are incorporated herein by reference in their entirety). The antisense effects of a chimeric HNA gapmer oligonucleotide comprising a phosphorothioate central sequence flanked by 5′ and 3′ HNA sequences have also been studied (See e.g., Kang et al., Nucleic Acids Research, vol. 32(4), 4411-4419 (2004), the contents of which are incorporated herein by reference in their entirety). The preparation and uses of modified nucleotides comprising 6-member rings in RNA interference, antisense therapy or other applications are disclosed in US Pat. Application No. 2008/0261905, US Pat. Application No. 2010/0009865, and PCT Application No. WO97/30064 to Herdewijn et al.; the contents of each of which are herein incorporated by reference in their entireties). Modified nucleic acids and their synthesis are disclosed in copending PCT applications No. PCT/US2012/058519 (Attorney Docket Number M09), the contents of which are incorporated herein by reference for their entirety. The synthesis and strategy of modified polynucleotides is reviewed by Verma and Eckstein in Annual Review of Biochemistry, vol. 76, 99-134 (1998), the contents of which are incorporated herein by reference in their entirety.


Either enzymatic or chemical ligation methods can be used to conjugate polynucleotides or their regions with different functional blocks, such as fluorescent labels, liquids, nanoparticles, delivery agents, etc. The conjugates of polynucleotides and modified polynucleotides are reviewed by Goodchild in Bioconjugate Chemistry, vol. 1(3), 165-187 (1990), the contents of which are incorporated herein by reference in their entirety. U.S. Pat. Nos. 6,835,827 and 6,525,183 to Vinayak et al. (the contents of each of which are herein incorporated by reference in their entireties) teach synthesis of labeled oligonucleotides using a labeled solid support.


In certain embodiments, it may desirable to intracellularly degrade a polynucleotide introduced into the cell. For example, degradation of a polynucleotide may be preferable if precise timing of protein production is desired. Thus, in some embodiments, the invention provides a polynucleotide containing a degradation domain, which is capable of being acted on in a directed manner within a cell.


Any of the regions of the polynucleotides may be chemically modified as taught herein or as taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 (Attorney Docket Number M9) and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 (Attorney Docket Number M36) the contents of each of which are incorporated herein by reference in its entirety.


Modified Polynucleotide Molecules

The present invention also includes building blocks, e.g., modified ribonucleosides, and modified ribonucleotides, of polynucleotide molecules, e.g., of the NAVs of the invention. For example, these building blocks can be useful for preparing the polynucleotides of the invention. Such building blocks are taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 (Attorney Docket Number M9) and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 (Attorney Docket Number M36) the contents of each of which are incorporated herein by reference in its entirety.


Modifications on the Sugar

The modified nucleosides and nucleotides (e.g., building block molecules), which may be incorporated into a polynucleotide (e.g., RNA or mRNA, as described herein), can be modified on the sugar of the ribonucleic acid. For example, the 2′ hydroxyl group (OH) can be modified or replaced with a number of different substituents. Exemplary substitutions at the 2′-position include, but are not limited to, H, halo, optionally substituted C1-6 alkyl: optionally substituted C1-6 alkoxy; optionally substituted C6-10 aryloxy; optionally substituted C3-10 cycloalkyl; optionally substituted C3-8 cycloalkoxy; optionally substituted C6-10 aryloxy; optionally substituted C6-10 aryl-C1-6 alkoxy, optionally substituted C1-12 (heterocyclyl)oxy; a sugar (e.g., ribose, pentose, or any described herein); a polyethyleneglycol (PEG), —O(CH2CH2O)nCH2CH2OR, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from 1 to 20, from 2 to 4, from 2 to 8, from 2 to 10, from 2 to 16, from 2 to 20, from 4 to 8, from 4 to 10, from 4 to 16, and from 4 to 20); “locked” nucleic acids (LNA) in which the 2′-hydroxyl is connected by a C1-6 alkylene or C1-6 heteroalkylene bridge to the 4′-carbon of the same ribose sugar, where exemplary bridges included methylene, propylene, ether, or amino bridges; aminoalkyl, as defined herein; aminoalkoxy, as defined herein; amino as defined herein; and amino acid, as defined herein


Generally, RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen. Exemplary, non-limiting modified nucleotides include replacement of the oxygen in ribose (e.g., with S, Se. or alkylene, such as methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, ahritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone); multicyclic forms (e.g., tricyclo; and “unlocked” forms, such as glycol nucleic acid (GNA) (e.g., R-GNA or S-GNA, where ribose is replaced by glycol units attached to phosphodiester bonds), threose nucleic acid (TNA, where ribose is replace with α-L-threofuranosyl-(3′-+2′)), and peptide nucleic acid (PNA, where 2-amino-ethyl-glycine linkages replace the ribose and phosphodiester backbone). The sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose. Thus, a polynucleotide molecule can include nucleotides containing, e.g., arabinose, as the sugar. Such sugar modifications are taught International Application Number PCT/2012/058519 filed Oct. 3, 2012 (Attorney Docket Number M9) and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 (Attorney Docket Number M36) the contents of each of which are incoroporated herein by reference in its entirety.


Modifications on the Nucleobase

The present disclosure provides for modified nucleosides and nucleotides. As described herein “nucleoside” is defined as a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”). As described herein, “nucleotide” is defined as a nucleoside including a phosphate group. The modified nucleotides may by synthesized by any useful method, as described herein (e.g., chemically, enzymatically, or recombinantly to include one or more modified or non-natural nucleosides). The polynucleotides may comprise a region or regions of linked nucleosides. Such regions may have variable backbone linkages. The linkages may be standard phosphoester linkages, in which case the polynucleotides would comprise regions of nucleotides.


The modified nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures. One example of such non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil.


The modified nucleosides and nucleotides can include a modified nucleobase. Examples of nucleobases found in RNA include, but are not limited to, adenine, guanine, cytosine, and uracil. Examples of nucleobase found in DNA include, but are not limited to, adenine, guanine, cytosine, and thymine. Such modified nucleobases (including the distinctions between naturally occurring and non-naturally occurring) are taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 (Attorney Docket Number M9) and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 (Attorney Docket Number M36) the contents of each of which are incoroporated herein by reference in its entirety.


Combinations of Modified Sugars, Nucleobases, and Internucleoside Linkages

The polynucleotides of the invention, e.g., the NAVs of the invention, can include a combination of modifications to the sugar, the nucleobase, and/or the internucleoside linkage. These combinations can include any one or more modifications described herein.


Examples of modified nucleotides and modified nucleotide combinations are provided below in Table 25. These combinations of modified nucleotides can be used to form the polynucleotides of the invention. Unless otherwise noted, the modified nucleotides may be completely substituted for the natural nucleotides of the polynucleotides of the invention. As a non-limiting example, the natural nucleotide uridine may be substituted with a modified nucleoside described herein. In another non-limiting example, the natural nucleotide uridine may be partially substituted (e.g., about 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99.9%) with at least one of the modified nucleoside disclosed herein. Any combination of base/sugar or linker may be incorporated into the polynucleotides of the invention and such modifications are taught in International Application Number PCT/2012/058519 filed Oct. 3, 2012 (Attorney Docket Number M9) and U.S. Provisional Application No. 61/837,297 filed Jun. 20, 2013 (Attorney Docket Number M36) the contents of each of which are incorporated herein by reference in its entirety.









TABLE 25







Combinations








Modified



Nucleotide
Modified Nucleotide Combination





α-thio-cytidine
α-thio-cytidine/5-iodo-uridine



α-thio-cytidine/N1-methyl-pseudouridine



α-thio-cytidine/α-thio-uridine



α-thio-cytidine/5-methyl-uridine



α-thio-cytidine/pseudo-uridine



about 50% of the cytosines are α-thio-cytidine


Pseudoisocytidine
pseudoisocytidine/5-iodo-uridine



pseudoisocytidine/N1-methyl-pseudouridine



pseudoisocytidine/α-thio-uridine



pseudoisocytidine/5-methyl-uridine



pseudoisocytidine/pseudouridine



about 25% of cytosines are pseudoisocytidine



pseudoisocytidine/about 50% of uridines are



N1-methyl-pseudouridine and about 50%



of uridines are pseudouridine



pseudoisocytidine/about 25% of uridines are



N1-methyl-pseudouridine and about



25% of uridines are pseudouridine


pyrrolo-cytidine
pyrrolo-cytidine/5-iodo-uridine



pyrrolo-cytidine/N1-methyl-pseudouridine



pyrrolo-cytidine/α-thio-uridine



pyrrolo-cytidine/5-methyl-uridine



pyrrolo-cytidine/pseudouridine



about 50% of the cytosines are pyrrolo-cytidine


5-methyl-cytidine
5-methyl-cytidine/5-iodo-uridine



5-methyl-cytidine/N1-methyl-pseudouridine



5-methyl-cytidine/α-thio-uridine



5-methyl-cytidine/5-methyl-uridine



5-methyl-cytidine/pseudouridine



about 25% of cytosines are 5-methyl-cytidine



about 50% of cytosines are 5-methyl-cytidine



5-methyl-cytidine/5-methoxy-uridine



5-methyl-cytidine/5-bromo-uridine



5-methyl-cytidine/2-thio-uridine



5-methyl-cytidine/about 50% of uridines



are 2-thio-uridine



about 50% of uridines are 5-methyl-cytidine/about



50% of uridines are 2-thio-uridine


N4-acetyl-cytidine
N4-acetyl-cytidine/5-iodo-uridine



N4-acetyl-cytidine/N1-methyl-pseudouridine



N4-acetyl-cytidine/α-thio-uridine



N4-acetyl-cytidine/5-methyl-uridine



N4-acetyl-cytidine/pseudouridine



about 50% of cytosines are N4-acetyl-cytidine



about 25% of cytosines are N4-acetyl-cytidine



N4-acetyl-cytidine/5-methoxy-uridine



N4-acetyl-cytidine/5-bromo-uridine



N4-acetyl-cytidine/2-thio-uridine



about 50% of cytosines are N4-acetyl-cytidine/



about 50% of uridines are 2-thio-uridine









V. Pharmaceutical Vaccine Compositions

Formulation, Administration, Delivery and Dosing


The present invention provides pharmaceutical compositions including NAVs and NAV compositions and/or complexes optionally in combination with one or more pharmaceutically acceptable excipients.


The present inventors have discovered that NAVs are superior to current vaccines in several ways. First, subcutaneous and/or intradermal injection is better than intramuscular administration as a route of delivery. Second, the lipid nanoparticle delivery is superior to other formulations including the protamine approach in the literature by a factor of between 10-100 fold and no additional adjuvants were found to be necessary. Third modified and formulated NAVs were superior to unmodified formulated NAVs by a factor of 50 fold.


The present invention provides NAVs and NAV pharmaceutical compositions and complexes optionally in combination with one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may optionally comprise one or more additional active substances, e.g. therapeutically and/or prophylactically active substances. Pharmaceutical compositions of the present invention may be sterile and/or pyrogen-free. General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety).


In some embodiments, compositions are administered to humans, human patients or subjects. For the purposes of the present disclosure, the phrase “active ingredient” generally refers to the NAVs or the polynucleotides contained therein, e.g., antigen-encoding polynucleotides, for example, RNA polynucleotides, to be delivered as described herein.


Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.


Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit.


Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100%. e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.


Formulations

The NAVs of the invention can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation); (4) alter the biodistribution (e.g., target to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein (antigen) in vivo. In addition to traditional excipients such as any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, excipients of the present invention can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with NAVs (e.g., for transplantation into a subject), hyaluronidase, nanoparticle mimics and combinations thereof.


Accordingly, the formulations of the invention can include one or more excipients, each in an amount that may increases the stability of the NAV, increases cell transfection by the NAV, increases the expression of polynucleotides encoded protein, and/or alters the release profile of polynucleotide encoded proteins. Further, the polynucleotides of the present invention may be formulated using self-assembled nucleic acid nanoparticles.


Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients.


A pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.


Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered. For example, the composition may comprise between 0.1% and 99% (w/w) of the active ingredient. By way of example, the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.


In some embodiments, the formulations described herein may contain at least one polynucleotide, e.g., antigen-encoding polynucleotide. As a non-limiting example, the formulations may contain 1, 2, 3, 4 or 5 polynucleotides.


In one embodiment, the formulations described herein may comprise more than one type of polynucleotide, e.g., antigen-encoding polynucleotide. In one embodiment, the formulation may comprise a chimeric polynucleotide in linear and circular form. In another embodiment, the formulation may comprise a circular polynucleotide and an IVT polynucleotide. In yet another embodiment, the formulation may comprise an IVT polynucleotide, a chimeric polynucleotide and a circular polynucleotide.


In one embodiment the formulation may contain polynucleotide encoding proteins selected from categories such as, but not limited to, human proteins, veterinary proteins, bacterial proteins, biological proteins, antibodies, immunogenic proteins, therapeutic peptides and proteins, secreted proteins, plasma membrane proteins, cytoplasmic and cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease and/or proteins associated with non-human diseases. In one embodiment, the formulation contains at least three polynucleotides encoding proteins. In one embodiment, the formulation contains at least five polynucleotide encoding proteins.


Pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.


In some embodiments, the particle size of the lipid nanoparticle may be increased and/or decreased. The change in particle size may be able to help counter biological reaction such as, but not limited to, inflammation or may increase the biological effect of the modified mRNA delivered to mammals.


Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, surface active agents and/or emulsifiers, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in the pharmaceutical formulations of the invention.


Lipidoids

The synthesis of lipidoids has been extensively described and formulations containing these compounds are particularly suited for delivery of polynucleotides (see Mahon et al., Bioconjug Chem. 2010 21:1448-1454; Schroeder et al., J Intern Med. 2010 267:9-21; Akinc et al., Nat Biotechnol. 2008 26:561-569; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Siegwart et al., Proc Natl Acad Sci USA. 2011 108:12996-3001: all of which are incorporated herein in their entireties).


While these lipidoids have been used to effectively deliver double stranded small interfering RNA molecules in rodents and non-human primates (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Frank-Kamenetsky et al., Proc Natl Acad Sci USA. 2008 105:11915-11920; Akinc et al., Mol Ther. 2009 17:872-879; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Leuschner et al., Nat Biotechnol. 2011 29:1005-1010; all of which is incorporated herein in their entirety), the present disclosure describes their formulation and use in delivering NAVs or polynucleotides contained therein.


Complexes, micelles, liposomes or particles can be prepared containing these lipidoids and therefore, can result in an effective delivery of the polynucleotide, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and/or systemic routes of administration. Lipidoid complexes of polynucleotides can be administered by various means including, but not limited to, intravenous, intramuscular, or subcutaneous routes.


In vivo delivery of nucleic acids may be affected by many parameters, including, but not limited to, the formulation composition, nature of particle PEGylation, degree of loading, polynucleotide to lipid ratio, and biophysical parameters such as, but not limited to, particle size (Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety). As an example, small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids may result in significant effects on in vivo efficacy. Formulations with the different lipidoids, including, but not limited to penta[3-(1-laurylaminopropionyl)]-triethylenetetramine hydrochloride (TETA-5LAP; aka 98N12-5, see Murugaiah et al., Analytical Biochemistry, 401:61 (2010); herein incorporated by reference in its entirety), C12-200 (including derivatives and variants), and MD1, can be tested for in vivo activity.


The lipidoid referred to herein as “98N12-5” is disclosed by Akinc et al., Mol Ther. 2009 17:872-879 and is incorporated by reference in its entirety.


The lipidoid referred to herein as “C12-200” is disclosed by Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869 and Liu and Huang, Molecular Therapy. 2010 669-670; both of which are herein incorporated by reference in their entirety. The lipidoid formulations can include particles comprising either 3 or 4 or more components in addition to polynucleotides. As an example, formulations with certain lipidoids, include, but are not limited to, 98N12-5 and may contain 42% lipidoid, 48% cholesterol and 10% PEG (C14 alkyl chain length). As another example, formulations with certain lipidoids, include, but are not limited to, C12-200 and may contain 50% lipidoid, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and 1.5% PEG-DMG.


In one embodiment, a polynucleotide formulated with a lipidoid for systemic intravenous administration can target the liver. For example, a final optimized intravenous formulation using polynucleotides, and comprising a lipid molar composition of 42% 98N12-5, 48% cholesterol, and 10% PEG-lipid with a final weight ratio of about 7.5 to 1 total lipid to polynucleotides, and a C14 alkyl chain length on the PEG lipid, with a mean particle size of roughly 50-60 nm, can result in the distribution of the formulation to be greater than 90% to the liver. (see, Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety). In another example, an intravenous formulation using a C12-200 (see U.S. provisional application 61/175,770 and published international application WO2010129709, each of which is herein incorporated by reference in their entirety) lipidoid may have a molar ratio of 50/10/38.5/1.5 of C12-200/disteroylphosphatidyl choline/cholesterol/PEG-DMG, with a weight ratio of 7 to 1 total lipid to polynucleotides, and a mean particle size of 80 nm may be effective to deliver polynucleotides to hepatocytes (see, Love et al., Proc Natd Acad Sci USA. 2010 107:1864-1869 herein incorporated by reference in its entirety). In another embodiment, an MD1 lipidoid-containing formulation may be used to effectively deliver polynucleotides to hepatocytes in vivo.


The characteristics of optimized lipidoid formulations for intramuscular or subcutaneous routes may vary significantly depending on the target cell type and the ability of formulations to diffuse through the extracellular matrix into the blood stream. While a particle size of less than 150 nm may be desired for effective hepatocyte delivery due to the size of the endothelial fenestrae (see, Akinc et al., Mol Ther. 2009 17:872-879 herein incorporated by reference in its entirety), use of a lipidoid-formulated NAVs to deliver the formulation to other cells types including, but not limited to, endothelial cells, myeloid cells, and muscle cells may not be similarly size-limited.


Use of lipidoid formulations to deliver siRNA in vivo to other non-hepatocyte cells such as myeloid cells and endothelium has been reported (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Leuschner et al., Nat Biotechnol. 2011 29:1005-1010; Cho et al. Adv. Funct. Mater. 2009 19:3112-3118; 8th International Judah Folkman Conference, Cambridge, MA Oct. 8-9, 2010; each of which is herein incorporated by reference in its entirety). Effective delivery to myeloid cells, such as monocytes, lipidoid formulations may have a similar component molar ratio. Different ratios of lipidoids and other components including, but not limited to, disteroylphosphatidyl choline, cholesterol and PEG-DMG, may be used to optimize the formulation of the RNAVs for delivery to different cell types including, but not limited to, hepatocytes, myeloid cells, muscle cells, etc. For example, the component molar ratio may include, but is not limited to, 50% C12-200, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and %1.5 PEG-DMG (see Leuschner et al., Nat Biotechnol 2011 29:1005-1010: herein incorporated by reference in its entirety). The use of lipidoid formulations for the localized delivery of nucleic acids to cells (such as, but not limited to, adipose cells and muscle cells) via either subcutaneous or intramuscular delivery, may not require all of the formulation components desired for systemic delivery, and as such may comprise only the lipidoid and the NAV.


Combinations of different lipidoids may be used to improve the efficacy of polynucleotides directed protein production as the lipidoids may be able to increase cell transfection by the RNAV; and/or increase the translation of encoded protein (see Whitehead et al., Mol. Ther. 2011, 19:1688-1694, herein incorporated by reference in its entirety).


Liposomes, Lipoplexes, and Lipid Nanoparticles

The NAVs of the invention can be formulated using one or more liposomes, lipoplexes, or lipid nanoparticles. In one embodiment, pharmaceutical compositions of NAVs include liposomes. Liposomes are artificially-prepared vesicles which may primarily be composed of a lipid bilayer and may be used as a delivery vehicle for the administration of nutrients and pharmaceutical formulations. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter. Liposome design may include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis. Liposomes may contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations.


The formation of liposomes may depend on the physicochemical characteristics such as, but not limited to, the pharmaceutical formulation entrapped and the liposomal ingredients, the nature of the medium in which the lipid vesicles are dispersed, the effective concentration of the entrapped substance and its potential toxicity, any additional processes involved during the application and/or delivery of the vesicles, the optimization size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products.


As a non-limiting example, liposomes such as synthetic membrane vesicles may be prepared by the methods, apparatus and devices described in US Patent Publication No. US20130177638, US20130177637, US20130177636, US20130177635, US20130177634, US20130177633. US20130183375, US20130183373 and US20130183372, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, pharmaceutical compositions described herein may include, without limitation, liposomes such as those formed from 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, WA), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), and MC3 (US20100324120; herein incorporated by reference in its entirety) and liposomes which may deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, PA).


In one embodiment, pharmaceutical compositions described herein may include, without limitation, liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy. 1999 6:271-281; Zhang et al. Gene Therapy. 1999 6:1438-1447; Jeffs et al. Pharm Res. 2005 22:362-372; Morrissey et al., Nat Biotechnol. 2005 2:1002-1007; Zimmermann et al., Nature. 2006 441:111-114; Heyes et al. J Contr Rel. 2005 107:276-287; Semple et al. Nature Biotech. 2010 28:172-176; Judge et al. J Clin Invest. 2009 119:661-673; deFougerolles Hum Gene Ther. 2008 19:125-132; U.S. Patent Publication No US20130122104; all of which are incorporated herein in their entireties). The original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al. and is referred to as the spontaneous vesicle formation method. The liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide. As an example a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), as described by Jeffs et al. As another example, certain liposome formulations may contain, but are not limited to, 48% cholesterol, 20% DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2-distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA), as described by Heyes et al.


In some embodiments, liposome formulations may comprise from about about 25.0% cholesterol to about 40.0% cholesterol, from about 30.0% cholesterol to about 45.0% cholesterol, from about 35.0% cholesterol to about 50.0% cholesterol and/or from about 48.5% cholesterol to about 60% cholesterol. In a preferred embodiment, formulations may comprise a percentage of cholesterol selected from the group consisting of 28.5%, 31.5%, 33.5%, 36.5%, 37.0%, 38.5%, 39.0% and 43.5%. In some embodiments, formulations may comprise from about 5.0% to about 10.0% DSPC and/or from about 7.0% to about 15.0% DSPC.


In one embodiment, pharmaceutical compositions may include liposomes which may be formed to deliver polynucleotides which may encode at least one immunogen (antigen) or any other polypeptide of interest. The NAV may be encapsulated by the liposome and/or it may be contained in an aqueous core which may then be encapsulated by the liposome (see International Pub. Nos. WO2012031046, WO2012031043, WO2012030901 and WO2012006378 and US Patent Publication No. US20130189351, US20130195969 and US20130202684; the contents of each of which are herein incorporated by reference in their entirety).


In another embodiment, liposomes may be formulated for targeted delivery. As a non-limiting example, the liposome may be formulated for targeted delivery to the liver. The liposome used for targeted delivery may include, but is not limited to, the liposomes described in and methods of making liposomes described in US Patent Publication No. US20130195967, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the polynucleotide which may encode an immunogen (antigen) may be formulated in a cationic oil-in-water emulsion where the emulsion particle comprises an oil core and a cationic lipid which can interact with the polynucleotide anchoring the molecule to the emulsion particle (see International Pub. No. WO2012006380; herein incorporated by reference in its entirety).


In one embodiment, the NAVs may be formulated in a water-in-oil emulsion comprising a continuous hydrophobic phase in which the hydrophilic phase is dispersed. As a non-limiting example, the emulsion may be made by the methods described in International Publication No. WO201087791, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the lipid formulation may include at least cationic lipid, a lipid which may enhance transfection and a least one lipid which contains a hydrophilic head group linked to a lipid moiety (International Pub. No. WO2011076807 and U.S. Pub. No. 20110200582; the contents of each of which is herein incorporated by reference in their entirety). In another embodiment, the polynucleotides encoding an immunogen may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers (see U.S. Pub. No. 20120177724, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the polynucleotides may be formulated in a liposome as described in International Patent Publication No. WO2013086526, the contents of which is herein incorporated by reference in its entirety. The NAVs may be encapsulated in a liposome using reverse pH gradients and/or optimized internal buffer compositions as described in International Patent Publication No. WO2013086526, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the NAV pharmaceutical compositions may be formulated in liposomes such as, but not limited to, DiLa2 liposomes (Marina Biotech, Bothell, WA), SMARTICLES® (Marina Biotech, Bothell, WA), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology & Therapy 2006 5(12)1708-1713); herein incorporated by reference in its entirety) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel).


In one embodiment, the cationic lipid may be a low molecular weight cationic lipid such as those described in US Patent Application No. 20130090372, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers.


In one embodiment, the NAVs may be formulated in a liposome comprising a cationic lipid. The liposome may have a molar ratio of nitrogen atoms in the cationic lipid to the phophates in the RNA (N:P ratio) of between 1:1 and 20:1 as described in International Publication No. WO2013006825, herein incorporated by reference in its entirety. In another embodiment, the liposome may have a N:P ratio of greater than 20:1 or less than 1:1.


In one embodiment, the NAVs may be formulated in a lipid-polycation complex. The formation of the lipid-polycation complex may be accomplished by methods known in the art and/or as described in U.S. Pub. No. 20120178702, herein incorporated by reference in its entirety. As a non-limiting example, the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and the cationic peptides described in International Pub. No. WO2012013326 or US Patent Pub. No. US20130142818; each of which is herein incorporated by reference in its entirety. In another embodiment, the NAVs may be formulated in a lipid-polycation complex which may further include a non-cationic lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE).


In one embodiment, the NAVs may be formulated in an aminoalcohol lipidoid. Aminoalcohol lipidoids which may be used in the present invention may be prepared by the methods described in U.S. Pat. No. 8,450,298, herein incorporated by reference in its entirety.


The liposome formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size. In one example by Semple et al. (Semple et al. Nature Biotech. 2010 28:172-176; herein incorporated by reference in its entirety), the liposome formulation was composed of 57.1% cationic lipid, 7.1% dipalmitoylphosphatidylcholine, 34.3% cholesterol, and 1.4% PEG-c-DMA. As another example, changing the composition of the cationic lipid could more effectively deliver siRNA to various antigen presenting cells (Basha et al. Mol Ther. 2011 19:2186-2200; herein incorporated by reference in its entirety). In some embodiments, liposome formulations may comprise from about 35 to about 45% cationic lipid, from about 40% to about 50% cationic lipid, from about 50% to about 60% cationic lipid and/or from about 55% to about 65% cationic lipid. In some embodiments, the ratio of lipid to mRNA in liposomes may be from about about 5:1 to about 20:1, from about 10:1 to about 25:1, from about 15:1 to about 30:1 and/or at least 30:1.


In some embodiments, the ratio of PEG in the lipid nanoparticle (LNP) formulations may be increased or decreased and/or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and/or biodistribution of the LNP formulations. As a non-limiting example, LNP formulations may contain from about 0.5% to about 3.0%, from about 1.0% to about 3.5%, from about 1.5% to about 4.0%, from about 2.0% to about 4.5%, from about 2.5% to about 5.0% and/or from about 3.0% to about 6.0% of the lipid molar ratio of PEG-c-DOMG (R-3-[(w-methoxy-poly(ethyleneglycol)2000)carbamoyl)]-1,2-dimyristyloxypropyl-3-amine) (also referred to herein as PEG-DOMG) as compared to the cationic lipid, DSPC and cholesterol. In another embodiment the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1,2-Disteamyl-sn-glycerol, methoxypolyethylene glycol), PEG-DMG (1,2-Dimyristoyl-sn-glycerol) and/or PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol). The cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA.


In one embodiment, the NAVs may be formulated in a lipid nanoparticle such as those described in International Publication No. WO2012170930, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the NAV formulation comprising the polynucleotide is a nanoparticle which may comprise at least one lipid. The lipid may be selected from, but is not limited to, DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2-DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In another aspect, the lipid may be a cationic lipid such as, but not limited to, DLin-DMA, DLin-D-DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid may be the lipids described in and/or made by the methods described in US Patent Publication No. US20130150625, herein incorporated by reference in its entirety. As a non-limiting example, the cationic lipid may be 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,2Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en-1-yloxy]-2-{[(9Z)-octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 2 in US20130150625); 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-[(octyloxy)methyl]propan-1-ol (Compound 3 in US20130150625); and 2-(dimethylamino)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]methyl}propan-1-ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof.


Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, for example, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), or di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid.


In one embodiment, the lipid nanoparticle formulation consists essentially of (i) at least one lipid selected from the group consisting of 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319); (ii) a neutral lipid selected from DSPC, DPPC, POPC, DOPE and SM; (iii) a sterol, e.g., cholesterol; and (iv) a PEG-lipid, e.g., PEG-DMG or PEG-cDMA, in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% sterol; 0.5-15% PEG-lipid.


In one embodiment, the formulation includes from about 25% to about 75% on a molar basis of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (1319), e.g., from about 35 to about 65%, from about 45 to about 65%, about 60%, about 57.5%, about 50% or about 40% on a molar basis.


In one embodiment, the formulation includes from about 0.5% to about 15% on a molar basis of the neutral lipid e.g., from about 3 to about 12%, from about 5 to about 10% or about 15%, about 10%, or about 7.5% on a molar basis. Exemplary neutral lipids include, but are not limited to, DSPC, POPC, DPPC, DOPE and SM. In one embodiment, the formulation includes from about 5% to about 50% on a molar basis of the sterol (e.g., about 15 to about 45%, about 20 to about 40%, about 40%, about 38.5%, about 35%, or about 31% on a molar basis. An exemplary sterol is cholesterol. In one embodiment, the formulation includes from about 0.5% to about 20% on a molar basis of the PEG or PEG-modified lipid (e.g., about 0.5 to about 10%, about 0.5 to about 5%, about 1.5%, about 0.5%, about 1.5%, about 3.5%, or about 5% on a molar basis. In one embodiment, the PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of 2,000 Da. In other embodiments, the PEG or PEG modified lipid comprises a PEG molecule of an average molecular weight of less than 2,000, for example around 1,500 Da, around 1,000 Da, or around 500 Da. Exemplary PEG-modified lipids include, but are not limited to, PEG-distearoyl glycerol (PEG-DMG) (also referred herein as PEG-C14 or C14-PEG), PEG-cDMA (further discussed in Reyes et al. J. Controlled Release, 107, 276-287 (2005) the contents of which are herein incorporated by reference in its entirety)


In one embodiment, the formulations of the inventions include 25-75% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 0.5-15% of the neutral lipid, 5-50% of the sterol, and 0.5-20% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include 35-65% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 3-12% of the neutral lipid, 15-45% of the sterol, and 0.5-10% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include 45-65% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), 5-10% of the neutral lipid, 25-40% of the sterol, and 0.5-10% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 60% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (1319), about 7.5% of the neutral lipid, about 31% of the sterol, and about 1.5% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 50% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 10% of the neutral lipid, about 38.5% of the sterol, and about 1.5% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 50% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 10% of the neutral lipid, about 35% of the sterol, about 4.5% or about 5% of the PEG or PEG-modified lipid, and about 0.5% of the targeting lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 40% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 15% of the neutral lipid, about 40% of the sterol, and about 5% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 57.2% of a cationic lipid selected from 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane (DLin-KC2-DMA), dilinoleyl-methyl-4-dimethylaminobutyrate (DLin-MC3-DMA), and di((Z)-non-2-en-1-yl) 9-((4-(dimethylamino)butanoyl)oxy)heptadecanedioate (L319), about 7.1% of the neutral lipid, about 34.3% of the sterol, and about 1.4% of the PEG or PEG-modified lipid on a molar basis.


In one embodiment, the formulations of the inventions include about 57.5% of a cationic lipid selected from the PEG lipid is PEG-cDMA (PEG-cDMA is further discussed in Reyes et al. (J. Controlled Release, 107, 276-287 (2005), the contents of which are herein incorporated by reference in its entirety), about 7.5% of the neutral lipid, about 31.5% of the sterol, and about 3.5% of the PEG or PEG-modified lipid on a molar basis.


In preferred embodiments, lipid nanoparticle formulation consists essentially of a lipid mixture in molar ratios of about 20-70% cationic lipid: 5-45% neutral lipid: 20-55% cholesterol: 0.5-15% PEG-modified lipid; more preferably in a molar ratio of about 20-60% cationic lipid: 5-25% neutral lipid: 25-55% cholesterol: 0.5-15% PEG-modified lipid.


In particular embodiments, the molar lipid ratio is approximately 50/10/38.5/1.5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG, PEG-DSG or PEG-DPG), 57.2/7.1134.3/1.4 (mol % cationic lipid/ neutral lipid, e.g., DPPC/Chol/PEG-modified lipid, e.g., PEG-cDMA), 40/15/40/5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Cho/PEG-modified lipid, e.g., PEG-DMG), 50/10/35/4.5/0.5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DSG), 50/10/35/5 (cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG), 40/10/40/10 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA), 35/15/40/10 (mol % cationic lipid/neutral lipid, e.g., DSPC/Chol/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA) or 52/13/30/5 (mol % cationic lipid/neutral lipid, e.g., DSPC/Cho/PEG-modified lipid, e.g., PEG-DMG or PEG-cDMA).


Exemplary lipid nanoparticle compositions and methods of making same are described, for example, in Semple et al. (2010) Nat. Biotechnol. 28:172-176; Jayarama et al. (2012), Angew. Chen. Int. Ed., 51: 8529-8533; and Maier et al. (2013) Molecular Therapy 21, 1570-1578 (the contents of each of which are incorporated herein by reference in their entirety).


In one embodiment, the lipid nanoparticle formulations described herein may comprise a cationic lipid, a PEG lipid and a structural lipid and optionally comprise a non-cationic lipid. As a non-limiting example, the lipid nanoparticle may comprise about 40-60% of cationic lipid, about 5-15% of a non-cationic lipid, about 1-2% of a PEG lipid and about 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise about 50% cationic lipid, about 10% non-cationic lipid, about 1.5% PEG lipid and about 38.5% structural lipid. As yet another non-limiting example, the lipid nanoparticle may comprise about 55% cationic lipid, about 10% non-cationic lipid, about 2.5% PEG lipid and about 32.5% structural lipid. In one embodiment, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.


In one embodiment, the lipid nanoparticle formulations described herein may be 4 component lipid nanoparticles. The lipid nanoparticle may comprise a cationic lipid, a non-cationic lipid, a PEG lipid and a structural lipid. As a non-limiting example, the lipid nanoparticle may comprise about 40-60% of cationic lipid, about 5-15% of a non-cationic lipid, about 1-2% of a PEG lipid and about 30-50% of a structural lipid. As another non-limiting example, the lipid nanoparticle may comprise about 50% cationic lipid, about 10% non-cationic lipid, about 1.5% PEG lipid and about 38.5% structural lipid. As yet another non-limiting example, the lipid nanoparticle may comprise about 55% cationic lipid, about 10% non-cationic lipid, about 2.5% PEG lipid and about 32.5% structural lipid. In one embodiment, the cationic lipid may be any cationic lipid described herein such as, but not limited to, DLin-KC2-DMA, DLin-MC3-DMA and L319.


In one embodiment, the lipid nanoparticle formulations described herein may comprise a cationic lipid, a non-cationic lipid, a PEG lipid and a structural lipid. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-KC2-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DOMG and about 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-MC3-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DOMG and about 38.5% of the structural lipid cholesterol. As a non-limiting example, the lipid nanoparticle comprise about 50% of the cationic lipid DLin-MC3-DMA, about 10% of the non-cationic lipid DSPC, about 1.5% of the PEG lipid PEG-DMG and about 38.5% of the structural lipid cholesterol. As yet another non-limiting example, the lipid nanoparticle comprise about 55% of the cationic lipid L319, about 10% of the non-cationic lipid DSPC, about 2.5% of the PEG lipid PEG-DMG and about 32.5% of the structural lipid cholesterol.


In one embodiment, the cationic lipid may be selected from, but not limited to, a cationic lipid described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865, WO2008103276, WO2013086373 and WO2013086354, U.S. Pat. Nos. 7,893,302, 7,404,969, 8,283,333, and 8,466,122 and US Patent Publication No. US20100036115, US20120202871, US20130064894, US20130129785. US20130150625, US20130178541 and US20130225836; the contents of each of which are herein incorporated by reference in their entirety. In another embodiment, the cationic lipid may be selected from, but not limited to, formula A described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638 and WO2013116126 or US Patent Publication No. US20130178541 and US20130225836; the contents of each of which is herein incorporated by reference in their entirety. In yet another embodiment, the cationic lipid may be selected from, but not limited to, formula CLI-CLXXIX of International Publication No. WO2008103276, formula CLI-CLXXIX of U.S. Pat. No. 7,893,302, formula CLI-CLXXXXII of U.S. Pat. No. 7,404,969 and formula I-VI of US Patent Publication No. US20100036115, formula I of US Patent Publication No US20130123338; each of which is herein incorporated by reference in their entirety. As a non-limiting example, the cationic lipid may be selected from (20Z,23Z)—N,N-dimethylnonacosa-20,23-dien-10-amine, (17Z,20Z)—N,N-dimemylhexacosa-17,20-dien-9-amine, (1Z,19Z)—N5N-dimethylpentacosa-16, 19-dien-8-amine, (13Z,16Z)—N,N-dimethyldocosa-13,16-dien-5-amine, (12Z,15Z)—N,N-dimethylhenicosa-12,15-dien-4-amine, (14Z,17Z)—N,N-dimethyluricosa-14,17-dien-6-amine, (15Z,18Z)—N,N-dimethyltetracosa-15,18-dien-7-amine, (18Z,21Z)—N,N-dimethylheptacosa-18,21-dien-10-amine, (15Z,18Z)—N,N-dimethyltetracosa-15,18-dien-5-amine, (14Z,17Z)—N,N-dimethyltricosa-14,17-dien-4-amine, (19Z,22Z)—N,N-dimeihyloctacosa-19,22-dien-9-amine, (18Z,21 Z)—N,N-dimethylheptacosa-18,21-dien-8-amine, (17Z,20Z)—N,N-dimethylhexacosa-17,20-dien-7-amine, (16Z,19Z)—N,N-dimethylpentacosa-16,19-dien-6-amine, (22Z,25Z)—N,N-dimethylhentriaconta-22,25-dien-10-amine, (21 Z,24Z)—N,N-dimethyltriaconta-21,24-dien-9-amine, (18Z)—N,N-dimetylheptacos-18-en-10-amine, (17Z)—N,N-dimethylhexacos-17-en-9-amine, (19Z,22Z)—N,N-dimethyloctacosa-19,22-dien-7-amine, N,N-dimethylheptacosan-10-amine, (20Z,23Z)—N-ethyl-N-methylnonacosa-20,23-dien-10-amine, 1-[(11Z,14Z)-1-nonylicosa-11,14-dien-1-yl] pyrrolidine, (20Z)—N,N-dimethylheptacos-20-en-1 O-amine, (15Z)—N,N-dimethyl eptacos-15-en-10-amine, (14Z)—N,N-dimethylnonacos-14-en-10-amine, (17Z)—N,N-dimethylnonacos-17-en-10-amine. (24Z)—N,N-dimethyltritriacont-24-en-10-amine, (20Z)—N,N-dimethylnonacos-20-en-1 O-amine, (22Z)—N,N-dimethylhentriacont-22-en-10-amine, (16Z)—N,N-dimethylpentacos-16-en-8-amine, (12Z,15Z)—N,N-dimethyl-2-nonylhenicosa-12,15-dien-1-amine, (13Z,16Z)—N,N-dimethyl-3-nonyldocosa-13,16-dien-1-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl] eptadecan-8-amine, 1-[(1S,2R)-2-hexylcyclopropyll-N,N-dimethylnonadecan-10-amine, N,N-dimethyl-1-1(1S,2R)-2-octylcyclopropyl]nonadecan-10-amine, N,N-dimethyl-21-[(1S,2R)-2-octylcyclopropyl]henicosan-O-amine,N,N-dimethyl-1-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]nonadecan-10-amine,N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]hexadecan-8-amine, N,N-dimethyl-[(1R,2S)-2-undecylcyclopropyl]tetradecan-5-amine. N,N-dimethyl-3-{7-[(1S,2R)-2-octylcyclopropyl]heptyl} dodecan-1-amine, 1-[(1R,2S)-2-hepty lcyclopropyll-N,N-dimethyloctadecan-9-amine, 1-[(1S,2R)-2-decylcyclopropyl]-N,N-dimethylpentadecan-6-amine, N,N-dimethyl-1-[(1S,2R)-2-octylcyclopropyl]pentadecan-8-amine, R—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine, S—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-(octyloxy)propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}pyrrolidine, (2S)—N,N-dimethyl-1-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-3-[(5Z)-oct-5-en-1-yloxy]propan-2-amine, 1-{2-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-1-[(octyloxy)methyl]ethyl}azetidine, (2S)-1-(hexyloxy)-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, (2S)-1-(heptyloxy)-N,N-dimethyl-3-1(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-(nonyloxy)-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine. N,N-dimethyl-1-[(9Z)-octadec-9-en-1-yloxy]-3-(octyloxy)propan-2-amine; (2S)—N,N-dimethyl-1-1(6Z,9Z,12Z)-octadeca-6,9,12-trien-1-yloxyl-3-(octyloxy)propan-2-amine, (2S)-1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(pentyloxy)propan-2-amine, (2S)-1-(hexyloxy)-3-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethylpropan-2-amine, 1-[(11Z,14Z)-icosa-11,14-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, (2S)-1-[(13Z,16Z)-docosa-13,16-dien-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine, (2S)-1-[(13Z)-docos-13-en-1-yloxy]-3-(hexyloxy)-N,N-dimethylpropan-2-amine, 1-[(13Z)-docos-13-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, 1-[(9Z)-hexadec-9-en-1-yloxy]-N,N-dimethyl-3-(octyloxy)propan-2-amine, (2R)—N,N-dimethyl-H(1-metoyloctyl)oxyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, (2R)-1-[(3,7-dimethyloctyl)oxy]-N,N-dimethyl-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]propan-2-amine, N,N-dimethyl-1-(octyloxy)-3-({8-[(1S,2S)-2-{[(1R,2R)-2-pentylcyclopropyl]methyl}cyclopropyl]octyl}oxy)propan-2-amine, N,N-dimethyl-1-{[8-(2-oc1ylcyclopropyl)octyl]oxy}-3-(octyloxy)propan-2-amine and (11E,20Z,23Z)—N,N-dimethylnonacosa-11,20,2-trien-10-amine or a pharmaceutically acceptable salt or stereoisomer thereof.


In one embodiment, the lipid may be a cleavable lipid such as those described in international Publication No. WO2012170889, herein incorporated by reference in its entirety.


In another embodiment, the lipid may be a cationic lipid such as, but not limited to, Formula (I) of U.S. Patent Application No. US20130064894, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the cationic lipid may be synthesized by methods known in the art and/or as described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259. WO2012054365, WO2012044638, WO2010080724. WO201021865, WO2013086373 and WO2013086354; the contents of each of which are herein incorporated by reference in their entirety.


In another embodiment, the cationic lipid may be a trialkyl cationic lipid. Non-limiting examples of trialkyl cationic lipids and methods of making and using the trialkyl cationic lipids are described in International Patent Publication No. WO2013126803, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the LNP formulations of the NAVs may contain PEG-c-DOMG at 3% lipid molar ratio. In another embodiment, the LNP formulations RNAVs may contain PEG-c-DOMG at 1.5% lipid molar ratio.


In one embodiment, the pharmaceutical compositions of the NAVs may include at least one of the PEGylated lipids described in International Publication No. WO2012099755, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the LNP formulation may contain PEG-DMG 2000 (1,2-dimyristoyl-sn-glycero-3-phophoethanolamine-N-[methoxy(polyethylene glycol)-2000). In one embodiment, the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art and at least one other component. In another embodiment, the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art. DSPC and cholesterol. As a non-limiting example, the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol. As another non-limiting example the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol in a molar ratio of 2:40:10:48 (see e.g., Geall et al., Nonviral delivery of self-amplifying RNA vaccines, PNAS 2012; PMID: 22908294; herein incorporated by reference in its entirety).


In one embodiment, the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which is herein incorporated by reference in their entirety. As a non-limiting example, the NAVs described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; each of which is herein incorporated by reference in their entirety.


In one embodiment, the NAVs described herein may be formulated in a nanoparticle to be delivered by a parenteral route as described in U.S. Pub. No. US20120207845; the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs may be formulated in a lipid nanoparticle made by the methods described in US Patent Publication No US20130156845 or International Publication No WO2013093648 or WO2012024526, each of which is herein incorporated by reference in its entirety.


The lipid nanoparticles described herein may be made in a sterile environment by the system and/or methods described in US Patent Publication No. US20130164400, herein incorporated by reference in its entirety.


In one embodiment, the LNP formulation may be formulated in a nanoparticle such as a nucleic acid-lipid particle described in U.S. Pat. No. 8,492,359, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, the lipid particle may comprise one or more active agents or therapeutic agents; one or more cationic lipids comprising from about 50 mol % to about 85 mol % of the total lipid present in the particle; one or more non-cationic lipids comprising from about 13 mol % to about 49.5 mol % of the total lipid present in the particle; and one or more conjugated lipids that inhibit aggregation of particles comprising from about 0.5 mol % to about 2 mol % of the total lipid present in the particle. The nucleic acid in the nanoparticle may be the polynucleotides described herein and/or are known in the art.


In one embodiment, the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, modified RNA described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; the contents of each of which are herein incorporated by reference in their entirety.


In one embodiment, LNP formulations described herein may comprise a polycationic composition. As a non-limiting example, the polycationic composition may be selected from formula 1-60 of US Patent Publication No. US20050222064; the content of which is herein incorporated by reference in its entirety. In another embodiment, the LNP formulations comprising a polycationic composition may be used for the delivery of the modified RNA described herein in vivo and/or in vitro.


In one embodiment, the LNP formulations described herein may additionally comprise a permeability enhancer molecule. Non-limiting permeability enhancer molecules are described in US Patent Publication No. US20050222064; the content of which is herein incorporated by reference in its entirety.


In one embodiment, the NAV pharmaceutical compositions may be formulated in liposomes such as, but not limited to. DiLa2 liposomes (Marina Biotech, Bothell, WA), SMARTICLES® (Marina Biotech, Bothell, WA), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology & Therapy 2006 5(12)1708-1713); herein incorporated by reference in its entirety) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel).


In one embodiment, the NAVs may be formulated in a lyophilized gel-phase liposomal composition as described in US Publication No. US2012060293, herein incorporated by reference in its entirety.


The nanoparticle formulations may comprise a phosphate conjugate. The phosphate conjugate may increase in vivo circulation times and/or increase the targeted delivery of the nanoparticle. Phosphate conjugates for use with the present invention may be made by the methods described in International Application No. WO2013033438 or US Patent Publication No. US20130196948, the contents of each of which are herein incorporated by reference in its entirety. As a non-limiting example, the phosphate conjugates may include a compound of any one of the formulas described in International Application No. WO2013033438, herein incorporated by reference in its entirety.


The nanoparticle formulation may comprise a polymer conjugate. The polymer conjugate may be a water soluble conjugate. The polymer conjugate may have a structure as described in U.S. Patent Application No. 20130059360, the contents of which are herein incorporated by reference in its entirety. In one aspect, polymer conjugates with the polynucleotides of the present invention may be made using the methods and/or segmented polymeric reagents described in U.S. Patent Application No. 20130072709, herein incorporated by reference in its entirety. In another aspect, the polymer conjugate may have pendant side groups comprising ring moieties such as, but not limited to, the polymer conjugates described in US Patent Publication No. US20130196948, the contents of which is herein incorporated by reference in its entirety.


The nanoparticle formulations may comprise a conjugate to enhance the delivery of nanoparticles of the present invention in a subject. Further, the conjugate may inhibit phagocytic clearance of the nanoparticles in a subject. In one aspect, the conjugate may be a “self” peptide designed from the human membrane protein CD47 (e.g., the “self” particles described by Rodriguez et al (Science 2013 339, 971-975), herein incorporated by reference in its entirety). As shown by Rodriguez et al. the self peptides delayed macrophage-mediated clearance of nanoparticles which enhanced delivery of the nanoparticles. In another aspect, the conjugate may be the membrane protein CD47 (e.g., see Rodriguez et al. Science 2013 339, 971-975, herein incorporated by reference in its entirety). Rodriguez et al. showed that, similarly to “self” peptides, CD47 can increase the circulating particle ratio in a subject as compared to scrambled peptides and PEG coated nanoparticles.


In one embodiment, the NAVs of the present invention are formulated in nanoparticles which comprise a conjugate to enhance the delivery of the nanoparticles of the present invention in a subject. The conjugate may be the CD47 membrane or the conjugate may be derived from the CD47 membrane protein, such as the “self” peptide described previously. In another aspect the nanoparticle may comprise PEG and a conjugate of CD47 or a derivative thereof. In yet another aspect, the nanoparticle may comprise both the “self” peptide described above and the membrane protein CD47.


In another aspect, a “self” peptide and/or CD47 protein may be conjugated to a virus-like particle or pseudovirion, as described herein for delivery of the NAVs of the present invention.


In another embodiment, NAV pharmaceutical compositions comprising the polynucleotides of the present invention and a conjugate which may have a degradable linkage. Non-limiting examples of conjugates include an aromatic moiety comprising an ionizable hydrogen atom, a spacer moiety, and a water-soluble polymer. As a non-limiting example, pharmaceutical compositions comprising a conjugate with a degradable linkage and methods for delivering such pharmaceutical compositions are described in US Patent Publication No. US20130184443, the contents of which are herein incorporated by reference in its entirety.


The nanoparticle formulations may be a carbohydrate nanoparticle comprising a carbohydrate carrier and a NAV. As a non-limiting example, the carbohydrate carrier may include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phytoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin. (See e.g., International Publication No. WO2012109121; the contents of which are herein incorporated by reference in its entirety).


Nanoparticle formulations of the present invention may be coated with a surfactant or polymer in order to improve the delivery of the particle. In one embodiment, the nanoparticle may be coated with a hydrophilic coating such as, but not limited to, PEG coatings and/or coatings that have a neutral surface charge. The hydrophilic coatings may help to deliver nanoparticles with larger payloads such as, but not limited to, NAVs within the central nervous system. As a non-limiting example nanoparticles comprising a hydrophilic coating and methods of making such nanoparticles are described in US Patent Publication No. US20130183244, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the lipid nanoparticles of the present invention may be hydrophilic polymer particles. Non-limiting examples of hydrophilic polymer particles and methods of making hydrophilic polymer particles are described in US Patent Publication No. US20130210991, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the lipid nanoparticles of the present invention may be hydrophobic polymer particles.


Lipid nanoparticle formulations may be improved by replacing the cationic lipid with a biodegradable cationic lipid which is known as a rapidly eliminated lipid nanoparticle (reLNP). Ionizable cationic lipids, such as, but not limited to, DLinDMA, DLin-KC2-DMA, and DLin-MC3-DMA, have been shown to accumulate in plasma and tissues over time and may be a potential source of toxicity. The rapid metabolism of the rapidly eliminated lipids can improve the tolerability and therapeutic index of the lipid nanoparticles by an order of magnitude from a 1 mg/kg dose to a 10 mg/kg dose in rat. Inclusion of an enzymatically degraded ester linkage can improve the degradation and metabolism profile of the cationic component, while still maintaining the activity of the reLNP formulation. The ester linkage can be internally located within the lipid chain or it may be terminally located at the terminal end of the lipid chain. The internal ester linkage may replace any carbon in the lipid chain.


In one embodiment, the internal ester linkage may be located on either side of the saturated carbon.


In one embodiment, an immune response may be elicited by delivering a lipid nanoparticle which may include a nanospecies, a polymer and an immunogen. (U.S. Publication No. 20120189700 and International Publication No. WO20l2099805; each of which is herein incorporated by reference in their entirety). The polymer may encapsulate the nanospecies or partially encapsulate the nanospecies. The immunogen may be a recombinant protein, a modified RNA and/or a polynucleotide described herein. In one embodiment, the lipid nanoparticle may be formulated for use in a vaccine such as, but not limited to, against a pathogen.


Lipid nanoparticles may be engineered to alter the surface properties of particles so the lipid nanoparticles may penetrate the mucosal barrier. Mucus is located on mucosal tissue such as, but not limited to, oral (e.g., the buccal and esophageal membranes and tonsil tissue), ophthalmic, gastrointestinal (e.g., stomach, small intestine, large intestine, colon, rectum), nasal, respiratory (e.g., nasal, pharyngeal, tracheal and bronchial membranes), genital (e.g., vaginal, cervical and urethral membranes). Nanoparticles larger than 10-200 nm which are preferred for higher drug encapsulation efficiency and the ability to provide the sustained delivery of a wide array of drugs have been thought to be too large to rapidly diffuse through mucosal barriers. Mucus is continuously secreted, shed, discarded or digested and recycled so most of the trapped particles may be removed from the mucosla tissue within seconds or within a few hours. Large polymeric nanoparticles (200 nm-500 nm in diameter) which have been coated densely with a low molecular weight polyethylene glycol (PEG) diffused through mucus only 4 to 6-fold lower than the same particles diffusing in water (Lai et al. PNAS 2007 104(5):1482-487; Lai et al. Adv Drug Deliv Rev. 2009 61(2): 158-171; each of which is herein incorporated by reference in their entirety). The transport of nanoparticles may be determined using rates of permeation and/or fluorescent microscopy techniques including, but not limited to, fluorescence recovery after photobleaching (FRAP) and high resolution multiple particle tracking (MPT). As a non-limiting example, compositions which can penetrate a mucosal barrier may be made as described in U.S. Pat. No. 8,241,670 or International Patent Publication No. WO2013110028, the contents of each of which are herein incorporated by reference in its entirety.


The lipid nanoparticle engineered to penetrate mucus may comprise a polymeric material (i.e. a polymeric core) and/or a polymer-vitamin conjugate and/or a tri-block co-polymer. The polymeric material may include, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, poly(styrenes), polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates. The polymeric material may be biodegradable and/or biocompatible. Non-limiting examples of biocompatible polymers are described in International Patent Publication No. WO2013116804, the contents of which are herein incorporated by reference in its entirety. The polymeric material may additionally be irradiated. As a non-limiting example, the polymeric material may be gamma irradiated (See e.g., International App. No. WO201282165, herein incorporated by reference in its entirety). Non-limiting examples of specific polymers include poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacralate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (HPMA), polyethyleneglycol, poly-L-glutamic acid, poly(hydroxy acids), polyanhydrides, polyorthoesters, poly(ester amides), polyamides, poly(ester ethers), polycarbonates, polyalkylenes such as polyethylene and polypropylene, polyalkylene glycols such as poly(ethylene glycol) (PEG), polyalkylene oxides (PEO), polyalkylene terephthalates such as poly(ethylene terephthalate), polyvinyl alcohols (PVA), polyvinyl ethers, polyvinyl esters such as poly(vinyl acetate), polyvinyl halides such as poly(vinyl chloride) (PVC), polyvinylpyrrolidone, polysiloxanes, polystyrene (PS), polyurethanes, derivatized celluloses such as alkyl celluloses, hydroxyalkyl celluloses, cellulose ethers, cellulose esters, nitro celluloses, hydroxypropylcellulose, carboxymethylcellulose, polymers of acrylic acids, such as poly(methyl(meth)acrylate) (PMMA), poly(ethyl(meth)acrylate), poly(butyl(meth)acrylate), poly(isobutyl(meth)acrylate), poly(hexyl(meth)acrylate), poly(isodecyl(meth)acrylate), poly(lauryl(meth)acrylate), poly(phenyl(meth)acrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate) and copolymers and mixtures thereof, polydioxanone and its copolymers, polyhydroxyalkanoates, polypropylene fumarate, polyoxymethylene, poloxamers, poly(ortho)esters, poly(butyric acid), poly(valeric acid), poly(lactide-co-caprolactone), PEG-PLGA-PEG and trimethylene carbonate, polyvinylpyrrolidone. The lipid nanoparticle may be coated or associated with a co-polymer such as, but not limited to, a block co-polymer (such as a branched polyether-polyamide block copolymer described in International Publication No. WO2013012476, herein incorporated by reference in its entirety), and (poly(ethylene glycol))-(poly(propylene oxide))-(poly(ethylene glycol)) triblock copolymer (see e.g., US Publication 20120121718 and US Publication 20100003337 and U.S. Pat. No. 8,263,665; each of which is herein incorporated by reference in their entirety). The co-polymer may be a polymer that is generally regarded as safe (GRAS) and the formation of the lipid nanoparticle may be in such a way that no new chemical entities are created. For example, the lipid nanoparticle may comprise poloxamers coating PLDA nanoparticles without forming new chemical entities which are still able to rapidly penetrate human mucus (Yang et al. Angew. Chem. Int. Ed. 2011 50:2597-2600; the contents of which are herein incorporated by reference in its entirety). A non-limiting scalable method to produce nanoparticles which can penetrate human mucus is described by Xu et al. (See e.g., J Control Release 2013, 170(2):279-86; the contents of which are herein incorporated by reference in its entirety).


The vitamin of the polymer-vitamin conjugate may be vitamin E. The vitamin portion of the conjugate may be substituted with other suitable components such as, but not limited to, vitamin A, vitamin E, other vitamins, cholesterol, a hydrophobic moiety, or a hydrophobic component of other surfactants (e.g., sterol chains, fatty acids, hydrocarbon chains and alkylene oxide chains).


The lipid nanoparticle engineered to penetrate mucus may include surface altering agents such as, but not limited to, polynucleotides, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as for example dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin, polyethylene glycol and poloxamer), mucolytic agents (e.g., N-acetylcysteine, mugwort, bromelain, papain, clerodendrum, acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin β4 dornase alfa, neltenexine, erdosteine) and various DNases including rhDNase. The surface altering agent may be embedded or enmeshed in the particle's surface or disposed (e.g., by coating, adsorption, covalent linkage, or other process) on the surface of the lipid nanoparticle. (see e.g., US Publication 20100215580 and US Publication 20080166414 and US20130164343; the contents of each of which is herein incorporated by reference in their entirety).


In one embodiment, the mucus penetrating lipid nanoparticles may comprise at least one polynucleotide described herein. The polynucleotide may be encapsulated in the lipid nanoparticle and/or disposed on the surface of the paricle. The polynucleotide may be covalently coupled to the lipid nanoparticle. Formulations of mucus penetrating lipid nanoparticles may comprise a plurality of nanoparticles. Further, the formulations may contain particles which may interact with the mucus and alter the structural and/or adhesive properties of the surrounding mucus to decrease mucoadhesion which may increase the delivery of the mucus penetrating lipid nanoparticles to the mucosal tissue.


In another embodiment, the mucus penetrating lipid nanoparticles may be a hypotonic formulation comprising a mucosal penetration enhancing coating. The formulation may be hypotonice for the epithelium to which it is being delivered. Non-limiting examples of hypotonic formulations may be found in International Patent Publication No. WO2013110028, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, in order to enhance the delivery through the mucosal barrier the NAV formulation may comprise or be a hypotonic solution. Hypotonic solutions were found to increase the rate at which mucoinert particles such as, but not limited to, mucus-penetrating particles, were able to reach the vaginal epithelial surface (See e.g., Ensign et al. Biomaterials 2013 34(28):6922-9; the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the NAV is formulated as a lipoplex, such as, without limitation, the ATUPLEX™ system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECT™ from STEMGENT® (Cambridge, MA), and polyethylenimine (PEI) or protamine-based targeted and non-targeted delivery of nucleic acids acids (Aleku et al. Cancer Res. 2008 68:9788-9798; Strumberg et al. Int J Clin Pharmacol Ther 2012 50:76-78; Santel et al., Gene Ther 2006 13:1222-1234; Santel et al., Gene Ther 2006 13:1360-1370; Gutbier et al., Pulm Pharmacol. Ther. 2010 23:334-344; Kaufmann et al. Microvasc Res 2010 80:286-293Weide et al. J Immunother. 2009 32:498-507; Weide et al. J Immunother. 2008 31:180-188; Pascolo Expert Opin. Biol. Ther. 4:1285-1294; Fotin-Mleczek et al., 2011 J. Immunother. 34:1-15; Song et al., Nature Biotechnol. 2005, 23:709-717; Peer et al., Proc Nati Acad Sci USA. 2007 6; 104:4095-4100; deFougerolles Hum Gene Ther. 2008 19:125-132; all of which are incorporated herein by reference in its entirety).


In one embodiment such formulations may also be constructed or compositions altered such that they passively or actively are directed to different cell types in vivo, including but not limited to hepatocytes, immune cells, tumor cells, endothelial cells, antigen presenting cells, and leukocytes (Akinc et al. Mol Ther. 2010 18:1357-1364; Song et al., Nat Biotechnol. 2005 23:709-717; Judge et al., J Clin invest. 2009 119:661-673; Kaufmann et al., Microvasc Res 2010 80:286-293; Santel et al., Gene Ther 2006 13:1222-1234; Santel et al., Gene Ther 2006 13:1360-1370; Gutbier et al., Pulm Pharmacol. Ther. 2010 23:334-344; Basha et al., Mol. Ther. 2011 19:2186-2200; Fenske and Cullis, Expert Opin Drug Deliv. 2008 5:25-44; Peer et al., Science. 2008 319:627-630; Peer and Lieberman, Gene Ther. 2011 18:1127-1133; all of which are incorporated herein by reference in its entirety). One example of passive targeting of formulations to liver cells includes the DLin-DMA, DLin-KC2-DMA and DLin-MC3-DMA-based lipid nanoparticle formulations which have been shown to bind to apolipoprotein E and promote binding and uptake of these formulations into hepatocytes in vivo (Akinc et al. Mol Ther. 2010 18:1357-1364; herein incorporated by reference in its entirety). Formulations can also be selectively targeted through expression of different ligands on their surface as exemplified by, but not limited by, folate, transferrin, N-acetylgalactosamine (GalNAc), and antibody targeted approaches (Kolhatkar et al., Curr Drug Discov Technol. 2011 8:197-206; Musacchio and Torchilin, Front Biosci. 2011 16:1388-1412; Yu et al., Mol Membr Biol. 2010 27:286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008 25:1-61; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Zhao et al., Expert Opin Drug Deliv. 2008 5:309-319; Akinc et al., Mol Ther. 2010 18:1357-1364; Srinivasan et al., Methods Mol Biol. 2012 820:105-116; Ben-Arie et al., Methods Mol Biol. 2012 757:497-507; Peer 2010 J Control Release. 20:63-68; Peer et al., Proc Natl Acad Sci USA. 2007 104:4095-4100; Kim et al., Methods Mol Biol. 2011 721:339-353; Subramanya et al., Mol Ther. 2010 18:2028-2037; Song et al., Nat Biotechnol. 2005 23:709-717; Peer et al., Science. 2008 319:627-630; Peer and Lieberman, Gene Ther. 2011 18:1127-1133; all of which are incorporated herein by reference in its entirety).


In one embodiment, the NAV is formulated as a solid lipid nanoparticle. A solid lipid nanoparticle (SLN) may be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and may be stabilized with surfactants and/or emulsifiers. In a further embodiment, the lipid nanoparticle may be a self-assembly lipid-polymer nanoparticle (see Zhang et al., ACS Nano, 2008, 2 (8), pp 1696-1702; the contents of which are herein incorporated by reference in its entirety). As a non-limiting example, the SLN may be the SLN described in International Patent Publication No. WO2013105101, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the SLN may be made by the methods or processes described in International Patent Publication No. WO2013105101, the contents of which are herein incorporated by reference in its entirety.


Liposomes, lipoplexes, or lipid nanoparticles may be used to improve the efficacy of polynucleotides directed protein production as these formulations may be able to increase cell transfection by the NAV; and/or increase the translation of encoded protein. One such example involves the use of lipid encapsulation to enable the effective systemic delivery of polyplex plasmid DNA (Heyes et al., Mol Ther. 2007 15:713-720; herein incorporated by reference in its entirety). The liposomes, lipoplexes, or lipid nanoparticles may also be used to increase the stability of the polynucleotide.


In one embodiment, the NAVs of the present invention can be formulated for controlled release and/or targeted delivery. As used herein, “controlled release” refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome. In one embodiment, the RNAVs may be encapsulated into a delivery agent described herein and/or known in the art for controlled release and/or targeted delivery. As used herein, the term “encapsulate” means to enclose, surround or encase. As it relates to the formulation of the compounds of the invention, encapsulation may be substantial, complete or partial. The term “substantially encapsulated” means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.9 or greater than 99.999% of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent. “Partially encapsulation” means that less than 10, 10, 20, 30, 40 50 or less of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent. Advantageously, encapsulation may be determined by measuring the escape or the activity of the pharmaceutical composition or compound of the invention using fluorescence and/or electron micrograph. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the pharmaceutical composition or compound of the invention are encapsulated in the delivery agent.


In one embodiment, the controlled release formulation may include, but is not limited to, tri-block co-polymers. As a non-limiting example, the formulation may include two different types of tri-block co-polymers (International Pub. No. WO2012131104 and WO2012131106; the contents of each of which is herein incorporated by reference in its entirety).


In another embodiment, the NAVs may be encapsulated into a lipid nanoparticle or a rapidly eliminated lipid nanoparticle and the lipid nanoparticles or a rapidly eliminated lipid nanoparticle may then be encapsulated into a polymer, hydrogel and/or surgical sealant described herein and/or known in the art. As a non-limiting example, the polymer, hydrogel or surgical sealant may be PLGA, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc. Alachua, FL), HYLENEX® (Halozyme Therapeutics, San Diego CA), surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, GA), TISSELL® (Baxter International, Inc Deerfield, IL), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, IL).


In another embodiment, the lipid nanoparticle may be encapsulated into any polymer known in the art which may form a gel when injected into a subject. As another non-limiting example, the lipid nanoparticle may be encapsulated into a polymer matrix which may be biodegradable.


In one embodiment, the NAV formulation for controlled release and/or targeted delivery may also include at least one controlled release coating. Controlled release coatings include, but are not limited to, OPADRY®, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, EUDRAGIT RL®, EUDRAGIT RS® and cellulose derivatives such as ethylcellulose aqueous dispersions (AQUACOAT® and SURELEASE®).


In one embodiment, the NAV controlled release and/or targeted delivery formulation may comprise at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.


In one embodiment, the NAV controlled release and/or targeted delivery formulation comprising at least one polynucleotide may comprise at least one PEG and/or PEG related polymer derivatives as described in U.S. Pat. No. 8,404,222, herein incorporated by reference in its entirety.


In another embodiment, the NAV controlled release delivery formulation comprising at least one polynucleotide may be the controlled release polymer system described in US20130130348, herein incorporated by reference in its entirety.


In one embodiment, the NAVs of the present invention may be encapsulated in a therapeutic nanoparticle, referred to herein as “therapeutic nanoparticle RNAVs.” Therapeutic nanoparticles may be formulated by methods described herein and known in the art such as, but not limited to, International Pub Nos. WO2010005740, WO2010030763, WO2010005721. WO2010005723, WO2012054923, US Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286, US20120288541, US20130123351 and US20130230567 and U.S. Pat. Nos. 8,206,747, 8,293,276, 8,318,208 and 8,318,211; the contents of each of which are herein incorporated by reference in their entirety. In another embodiment, therapeutic polymer nanoparticles may be identified by the methods described in US Pub No. US20120140790, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the therapeutic nanoparticle NAV may be formulated for sustained release. As used herein, “sustained release” refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time may include, but is not limited to, hours, days, weeks, months and years. As a non-limiting example, the sustained release nanoparticle may comprise a polymer and a therapeutic agent such as, but not limited to, the polynucleotides of the present invention (see International Pub No. 2010075072 and US Pub No. US20100216804, US20110217377 and US20120201859, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the sustained release formulation may comprise agents which permit persistent bioavailability such as, but not limited to, crystals, macromolecular gels and/or particulate suspensions (see US Patent Publication No US20130150295, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the therapeutic nanoparticle NAVs may be formulated to be target specific. As a non-limiting example, the therapeutic nanoparticles may include a corticosteroid (see International Pub. No. WO2011084518; herein incorporated by reference in its entirety). As a non-limiting example, the therapeutic nanoparticles may be formulated in nanoparticles described in international Pub No. WO2008121949, WO2010005726, WO2010005725, WO2011084521 and US Pub No. US20100069426, US20120004293 and US20100104655, each of which is herein incorporated by reference in their entirety.


In one embodiment, the nanoparticles of the present invention may comprise a polymeric matrix. As a non-limiting example, the nanoparticle may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof.


In one embodiment, the therapeutic nanoparticle comprises a diblock copolymer. In one embodiment, the diblock copolymer may include PEG in combination with a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof. In another embodiment, the diblock copolymer may comprise the diblock copolymers described in European Patent Publication No. the contents of which are herein incorporated by reference in its entirety. In yet another embodiment, the diblock copolymer may be a high-X diblock copolymer such as those described in International Patent Publication No. WO2013120052, the contents of which are herein incorporated by reference in its entirety.


As a non-limiting example the therapeutic nanoparticle comprises a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, each of which is herein incorporated by reference in their entirety). In another non-limiting example, the therapeutic nanoparticle is a stealth nanoparticle comprising a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968 and International Publication No. WO2012166923, the contents of each of which are herein incorporated by reference in its entirety). In yet another non-limiting example, the therapeutic nanoparticle is a stealth nanoparticle or a target-specific stealth nanoparticle as described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the therapeutic nanoparticle may comprise a multiblock copolymer (See e.g., U.S. Pat. No. 8,263,665 and 8287,910 and US Patent Pub. No. US20130195987; the contents of each of which are herein incorporated by reference in its entirety).


In yet another non-limiting example, the lipid nanoparticle comprises the block copolymer PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety). The NAVs of the present invention may be formulated in lipid nanoparticles comprising the PEG-PLGA-PEG block copolymer.


In one embodiment, the therapeutic nanoparticle may comprise a multiblock copolymer (See e.g., U.S. Pat. Nos. 8,263,665 and 8,287,910 and US Patent Pub. No. US20130195987; the contents of each of which are herein incorporated by reference in its entirety).


In one embodiment, the block copolymers described herein may be included in a polyion complex comprising a non-polymeric micelle and the block copolymer. (See e.g., U.S. Pub. No. 20120076836; herein incorporated by reference in its entirety).


In one embodiment, the therapeutic nanoparticle may comprise at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.


In one embodiment, the therapeutic nanoparticles may comprise at least one poly(vinyl ester) polymer. The poly(vinyl ester) polymer may be a copolymer such as a random copolymer. As a non-limiting example, the random copolymer may have a structure such as those described in International Application No. WO2013032829 or US Patent Publication No US20130121954, the contents of which are herein incorporated by reference in its entirety. In one aspect, the poly(vinyl ester) polymers may be conjugated to the polynucleotides described herein. In another aspect, the poly(vinyl ester) polymer which may be used in the present invention may be those described in, herein incorporated by reference in its entirety.


In one embodiment, the therapeutic nanoparticle may comprise at least one diblock copolymer. The diblock copolymer may be, but it not limited to, a poly(lactic) acid-poly(ethylene)glycol copolymer (see e.g., International Patent Publication No. WO2013044219; herein incorporated by reference in its entirety). As a non-limiting example, the therapeutic nanoparticle may be used to treat cancer (see International publication No. WO2013044219; herein incorporated by reference in its entirety).


In one embodiment, the therapeutic nanoparticles may comprise at least one cationic polymer described herein and/or known in the art.


In one embodiment, the therapeutic nanoparticles may comprise at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; herein incorporated by reference in its entirety) and combinations thereof.


In another embodiment, the nanoparticles described herein may comprise an amine cationic lipid such as those described in International Patent Application No. WO2013059496, the contents of which are herein incorporated by reference in its entirety. In one aspect the cationic lipids may have an amino-amine or an amino-amide moiety.


In one embodiment, the therapeutic nanoparticles may comprise at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.


In another embodiment, the therapeutic nanoparticle may include a conjugation of at least one targeting ligand. The targeting ligand may be any ligand known in the art such as, but not limited to, a monoclonal antibody. (Kirpotin et al, Cancer Res. 2006 66:6732-6740; herein incorporated by reference in its entirety).


In one embodiment, the therapeutic nanoparticle may be formulated in an aqueous solution which may be used to target cancer (see International Pub No. WO2011084513 and US Pub No. US20110294717, each of which is herein incorporated by reference in their entirety).


In one embodiment, the therapeutic nanoparticle NAVs, e.g., therapeutic nanoparticles comprising at least one NAV may be formulated using the methods described by Podobinski et al in U.S. Pat. No. 8,404,799, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs may be encapsulated in, linked to and/or associated with synthetic nanocarriers. Synthetic nanocarriers include, but are not limited to, those described in International Pub. Nos. WO2010005740, WO2010030763, WO201213501, WO2012149252, WO2012149255, WO2012149259, WO2012149265, WO2012149268, WO2012149282, WO2012149301, WO2012149393, WO2012149405, WO2012149411, WO2012149454 and WO2013019669, and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US20120244222, each of which is herein incorporated by reference in their entirety. The synthetic nanocarriers may be formulated using methods known in the art and/or described herein. As a non-limiting example, the synthetic nanocarriers may be formulated by the methods described in International Pub Nos. WO2010005740, WO2010030763 and WO201213501 and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US2012024422, each of which is herein incorporated by reference in their entirety. In another embodiment, the synthetic nanocarrier formulations may be lyophilized by methods described in International Pub. No. WO2011072218 and U.S. Pat. No. 8,211,473; the content of each of which is herein incorporated by reference in their entirety. In yet another embodiment, formulations of the present invention, including, but not limited to, synthetic nanocarriers, may be lyophilized or reconstituted by the methods described in US Patent Publication No. US20130230568, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the synthetic nanocarriers may contain reactive groups to release the polynucleotides described herein (see International Pub. No. WO20120952552 and US Pub No. US20120171229, each of which is herein incorporated by reference in their entirety).


In one embodiment, the synthetic nanocarriers may contain an immunostimulatory agent to enhance the immune response from delivery of the synthetic nanocarrier. As a non-limiting example, the synthetic nanocarrier may comprise a Th1 immunostimulatory agent which may enhance a Th1-based response of the immune system (see International Pub No. WO2010123569 and US Pub. No. US20110223201, each of which is herein incorporated by reference in its entirety).


In one embodiment, the synthetic nanocarriers may be formulated for targeted release. In one embodiment, the synthetic nanocarrier is formulated to release the polynucleotides at a specified pH and/or after a desired time interval. As a non-limiting example, the synthetic nanoparticle may be formulated to release the NAVs after 24 hours and/or at a pH of 4.5 (see International Pub. Nos. WO2010138193 and WO2010138194 and US Pub Nos. US20110020388 and US20110027217, each of which is herein incorporated by reference in their entireties).


In one embodiment, the synthetic nanocarriers may be formulated for controlled and/or sustained release of the polynucleotides described herein. As a non-limiting example, the synthetic nanocarriers for sustained release may be formulated by methods known in the art, described herein and/or as described in International Pub No. WO2010138192 and US Pub No. 20100303850, each of which is herein incorporated by reference in their entirety.


In one embodiment, the NAV may be formulated for controlled and/or sustained release wherein the formulation comprises at least one polymer that is a crystalline side chain (CYSC) polymer. CYSC polymers are described in U.S. Pat. No. 8,399,007, herein incorporated by reference in its entirety.


In one embodiment, the synthetic nanocarrier may be formulated for use as a vaccine. In one embodiment, the synthetic nanocarrier may encapsulate at least one polynucleotide which encode at least one antigen. As a non-limiting example, the synthetic nanocarrier may include at least one antigen and an excipient for a vaccine dosage form (see International Pub No. WO2011150264 and US Pub No. US20110293723, each of which is herein incorporated by reference in their entirety). As another non-limiting example, a vaccine dosage form may include at least two synthetic nanocarriers with the same or different antigens and an excipient (see International Pub No. WO2011150249 and US Pub No. US20110293701, each of which is herein incorporated by reference in their entirety). The vaccine dosage form may be selected by methods described herein, known in the art and/or described in international Pub No. WO2011150258 and US Pub No. US20120027806, each of which is herein incorporated by reference in their entirety).


In one embodiment, the synthetic nanocarrier may comprise at least one polynucleotide which encodes at least one adjuvant. As non-limiting example, the adjuvant may comprise dimethyldioctadecylammonium-bromide, dimethyldioctadecylammonium-chloride, dimethyldioctadecylammonium-phosphate or dimethyldioctadecylammonium-acetate (DDA) and an apolar fraction or part of said apolar fraction of a total lipid extract of a mycobacterium (See e.g, U.S. Pat. No. 8,241,610; herein incorporated by reference in its entirety). In another embodiment, the synthetic nanocarrier may comprise at least one polynucleotide and an adjuvant. As a non-limiting example, the synthetic nanocarrier comprising and adjuvant may be formulated by the methods described in International Pub No. WO2011150240 and US Pub No. US20110293700, each of which is herein incorporated by reference in its entirety.


In one embodiment, the synthetic nanocarrier may encapsulate at least one polynucleotide which encodes a peptide, fragment or region from a virus. As a non-limiting example, the synthetic nanocarrier may include, but is not limited to, the nanocarriers described in International Pub No. WO2012024621, WO201202629, WO2012024632 and US Pub No. US20120064110, US20120058153 and US20120058154, each of which is herein incorporated by reference in their entirety.


In one embodiment, the synthetic nanocarrier may be coupled to a polynucleotide which may be able to trigger a humoral and/or cytotoxic T lymphocyte (CTL) response (See e.g., International Publication No. WO2013019669, herein incorporated by reference in its entirety).


In one embodiment, the NAV may be encapsulated in, linked to and/or associated with zwitterionic lipids. Non-limiting examples of zwitterionic lipids and methods of using zwitterionic lipids are described in US Patent Publication No. US20130216607, the contents of which are herein incorporated by reference in its entirety. In one aspect, the zwitterionic lipids may be used in the liposomes and lipid nanoparticles described herein.


In one embodiment, the NAV may be formulated in colloid nanocarriers as described in US Patent Publication No. US20130197100, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the nanoparticle may be optimized for oral administration. The nanoparticle may comprise at least one cationic biopolymer such as, but not limited to, chitosan or a derivative thereof. As a non-limiting example, the nanoparticle may be formulated by the methods described in U.S. Pub. No. 20120282343; herein incorporated by reference in its entirety.


In some embodiments, LNPs comprise the lipid KL52 (an amino-lipid disclosed in U.S. Application Publication No. 2012/0295832 expressly incorporated herein by reference in its entirety). Activity and/or safety (as measured by examining one or more of ALT/AST, white blood cell count and cytokine induction) of LNP administration may be improved by incorporation of such lipids. LNPs comprising KL52 may be administered intravenously and/or in one or more doses. In some embodiments, administration of LNPs comprising KL52 results in equal or improved mRNA and/or protein expression as compared to LNPs comprising MC3.


In some embodiments, NAV may be delivered using smaller LNPs. Such particles may comprise a diameter from below 0.1 um up to 100 nm such as, but not limited to, less than 0.1 um, less than 1.0 um, less than 5 um, less than 10 um, less than 15 um, less than 20 um, less than 25 um, less than 30 um, less than 35 um, less than 40 um, less than 50 um, less than 55 um, less than 60 um, less than 65 um, less than 70 um, less than 75 um, less than 80 um, less than 85 um, less than 90 um, less than 95 um, less than 100 um, less than 125 um, less than 150 um, less than 175 um, less than 200 um, less than 225 um, less than 250 um, less than 275 um, less than 300 um, less than 325 um, less than 350 um, less than 375 um, less than 400 um, less than 425 um, less than 450 um, less than 475 um, less than 500 um, less than 525 um, less than 550 um, less than 575 um, less than 600 um, less than 625 um, less than 650 um, less than 675 um, less than 700 um, less than 725 um, less than 750 um, less than 775 um, less than 800 um, less than 825 um, less than 850 um, less than 875 um, less than 900 um, less than 925 um, less than 950 um, less than 975 um,


In another embodiment, NAVs may be delivered using smaller LNPs which may comprise a diameter from about 1 nm to about 100 nm, from about 1 nm to about 10 nm, about 1 nm to about 20 nm, from about 1 nm to about 30 nm, from about 1 nm to about 40 nm, from about 1 nm to about 50 nm, from about 1 nm to about 60 nm, from about 1 nm to about 70 nm, from about 1 nm to about 80 nm, from about 1 nm to about 90 nm, from about 5 nm to about from 100 nm, from about 5 nm to about 10 nm, about 5 nm to about 20 nm, from about 5 nm to about 30 nm, from about 5 nm to about 40 nm, from about 5 nm to about 50 nm, from about 5 nm to about 60 nm, from about 5 nm to about 70 nm, from about 5 nm to about 80 nm, from about 5 nm to about 90 nm, about 10 to about 50 nM, from about 20 to about 50 nm, from about 30 to about 50 nm, from about 40 to about 50 nm, from about 20 to about 60 nm, from about 30 to about 60 nm, from about 40 to about 60 nm, from about 20 to about 70 nm, from about 30 to about 70 nm, from about 40 to about 70 nm, from about 50 to about 70 nm, from about 60 to about 70 nm, from about 20 to about 80 nm, from about 30 to about 80 nm, from about 40 to about 80 nm, from about 50 to about 80 nm, from about 60 to about 80 nm, from about 20 to about 90 nm, from about 30 to about 90 nm, from about 40 to about 90 nm, from about 50 to about 90 nm, from about 60 to about 90 nm and/or from about 70 to about 90 rnm.


In some embodiments, such LNPs are synthesized using methods comprising microfluidic mixers. Exemplary microfluidic mixers may include, but are not limited to a slit interdigitial micromixer including, but not limited to those manufactured by Microinnova (Allerheiligen bei Wildon, Austria) and/or a staggered herringbone micromixer (SHM) (Zhigaltsev, I. V. et al., Bottom-up design and synthesis of limit size lipid nanoparticle systems with aqueous and triglyceride cores using millisecond microfluidic mixing have been published (Langmuir. 2012. 28:3633-40; Belliveau, N. M. et al., Microfluidic synthesis of highly potent limit-size lipid nanoparticles for in vivo delivery of siRNA. Molecular Therapy-Nucleic Acids. 2012. 1:e37; Chen, D. et al., Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation. J Am Chem Soc. 2012. 134(16):6948-51; each of which is herein incorporated by reference in its entirety). In some embodiments, methods of LNP generation comprising SHM, further comprise the mixing of at least two input streams wherein mixing occurs by microstructure-induced chaotic advection (MICA). According to this method, fluid streams flow through channels present in a herringbone pattern causing rotational flow and folding the fluids around each other. This method may also comprise a surface for fluid mixing wherein the surface changes orientations during fluid cycling. Methods of generating LNPs using SHM include those disclosed in U.S. Application Publication Nos. 2004/0262223 and 2012/0276209, each of which is expressly incorporated herein by reference in their entirety.


In one embodiment, the NAV of the present invention may be formulated in lipid nanoparticles created using a micromixer such as, but not limited to, a Slit Interdigital Microstnuctured Mixer (SIMM-V2) or a Standard Slit Interdigital Micro Mixer (SSIMM) or Caterpillar (CPMM) or Impinging-jet (UMM) from the Institut for Mikrotechnik Mainz GmbH, Mainz Germany).


In one embodiment, the NAVs of the present invention may be formulated in lipid nanoparticles created using microfluidic technology (see Whitesides, George M. The Origins and the Future of Microfluidics. Nature, 2006 442: 368-373; and Abraham et al. Chaotic Mixer for Microchannels. Science, 2002 295: 647-651; each of which is herein incorporated by reference in its entirety). As a non-limiting example, controlled microfluidic formulation includes a passive method for mixing streams of steady pressure-driven flows in micro channels at a low Reynolds number (See e.g., Abraham et al. Chaotic Mixer for Microchannels. Science, 2002 295: 647-651; which is herein incorporated by reference in its entirety).


In one embodiment, the NAVs of the present invention may be formulated in lipid nanoparticles created using a micromixer chip such as, but not limited to, those from Harvard Apparatus (Holliston, MA) or Dolomite Microfluidics (Royston, UK). A micromixer chip can be used for rapid mixing of two or more fluid streams with a split and recombine mechanism.


In one embodiment, the NAVs of the invention may be formulated for delivery using the drug encapsulating microspheres described in International Patent Publication No. WO2013063468 or U.S. Pat. No. 8,440,614, each of which is herein incorporated by reference in its entirety. The microspheres may comprise a compound of the formula (I), (II), (III), (IV). (V) or (VI) as described in International Patent Publication No. WO2013063468, the contents of which are herein incorporated by reference in its entirety. In another aspect, the amino acid, peptide, polypeptide, lipids (APPL) are useful in delivering the NAVs of the invention to cells (see International Patent Publication No. WO2013063468, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the NAVs of the invention may be formulated in lipid nanoparticles having a diameter from about 10 to about 100 nm such as, but not limited to, about 10 to about 20 nm, about 10 to about 30 nm, about 10 to about 40 nm, about 10 to about 50 nm, about 10 to about 60 nm, about 10 to about 70 nm, about 10 to about 80 nm, about 10 to about 90 nm, about 20 to about 30 nm, about 20 to about 40 nm, about 20 to about 50 nm, about 20 to about 60 nm, about 20 to about 70 nm, about 20 to about 80 nm, about 20 to about 90 nm, about 20 to about 100 nm, about 30 to about 40 nm, about 30 to about 50 nm, about 30 to about 60 nm, about 30 to about 70 nm, about 30 to about 80 nm, about 30 to about 90 nm, about 30 to about 100 nm, about 40 to about 50 nm, about 40 to about 60 nm, about 40 to about 70 nm, about 40 to about 80 nm, about 40 to about 90 nm, about 40 to about 100 nm, about 50 to about 60 nm, about 50 to about 70 nm about 50 to about 80 nm, about 50 to about 90 nm, about 50 to about 100 nm, about 60 to about 70 nm, about 60 to about 80 nm, about 60 to about 90 nm, about 60 to about 100 nm, about 70 to about 80 nm, about 70 to about 90 nm, about 70 to about 100 nm, about 80 to about 90 nm, about 80 to about 100 nm and/or about 90 to about 100 nm.


In one embodiment, the lipid nanoparticles may have a diameter from about 10 to 500 nm.


In one embodiment, the lipid nanoparticle may have a diameter greater than 100 nm, greater than 150 nm, greater than 200 nm, greater than 250 nm, greater than 300 nm, greater than 350 nm, greater than 400 nm, greater than 450 nm, greater than 500 nm, greater than 550 nm, greater than 600 nm, greater than 650 nm, greater than 700 nm, greater than 750 nm, greater than 800 nm, greater than 850 nm, greater than 900 nm, greater than 950 nm or greater than 1000 nm.


In one aspect, the lipid nanoparticle may be a limit size lipid nanoparticle described in International Patent Publication No. WO2013059922, the contents of which are herein incorporated by reference in its entirety. The limit size lipid nanoparticle may comprise a lipid bilayer surrounding an aqueous core or a hydrophobic core; where the lipid bilayer may comprise a phospholipid such as, but not limited to, diacylphosphatidylcholine, a diacylphosphatidylethanolamine, a ceramide, a sphingomyelin, a dihydrosphingomyelin, a cephalin, a cerebroside, a C8-C20 fatty acid diacylphophatidylcholine, and 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC). In another aspect the limit size lipid nanoparticle may comprise a polyethylene glycol-lipid such as, but not limited to, DLPE-PEG, DMPE-PEG, DPPC-PEG and DSPE-PEG.


In one embodiment, the NAVs may be delivered, localized and/or concentrated in a specific location using the delivery methods described in International Patent Publication No. WO2013063530, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, a subject may be administered an empty polymeric particle prior to, simultaneously with or after delivering the NAVs to the subject. The empty polymeric particle undergoes a change in volume once in contact with the subject and becomes lodged, embedded, immobilized or entrapped at a specific location in the subject.


In one embodiment, the NAVs may be formulated in an active substance release system (See e.g., US Patent Publication No. US20130102545, the contents of which is herein incorporated by reference in its entirety). The active substance release system may comprise 1) at least one nanoparticle bonded to an oligonucleotide inhibitor strand which is hybridized with a catalytically active nucleic acid and 2) a compound bonded to at least one substrate molecule bonded to a therapeutically active substance (e.g., polynucleotides described herein), where the therapeutically active substance is released by the cleavage of the substrate molecule by the catalytically active nucleic acid.


In one embodiment, the NAVs may be formulated in a nanoparticle comprising an inner core comprising a non-cellular material and an outer surface comprising a cellular membrane. The cellular membrane may be derived from a cell or a membrane derived from a virus. As a non-limiting example, the nanoparticle may be made by the methods described in International Patent Publication No. WO2013052167, herein incorporated by reference in its entirety. As another non-limiting example, the nanoparticle described in International Patent Publication No. WO2013052167, herein incorporated by reference in its entirety, may be used to deliver the NAVs described herein.


In one embodiment, the NAVs may be formulated in porous nanoparticle-supported lipid bilayers (protocells). Protocells are described in International Patent Publication No. WO2013056132, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs described herein may be formulated in polymeric nanoparticles as described in or made by the methods described in U.S. Pat. Nos. 8,420,123 and 8,518,963 and European Patent No. EP2073848B1, the contents of each of which are herein incorporated by reference in their entirety. As a non-limiting example, the polymeric nanoparticle may have a high glass transition temperature such as the nanoparticles described in or nanoparticles made by the methods described in U.S. Pat. No. 8,518,963, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the polymer nanoparticle for oral and parenteral formulations may be made by the methods described in European Patent No. EP2073848B1, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the NAVs described herein may be formulated in nanoparticles used in imaging. The nanoparticles may be liposome nanoparticles such as those described in US Patent Publication No US20130129636, herein incorporated by reference in its entirety. As a non-limiting example, the liposome may comprise gadolinium(II)2-{4,7-bis-carboxymethyl-10-[(N,N-distearylamidomethyl-N′-amido-methyl]-1,4,7,10-tetra-azacyclododec-1-yl}-acetic acid and a neutral, fully saturated phospholipid component (see e.g., US Patent Publication No US20130129636, the contents of which is herein incorporated by reference in its entirety).


In one embodiment, the nanoparticles which may be used in the present invention are formed by the methods described in U.S. Patent Application No. US20130130348, the contents of which is herein incorporated by reference in its entirety.


The nanoparticles of the present invention may further include nutrients such as, but not limited to, those which deficiencies can lead to health hazards from anemia to neural tube defects (see e.g, the nanoparticles described in International Patent Publication No WO2013072929, the contents of which is herein incorporated by reference in its entirety). As a non-limiting example, the nutrient may be iron in the form of ferrous, ferric salts or elemental iron, iodine, folic acid, vitamins or micronutrients.


In one embodiment, the NAVs of the present invention may be formulated in a swellable nanoparticle. The swellable nanoparticle may be, but is not limited to, those described in U.S. Pat. No. 8,440,231, the contents of which is herein incorporated by reference in its entirety. As a non-limiting embodiment, the swellable nanoparticle may be used for delivery of the NAVs of the present invention to the pulmonary system (see e.g., U.S. Pat. No. 8,440,231, the contents of which is herein incorporated by reference in its entirety).


The NAVs of the present invention may be formulated in polyanhydride nanoparticles such as, but not limited to, those described in U.S. Pat. No. 8,449,916, the contents of which is herein incorporated by reference in its entirety.


The nanoparticles and microparticles of the present invention may be geometrically engineered to modulate macrophage and/or the immune response. In one aspect, the geometrically engineered particles may have varied shapes, sizes and/or surface charges in order to incorporated the polynucleotides of the present invention for targeted delivery such as, but not limited to, pulmonary delivery (see e.g., International Publication No WO2013082111, the contents of which is herein incorporated by reference in its entirety). Other physical features the geometrically engineering particles may have include, but are not limited to, fenestrations, angled arms, asymmetry and surface roughness, charge which can alter the interactions with cells and tissues. As a non-limiting example, nanoparticles of the present invention may be made by the methods described in International Publication No WO2013082111, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the nanoparticles of the present invention may be water soluble nanoparticles such as, but not limited to, those described in International Publication No. WO2013090601, the contents of which is herein incorporated by reference in its entirety. The nanoparticles may be inorganic nanoparticles which have a compact and zwitterionic ligand in order to exhibit good water solubility. The nanoparticles may also have small hydrodynamic diameters (HD), stability with respect to time, pH, and salinity and a low level of non-specific protein binding.


In one embodiment the nanoparticles of the present invention may be developed by the methods described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the nanoparticles of the present invention are stealth nanoparticles or target-specific stealth nanoparticles such as, but not limited to, those described in US Patent Publication No. US20130172406: the contents of which is herein incorporated by reference in its entirety. The nanoparticles of the present invention may be made by the methods described in US Patent Publication No. US20130172406, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the stealth or target-specific stealth nanoparticles may comprise a polymeric matrix. The polymeric matrix may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polyesters, polyanhydrides, polyethers, polyurethanes, polymethacrylates, polyacrylates, polycyanoacrylates or combinations thereof.


In one embodiment, the nanoparticle may be a nanoparticle-nucleic acid hybrid structure having a high density nucleic acid layer. As a non-limiting example, the nanoparticle-nucleic acid hybrid structure may made by the methods described in US Patent Publication No. US20130171646, the contents of which are herein incorporated by reference in its entirety. The nanoparticle may comprise a nucleic acid such as, but not limited to, polynucleotides described herein and/or known in the art.


At least one of the nanoparticles of the present invention may be embedded in in the core a nanostructure or coated with a low density porous 3-D structure or coating which is capable of carrying or associating with at least one payload within or on the surface of the nanostructure. Non-limiting examples of the nanostructures comprising at least one nanoparticle are described in International Patent Publication No. WO2013123523, the contents of which are herein incorporated by reference in its entirety.


Polymers, Biodegradable Nanoparticles, and Core-Shell Nanoparticles

The NAVs of the invention can be formulated using natural and/or synthetic polymers. Non-limiting examples of polymers which may be used for delivery include, but are not limited to, DYNAMIC POLYCONJUGATE® (Arrowhead Research Corp., Pasadena, CA) formulations from MIRUS® Bio (Madison, WI) and Roche Madison (Madison, WI), PHASERX™ polymer formulations such as, without limitation, SMARTT POLYMER TECHNOLOGY™ (PHASERX®, Seattle, WA), DMRI/DOPE, poloxamer, VAXFECTIN® adjuvant from Vical (San Diego, CA), chitosan, cyclodextrin from Calando Pharmaceuticals (Pasadena, CA), dendrimers and poly(lactic-co-glycolic acid) (PLGA) polymers. RONDEL™ (RNAi/Oligonucleotide Nanoparticle Delivery) polymers (Arrowhead Research Corporation, Pasadena, CA) and pH responsive co-block polymers such as, but not limited to, PHASERX® (Seattle, WA).


A non-limiting example of chitosan formulation includes a core of positively charged chitosan and an outer portion of negatively charged substrate (U.S. Pub. No. 20120258176; herein incorporated by reference in its entirety). Chitosan includes, but is not limited to N-trimethyl chitosan, mono-N-carboxymethyl chitosan (MCC), N-palmitoyl chitosan (NPCS), EDTA-chitosan, low molecular weight chitosan, chitosan derivatives, or combinations thereof.


In one embodiment, the polymers used in the present invention have undergone processing to reduce and/or inhibit the attachement of unwanted substances such as, but not limited to, bacteria, to the surface of the polymer. The polymer may be processed by methods known and/or described in the art and/or described in International Pub. No. WO2012150467, herein incorporated by reference in its entirety.


A non-limiting example of PLGA formulations include, but are not limited to, PLGA injectable depots (e.g., ELIGARD® which is formed by dissolving PLGA in 66% N-methyl-2-pyrrolidone (NMP) and the remainder being aqueous solvent and leuprolide. Once injected, the PLGA and leuprolide peptide precipitates into the subcutaneous space).


Many of these polymer approaches have demonstrated efficacy in delivering oligonucleotides in vivo into the cell cytoplasm (reviewed in deFougerolles Hum Gene Ther. 2008 19:125-132; herein incorporated by reference in its entirety). Two polymer approaches that have yielded robust in vivo delivery of nucleic acids, in this case with small interfering RNA (siRNA), are dynamic polyconjugates and cyclodextrin-based nanoparticles (see e.g., US Patent Publication No. US20130156721, herein incorporated by reference in its entirety). The first of these delivery approaches uses dynamic polyconjugates and has been shown in vivo in mice to effectively deliver siRNA and silence endogenous target mRNA in hepatocytes (Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; herein incorporated by reference in its entirety). This particular approach is a multicomponent polymer system whose key features include a membrane-active polymer to which nucleic acid, in this case siRNA, is covalently coupled via a disulfide bond and where both PEG (for charge masking) and N-acetylgalactosamine (for hepatocyte targeting) groups are linked via pH-sensitive bonds (Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; herein incorporated by reference in its entirety). On binding to the hepatocyte and entry into the endosome, the polymer complex disassembles in the low-pH environment, with the polymer exposing its positive charge, leading to endosomal escape and cytoplasmic release of the siRNA from the polymer. Through replacement of the N-acetylgalactosamine group with a mannose group, it was shown one could alter targeting from asialoglycoprotein receptor-expressing hepatocytes to sinusoidal endothelium and Kupffer cells. Another polymer approach involves using transferrin-targeted cyclodextrin-containing polycation nanoparticles. These nanoparticles have demonstrated targeted silencing of the EWS-FLIJ gene product in transferrin receptor-expressing Ewing's sarcoma tumor cells (Hu-Lieskovan et al., Cancer Res. 2005 65: 8984-8982; herein incorporated by reference in its entirety) and siRNA formulated in these nanoparticles was well tolerated in non-human primates (Heidel et al., Proc Natl Acad Sci USA 2007 104:5715-21; herein incorporated by reference in its entirety). Both of these delivery strategies incorporate rational approaches using both targeted delivery and endosomal escape mechanisms.


The polymer formulation can permit the sustained or delayed release of polynucleotides (e.g., following intramuscular or subcutaneous injection). The altered release profile for the polynucleotide can result in, for example, translation of an encoded protein over an extended period of time. The polymer formulation may also be used to increase the stability of the polynucleotide. Biodegradable polymers have been previously used to protect nucleic acids other than polynucleotide from degradation and been shown to result in sustained release of payloads in vivo (Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; Sullivan et al., Expert Opin Drug Deliv. 2010 7:1433-1446; Convertine et al., Biomacromolecules. 2010 Oct. 1; Chu et al., Acc Chem Res. 2012 Jan. 13; Manganiello et al., Biomaterials. 2012 33:2301-2309; Benoit et al., Biomacromolecules. 2011 12:2708-2714; Singha et al., Nucleic Acid Ther. 2011 2:133-147; deFougerolles Hum Gene Ther. 2008 19:125-132; Schaffert and Wagner, Gene Ther. 2008 16:1131-1138; Chaturvedi et al., Expert Opin Drug Deliv. 2011 8:1455-1468; Davis, Mol Pharm. 2009 6:659-668; Davis, Nature 2010 464:1067-1070; each of which is herein incorporated by reference in its entirety).


In one embodiment, the NAV pharmaceutical compositions may be sustained release formulations. In a further embodiment, the sustained release formulations may be for subcutaneous delivery. Sustained release formulations may include, but are not limited to, PLGA microspheres, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc. Alachua, FL), HYLENEX® (Halozyme Therapeutics, San Diego CA), surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, GA), TISSELL® (Baxter International, Inc Deerfield, IL), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, IL).


As a non-limiting example NAVs may be formulated in PLGA microspheres by preparing the PLGA microspheres with tunable release rates (e.g., days and weeks) and encapsulating the modified mRNA in the PLGA microspheres while maintaining the integrity of the modified mRNA during the encapsulation process. EVAc are non-biodegradeable, biocompatible polymers which are used extensively in pre-clinical sustained release implant applications (e.g., extended release products Ocusert a pilocarpine ophthalmic insert for glaucoma or progestasert a sustained release progesterone intrauterine deivce; transdermal delivery systems Testoderm, Duragesic and Selegiline; catheters). Poloxamer F-407 NF is a hydrophilic, non-ionic surfactant triblock copolymer of polyoxyethylene-polyoxypropylene-polyoxyethylene having a low viscosity at temperatures less than 5° C. and forms a solid gel at temperatures greater than 15° C. PEG-based surgical sealants comprise two synthetic PEG components mixed in a delivery device which can be prepared in one minute, seals in 3 minutes and is reabsorbed within 30 days. GELSITE® and natural polymers are capable of in-situ gelation at the site of administration. They have been shown to interact with protein and peptide therapeutic candidates through ionic ineraction to provide a stabilizing effect.


Polymer formulations can also be selectively targeted through expression of different ligands as exemplified by, but not limited by, folate, transferrin, and N-acetylgalactosamine (GalNAc) (Benoit et al., Biomacromolecules. 2011 12:2708-2714; Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; Davis, Mol Pharm. 2009 6:659-668; Davis, Nature 2010 464:1067-1070; each of which is herein incorporated by reference in its entirety).


The NAVs of the invention may be formulated with or in a polymeric compound. The polymer may include at least one polymer such as, but not limited to, polyethenes, polyethylene glycol (PEG), poly(l-lysine)(PLL), PEG grafted to PLL, cationic lipopolymer, biodegradable cationic lipopolymer, polyethyleneimine (PEI), cross-linked branched poly(alkylene imines), a polyamine derivative, a modified poloxamer, a biodegradable polymer, elastic biodegradable polymer, biodegradable block copolymer, biodegradable random copolymer, biodegradable polyester copolymer, biodegradable polyester block copolymer, biodegradable polyester block random copolymer, multiblock copolymers, linear biodegradable copolymer, poly[α-(4-aminobutyl)-L-glycolic acid) (PAGA), biodegradable cross-linked cationic multi-block copolymers, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), acrylic polymers, amine-containing polymers, dextran polymers, dextran polymer derivatives or or combinations thereof.


As a non-limiting example, the NAVs of the invention may be formulated with the polymeric compound of PEG grafted with PLL as described in U.S. Pat. No. 6,177,274; herein incorporated by reference in its entirety. The formulation may be used for transfecting cells in vitro or for in vivo delivery of polynucleotides. In another example, the polynucleotide may be suspended in a solution or medium with a cationic polymer, in a dry pharmaceutical composition or in a solution that is capable of being dried as described in U.S. Pub. Nos. 20090042829 and 20090042825: each of which are herein incorporated by reference in their entireties.


As another non-limiting example the NAVs of the invention may be formulated with a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, herein incorporated by reference in their entireties) or PLGA-PEG-PLGA block copolymers (See U.S. Pat. No. 6,004,573, herein incorporated by reference in its entirety). As a non-limiting example, the NAVs of the invention may be formulated with a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968, herein incorporated by reference in its entirety).


A polyamine derivative may be used to deliver nucleic acids or to treat and/or prevent a disease or to be included in an implantable or injectable device (U.S. Pub. No. 20100260817 (now U.S. Pat. No. 8,460,696) the contents of each of which is herein incorporated by reference in its entirety). As a non-limiting example, a pharmaceutical composition may include the NAV and the polyamine derivative described in U.S. Pub. No. 20100260817 (now U.S. Pat. No. 8,460,696; the contents of which are incorporated herein by reference in its entirety. As a non-limiting example the NAVs of the present invention may be delivered using a polyaminde polymer such as, but not limited to, a polymer comprising a 1,3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dilkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; herein incorporated by reference in its entirety).


The NAVs of the invention may be formulated with at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.


In one embodiment, the NAVs of the present invention may be formulated with at least one polymer and/or derivatives thereof described in International Publication Nos. WO2011115862, WO2012082574 and WO2012068187 and U.S. Pub. No. 20120283427, each of which are herein incorporated by reference in their entireties.


In another embodiment, the NAVs of the present invention may be formulated with a polymer of formula Z as described in WO2011115862, herein incorporated by reference in its entirety. In yet another embodiment, the NAVs may be formulated with a polymer of formula Z, Z′ or Z″ as described in International Pub. Nos. WO2012082574 or WO2012068187 and U.S. Pub. No. 2012028342, each of which are herein incorporated by reference in their entireties. The polymers formulated with the modified RNA of the present invention may be synthesized by the methods described in International Pub. Nos. WO2012082574 or WO2012068187, each of which are herein incorporated by reference in their entireties.


The NAVs of the invention may be formulated with at least one acrylic polymer. Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof.


Formulations of NAVs of the invention may include at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(amine-co-esters) or combinations thereof. As a non-limiting example, the poly(amine-co-esters) may be the polymers described in and/or made by the methods described in International Publication No WO2013082529, the contents of which are herein incorporated by reference in its entirety.


For example, the NAVs of the invention may be formulated in a pharmaceutical compound including a poly(alkylene imine), a biodegradable cationic lipopolymer, a biodegradable block copolymer, a biodegradable polymer, or a biodegradable random copolymer, a biodegradable polyester block copolymer, a biodegradable polyester polymer, a biodegradable polyester random copolymer, a linear biodegradable copolymer, PAGA, a biodegradable cross-linked cationic multi-block copolymer or combinations thereof. The biodegradable cationic lipopolymer may be made by methods known in the art and/or described in U.S. Pat. No. 6,696,038, U.S. App. Nos. 20030073619 and 20040142474 each of which is herein incorporated by reference in their entireties. The poly(alkylene imine) may be made using methods known in the art and/or as described in U.S. Pub. No. 20100004315, herein incorporated by reference in its entirety. The biodegradabale polymer, biodegradable block copolymer, the biodegradable random copolymer, biodegradable polyester block copolymer, biodegradable polyester polymer, or biodegradable polyester random copolymer may be made using methods known in the art and/or as described in U.S. Pat. Nos. 6,517,869 and 6,267,987, the contents of which are each incorporated herein by reference in their entirety. The linear biodegradable copolymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,652,886. The PAGA polymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,217,912 herein incorporated by reference in its entirety. The PAGA polymer may be copolymerized to form a copolymer or block copolymer with polymers such as but not limited to, poly-L-lysine, polyargine, polyornithine, histones, avidin, protamines, polylactides and poly(lactide-co-glycolides). The biodegradable cross-linked cationic multi-block copolymers may be made my methods known in the art and/or as described in U.S. Pat. Nos. 8,057,821, 8,444,992 or U.S. Pub. No. 2012009145 each of which are herein incorporated by reference in their entireties. For example, the multi-block copolymers may be synthesized using linear polyethyleneimine (LPEI) blocks which have distinct patterns as compared to branched polyethyleneimines. Further, the composition or pharmaceutical composition may be made by the methods known in the art, described herein, or as described in U.S. Pub. No. 20100004315 or U.S. Pat. Nos. 6,267,987 and 6,217,912 each of which are herein incorporated by reference in their entireties.


The NAVs of the invention may be formulated with at least one degradable polyester which may contain polycationic side chains. Degradeable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof. In another embodiment, the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.


The NAVs of the invention may be formulated with at least one crosslinkable polyester. Crosslinkable polyesters include those known in the art and described in US Pub. No. 20120269761, the contents of which is herein incorporated by reference in its entirety.


The NAVs of the invention may be formulated in or with at least one cyclodextrin polymer. Cyclodextrin polymers and methods of making cyclodextrin polymers include those known in the art and described in US Pub. No. 20130184453, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs of the invention may be formulated in or with at least one crosslinked cation-binding polymers. Crosslinked cation-binding polymers and methods of making crosslinked cation-binding polymers include those known in the art and described in International Patent Publication No. WO2013106072, WO2013106073 and WO2013106086, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs of the invention may be formulated in or with at least one branched polymer. Branched polymers and methods of making branched polymers include those known in the art and described in International Patent Publication No. WO2013113071, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs of the invention may be formulated in or with at least PEGylated albumin polymer. PEGylated albumin polymer and methods of making PEGylated albumin polymer include those known in the art and described in US Patent Publication No. US20130231287, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, the polymers described herein may be conjugated to a lipid-terminating PEG. As a non-limiting example, PLGA may be conjugated to a lipid-terminating PEG forming PLGA-DSPE-PEG. As another non-limiting example, PEG conjugates for use with the present invention are described in International Publication No. WO2008103276, herein incorporated by reference in its entirety. The polymers may be conjugated using a ligand conjugate such as, but not limited to, the conjugates described in U.S. Pat. No. 8,273,363, herein incorporated by reference in its entirety.


In one embodiment, the NAVs disclosed herein may be mixed with the PEGs or the sodium phosphate/sodium carbonate solution prior to administration.


In another embodiment, a polynucleotides encoding a protein of interest may be mixed with the PEGs and also mixed with the sodium phosphate/sodium carbonate solution.


In yet another embodiment, polynucleotides encoding a protein of interest may be mixed with the PEGs and a polynucleotides encoding a second protein of interest may be mixed with the sodium phosphate/sodium carbonate solution.


In one embodiment, the NAVs described herein may be conjugated with another compound. Non-limiting examples of conjugates are described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties. In another embodiment, the NAVs of the present invention may be conjugated with conjugates of formula 1-122 as described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties. The NAVs described herein may be conjugated with a metal such as, but not limited to, gold. (See e.g., Giljohann et al. Journ. Amer. Chem. Soc. 2009 131(6): 2072-2073; herein incorporated by reference in its entirety). In another embodiment, the NAVs described herein may be conjugated and/or encapsulated in gold-nanoparticles. (International Pub. No. WO201216269 and U.S. Pub. No. 20120302940 and US20130177523; the contents of each of which is herein incorporated by reference in its entirety).


As described in U.S. Pub. No. 20100004313, herein incorporated by reference in its entirety, a gene delivery composition may include a nucleotide sequence and a poloxamer. For example, the NAVs of the present invention may be used in a gene delivery composition with the poloxamer described in U.S. Pub. No. 20100004313, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the polymer formulation of the present invention may be stabilized by contacting the polymer formulation, which may include a cationic carrier, with a cationic lipopolymer which may be covalently linked to cholesterol and polyethylene glycol groups. The polymer formulation may be contacted with a cationic lipopolymer using the methods described in U.S. Pub. No. 20090042829 herein incorporated by reference in its entirety. The cationic carrier may include, but is not limited to, polyethylenimine, poly(trimethylenimine), poly(tetramethylenimine), polypropylenimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodexuin, spermine, spermidine, poly(2-dimethylamino)ethyl methacrylate, poly(lysine), poly(histidine), poly(arginine), cationized gelatin, dendrimers, chitosan, 1,2-Dioleoyl-3-Trimethylammonium-Propane(DOTAP), N-[l-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1-[2-(oleoyloxy)ethyl]-2-oleyl-3-(2-hydroxyethyl)imidazolinium chloride (DOTIM), 2,3-dioleyloxy-N-[2(sperminecarboxamido)ethyl]-N,N-dimethyl-1-propanaminium trifluoroacetate (DOSPA), 3B—[N—(N′,N′-Dimethylaminoethane)-carbamoyl]Cholesterol Hydrochloride (DC-Cholesterol HCl) diheptadecylamidoglycyl spermidine (DOGS), N,N-distearyl-N,N-dimethylammonium bromide (DDAB), N-(1,2-dimyristyloxyprop-3-yl)-N,N-dimethyl-N-hydroxyethyl ammonium bromide (DMRIE), N,N-dioleyl-N,N-dimethylammonium chloride DODAC) and combinations thereof. As a non-limiting example, the NAVs may be formulated with a cationic lipopolymer such as those described in U.S. Patent Application No. 20130065942, the contents of which are herein incorporated by reference in its entirety.


The NAVs of the invention may be formulated in a polyplex of one or more polymers (See e.g., U.S. Pat. No. 8,501,478, U.S. Pub. No. 20120237565 and 20120270927 and 20130149783 and International Patent Pub. No. WO2013090861; the contents of each of which is herein incorporated by reference in its entirety). As a non-limiting example, the polyplex may be formed using the noval alpha-aminoamidine polymers described in International Publication No. WO2013090861, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the polyplex may be formed using the click polymers described in U.S. Pat. No. 8,501,478, the contents of which is herein incorporated by reference in its entirety.


In one embodiment, the polyplex comprises two or more cationic polymers. The catioinic polymer may comprise a poly(ethylene imine) (PEI) such as linear PEI. In another embodiment, the polyplex comprises p(TETA/CBA) its PEGylated analog p(TETA/CBA)-g-PEG2k and mixtures thereof (see e.g., US Patent Publication No. US20130149783, the contents of which are herein incorporated by reference in its entirety.


The NAVs of the invention can also be formulated as a nanoparticle using a combination of polymers, lipids, and/or other biodegradable agents, such as, but not limited to, calcium phosphate. Components may be combined in a core-shell, hybrid, and/or layer-by-layer architecture, to allow for fine-tuning of the nanoparticle so to delivery of the NAV, may be enhanced (Wang et al., Nat Mater. 2006 5:791-796; Fuller et al., Biomaterials. 2008 29:1526-1532; DeKoker et al., Adv Drug Deliv Rev. 2011 63:748-761; Endres et al., Biomaterials. 2011 32:7721-7731; Su et al., Mol Pharm. 2011 Jun. 6; 8(3):774-87; herein incorporated by reference in its entirety). As a non-limiting example, the nanoparticle may comprise a plurality of polymers such as, but not limited to hydrophilic-hydrophobic polymers (e.g., PEG-PLGA), hydrophobic polymers (e.g., PEG) and/or hydrophilic polymers (International Pub. No. WO20120225129; the contents of which is herein incorporated by reference in its entirety).


As another non-limiting example the nanoparticle comprising hydrophilic polymers for the NAVs may be those described in or made by the methods described in International Patent Publication No. WO2013119936, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the biodegradable polymers which may be used in the present invention are poly(ether-anhydride) block copolymers. As a non-limiting example, the biodegradable polymers used herein may be a block copolymer as described in International Patent Publication No WO2006063249, herein incorporated by reference in its entirety, or made by the methods described in International Patent Publication No WO2006063249, herein incorporated by reference in its entirety.


In another embodiment, the biodegradable polymers which may be used in the present invention are alkyl and cycloalkyl terminated biodegradable lipids. As a non-limiting example, the alkyl and cycloalkyl terminated biodegradable lipids may be those described in International Publication No. WO2013086322 and/or made by the methods described in international Publication No. WO2013086322; the contents of which are herein incorporated by reference in its entirety.


In yet another embodiment, the biodegradable polymers which may be used in the present invention are cationic lipids having one or more biodegradable group located in a lipid moiety. As a non-limiting example, the biodegradable lipids may be those described in US Patent Publication No. US20130195920, the contents of which are herein incorporated by reference in its entirety.


Biodegradable calcium phosphate nanoparticles in combination with lipids and/or polymers have been shown to deliver polynucleotides in vivo. In one embodiment, a lipid coated calcium phosphate nanoparticle, which may also contain a targeting ligand such as anisamide, may be used to deliver the NAVof the present invention. For example, to effectively deliver siRNA in a mouse metastatic lung model a lipid coated calcium phosphate nanoparticle was used (Li et al., J Contr Rel. 2010 142: 416-421; Li et al., J Contr Rel. 2012 158:108-114; Yang et al., Mol Ther. 2012 20:609-615; herein incorporated by reference in its entirety). This delivery system combines both a targeted nanoparticle and a component to enhance the endosomal escape, calcium phosphate, in order to improve delivery of the siRNA.


In one embodiment, calcium phosphate with a PEG-polyanion block copolymer may be used to delivery NAVs (Kazikawa et al., J Contr Rel. 2004 97:345-356: Kazikawa et al., J Contr Rel. 2006 111:368-370; the contents of each of which are herein incorporated by reference in its entirety).


In one embodiment, a PEG-charge-conversional polymer (Pitella et al., Biomaterials. 2011 32:3106-3114; the contents of which are herein incorporated by reference in its entirety) may be used to form a nanoparticle to deliver the NAVs of the present invention. The PEG-charge-conversional polymer may improve upon the PEG-polyanion block copolymers by being cleaved into a polycation at acidic pH, thus enhancing endosomal escape.


In one embodiment, a polymer used in the present invention may be a pentablock polymer such as, but not limited to, the pentablock polymers described in International Patent Publication No. WO2013055331, herein incorporated by reference in its entirety. As a non-limiting example, the pentablock polymer comprises PGA-PCL-PEG-PCL-PGA, wherein PEG is polyethylene glycol, PCL is poly(E-caprolactone), PGA is poly(glycolic acid), and PLA is poly(lactic acid). As another non-limiting example, the pentablock polymer comprises PEG-PCL-PLA-PCL-PEG, wherein PEG is polyethylene glycol, PCL is poly(E-caprolactone), PGA is poly(glycolic acid), and PLA is poly(lactic acid).


In one embodiment, a polymer which may be used in the present invention comprises at least one diepoxide and at least one aminoglycoside (See e.g., International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety). The diepoxide may be selected from, but is not limited to, 1,4 butanediol diglycidyl ether (1,4 B), 1,4-cyclohexanedimethanol diglycidyl ether (1,4 C), 4-vinylcyclohexene diepoxide (4VCD), ethyleneglycol diglycidyl ether (EDGE), glycerol diglycidyl ether (GDE), neopentylglycol diglycidyl ether (NPDGE), poly(ethyleneglycol) diglycidyl ether (PEGDE), poly(propyleneglycol) diglycidyl ether (PPGDE) and resorcinol diglycidyl ether (RDE). The aminoglycoside may be selected from, but is not limited to, streptomycin, neomycin, framycetin, paromomycin, ribostamycin, kanamycin, amikacin, arbekacin, bekanamycin, dibekacin, tobramycin, spectinomycin, hygromycin, gentamicin, netilmicin, sisomicin, isepamicin, verdamicin, astromicin, and apramycin. As a non-limiting example, the polymers may be made by the methods described in International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, compositions comprising any of the polymers comprising at least one least one diepoxide and at least one aminoglycoside may be made by the methods described in International Patent Publication No. WO2013055971, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, a polymer which may be used in the present invention may be a cross-linked polymer. As a non-limiting example, the cross-linked polymers may be used to form a particle as described in U.S. Pat. No. 8,414,927, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the cross-linked polymer may be obtained by the methods described in US Patent Publication No. US20130172600, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, a polymer which may be used in the present invention may be a cross-linked polymer such as those described in U.S. Pat. No. 8,461,132, the contents of which are herein incorporated by reference in its entirety. As a non-limiting example, the cross-linked polymer may be used in a therapeutic composition for the treatment of a body tissue. The therapeutic composition may be administered to damaged tissue using various methods known in the art and/or described herein such as injection or catheterization.


In one embodiment, a polymer which may be used in the present invention may be a di-alphatic substituted pegylated lipid such as, but not limited to, those described in International Patent Publication No. WO2013049328, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, a block copolymer is PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety) may be used in the present invention. The present invention may be formulated with PEG-PLGA-PEG for administration such as, but not limited to, intramuscular and subcutaneous administration.


In another embodiment, the PEG-PLGA-PEG block copolymer is used in the present invention to develop a biodegradable sustained release system. In one aspect, the NAVs of the present invention are mixed with the block copolymer prior to administration. In another aspect, the NAVs of the present invention are co-administered with the block copolymer.


In one embodiment, the polymer used in the present invention may be a multi-functional polymer derivative such as, but not limited to, a multi-functional N-maleimidyl polymer derivatives as described in U.S. Pat. No. 8,454,946, the contents of which are herein incorporated by reference in its entirety.


The use of core-shell nanoparticles has additionally focused on a high-throughput approach to synthesize cationic cross-linked nanogel cores and various shells (Siegwart et al., Proc Natl Acad Sci USA. 2011 108:12996-13001; the contents of which are herein incorporated by reference in its entirety). The complexation, delivery, and internalization of the polymeric nanoparticles can be precisely controlled by altering the chemical composition in both the core and shell components of the nanoparticle. For example, the core-shell nanoparticles may efficiently deliver siRNA to mouse hepatocytes after they covalently attach cholesterol to the nanoparticle.


In one embodiment, a hollow lipid core comprising a middle PLGA layer and an outer neutral lipid layer containing PEG may be used to delivery of the NAV of the present invention. As a non-limiting example, in mice bearing a luciferease-expressing tumor, it was determined that the lipid-polymer-lipid hybrid nanoparticle significantly suppressed luciferase expression, as compared to a conventional lipoplex (Shi et al, Angew Chem Int Ed. 2011 50:7027-7031; herein incorporated by reference in its entirety).


In one embodiment, the lipid nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the polynucleotides in the core.


Core-shell nanoparticles for use with the NAVs of the present invention are described and may be formed by the methods described in U.S. Pat. No. 8,313,777 or International Patent Publication No. WO2013124867, the contents of each of which are herein incorporated by reference in their entirety.


In one embodiment, the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in International Publication No. WO2011120053, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the formulation may be a polymeric carrier cargo complex comprising a polymeric carrier and at least one nucleic acid molecule. Non-limiting examples of polymeric carrier cargo complexes are described in International Patent Publications Nos. WO2013113326, WO2013113501, WO2013113325, WO2013113502 and WO2013113736 and European Patent Publication No. EP2623121, the contents of each of which are herein incorporated by reference in their entireties. In one aspect the polymeric carrier cargo complexes may comprise a negatively charged nucleic acid molecule such as, but not limited to, those described in International Patent Publication Nos. WO2013113325 and WO2013113502, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, a pharmaceutical composition may comprise NAVs of the invention and a polymeric carrier cargo complex. The polynucleotides may encode a protein of interest such as, but not limited to, an antigen from a pathogen associated with infectious disease, an antigen associated with allergy or allergic disease, an antigen associated with autoimmune disease or an antigen associated with cancer or tumour disease (See e.g., the antigens described in International Patent Publications Nos. WO2013113326, WO2013113501, WO2013113325, WO2013113502 and WO2013113736 and European Patent Publication No. EP2623121, the contents of each of which are herein incorporated by reference in their entireties).


As a non-limiting example, the core-shell nanoparticle may be used to treat an eye disease or disorder (See e.g. US Publication No. 20120321719, the contents of which are herein incorporated by reference in its entirety).


In one embodiment, the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in International Publication No. WO2011120053, the contents of which are herein incorporated by reference in its entirety.


Peptides and Proteins

The NAVs of the invention can be formulated with peptides and/or proteins in order to increase transfection of cells by the polynucleotide. In one embodiment, peptides such as, but not limited to, cell penetrating peptides and proteins and peptides that enable intracellular delivery may be used to deliver pharmaceutical formulations. A non-limiting example of a cell penetrating peptide which may be used with the pharmaceutical formulations of the present invention includes a cell-penetrating peptide sequence attached to polycations that facilitates delivery to the intracellular space, e.g., HIV-derived TAT peptide, penetratins, transportans, or hCT derived cell-penetrating peptides (see, e.g., Caron et al., Mol. Ther. 3(3):310-8 (2001); Langel, Cell-Penetrating Peptides: Processes and Applications (CRC Press, Boca Raton FL, 2002); El-Andaloussi et al., Curr. Pharm. Des. 1 1(28):3597-611 (2003); and Deshayes et al., Cell. Mol. Life Sci. 62(16):1839-49 (2005), all of which are incorporated herein by reference in their entirety). The compositions can also be formulated to include a cell penetrating agent, e.g., liposomes, which enhance delivery of the compositions to the intracellular space. NAVs of the invention may be complexed to peptides and/or proteins such as, but not limited to, peptides and/or proteins from Aileron Therapeutics (Cambridge, MA) and Permeon Biologics (Cambridge, MA) in order to enable intracellular delivery (Cronican et al., ACS Chem. Biol. 2010 5:747-752; McNaughton et al., Proc. Natl. Acad. Sci. USA 2009 106:6111-6116; Sawyer, Chem Biol Drug Des. 2009 73:3-6; Verdine and Hilinski, Methods Enzymol. 2012; 503:3-33; all of which are herein incorporated by reference in its entirety).


In one embodiment, the cell-penetrating polypeptide may comprise a first domain and a second domain. The first domain may comprise a supercharged polypeptide. The second domain may comprise a protein-binding partner. As used herein, “protein-binding partner” includes, but are not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides. The cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner. The cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotide may be introduced.


Formulations of the including peptides or proteins may be used to increase cell transfection by the NAV, alter the biodistribution of the polynucleotide (e.g., by targeting specific tissues or cell types), and/or increase the translation of encoded protein. (See e.g., International Pub. No. WO2012110636 and WO2013123298; the contents of which are herein incorporated by reference in its entirety).


In one embodiment, the cell penetrating peptide may be, but is not limited to, those described in US Patent Publication No US20130129726, US20130137644 and US20130164219, each of which is herein incorporated by reference in its entirety.


Cells

The NAVs of the invention can be transfected ex vivo into cells, which are subsequently transplanted into a subject.


As one non-limiting example, a sample of blood from a patient or subject may be treated with an antigen or adjuvant or both where one or more are encoded by the NAVs of the invention to activate the PBMC population. This activated sample or a subset of specific cells may then be given back to the donor patient thereby activating the immune system. This activated PBMC vaccine may be designed using any of the NAVs of the present disclosure.


As non-limiting examples, the pharmaceutical compositions may include red blood cells to deliver modified RNA to liver and myeloid cells, virosomes to deliver modified RNA in virus-like particles (VLPs), and electroporated cells such as, but not limited to, from MAXCYTE® (Gaithersburg, MD) and from ERYTECH® (Lyon, France) to deliver modified RNA. Examples of use of red blood cells, viral particles and electroporated cells to deliver payloads other than polynucleotides have been documented (Godfrin et al., Expert Opin Biol Ther. 2012 12:127-133; Fang et al., Expert Opin Biol Ther. 2012 12:385-389; Hu et al., Proc Natd Acad Sci USA. 2011 108:10980-10985; Lund et al., Pharm Res. 2010 27:400-420; Huckriede et al., J Liposome Res. 2007; 17:39-47; Cusi, Hum Vaccin. 2006 2:1-7; de Jonge et al., Gene Ther. 2006 13:400-411; all of which are herein incorporated by reference in its entirety).


The NAVs may be delivered in synthetic VLPs synthesized by the methods described in International Pub No. WO2011085231 and WO2013116656 and US Pub No. 20110171248, the contents of each of which are herein incorporated by reference in their entireties.


Cell-based formulations of the NAVs of the invention may be used to ensure cell transfection (e.g., in the cellular carrier), alter the biodistribution of the polynucleotide (e.g., by targeting the cell carrier to specific tissues or cell types), and/or increase the translation of encoded protein.


Introduction into Cells


A variety of methods are known in the art and suitable for introduction of nucleic acid into a cell, including viral and non-viral mediated techniques and any of these may be used to introduce the NAVs of the present invention. Examples of typical non-viral mediated techniques include, but are not limited to, electroporation, calcium phosphate mediated transfer, nucleofection, sonoporation, heat shock, magnetofection, liposome mediated transfer, microinjection, microprojectile mediated transfer (nanoparticles), cationic polymer mediated transfer (DEAE-dextran, polyethylenimine, polyethylene glycol (PEG) and the like) or cell fusion.


The technique of sonoporation, or cellular sonication, is the use of sound (e.g., ultrasonic frequencies) for modifying the permeability of the cell plasma membrane. Sonoporation methods are known to those in the art and are used to deliver nucleic acids in vivo (Yoon and Park, Expert Opin Drug Deliv. 2010 7:321-330; Postema and Gilja, Curr Pharm Biotechnol. 2007 8:355-361; Newman and Bettinger, Gene Ther. 2007 14:465-475; all herein incorporated by reference in their entirety). Sonoporation methods are known in the art and are also taught for example as it relates to bacteria in US Patent Publication 20100196983 and as it relates to other cell types in, for example, US Patent Publication 20100009424, each of which are incorporated herein by reference in their entirety.


Electroporation techniques are also well known in the art and are used to deliver nucleic acids in vivo and clinically (Andre et al., Cuff Gene Ther. 2010 10:267-280; Chiarella et al., Curr Gene Ther. 2010 10:281-286; Hojman, Curr Gene Ther. 2010 10:128-138; all herein incorporated by reference in their entirety). Electroporation devices are sold by many companies worldwide including, but not limited to BTX® Instruments (Holliston, MA) (e.g., the AgilePulse In Vivo System) and Inovio (Blue Bell, PA) (e.g., Inovio SP-5P intramuscular delivery device or the CELLECTRA® 3000 intradermal delivery device). In one embodiment, NAVs may be delivered by electroporation as described in Example 9.


Micro-Organ

The NAVs may be contained in a micro-organ which can then express an encoded polypeptide of interest in a long-lasting therapeutic formulation. In one aspect, the micro-organ may comprise a vector comprising a nucleic acid sequence (e.g., a polynucleotides of the present invention) encoding a polypeptide of interest, operably linked to one or more regulatory sequences. As a non-limiting example, the long-lasting therapeutic micro-organ used with the present invention may be those described in U.S. Pat. No. 845,948, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the micro-organ may be used to maintain a desired level of a polypeptide of interest for a sustained period of time (e.g., maintaining physiological hemoglobin levels as described in U.S. Pat. No. 845,948, the contents of which are herein incorporated by reference in its entirety).


The micro-organ may be able to produce the polypeptide of interest for at least a day, at least two days, at least three days, at least four days, at least five days, at least six days, a least 7 days, at least 8 days, at least 9 days, at least 10 days, at least 11 days, at least 12 days, at least 13 days, at least 14 days, at least 3 weeks, at least 1 month and/or at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months or greater than 6 months.


In one embodiment, the micro-organ may have a diameter of at least 0.5 mm to at least 20 mm such as, but not limited to, at least 0.5 mm, at least 1 mm, at least 1.5 mm, at least 2 mm, at least 2.5 mm, at least 3 mm, at least 3.5 mm, at least 4 mm, at least 4.5 mm, at least 5 mm, at least 5.5 mm, at least 6 mm, at least 6.5 mm, at least 7 mm, at least 7.5 mm, at least 8 mm, at least 8.5 mm, at least 9 mm, at least 9.5 mm, at least 10 mm, at least 10.5 mm, at least 11 mm, at least 11.5 mm, at least 12 mm, at least 12.5 mm, at least 13 mm, at least 13.5 mm, at least 14 mm, at least 14.5 mm, at least 15 mm, at least 15.5. mm, at least 16 mm, at least 16.5 mm, at least 17 mm, at least 17.5 mm, at least 18 mm, at least 18.5 mm, at least 19 mm, at least 19.5 mm or at least 20 mm. In another embodiment, the micro-organ may have a diameter of 0.5-2.5 mm, 1-2.5 mm, 1.5-2.5 mm, 0.5-3 mm, 1-3 mm, 1.5-3 mm, 0.5-3.5 mm, 1-3.5 mm, 1.5-3.5 mm, 0.5-4 mm, 1-4 mm, 1.5-4 mm, 2-4 mm, 0.5-5 mm, 1-5 mm, 1.5-5 mm, 2-5 mm, 2.5-5 mm, 3-5 mm, 0.5-6 mm, 1-6 mm, 1.5-6 mm, 2-6 mm, 2.5-6 mm, 3-6 mm, 3.5-6 mm, 4-6 mm, 0.5-7 mm, 1-7 mm, 1.5-7 mm, 2-7 mm, 2.5-7 mm, 3-7 mm, 3.5-7 mm, 4-7 mm, 4.5-7 mm, 5-7 mm, 0.5-8 mm, 1-8 mm, 1.5-8 mm, 2-8 mm, 2.5-8 mm, 3-8 mm, 3.5-8 mm, 4-8 mm, 4.5-8 mm, 5-8 mm, 5.5-8 mm, 6-8 mm, 0.5-9 mm, 1-9 mm, 1.5-9 mm, 2-9 mm, 2.5-9 mm, 3-9 mm, 3.5-9 mm, 4-9 mm, 4.5-9 mm, 5-9 mm, 5.5-9 mm, 6-9 mm, 6.5-9 mm, 7-9 mm, 0.5-10 mm, 1-10 mm, 1.5-10 mm, 2-10 mm, 2.5-10 mm, 3-10 mm, 3.5-10 mm, 4-10 mm, 4.5-10 mm, 5-10 mm, 5.5-10 mm, 6-10 mm, 6.5-10 mm, 7-10 mm, 7.5-10 nm or 8-10 nm.


In one embodiment, the micro-organ may have a length of at least 2 mm to at least 150 mm such as, but not limited to, at least 2 mm, at least 3 mm, at least 4 mm, at least 5 mm, at least 6 mm, at least 7 mm, at least 8 mm, at least 9 mm, at least 10 mm, at least 15 mm, at least 20 mm, at least 25 mm, at least 30 mm, at least 35 mm, at least 40 mm, at least 45 mm, at least 50 mm, at least 55 mm, at least 60 mm, at least 65 mm, at least 70 mm, at least 75 mm, at least 80 mm, at least 85 mm, at least 90 mm, at least 95 mm, at least 100 mm, at least 105 mm, at least 110 mm, at least 115 mm, at least 120 mm, at least 125 mm, at least 130 mm, at least 135 mm, at least 140 mm, at least 145 mm or at least 150 mm. In another embodiment, the micro-organ may have a length of 5-100 mm, 10-100 mm, 15-100 mm, 20-100 mm, 25-10 mm, 30-100 mm, 35-100 mm, 40-100 mm, 45-100 mm, 50-100 mm, 55-100 mm, 60-100 mm, 65-100 mm, 70-100 mm, 75-100 mm, 80-100 mm, 85-100 mm, 90-100 mm, 5-90 mm, 10-90 mm, 15-90 mm, 20-90 mm, 25-10 mm, 30-90 mm, 35-90 mm, 40-90 mm, 45-90 mm, 50-90 mm, 55-90 mm, 60-90 mm, 65-90 mm, 70-90 mm, 75-90 mm, 80-90 mm, 5-80 mm, 10-80 mm, 15-80 mm, 20-80 mm, 25-10 mm, 30-80 mm, 35-80 mm, 40-80 mm, 45-80 mm, 50-80 mm, 55-80 mm, 60-80 mm, 65-80 mm, 70-80 mm, 5-70 mm, 10-70 mm, 15-70 mm, 20-70 mm, 25-10 mm, 30-70 mm, 35-70 mm, 40-70 mm, 45-70 mm, 50-70 mm, 55-70 mm, 60-70 mm, 5-60 mm, 10-60 mm, 15-60 mm, 20-60 mm, 25-10 mm, 30-60 mm, 35-60 mm, 40-60 mm, 45-60 mm, 50-60 mm, 5-50 mm, 10-50 mm, 15-50 mm, 20-50 mm, 25-10 mm, 30-50 mm, 35-50 mm, 40-50 mm, 5-40 mm, 10-40 mm, 15-40 mm, 20-40 mm, 25-10 mm, 30-40 mm, 5-30 mm, 10-30 mm, 15-30 mm, 20-30 mm, 5-20 mm, 10-20 mm or 5-10 mm.


Hyaluronidase

The intramuscular or subcutaneous localized injection of NAVs of the invention can include hyaluronidase, which catalyzes the hydrolysis of hyaluronan. By catalyzing the hydrolysis of hyaluronan, a constituent of the interstitial barrier, hyaluronidase lowers the viscosity of hyaluronan, thereby increasing tissue permeability (Frost, Expert Opin. Drug Deliv. (2007) 4:427-440; herein incorporated by reference in its entirety). It is useful to speed their dispersion and systemic distribution of encoded proteins produced by transfected cells. Alternatively, the hyaluronidase can be used to increase the number of cells exposed to a polynucleotide of the invention administered intramuscularly or subcutaneously.


Nanoparticle Mimics

The NAVs of the invention may be encapsulated within and/or absorbed to a nanoparticle mimic. A nanoparticle mimic can mimic the delivery function organisms or particles such as, but not limited to, pathogens, viruses, bacteria, fungus, parasites, prions and cells. As a non-limiting example the NAVs of the invention may be encapsulated in a non-viron particle which can mimic the delivery function of a virus (see International Pub. No. WO2012006376 and US Patent Publication No. US20130171241 and US20130195968, the contents of each of which are herein incorporated by reference in its entirety).


Nanotubes

The NAVs of the invention can be attached or otherwise bound to at least one nanotube such as, but not limited to, rosette nanotubes, rosette nanotubes having twin bases with a linker, carbon nanotubes and/or single-walled carbon nanotubes. The NAVs may be bound to the nanotubes through forces such as, but not limited to, steric, ionic, covalent and/or other forces.


In one embodiment, the nanotube can release one or more NAVs into cells. The size and/or the surface structure of at least one nanotube may be altered so as to govern the interaction of the nanotubes within the body and/or to attach or bind to the NAVs disclosed herein. In one embodiment, the building block and/or the functional groups attached to the building block of the at least one nanotube may be altered to adjust the dimensions and/or properties of the nanotube. As a non-limiting example, the length of the nanotubes may be altered to hinder the nanotubes from passing through the holes in the walls of normal blood vessels but still small enough to pass through the larger holes in the blood vessels of tumor tissue.


In one embodiment, at least one nanotube may also be coated with delivery enhancing compounds including polymers, such as, but not limited to, polyethylene glycol. In another embodiment, at least one nanotube and/or the NAVs may be mixed with pharmaceutically acceptable excipients and/or delivery vehicles.


In one embodiment, the NAVs are attached and/or otherwise bound to at least one rosette nanotube. The rosette nanotubes may be formed by a process known in the art and/or by the process described in international Publication No. WO2012094304, herein incorporated by reference in its entirety. At least one NAV may be attached and/or otherwise bound to at least one rosette nanotube by a process as described in International Publication No. WO2012094304, herein incorporated by reference in its entirety, where rosette nanotubes or modules forming rosette nanotubes are mixed in aqueous media with at least one NAV under conditions which may cause at least one RNAVs to attach or otherwise bind to the rosette nanotubes.


In one embodiment, the NAVs may be attached to and/or otherwise bound to at least one carbon nanotube. As a non-limiting example, the NAVs may be bound to a linking agent and the linked agent may be bound to the carbon nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety). The carbon nanotube may be a single-walled nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety).


Conjugates

The NAVs of the invention include conjugates, such as a polynucleotide covalently linked to a carrier or targeting group, or including two encoding regions that together produce a fusion protein (e.g., bearing a targeting group and therapeutic protein or peptide).


The conjugates of the invention include a naturally occurring substance, such as a protein (e.g., human serum albumin (HSA), low-density lipoprotein (LDL), high-density lipoprotein (HDL), or globulin); an carbohydrate (e.g., a dextran, pullulan, chitin, chitosan, inulin, cyclodextrin or hyaluronic acid); or a lipid. The ligand may also be a recombinant or synthetic molecule, such as a synthetic polymer, e.g., a synthetic polyamino acid, an oligonucleotide (e.g. an aptamer). Examples of polyamino acids include polyamino acid is a polylysine (PLL), poly L-aspartic acid, poly L-glutamic acid, styrene-maleic acid anhydride copolymer, poly(L-lactide-co-glycolied) copolymer, divinyl ether-maleic anhydride copolymer, N-(2-hydroxypropyl)methacrylamide copolymer (HMPA), polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyurethane, poly(2-ethylacryllic acid), N-isopropylacrylamide polymers, or polyphosphazine. Example of polyamines include: polyethylenimine, polylysine (PLL), spermine, spermidine, polyamine, pseudopeptide-polyamine, peptidomimetic polyamine, dendrimer polyamine, arginine, amidine, protamine, cationic lipid, cationic porphyrin, quaternary salt of a polyamine, or an alpha helical peptide.


Representative U.S. patents that teach the preparation of polynucleotide conjugates, particularly to RNA, include, but are not limited to, U.S. Pat. Nos. 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941; 6,294,664; 6,320,017; 6,576,752; 6,783,931; 6,900,297; 7,037,646; each of which is herein incorporated by reference in their entireties.


In one embodiment, the conjugate of the present invention may function as a carrier for the NAVs of the present invention. The conjugate may comprise a cationic polymer such as, but not limited to, polyamine, polylysine, polyalkylenimine, and polyethylenimine which may be grafted to with poly(ethylene glycol). As a non-limiting example, the conjugate may be similar to the polymeric conjugate and the method of synthesizing the polymeric conjugate described in U.S. Pat. No. 6,586,524 herein incorporated by reference in its entirety.


A non-limiting example of a method for conjugation to a substrate is described in US Patent Publication No. US20130211249, the contents of which are herein incorporated by reference in its entirety. The method may be used to make a conjugated polymeric particle comprising a NAV.


The conjugates can also include targeting groups, e.g., a cell or tissue targeting agent, e.g., a lectin, glycoprotein, lipid or protein, e.g., an antibody, that binds to a specified cell type such as a kidney cell. A targeting group can be a thyrotropin, melanotropin, lectin, glycoprotein, surfactant protein A, Mucin carbohydrate, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, glycosylated polyaminoacids, multivalent galactose, transferrin, bisphosphonate, polyglutamate, polyaspartate, a lipid, cholesterol, a steroid, bile acid, folate, vitamin B12, biotin, an RGD peptide, an ROD peptide mimetic or an aptamer.


Targeting groups can be proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell. Targeting groups may also include hormones and hormone receptors. They can also include non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, multivalent lactose, multivalent galactose, N-acetyl-galactosamine, N-acetyl-gulucosamine multivalent mannose, multivalent fucose, or aptamers. The ligand can be, for example, a lipopolysaccharide, or an activator of p38 MAP kinase.


The targeting group can be any ligand that is capable of targeting a specific receptor. Examples include, without limitation, folate, GalNAc, galactose, mannose, mannose-6P, apatamers, integrin receptor ligands, chemokine receptor ligands, transferrin, biotin, serotonin receptor ligands, PSMA, endothelin, GCPTT, somatostatin, LDL, and HDL ligands. In particular embodiments, the targeting group is an aptamer. The aptamer can be unmodified or have any combination of modifications disclosed herein.


As a non-limiting example, the targeting group may be a glutathione receptor (GR)-binding conjugate for targeted delivery across the blood-central nervious system barrier (See e.g., US Patent Publication No. US2013021661012, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the conjugate of the present invention may be a synergistic biomolecule-polymer conjugate. The synergistic biomolecule-polymer conjugate may be long-acting continuous-release system to provide a greater therapeutic efficacy. The synergistic biomolecule-polymer conjugate may be those described in US Patent Publication No. US20130195799, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the conjugate which may be used in the present invention may be an aptamer conjugate. Non-limiting examples of apatamer conjugates are described in International Patent Publication No. WO2012040524, the contents of which are herein incorporated by reference in its entirety. The aptamer conjugates may be used to provide targeted delivery of formulations comprising NAVs.


In one embodiment, the conjugate which may be used in the present invention may be an amine containing polymer conjugate. Non-limiting examples of amine containing polymer conjugate are described in U.S. Pat. No. 8,507,653, the contents of which are herein incorporated by reference in its entirety. The factor IX moiety polymer conjugate may be comprise releasable linkages to release the NAVs upon and/or after delivery to a subject.


In one embodiment, pharmaceutical compositions of the present invention may include chemical modifications such as, but not limited to, modifications similar to locked nucleic acids.


Representative U.S. patents that teach the preparation of locked nucleic acid (LNA) such as those from Santaris, include, but are not limited to, the following: U.S. Pat. Nos. 6,268,490; 6,670,461; 6,794,499; 6,998,484; 7,053,207; 7,084,125; and 7,399,845, each of which is herein incorporated by reference in its entirety.


Representative U.S. patents that teach the preparation of PNA compounds include, but are not limited to, U.S. Pat. Nos. 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found, for example, in Nielsen et al., Science, 1991, 254, 1497-1500.


Some embodiments featured in the invention include polynucleotides with phosphorothioate backbones and oligonucleosides with other modified backbones, and in particular —CH2—NH—CH2—, —CH2—N(CH3)—O—CH2— [known as a methylene (methylimino) or MMI backbone], —CH2—O—N(CH3)—CH2—, —CH2—N(CH3)—N(CH3)—CH2— and —N(CH3)—CH2—CH2— [wherein the native phosphodiester backbone is represented as —O—P(O)2—O—CH2—] of the above-referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above-referenced U.S. Pat. No. 5,602,240. In some embodiments, the polynucletotides featured herein have morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.


Modifications at the 2′ position may also aid in delivery. Preferably, modifications at the 2′ position are not located in a polypeptide-coding sequence, i.e., not in a translatable region. Modifications at the 2′ position may be located in a 5′UTR, a 3′UTR and/or a tailing region. Modifications at the 2′ position can include one of the following at the 2′ position: H (i.e., 2′-deoxy); F; O—, S—, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C1 to C10 alkyl or C2 to C10 alkenyl and alkynyl. Exemplary suitable modifications include O[(CH2)nO]mCH3, O(CH2nOCH3, O(CH2)nNH2, O(CH2)nCH3, O(CH2)nONH2, and O(CH2)nON[(CH2)nCH3)]2, where n and m are from 1 to about 10. In other embodiments, the polynucleotides include one of the following at the 2′ position: C1 to C10 lower alkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties, or a group for improving the pharmacodynamic properties, and other substituents having similar properties. In some embodiments, the modification includes a 2-methoxyethoxy (2′-O—CH2CH2OCH3, also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv. Chin. Acta, 1995, 78:486-504) i.e., an alkoxy-alkoxy group. Another exemplary modification is 2′-dimethylaminooxyethoxy, i.e., a O(CH2)2ON(CH3)2 group, also known as 2′-DMAOE, as described in examples herein below, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethylaminoethoxyethyl or 2′-DMAEOE), i.e., 2′-O—CH2—O—CH2—N(CH2)2, also described in examples herein below. Other modifications include 2′-methoxy (2′-OCH3), 2′-aminopropoxy (2′-OCH2CH2CH2NH2) and 2′-fluoro (2′-F). Similar modifications may also be made at other positions, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked dsRNAs and the 5′ position of 5′ terminal nucleotide. Polynucleotides of the invention may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar. Representative U.S. patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos. 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; and 5,700,920; the contents of each of which is herein incorporated by reference in their entirety.


In one embodiment, the NAVs may be conjugated to an agent to enhance delivery. As a non-limiting example, the agent may be a monomer or polymer such as a targeting monomer or a polymer having targeting blocks as described in international Publication No. WO2011062965, herein incorporated by reference in its entirety. In another non-limiting example, the agent may be a transport agent covalently coupled to the polynucleotides of the present invention (See e.g., U.S. Pat. Nos. 6,835,393 and 7,374,778, each of which is herein incorporated by reference in its entirety). In yet another non-limiting example, the agent may be a membrane barrier transport enhancing agent such as those described in U.S. Pat. Nos. 7,737,108 and 8,003,129, each of which is herein incorporated by reference in its entirety.


In another embodiment, polynucleotides may be conjugated to SMARTT POLYMER TECHNOLOGY® (PHASERX®, Inc. Seattle, WA).


In another aspect, the conjugate may be a peptide that selectively directs the nanoparticle to neurons in a tissue or organism. As a non-limiting example, the peptide used may be, but is not limited to, the peptides described in US Patent Publication No US20130129627, herein incorporated by reference in its entirety.


In yet another aspect, the conjugate may be a peptide that can assist in crossing the blood-brain barrier.


Self-Assembled Nanoparticles

Nucleic Acid Self-Assembled Nanoparticles Self-assembled nanoparticles have a well-defined size which may be precisely controlled as the nucleic acid strands may be easily reprogrammable. For example, the optimal particle size for a cancer-targeting nanodelivery carrier is 20-100 nm as a diameter greater than 20 nm avoids renal clearance and enhances delivery to certain tumors through enhanced permeability and retention effect. (Lee et al., Nature Nanotechnology 2012 7:389-393; herein incorporated by reference in its entirety). Such self-assembling nanoparticles may be useful in formulating the NAVs of the invention.


In one embodiment, the NAVs disclosed herein may be formulated as self-assembled nanoparticles. As a non-limiting example, nucleic acids may be used to make nanoparticles which may be used in a delivery system for the NAVs of the present invention (See e.g., International Pub. No. WO2012125987; herein incorporated by reference in its entirety).


In one embodiment, the nucleic acid self-assembled nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.


The metallic nanoparticle which may be used in the present invention may be a pH-sensitive nanoparticle such as, but not limited to, those described in US Patent Publication No US20130138032, herein incorporated by reference in its entirety.


In one aspect, the metallic and/or metal-allow nanoparticles may be made by the methods described in US Patent Publication No US20130133483, herein incorporated by reference in its entirety


Polymer-Based Self-Assembled Nanoparticles

Polymers may be used to form sheets which self-assembled into nanoparticles. These nanoparticles may be used to deliver the NAVs of the present invention. In one embodiment, these self-assembled nanoparticles may be microsponges formed of long polymers of RNA hairpins which form into crystalline ‘pleated’ sheets before self-assembling into microsponges. These microsponges are densely-packed sponge like microparticles which may function as an efficient carrier and may be able to deliver cargo to a cell. The microsponges may be from 1 μm to 300 nm in diameter. The microsponges may be complexed with other agents known in the art to form larger microsponges. As a non-limiting example, the microsponge may be complexed with an agent to form an outer layer to promote cellular uptake such as polycation polyethyleneime (PEI). This complex can form a 250-nm diameter particle that can remain stable at high temperatures (150° C.) (Grabow and Jaegar, Nature Materials 2012, 11:269-269; herein incorporated by reference in its entirety). Additionally these microsponges may be able to exhibit an extraordinary degree of protection from degradation by ribonucleases.


In another embodiment, the polymer-based self-assembled nanoparticles such as, but not limited to, microsponges, may be fully programmable nanoparticles. The geometry, size and stoichiometry of the nanoparticle may be precisely controlled to create the optimal nanoparticle for delivery of cargo such as, but not limited to, NAVs.


In yet another embodiment, the polymer based nanoparticle may comprise a non-nucleic acid polymer comprising a plurality of heterogenous monomers such as those described in International Publication No. WO2013009736, the contents of which are herein incorporated by reference in its entirety.


Self-Assembled Macromolecules

The NAVs may be formulated in amphiphilic macromolecules (AMs) for delivery. AMs comprise biocompatible amphiphilic polymers which have an alkylated sugar backbone covalently linked to poly(ethylene glycol). In aqueous solution, the AMs self-assemble to form micelles. Non-limiting examples of methods of forming AMs and AMs are described in US Patent Publication No. US20130217753, the contents of which are herein incorporated by reference in its entirety.


Inorganic Nanoparticles

The NAVs of the present invention may be formulated in inorganic nanoparticles (U.S. Pat. No. 8,257,745, herein incorporated by reference in its entirety). The inorganic nanoparticles may include, but are not limited to, clay substances that are water swellable. As a non-limiting example, the inorganic nanoparticle may include synthetic smectite clays which are made from simple silicates (See e.g., U.S. Pat. Nos. 5,585,108 and 8,257,745 each of which are herein incorporated by reference in their entirety).


In one embodiment, the inorganic nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.


Semi-conductive and Metallic Nanoparticles

The NAVs of the present invention may be formulated in water-dispersible nanoparticle comprising a semiconductive or metallic material (U.S. Pub. No. 20120228565: herein incorporated by reference in its entirety) or formed in a magnetic nanoparticle (U.S. Pub. No. 20120265001 and 20120283503; each of which is herein incorporated by reference in its entirety). The water-dispersible nanoparticles may be hydrophobic nanoparticles or hydrophilic nanoparticles.


In one embodiment, the semi-conductive and/or metallic nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.


Surgical Sealants: Gels and Hydrogels

In one embodiment, the NAVs disclosed herein may be encapsulated into any hydrogel known in the art which may form a gel when injected into a subject. Hydrogels are a network of polymer chains that are hydrophilic, and are sometimes found as a colloidal gel in which water is the dispersion medium. Hydrogels are highly absorbent (they can contain over 99% water) natural or synthetic polymers. Hydrogels also possess a degree of flexibility very similar to natural tissue, due to their significant water content. The hydrogel described herein may used to encapsulate lipid nanoparticles which are biocompatible, biodegradable and/or porous. A hydrogel can be made in situ from solution injection or implanted.


As a non-limiting example, the hydrogel may be an aptamer-functionalized hydrogel. The aptamer-functionalized hydrogel may be programmed to release one or more polynucleotides using nucleic acid hybridization. (Battig et al., J. Am. Chem. Society. 2012 134:12410-12413; the contents of which is herein incorporated by reference in its entirety).


As another non-limiting example, the hydrogel may be a shaped as an inverted opal. The opal hydrogels exhibit higher swelling ratios and the swelling kinetics is an order of magnitude faster than conventional hydrogels as well. Methods of producing opal hydrogels and description of opal hydrogels are described in International Pub. No. WO2012148684, the contents of which is herein incorporated by reference in its entirety.


In yet another non-limiting example, the hydrogel may be an antibacterial hydrogel. The antibacterial hydrogel may comprise a pharmaceutical acceptable salt or organic material such as, but not limited to pharmaceutical grade and/or medical grade silver salt and aloe vera gel or extract. (International Pub. No. WO2012151438, the contents of which are herein incorporated by reference in its entirety).


In one embodiment, a NAV may be encapsulated in a lipid nanoparticle and then the lipid nanoparticle may be encapsulated into a hydrogel.


In one embodiment, the NAVs disclosed herein may be encapsulated into any gel known in the art. As a non-limiting example the gel may be a fluorouracil injectable gel or a fluorouracil injectable gel containing a chemical compound and/or drug known in the art. As another example, the NAVs may be encapsulated in a fluorouracil gel containing epinephrine (See e.g., Smith et al. Cancer Chemotherapty and Pharmacology, 1999 44(4):267-274; the contents of which are herein incorporated by reference in its entirety).


In one embodiment, the NAVs disclosed herein may be encapsulated into a fibrin gel, fibrin hydrogel or fibrin glue.


In another embodiment, the NAVs may be formulated in a lipid nanoparticle or a rapidly eliminated lipid nanoparticle prior to being encapsulated into a fibrin gel, fibrin hydrogel or a fibrin glue. In yet another embodiment, the NAVs may be formulated as a lipoplex prior to being encapsulated into a fibrin gel, hydrogel or a fibrin glue. Fibrin gels, hydrogels and glues comprise two components, a fibrinogen solution and a thrombin solution which is rich in calcium (See e.g., Spicer and Mikos, Journal of Controlled Release 2010. 148: 49-55; Kidd et al. Journal of Controlled Release 2012. 157:80-85: each of which is herein incorporated by reference in its entirety). The concentration of the components of the fibrin gel, hydrogel and/or glue can be altered to change the characteristics, the network mesh size, and/or the degradation characteristics of the gel, hydrogel and/or glue such as, but not limited to changing the release characteristics of the fibrin gel, hydrogel and/or glue. (See e.g., Spicer and Mikos, Journal of Controlled Release 2010. 148: 49-55; Kidd et al. Journal of Controlled Release 2012. 157:80-85; Catelas et al. Tissue Engineering 2008. 14:119-128; each of which is herein incorporated by reference in its entirety). This feature may be advantageous when used to deliver the modified mRNA disclosed herein. (See e.g., Kidd et al. Journal of Controlled Release 2012. 157:80-85; Catelas et al. Tissue Engineering 2008. 14:119-128; each of which is herein incorporated by reference in its entirety).


In one embodiment, the NAVs disclosed herein may be used with hydrogels such as, but not limited to, the hydrogels described in U.S. Patent Application No. 20130071450 or 20130211249, the contents of each of which is herein incorporated by reference in its entirety.


As a non-limiting example, the hydrogels which may be used in the present invention may be made by the methods described in International Patent Publication No. WO2013124620, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the NAVs disclosed herein may be formulated for transdermal delivery. The formulation may comprise at least one hydrogel described in U.S. Patent Application No. 20130071450, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the hydrogel which may be used in the present invention is described in U.S. Pat. Nos. 8,420,605, 8,415,325 and/or International Patent Publication No. WO2013091001 and WO2013124620, the contents of each of which are herein incorporated by reference in its entirety.


In one embodiment, the hydrogel which may be used in the present invention may be, but is not limited to. ATRIGEL® (QLT Inc. Vancouver, British Columbia), chitosan, aliginate, collagen or hyaluronic acid hydrogel.


In another embodiment, the hydrogel which may be used in the present invention is a crosslinked methacrylate. As a non-limiting example, the hydrogel of the present invention may be used in wound dressings.


The hydrogel which may be used in the present invention may also be complexed with agents and excipients described herein including, but not limited to PEI, PVA, poly-lysine, Poloxamer 124, Poloxamer 181, Poloxamer 182, Poloxamer 407. Poloxamer 237, Poloxamer 331 and Poloxamer 338. Complexing the hydrogel with agents and/or excipients may help improve mRNA stability and uptake in a cell, tissue and/or organism. As a non-limiting example, a hydrogel may be complexed with Poloxamer 188 to improve the stability and uptake of mRNA.


In one embodiment, the NAVs disclosed herein may be formulated in a surgical sealant. The surgical sealant may be, but is not limited to, fibrinogen polymer based sealants (Ethicon Inc. Cornelia, GA), TISSELL® (Baxter International, Inc Deerfield, IL) or PEG-based sealants such as, but not limited to, COSEAL® (Baxter International, Inc Deerfield, IL) and DURASEAL™ (trilysine amine/PEG-ester) (Covidien, Waltham, MA).


In one embodiment, NAVs may be formulated in COSEAL® or co-administered with or administered after a cell, tissue or organism is administered COSEAL®. COSEAL® comprises two synthetic polyethylene glycols (PEGs) (pentaerythritol PEG ester tetra-succinimidyl and pentaerythritol PEG ether tetra-thiol), a dilute hydrogen chloride solution, and a sodium phosphate/sodium carbonate solution. The PEGs are kept separate from the sodium phosphate/sodium carbonate solution in the dilute hydrogen chloride solution until administration. After administration a hydrogel is formed, which may adhere to tissue, and forms a stiff gel in seconds which is resorbed within 30 days.


In another embodiment, the NAVs disclosed herein may be formulated in a hydrogel comprising a macromolecular matrix. The macromolecular matrix may comprise a hyaluronic acid component which may be crosslinked to a collagent component. The hydrogel used in the present invention may be, but is not limited to, the hydrogels described in International Patent Publication No. WO2013106715, the contents of which are herein incorporated by reference in its entirety.


In yet another embodiment, the NAVs disclosed herein may be formulated in a chitosan glycerophosphate (CGP) hydrogel. The formulation may further comprise a chitosanase in an effect amount to dissolve the COP hydrogel and release the NAVs associated with the COP hydrogel. As a non-limiting example, the NAVs may be formulated in the controlled release delivery system comprising a COP hydrogel described in US Patent Publication No. US20130189241, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs disclosed herein may be formulated in a hydrogel formulated for controlled release such as, but not limited to, the porous matrix composites and formulations described in US Patent Publication No. US20130196915, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the NAVs disclosed herein may be formulated in a hydrogel comprising heterobifunctional poly(alkylene oxides) which may have degradable linkages. Non-limiting examples of heterobifunctional poly(alkylene oxides) are described in U.S. Pat. No. 8,497,357, the contents of which are herein incorporated by reference in its entirety.


In yet another embodiment, the NAVs may be formulated in a hydrogel which may be used as an insulin delivery system. As a non-limiting example, the hydrogel may be a glucose binding amphiphilic peptide hydrogel as described in International Patent Publication No. WO2013123491, the contents of which are herein incorporated by reference in its entirety. As another non-limiting example, the hydrogel may be a microgel such as the glucose-responsive microgels described in International Patent Publication No. WO2013123492, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs may be formulated in a hydrogel system such as, but not limited to, a multi-compartment hydrogel. A non-limiting example of a multi-compartment hydrogel and methods of making the hydrogel is described in International Patent Publication No. WO2013124855, the contents of which are herein incorporated by reference in its entirety. The multi-compartment hydrogel may be used to repair or regenerate damaged tissue in a subject.


In another embodiment, the NAVs may be formulated in a cucurbituril-based hydrogel. A non-limiting example of a cucurbituril-based hydrogel is described in international Patent Publication No. WO2013124654, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the NAVs disclosed herein may be formulated in a PEG-based surgical sealant or hydrogel.


In one embodiment, the surgical sealant or hydrogel may include at least one, at least two, at least three, at least four, at least five, at least six or more than six PEG lipids. The PEG lipids may be selected from, but are not limited to, pentaerythritol PEG ester tetra-succinimidyl and pentaerythritol PEG ether tetra-thiol, PEG-c-DOMG, PEG-DMG (1,2-Dimyristoyl-sn-glycerol, methoxypolyethylene Glycol), PEG-DSG (1,2-Distearoyl-sn-glycerol, methoxypolyethylene Glycol), PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol), PEG-DSA (PEG coupled to 1,2-distearyloxypropyl-3-amine), PEG-DMA (PEG coupled to 1,2-dimyristyloxypropyl-3-amine, PEG-c-DNA, PEG-c-DMA, PEG-S-DSG, PEG-c-DMA, PEG-DPG, PEG-DMG 2000 and those described herein and/or known in the art. The concentration and/or ratio of the PEG lipids in the surgical sealant or hydrogel may be varied in order to optimize the formulation for delivery and/or administration.


The amount of buffer and/or acid used in combination with the PEG lipids of the surgical sealant or hydrogel may also be varied. In one non-limiting example, the ratio of buffer and/or acid with PEG lipids is 1:1. As a non-limiting example, the amount of buffer and/or acid used with the PEG lipids may be increased to alter the ratio of buffer/acid to PEG in order to optimize the surgical sealant or hydrogel. As another non-limiting example, the amount of buffer and/or acid used with the PEG lipids may be decreased to alter the ratio of buffer/acid to PEG in order to optimize the surgical sealant or hydrogel.


The amount of NAVs loaded into the buffer, acid and/or PEG lipid may be varied. The amount of NAVs loaded into the buffer, acid and/or PEG lipid may be, but is not limited to, at least 1 uL, at least 2 uL, at least 5 uL, at least 10 uL, at least 15 uL, at least 20 uL, at least 25 uL, at least 30 uL, at least 35 uL, at least 40 uL, at least 45 ul, at least 50 uL, at least 55 uL, at least 60 uL, at least 65 uL, at least 70 uL, at least 75 uL, at least 80 uL, at least 85 uL, at least 90 uL, at least 100 uL, at least 125 uL, at least 150 uL, at least 200 uL, at least 250 uL, at least 300 uL, at least 350 uL, at least 400 uL, at least 450 uL, at least 500 uL or more than 500 uL.


In one embodiment, the NAVs of the present invention may be loaded in PEGs and also in the buffer or the acid. The amount of NAVs loaded in the PEG may be the same, greater or less than the amount loaded in the buffer or acid. In another embodiment, the NAVs may be formulated, by the methods described herein and/or known in the art, prior to loading in the PEGs, buffer or acid.


A non-limiting example of a PEG-based hydrogel which may be used in the present invention is described in U.S. Pat. No. 8,524,215, the contents of which is herein incorporated by reference in its entirety. The PEG-based hyrdrogel may be an absorbable hydrogel prepared from a multi-arm PEG-vinylsulfone having about 3 to about 8 arms and a multi-arm-PEG-R-sulfhydryl having about 3 to about 8 arms (See e.g., U.S. Pat. No. 8,524,215). In one embodiment, the PEG-based hydrogel may be an absorbable hydrogel. While not wishing to be bound by theory, an absorbable PEG-based hydrogel may be beneficial to reduce the permanent chronic foreign body reaction since the absorbable hydrogel can be absorbed and passed by the body.


In one embodiment, the hydrogel may be a thermosensitive hydrogel. In one aspect the thermosensitive hydrogel may be, but is not limited to, a triblock polymer such as those described herein and known in the art. As a non-limiting example, the tri-block polymer may be PEG-PLGA-PEG (see e.g., the thermosensitive hydrogel (PEG-PLGA-PEG) was used as a TGF-beta1 gene delivery vehicle in Lee et al. Thermosensitive Hydrogel as a Tgf-β1 Gene Delivery Vehicle Enhances Diabetic Wound Healing. Pharmaceutical Research, 2003 20(12): 1995-2000; as a controlled gene delivery system in Li et al. Controlled Gene Delivery System Based on Thermosensitive Biodegradable Hydrogel. Pharmaceutical Research 2003 20(6):884-888; and Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253; each of which is herein incorporated by reference in its entirety). As a non-limiting example, the thermosensitive hydrogel may be used to make nanoparticles and liposomes by the methods described in International Publication No. WO2013123407, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the hydrogel may be a biodegradable copolymer hydrogel (see e.g., the biodegradable hydrogels described by Nguyen and Lee (Injectable Biodegradable Hydrogels. Macromolecular Bioscience. 2010 10:563-579), herein incorporated by reference in its entirety). These hydrogels may exhibit a sol-gel phase transition that respond to external stimuli such as, but not limited to, temperature changes, pH alternations or both. Non-limiting examples of biodegradable copolymer hydrogels include triblock copolymers PEG-PLLA-PEG, PEG-PLA-PEG (see e.g., Chang et al., Non-ionic amphiphilic biodegradable PEG-PLGA-PEG copolymer enhances gene delivery efficiency in rat skeletal muscle. J Controlled Release. 2007 118:245-253, herein incorporated by reference in its entirety), PLGA-PEG-PLGA, PEG-PCL-PEG, PCL-PEG-PCL, polyesters such as poly[(R)-3-hydroxybutyrate] (PHB), polyphosphazenes such as L-sioleucine ethyl ester (IIeOEt), D,L-leucine ethyl ester (LeuOEt), L-valine ethyl ester (ValOEt), or di-, tri- and oligo-peptides, polypeptides and chitosan. Temperature and pH sensitive polymers which may be used to form the biodegradable copolymer hydrogels include, but are not limited to, sulfamethazine-, poly(O-amino ester)-, poly(amino urethane)-, and poly(amidoamine)-based polymers. Formulations of the biodegradable copolymer hydrogels and NAVs may be administered using site-specific control of release behavior.


In one embodiment, the hydrogel used in the present invention may be a PEG based hydrogel such as, but not limited to, those described in International Patent Publication No WO2013082590, herein incorporated by reference in its entirety. The PEG based hydrogel may have, but is not limited to, an overall polymer weight concentration of less than or equal to 50% at the time of curing. As a non-limiting example, the PEG based hydrogel may be made by the methods described in International Patent Publication No WO2013082590, the contents of which are herein incorporated by reference in its entirety.


In another embodiment, the NAVs may be formulated in a nanostructured gel composition. The nanostructured gel may be capable of controlled release of the encapsulated NAVs. Non-limiting examples of nanostructed gels or self-assembled gels are described in International Patent Publication No. WO2012040623, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the concentration of the NAVs of the present invention in the surgical sealants, gels and/or hydrogels may be selected to provide a dosage within the range to have the desired therapeutic effect.


In one embodiment, the concentration of the polynucleotides of the NAV of the present invention in the surgical sealants, gels and/or hydrogels may be at least 0.001 mg to at least 150 mg in at least 0.1 ml to at least 30 ml of the surgical sealant, gel or hydrogel. The concentration of the polynucleotides of the present invention may be at least 0.001 mg, at least 0.005 mg, at least 0.01 mg, at least 0.05 mg, at least 0.1 mg, at least 0.5 mg, at least 1 mg, at least 5 mg, at least 7 mg, at least 10 mg, at least 12, at least 15 mg, at least 17 mg, at least 20 mg, at least 22 mg, at least 25 mg, at least 27 mg, at least 30 mg, at least 32 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, at least 100 mg, at least 105 mg, at least 110 mg, at least 115 mg, at least 120 mg, at least 125 mg, at least 130 mg, at least 135 mg, at least 140 mg, at least 145 mg or at least 150 mg in at least 0.1 ml, at least 0.2 ml, at least 0.3 ml, at least 0.4 ml, at least 0.5 ml, at least 0.6 ml, at least 0.7 ml, at least 0.8 ml, at least 0.9 ml, at least 1 ml, at least 2 ml, at least 3 ml, at least 4 ml, at least 5 ml, at least 6 ml, at least 7 ml, at least 8 ml, at least 9 ml, at least 10 ml, at least 11 ml, at least 12 ml, at least 13 ml, at least 14 ml, at least 15 ml, at least 16 ml, at least 17 ml, at least 18 ml, at least 19 ml, at least 20 ml, at least 21 ml, at least 22 ml, at least 23 ml, at least 24 ml, at least 25 ml, at least 26 ml, at least 27 ml, at least 28 ml, at least 29 ml or at least 30 ml of the surgical sealant, gel or hydrogel.


In another embodiment, concentration of the polynucleotides of the NAV of the present invention in the surgical sealants, gels and/or hydrogels may be at least 0.001 mg/ml at least 0.005 mg/ml, at least 0.01 mg/ml, at least 0.05 mg/ml, at least 0.1 mg/ml, at least 0.5 mg/ml, at least 1 mg/ml, at least 5 mg/ml, at least 7 mg/ml, at least 10 mg/ml, at least 12, at least 15 mg/ml, at least 17 mg/ml, at least 20 mg/ml, at least 22 mg/ml, at least 25 mg/ml, at least 27 mg/ml, at least 30 mg/ml, at least 32 mg/ml, at least 35 mg/ml, at least 40 mg/ml, at least 45 mg/ml or at least 50 mg/ml.


Technology allowing for large subcutaneous infusion volumes which are known in the art, such as, but not limited to, HYLENEX® (Halozyme Therapeutics, San Diego, CA) may also be used. The dispersion and/or adsorption of the modified mRNA described herein may be increased with the use of HYLENEX® as HYLENEX® temporarily breaks down hyaluronic acid causing a temporty degradation in the subcutaneous space (for about 24 hours) just beneath the outside surface of the skin opening microscopic channels and allowing fluid or drugs to be dispersed and absorbed in the body.


Suspension Formulations

In some embodiments, suspension formulations are provided comprising NAVs, water immiscible oil depots, surfactants and/or co-surfactants and/or co-solvents. Combinations of oils and surfactants may enable suspension formulation with NAVs. Delivery of NAVs in a water immiscible depot may be used to improve bioavailability through sustained release of NAVs from the depot to the surrounding physiologic environment and prevent polynucleotides degradation by nucleases.


In some embodiments, suspension formulations of NAV may be prepared using combinations of polynucleotides, oil-based solutions and surfactants. Such formulations may be prepared as a two-part system comprising an aqueous phase comprising polynucleotides and an oil-based phase comprising oil and surfactants. Exemplary oils for suspension formulations may include, but are not limited to sesame oil and Miglyol (comprising esters of saturated coconut and palmkernel oil-derived caprylic and capric fatty acids and glycerin or propylene glycol), corn oil, soybean oil, peanut oil, beeswax and/or palm seed oil. Exemplary surfactants may include, but are not limited to Cremophor, polysorbate 20, polysorbate 80, polyethylene glycol, transcutol, Capmul®, labrasol, isopropyl myristate, and/or Span 80. In some embodiments, suspensions may comprise co-solvents including, but not limited to ethanol, glycerol and/or propylene glycol.


Suspensions may be formed by first preparing NAV formulation comprising an aqueous solution of polynucleotide and an oil-based phase comprising one or more surfactants. Suspension formation occurs as a result of mixing the two phases (aqueous and oil-based). In some embodiments, such a suspension may be delivered to an aqueous phase to form an oil-in-water emulsion. In some embodiments, delivery of a suspension to an aqueous phase results in the formation of an oil-in-water emulsion in which the oil-based phase comprising polynucleotides forms droplets that may range in size from nanometer-sized droplets to micrometer-sized droplets.


In some embodiments, specific combinations of oils, surfactants, cosurfactants and/or co-solvents may be utilized to suspend NAVs in the oil phase and/or to form oil-in-water emulsions upon delivery into an aqueous environment.


In some embodiments, suspensions may provide modulation of the release of NAVs into the surrounding environment. In such embodiments, NAV release may be modulated by diffusion from a water immiscible depot followed by resolubilization into a surrounding environment (e.g. an aqueous environment).


In some embodiments, NAVs within a water immiscible depot (e.g. suspended within an oil phase) may result in altered polynucleotides stability (e.g. altered degradation by nucleases).


In some embodiments, NAVs may be formulated such that upon injection, an emulsion forms spontaneously (e.g. when delivered to an aqueous phase). Such particle formation may provide a high surface area to volume ratio for release of polynucleotides from an oil phase to an aqueous phase.


In one embodiment, the NAVs may be formulated in a nanoemulsion such as, but not limited to, the nanoemulsions described in U.S. Pat. No. 8,496,945, the contents of which are herein incorporated by reference in its entirety. The nanoemulsions may comprise nanoparticles described herein. As a non-limiting example, the nanoparticles may comprise a liquid hydrophobic core which may be surrounded or coated with a lipid or surfactant layer. The lipid or surfactant layer may comprise at least one membrane-integrating peptide and may also comprise a targeting ligand (see e.g., U.S. Pat. No. 8,496,945, the contents of which are herein incorporated by reference in its entirety).


Cations and Anions

Formulations of NAVs disclosed herein may include cations or anions. In one embodiment, the formulations include metal cations such as, but not limited to, Zn2+, Ca2+, Cu2+, Mg+ and combinations thereof. As a non-limiting example, formulations may include polymers and a RNAV complexed with a metal cation (See e.g., U.S. Pat. Nos. 6,265,389 and 6,555,525, each of which is herein incorporated by reference in its entirety).


In some embodiments, cationic nanoparticles comprising combinations of divalent and monovalent cations may be formulated with NAVs. Such nanoparticles may form spontaneously in solution over a give period (e.g. hours, days, etc). Such nanoparticles do not form in the presence of divalent cations alone or in the presence of monovalent cations alone. The delivery of NAVs in cationic nanoparticles or in one or more depot comprising cationic nanoparticles may improve NAV bioavailability by acting as a long-acting depot and/or reducing the rate of degradation by nucleases.


Molded Nanoparticles and Microparticles

The NAVs disclosed herein may be formulated in nanoparticles and/or microparticles. These nanoparticles and/or microparticles may be molded into any size shape and chemistry. As an example, the nanoparticles and/or microparticles may be made using the PRINT® technology by LIQUIDA TECHNOLOGIES® (Morrisville, NC) (See e.g., International Pub. No. WO2007024323; the contents of which are herein incorporated by reference in its entirety).


In one embodiment, the molded nanoparticles may comprise a core of the NAVs disclosed herein and a polymer shell. The polymer shell may be any of the polymers described herein and are known in the art. In an additional embodiment, the polymer shell may be used to protect the NAVs in the core.


In one embodiment, the NAVs of the present invention may be formulated in microparticles. The microparticles may contain a core of the NAVs and a cortext of a biocompatible and/or biodegradable polymer. As a non-limiting example, the microparticles which may be used with the present invention may be those described in U.S. Pat. No. 8,460,709, U.S. Patent Publication No. US20130129830 and International Patent Publication No WO2013075068, each of which is herein incorporated by reference in its entirety. As another non-limiting example, the microparticles may be designed to extend the release of the NAVs of the present invention over a desired period of time (see e.g, extended release of a therapeutic protein in U.S. Patent Publication No. US20130129830, herein incorporated by reference in its entirety).


The microparticle for use with the present invention may have a diameter of at least 1 micron to at least 100 microns (e.g., at least 1 micron, at least 5 micron, at least 10 micron, at least 15 micron, at least 20 micron, at least 25 micron, at least 30 micron, at least 35 micron, at least 40 micron, at least 45 micron, at least 50 micron, at least 55 micron, at least 60 micron, at least 65 micron, at least 70 micron, at least 75 micron, at least 80 micron, at least 85 micron, at least 90 micron, at least 95 micron, at least 97 micron, at least 99 micron, and at least 100 micron).


NanoJackets and NanoLiposomes

The NAVs disclosed herein may be formulated in NanoJackets and NanoLiposomes by Keystone Nano (State College, PA). NanoJackets are made of compounds that are naturally found in the body including calcium, phosphate and may also include a small amount of silicates. Nanojackets may range in size from 5 to 50 nm and may be used to deliver hydrophilic and hydrophobic compounds such as, but not limited to, NAVs.


NanoLiposomes are made of lipids such as, but not limited to, lipids which naturally occur in the body. NanoLiposomes may range in size from 60-80 nm and may be used to deliver hydrophilic and hydrophobic compounds such as, but not limited to, NAVs. In one aspect, the NAVs disclosed herein are formulated in a NanoLiposome such as, but not limited to, Ceramide NanoLiposomes.


Pseudovirions

In one embodiment, the NAVs disclosed herein may be formulated in Pseudovirions (e.g., pseudo-virions). As a non-limiting example, the pseudovirions may be those developed and/or are described by Aura Biosciences (Cambridge, MA). In one aspect, the pseudovirion may be developed to deliver drugs to keratinocytes and basal membranes (See e.g., US Patent Publication Nos. US20130012450, US20130012566, US21030012426 and US20120207840 and International Publication No. WO2013009717, each of which is herein incorporated by reference in its entirety).


In one embodiment, the pseudovirion used for delivering the NAVs of the present invention may be derived from viruses such as, but not limited to, herpes and papillomaviruses (See e.g., US Patent Publication Nos. US Patent Publication Nos. US20130012450, US20130012566, US21030012426 and US20120207840 and International Publication No. WO2013009717, each of which is herein incorporated by reference in its entirety; and Ma et al. HPV pseudovirions as DNA delivery vehicles. Ther Deliv. 2011: 2(4): 427-430; Kines et al. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. PNAS 2009:106(48), 20458-20463; Roberts et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nature Medicine. 2007:13(7) 857-861; Gordon et al., Targeting the Vaginal Mucosa with Human Papillomavirus Psedudovirion Vaccines delivering SIV DNA. J Immunol. 2012 188(2) 714-723; Cuburu et al., Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. The Journal of Clinical Investigation. 2012: 122(12) 4606-4620; Hung et al., Ovarian Cancer Gene Therapy Using HPV-16 Psedudovirion Carrying the HSV-tk Gene. PLoS ONE. 2012: 7(7) e40983; Johnson et al., Role of Heparan Sulfate in Attachment to and Infection of the Murine Femal Genital Tract by Human Papillomavirus. J Virology. 2009: 83(5) 2067-2074; each of which is herein incorporated by reference in its entirety).


The pseudovirion may be a virus-like particle (VLP) prepared by the methods described in US Patent Publication No. US20120015899 and US20130177587 and International Patent Publication No. WO2010047839 WO2013116656, WO2013106525 and WO2013122262, the contents of each of which is herein incorporated by reference in its entirety. In one aspect, the VLP may be, but is not limited to, bacteriophages MS, Qp, R17, fr. GA, Sp, MI, I, MXI, NL95, AP205, f2, PP7, and the plant viruses Turnip crinkle virus (TCV), Tomato bushy stunt virus (TBSV), Southern bean mosaic virus (SBMV) and members of the genus Bromovirus including Broad bean mottle virus, Brome mosaic virus, Cassia yellow blotch virus, Cowpea chlorotic mottle virus (CCMV), Melandrium yellow fleck virus, and Spring beauty latent virus. In another aspect, the VLP may be derived from the influenza virus as described in US Patent Publication No. US20130177587 or U.S. Pat. No. 8,506,967, the contents of each of which are herein incorporated by reference in its entirety. In yet another aspect, the VLP may comprise a B7-1 and/or B7-2 molecule anchored to a lipid membrane or the exterior of the particle such as described in International Patent Publication No. WO2013116656, the contents of which are herein incorporated by reference in its entirety. In one aspect, the VLP may be derived from norovirus, rotavirus recombinant VP6 protein or double layered VP2/VP6 such as the VLP described in International Patent Publication No. WO2012049366, the contents of which are herein incorporated by reference in its entirety.


The pseudovirion may be a human papilloma virus-like particle such as, but not limited to, those described in International Publication No. WO2010120266 and US Patent Publication No. US20120171290, each of which is herein incorporated by reference in its entirety and Ma et al. HPV pseudovirions as DNA delivery vehicles. Ther Deliv. 2011: 2(4): 427-430; Kines et al. The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. PNAS 2009:106(48), 20458-20463; Roberts et al. Genital transmission of HPV in a mouse model is potentiated by nonoxynol-9 and inhibited by carrageenan. Nature Medicine. 2007:13(7) 857-861; Gordon et al., Targeting the Vaginal Mucosa with Human Papillomavirus Psedudovirion Vaccines delivering SIV DNA. J Immunol. 2012 188(2) 714-723; Cuburu et al., Intravaginal immunization with HPV vectors induces tissue-resident CD8+ T cell responses. The Journal of Clinical Investigation. 2012: 122(12) 4606-4620; Hung et al., Ovarian Cancer Gene Therapy Using HPV-16 Psedudovirion Carrying the HSV-tk Gene. PLoS ONE. 2012: 7(7) e40983; Johnson et al., Role of Heparan Sulfate in Attachment to and Infection of the Murine Femal Genital Tract by Human Papillomavirus. J Virology. 2009: 83(5) 2067-2074; each of which is herein incorporated by reference in its entirety.


In one aspect, the pseudovirions may be virion derived nanoparticles such as, but not limited to, those described in US Patent Publication No. US20130116408 and US20130115247, each of which is herein incorporated by reference in their entirety. As a non-limiting example, the virion derived nanoparticles may be used to deliver NAVs which may be used in the treatment for cancer and/or enhance the immune system's recognition of the tumor. As a non-limiting example, the virion-derived nanoparticle which may selectively deliver an agent to at least one tumor may be the papilloma-derived particles described in International Patent Publication No. WO2013119877, the contents of which are herein incorporated by reference in its entirety. The virion derived nanoparticles may be made by the methods described in US Patent Publication No. US20130116408 and US20130115247 or international Patent Publication No. WO2013119877, each of which is herein incorporated by reference in their entirety.


In one embodiment, the virus-like particle (VLP) may be a self-assembled particle. Non-limiting examples of self-assembled VLPs and methods of making the self-assembled VLPs are described in International Patent Publication No. WO2013122262, the contents of which are herein incorporated by reference in its entirety.


Minicells

In one aspect, the NAVs may be formulated in bacterial minicells. As a non-limiting example, bacterial minicells may be those described in international Publication No. WO2013088250 or US Patent Publication No. US20130177499, the contents of each of which are herein incorporated by reference in its entirety. The bacterial minicells comprising therapeutic agents such as NAVs described herein may be used to deliver the therapeutic agents to brain tumors.


Semi-Solid Compositions

In one embodiment, the NAVs may be formulated with a hydrophobic matrix to form a semi-solid composition. As a non-limiting example, the semi-solid composition or paste-like composition may be made by the methods described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety. The semi-solid composition may be a sustained release formulation as described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety.


In another embodiment, the semi-solid composition may further have a micro-porous membrane or a biodegradable polymer formed around the composition (see e.g., International Patent Publication No WO201307604, herein incorporated by reference in its entirety).


The semi-solid composition using the NAVs of the present invention may have the characteristics of the semi-solid mixture as described in International Patent Publication No WO201307604, herein incorporated by reference in its entirety (e.g., a modulus of elasticity of at least 10−4 N·mm−2, and/or a viscosity of at least 100 mPa·s).


Exosomes

In one embodiment, the NAVs may be formulated in exosomes. The exosomes may be loaded with at least one NAV and delivered to cells, tissues and/or organisms. As a non-limiting example, the NAVs may be loaded in the exosomes described in International Publication No. WO2013084000, herein incorporated by reference in its entirety.


Silk-Based Delivery

In one embodiment, the NAVs may be formulated in a sustained release silk-based delivery system. The silk-based delivery system may be formed by contacting a silk fibroin solution with a therapeutic agent such as, but not limited to, the NAVs described herein and/or known in the art. As a non-limiting example, the sustained release silk-based delivery system which may be used in the present invention and methods of making such system are described in US Patent Publication No. US20130177611, the contents of which are herein incorporated by reference in its entirety.


Microparticles

In one embodiment, formulations comprising NAVs may comprise microparticles. The microparticles may comprise a polymer described herein and/or known in the art such as, but not limited to, poly(α-hydroxy acid), a polyhydroxy butyric acid, a polycaprolactone, a polyorthoester and a polyanhydride. The microparticle may have adsorbent surfaces to adsorb biologically active molecules such as NAVs. As a non-limiting example microparticles for use with the present invention and methods of making microparticles are described in US Patent Publication No. US2013195923 and US20130195898 and U.S. Pat. Nos. 8,309,139 and 8,206,749, the contents of each of which are herein incorporated by reference in its entirety.


In another embodiment, the formulation may be a microemulsion comprising microparticles and NAVs. As a non-limiting example, microemulsions comprising microparticles are described in US Patent Publication No. US2013195923 and US20130195898 and U.S. Pat. Nos. 8,309,139 and 8,206,749, the contents of each of which are herein incorporated by reference in its entirety.


Amino Acid Lipids

In one embodiment, the NAVs may be formulated in amino acid lipids. Amino acid lipids are lipophilic compounds comprising an amino acid residue and one or more lipophilic tails. Non-limiting examples of amino acid lipids and methods of making amino acid lipids are described in U.S. Pat. No. 8,501,824, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the amino acid lipids have a hydrophilic portion and a lipophilic portion. The hydrophilic portion may be an amino acid residue and a lipophilic portion may comprise at least one lipophilic tail.


In one embodiment, the amino acid lipid formulations may be used to deliver the NAVs to a subject.


In another embodiment, the amino acid lipid formulations may deliver a NAV in releasable form which comprises an amino acid lipid that binds and releases the NAV. As a non-limiting example, the release of the NAVs may be provided by an acid-labile linker such as, but not limited to, those described in U.S. Pat. Nos. 7,098,032, 6,897,196, 6,426,086, 7,138,382, 5,563,250, and 5,505,931, the contents of each of which are herein incorporated by reference in its entirety.


Microvesicles

In one embodiment, NAVs may be formulated in microvesicles. Non-limiting examples of microvesicles include those described in US Patent Publication No. US20130209544, the contents of which are herein incorporated by reference in its entirety.


In one embodiment, the microvesicle is an ARRDC1-mediated microvesicles (ARMMs). Non-limiting examples of ARMMs and methods of making ARMMs are described in International Patent Publication No. WO2013119602, the contents of which are herein incorporated by reference in its entirety.


Interpolyelectrolyte Complexes

In one embodiment, the NAVs may be formulated in an interpolyelectrolyte complex. Interpolyelectrolyte complexes are formed when charge-dynamic polymers are complexed with one or more anionic molecules. Non-limiting examples of charge-dynamic polymers and interpolyelectrolyte complexes and methods of making interpolyelectrolyte complexes are described in U.S. Pat. No. 8,524,368, the contents of which is herein incorporated by reference in its entirety.


Crystalline Polymeric Systems

In one embodiment, the NAVs may be formulated in crystalline polymeric systems. Crystalline polymeric systems are polymers with crystalline moieties and/or terminal units comprising crystalline moieties. Non-limiting examples of polymers with crystalline moieties and/or terminal units comprising crystalline moieties termed “CYC polymers,” crystalline polymer systems and methods of making such polymers and systems are described in U.S. Pat. No. 8,524,259, the contents of which are herein incorporated by reference in its entirety.


Excipients

NAV pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but are not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, flavoring agents, stabilizers, antioxidants, osmolality adjusting agents. pH adjusting agents and the like, as suited to the particular dosage form desired. Various excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21st Edition, A. R. Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference in its entirety). The use of a conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.


In some embodiments, a pharmaceutically acceptable excipient may be at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure. In some embodiments, an excipient is approved for use for humans and for veterinary use. In some embodiments, an excipient may be approved by United States Food and Drug Administration. In some embodiments, an excipient may be of pharmaceutical grade. In some embodiments, an excipient may meet the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British Pharmacopoeia, and/or the International Pharmacopoeia.


Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical compositions. The composition may also include excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents.


Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.


Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (VEEGUM®), sodium lauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof.


Exemplary surface active agents and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and VEEGUM® [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [TWEEN®20], polyoxyethylene sorbitan [TWEEN®60], polyoxyethylene sorbitan monooleate [TWEEN®80], sorbitan monopalmitate [SPAN®40], sorbitan monostearate [SPAN®60], sorbitan tristearate [SPAN®65], glyceryl monooleate, sorbitan monooleate [SPAN®80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [MYRJ®45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and SOLUTOL®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. CREMOPHOR®), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [BRU®30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, PLUORINC®F 68, POLOXAMER®188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.


Exemplary binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); amino acids (e.g., glycine); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (VEEGUM®), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; waxes; water, alcohol; etc.; and combinations thereof.


Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Oxidation is a potential degradation pathway for mRNA, especially for liquid mRNA formulations. In order to prevent oxidation, antioxidants can be added to the formulation. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyl palmitate, benzyl alcohol, butylated hydroxyanisole, EDTA, m-cresol, methionine, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, thioglycerol and/or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and/or thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, GLYDANT PLUS*, PHENONIP*, methylparaben, GERMALL®115, GERMABEN®II, NEOLONE™, KATHON™, and/or EUXYL®.


In some embodiments, the pH of the NAV solutions are maintained between pH 5 and pH 8 to improve stability. Exemplary buffers to control pH may include, but are not limited to sodium phosphate, sodium citrate, sodium succinate, histidine (or histidine-HCl), sodium carbonate, and/or sodium malate. In another embodiment, the exemplary buffers listed above may be used with additional monovalent counterions (including, but not limited to potassium). Divalent cations may also be used as buffer counterions; however, these are not preferred due to complex formation and/or mRNA degradation.


Exemplary buffering agents may also include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and/or combinations thereof.


Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.


Exemplary oils include, but are not limited to, almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, Litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.


Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or perfuming agents can be present in the composition, according to the judgment of the formulator.


Exemplary additives include physiologically biocompatible buffers (e.g., trimethylamine hydrochloride), addition of chelants (such as, for example, DTPA or DTPA-bisamide) or calcium chelate complexes (as for example calcium DTPA, CaNaDTPA-bisamide), or, optionally, additions of calcium or sodium salts (for example, calcium chloride, calcium ascorbate, calcium gluconate or calcium lactate). In addition, antioxidants and suspending agents can be used.


Cryoprotectants

In some embodiments, NAV formulations may comprise cyroprotectants. As used herein, there term “cryoprotectant” refers to one or more agent that when combined with a given substance, helps to reduce or eliminate damage to that substance that occurs upon freezing. In some embodiments, cryoprotectants are combined with NAVs in order to stabilize them during freezing. Frozen storage of NAVs between −20° C. and −80° C. may be advantageous for long term (e.g. 36 months) stability of polynucleotide. In some embodiments, cryoprotectants are included in NAV formulations to stabilize polynucleotide through freeze/thaw cycles and under frozen storage conditions. Cryoprotectants of the present invention may include, but are not limited to sucrose, trehalose, lactose, glycerol, dextrose, raffinose and/or mannitol. Trehalose is listed by the Food and Drug Administration as being generally regarded as safe (GRAS) and is commonly used in commercial pharmaceutical formulations.


Bulking Agents

In some embodiments, NAV formulations may comprise bulking agents. As used herein, the term “bulking agent” refers to one or more agents included in formulations to impart a desired consistency to the formulation and/or stabilization of formulation components. In some embodiments, bulking agents are included in lyophilized NAV formulations to yield a “pharmaceutically elegant” cake, stabilizing the lyophilized NAVs during long term (e.g. 36 month) storage. Bulking agents of the present invention may include, but are not limited to sucrose, trehalose, mannitol, glycine, lactose and/or raffinose. In some embodiments, combinations of cryoprotectants and bulking agents (for example, sucrose/glycine or trehalose/mannitol) may be included to both stabilize NAVs during freezing and provide a bulking agent for lyophilization.


Non-limiting examples of formulations and methods for formulating the NAVs of the present invention are also provided in International Publication No WO2013090648 filed Dec. 14, 2012, the contents of which are incorporated herein by reference in their entirety.


Inactive Ingredients

In some embodiments, NAV formulations may comprise at least one excipient which is an inactive ingredient. As used herein, the term “inactive ingredient” refers to one or more inactive agents included in formulations. In some embodiments, all, none or some of the inactive ingredients which may be used in the formulations of the present invention may be approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients and the routes of administration the inactive ingredients may be formulated in are described in Table 26. In Table 26, “AN” means anesthetic, “CNBLK” means cervical nerve block, “NBLK” means nerve block, “IV” means intravenous, “IM” means intramuscular and “SC” means subcutaneous









TABLE 26







Inactive Ingredients








Inactive Ingredient
Route of Administration





Alpha-Terpineol
Topical


Alpha-Tocopherol
Intravenous; Topical


Alpha-Tocopherol Acetate, Dl-
Topical


Alpha-Tocopherol, Dl-
Intravenous; Topical


1,2,6-Hexanetriol
Topical


1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S-
Intravenous; Infusion (IV)


(1-Glycerol))



1,2-Dimyristoyl-Sn-Glycero-3-
Intravenous; Infusion (IV)


Phosphocholine



1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine
Epidural


1,2-Dipalmitoyl-Sn-Glycero-3-(Phospho-
Epidural


Rac-(1-Glycerol))



1,2-Distearoyl-Sn-Glycero-3-(Phospho-Rac-
Intravenous


(1-Glycerol))



1,2-Distearoyl-Sn-Glycero-3-Phosphocholine
Intravenous


1-O-Tolylbiguanide
Topical


2-Ethyl-1,6-Hexanediol
Topical


Acetic Acid
Infiltration; Auricular (Otic); Extracorporeal;



Intramuscular; Intravenous; Subcutaneous; Intra-



articualr; Intralesional; Intramuscular; Intrasynovial;



Intratracheal; Intravenous; Irrigation; Infusion (IV);



Nasal; Nerve block; Ophthalmic; Photopheresis; Soft



Tissue; Submucosal; Topical


Acetic Acid, Glacial
Intravenous; Infusion (IV); Subcutaneous


Acetic Anhydride
Intravenous


Acetone
Implantation; Topical


Acetone Sodium Bisulfite
Intrathecal (AN, CNBLK); Infiltration (AN); Dental;



Inhalation; Nerve Block


Acetylated Lanolin Alcohols
Topical


Acetylated Monoglycerides
Intravenous


Acetylcysteine
Inhalation


Acetyltryptophan, DL-
Intravenous


Acrylates Copolymer
Topical; Transdermal


Acrylic Acid-Isooctyl Acrylate Copolymer
Transdermal


Acrylic Adhesive 788
Transdermal


Activated Charcoal
Intramuscular; Intravenous; Irrigation; Infusion (IV)


Adcote 72A103
Transdermal


Adhesive Tape
Topical


Adipic Acid
Intramuscular; Vaginal


Aerotex Resin 3730
Transdermal


Alanine
Infusion (IV)


Albumin Aggregated
Intravenous


Albumin Colloidal
Intravenous


Albumin Human
Intravenous; Infusion (IV); Subcutaneous


Alcohol
Dental; Intramuscular; Intravenous; Subcutaneous;



Inhalation; Intravascular; Infusion (IV); Ophthalmic;



Rectal; Respiratory (Inhalation); Topical;



Transdermal


Alcohol, Dehydrated
Dental; Extracorporeal; Intramuscular; Intravenous;



Subcutaneous; Inhalation; Intracavitary;



Intravascular; Intravesical; Nasal, Ophthalmic;



Photopheresis, Rectal; Respiratory (Inhalation);



Sublingual; Topical; Transdermal


Alcohol, Denatured
Denatal; Intravenous; Topical; Vaginal


Alcohol, Diluted
Intramuscular; Intravenous; Topical


Alfadex
Intracavitary


Alginic Acid
Ophthalmic


Alkyl Ammonium Sulfonic Acid Betaine
Topical


Alkyl Aryl Sodium Sulfonate
Topical


Allantoin
Topical; Vaginal


Allyl.Alpha.-Ionone
Nasal


Almond Oil
Topical


Aluminum Acetate
Auricular (Otic); Topical


Aluminum Chlorhydroxy Allantoinate
Topical


Aluminum Hydroxide
Topical


Aluminum Hydroxide-Sucrose, Hydrated
Topical


Aluminum Hydroxide Gel
Topical


Aluminum Hydroxide Gel F 500
Topical


Aluminum Hydroxide Gel F 5000
Topical


Aluminum Monostearate
Topical


Aluminum Oxide
Topical


Aluminum Polyester
Transdermal


Aluminum Silicate
Topical


Aluminum Starch Octenylsuccinate
Topical


Aluminum Stearate
Topical


Aluminum Subacetate
Rectal


Aluminum Sulfate Anhydrous
Auricular (Otic); Topical


Amerchol C
Topical


Amerchol-Cab
Ophthalmic; Topical


Aminomethylpropanol
Topical


Ammonia
Inhalation


Ammonia Solution
Topical


Ammonia Solution, Strong
Topical


Ammonium Acetate
Intramuscular; Intravenous; Infusion (IV)


Ammonium Hydroxide
Intravenous; Ophthalmic; Subcutaneous; Topical


Ammonium Lauryl Sulfate
Topical


Ammonium Nonoxynol-4 Sulfate
Topical


Ammonium Salt Of C-12-C-15 Linear
Topical


Primary Alcohol Ethoxylate



Ammonium Sulfate
Intravenous


Ammonyx
Topical


Amphoteric-2
Topical


Amphoteric-9
Topical


Anethole
Dental


Anhydrous Citric Acid
Intravenous; Infusion (IV); Rectal; Topical


Anhydrous Dextrose
Intramuscular; Intravenous; Subcutaneous; Infusion



(IV); Nasal; Spinal


Anhydrous Lactose
Intramuscular; Intravenous; Intracavitary;



Intravenous; Infusion (IV); Vaginal


Anhydrous Trisodium Citrate
Intramuscular; Intravenous; Intra-arterial; Intra-



articular; Intrabursal; Infusion (IV); Nasal;



Ophthalmic; Soft Tissue; Topical


Aniseed Oil
Rectal


Anoxid Sbn
Topical


Antifoam
Topical


Antipyrine
Ophthalmic


Apaflurane
Respiratory (Inhalation)


Apricot Kernel Oil Peg-6 Esters
Topical; Vaginal


Aquaphor
Topical


Arginine
Intramuscular; Intravenous; Infusion (IV)


Arlacel
Topical


Ascorbic Acid
Infiltration (AN); Caudal Block; Epidural;



Intramuscular; Intravenous; Inhalation; Infusion



(IV); Nerve Block; Rectal; Subctaneous; Topical


Ascorbyl Palmitate
Rectal; Topical


Aspartic Acid
Infusion (IV)


Balsam Peru
Rectal


Barium Sulfate
Intrauterine; Vaginal


Beeswax
Topical; Vaginal


Beeswax, Synthetic
Topical


Beheneth-10
Topical


Bentonite
Topical; Transdermal; Vaginal


Benzalkonium Chloride
Auricular (Otic); Inhalation; Intra-Articular;



Intrabursal; Intradermal; Intralesional; Intramuscular;



Intraocular; Nasal; Ophthalmic; Respiratory



(Inhalation); Topical


Benzenesulfonic Acid
Intravenous; Infusion (IV)


Benzethonium Chloride
Auricular (Otic); Intramuscular; Intravenous;



Infusion (IV); Nasal; Ophthalmic


Benzododecinium Bromide
Ophthalmic


Benzoic Acid
Intramuscular; Intravenous; Irrigation; Infusion (IV);



Rectal; Topical; Vaginal


Benzyl Alcohol
Infiltration (AN); Auricular (Otic); Dental; Epidural;



Extracorporeal; Interstitial; Intra-Arterial; Intra-



Articular; Intrabursal; Intracavitary; Intradermal;



Intralesional; Intramuscular; Intraperitoneal;



Intrapleural; Intrasynovial; Intrathecal; Intratracheal;



Intratumor; Intravenous; Infusion(IV); Nasal; Nerve



Block; Rectal; Soft Tissue; Subconjunctival;



Subcutaneous; Topical; Ureteral; Vaginal


Benzyl Benzoate
Intramuscular


Benzyl Chloride
Intravenous


Betadex
Topical


Bibapcitide
Intravenous


Bismuth Subgallate
Rectal


Boric Acid
Auricular (Otic); Intravenous; Ophthalmic; Topical


Brocrinat
Infusion (IV)


Butane
Topical


Butyl Alcohol
Topical


Butyl Ester Of Vinyl Methyl Ether/Maleic
Topical


Anhydride Copolymer (125000 Mw)



Butyl Stearate
Topical


Butylated Hydroxyanisole
Intramuscular; Infusion (IV); Nasal; Rectal; Topical;



Vaginal


Butylated Hydroxytoluene
Intramuscular; Intravenous; Infusion (IV); Nasal;



Rectal; Topical; Transdermal; Vaginal


Butylene Glycol
Topical; Transdermal


Butylparaben
Intramuscular; Rectal; Topical


Butyric Acid
Transdermal


C20-40 Pareth-24
Topical


Caffeine
Nasal; Ophthalmic


Calcium
Intramuscular


Calcium Carbonate
Auricular (Otic); Respiratory (Inhalation)


Calcium Chloride
Infiltration (AN); Caudal Block; Epidural;



Intramuscular; Intravenous; Intraocular;



Intraperitoneal; Intravascular; Intravitreal; Nerve



Block; Ophthalmic; Subctaneous; Topical


Calcium Gluceptate
Intravenous


Calcium Hydroxide
Intravenous; Subcutaneous; Topical


Calcium Lactate
Vaginal


Calcobutrol
Intravenous


Caldiamide Sodium
Intravenous


Caloxetate Trisodium
Intravenous


Calteridol Calcium
Intravenous


Canada Balsam
Topical


Caprylic/Capric Triglyceride
Topical; Transdermal


Caprylic/Capric/Stearic Triglyceride
Topical


Captan
Topical


Captisol
Intravenous


Caramel
Rectal; Topical


Carbomer 1342
Ophthalmic; Topical; Transdermal


Carbomer 1382
Topical


Carbomer 934
Rectal; Topical; Vaginal


Carbomer 934p
Ophthalmic; Rectal; Topical; Vaginal


Carbomer 940
Ophthalmic; Topical; Transdermal


Carbomer 941
Topical


Carbomer 980
Topical; Transdermal


Carbomer 981
Topical


Carbomer Homopolymer Type B (Allyl
Ophthalmic; Topical


Pentaerythritol Crosslinked)



Carbomer Homopolymer Type C (Allyl
Topical


Pentaerythritol Crosslinked)



Carbon Dioxide
Infiltration (AN); Intramuscular (IM); Infusion (IV);



Inhalation; Intra-arterial; Intracardiac; Intrathecal;



Intravascular; Intravenous


Carboxy Vinyl Copolymer
Topical


Carboxymethylcellulose
Intra-articular; Intrabursal; Intralesional;



Intramuscular; Soft tissue; Topical


Carboxymethylcellulose Sodium
Dental; Intra-articular; Intrabursal; Intradermal;



Intramuscular; Intrasynovial; Intratracheal; Nasal;



Ophthalmic; Soft tissue; Subcutaneous; Topical


Carboxypolymethylene
Rectal; Topical


Carrageenan
Dental; Topical; Transdermal


Carrageenan Salt
Topical


Castor Oil
Intramuscular; Ophthalmic; Topical


Cedar Leaf Oil
Topical


Cellulose
Topical


Cellulose, Microcrystalline
Intra-articular; Intramuscular; Intravenous;



Intravitreal; Nasal; Vaginal


Cerasynt-Se
Rectal; Topical


Ceresin
Topical


Ceteareth-12
Topical


Ceteareth-15
Topical


Ceteareth-30
Topical


Cetearyl Alcohol/Ceteareth-20
Topical


Cetearyl Ethylhexanoate
Topical


Ceteth-10
Topical


Ceteth-2
Topical


Ceteth-20
Topical; Vaginal


Ceteth-23
Topical


Cetostearyl Alcohol
Topical; Vaginal


Cetrimonium Chloride
Topical


Cetyl Alcohol
Auricular (Otic); Ophthalmic; Rectal; Topical;


Vaginal



Cetyl Esters Wax
Topical; Vaginal


Cetyl Palmitate
Topical; Vaginal


Cetylpyridinium Chloride
Inhalation; Iontophoresis; Transdermal


Chlorobutanol
Infiltration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Subcutaneous (SC); Inhalation;



Intravenous; Nasal; Nerve Block; Ophthalmic;



Topical


Chlorobutanol Hemihydrate
Intramuscular; Intravenous


Chlorobutanol, Anhydrous
Intramuscular; Intravenous; Ophthalmic


Chlorocresol
Topical


Chloroxylenol
Auricular (Otic); Topical


Cholesterol
Epidural; Infiltration; Intravecous; Ophthalmic;



Topical; Vaginal


Choleth
Vaginal


Choleth-24
Topical


Citrate
Intravenous


Citric Acid
Intrathecal (AN, CNBLK); Infiltration (AN);



Auricular (Otic); Caudal Block; Epidural;



Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Infiltration; Inhalation; Intra-amniotic; Intra-



arterial; Intra-articular; Intrabursal; Intracardiac;



Intralesional; Iintrapleural; Intrasynovial; Intrathecal;



Intravascular; Intravenous; Iontophoresis; Nasal;



Nerve Block; Ophthalmic; Peridural; Soft tissue;



Topical; Transdermal; Vaginal


Citric Acid Monohydrate
Infiltration (AN); Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intracardiac; Intraocular;



Intravenous; Nasal; Nerve Block; Ophthalmic;



Topical; Vaginal


Citric Acid, Hydrous
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intravenous


Cocamide Ether Sulfate
Topical


Cocamine Oxide
Topical


Coco Betaine
Topical


Coco Diethanolamide
Topical


Coco Monoethanolamide
Topical


Cocoa Butter
Rectal; Topical


Coco-Glycerides
Topical


Coconut Oil
Topical


Coconut Oil, Hydrogenated
Rectal


Coconut Oil/Palm Kernel Oil Glycerides,
Rectal; Vaginal


Hydrogenated



Cocoyl Caprylocaprate
Topical


Cola Nitida Seed Extract
Rectal


Collagen
Topical


Coloring Suspension
Topical


Corn Oil
Intramuscular


Cottonseed Oil
Intramuscular


Cream Base
Topical


Creatine
Intra-articular; Intralesional; Intramuscular


Creatinine
Auricular (Otic); Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intra-articular; Intrabursal;



Intradermal; Intralesional; Intrasynovial;



Ophthalmic; Soft tissue; Topical


Cresol
Subcutaneous


Croscarmellose Sodium
Intramuscular


Crospovidone
Implantation; Intra-articluar; Intramuscular;



Intrauterine; Topical; Transdermal; Vagiinal


Cupric Sulfate
Auricular (Otic)


Cupric Sulfate Anhydrous
Auricular (Otic)


Cyclomethicone
Topical


Cyclomethicone/Dimethicone Copolyol
Topical


Cysteine
Intramuscular (IM); Subcutaneous (SC);



Intravenous; Infusion (IV)


Cysteine Hydrochloride
Intravenous; Infusion (IV)


Cysteine Hydrochloride Anhydrous
Intradiscal


Cysteine, Dl-
Intradiscal


D&C Red No. 28
Topical


D&C Red No. 33
Topical


D&C Red No. 36
Topical


D&C Red No. 39
Topical


D&C Yellow No. 10
Dental; Inhalation; Rectal; Topical


Dalfampridine
Intravenous


Daubert 1-5 Pestr (Matte) 164z
Transdermal


Decyl Methyl Sulfoxide
Topical


Dehydag Wax Sx
Topical


Dehydroacetic Acid
Topical


Dehymuls E
Topical


Denatonium Benzoate
Topical


Deoxycholic Acid
Infusion (IV)


Dextran
Intravenous


Dextran 40
Intravenous


Dextrin
Topical


Dextrose
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Interstitial; Intracavitary; Intraperitoneal;



Intrapleural; Intraspinal; Intravenous; Nasal; Spinal


Dextrose Monohydrate
Intravenous


Dextrose Solution
Intravenous; Infusion (IV)


Diatrizoic Acid
Intra-arterial; Intra-articular; Intracardiac;



Intradiscal; Intramuscular; Intrauterine;



Intravascular; Intravenous; Infusion (IV);



Periarticular; Subcutaneous; Ureteral; Urethral


Diazolidinyl Urea
Topical


Dichlorobenzyl Alcohol
Topical


Dichlorodifluoromethane
Inhalation; Intrapleural; Nasal; Rectal; Topical


Dichlorotetrafluoroethane
Inhalation; Nasal; Rectal; Topical


Diethanolamine
Infusion (IV); Ophthalmic; Topical


Diethyl Pyrocarbonate
Inflitration


Diethyl Sebacate
Topical


Diethylene Glycol Monoethyl Ether
Topical; Transdermal


Diethylhexyl Phthalate
Ophthalmic; Transdermal


Dihydroxyaluminum Aminoacetate
Topical


Diisopropanolamine
Topical


Diisopropyl Adipate
Topical


Diisopropyl Dilinoleate
Topical


Dimethicone 350
Topical


Dimethicone Copolyol
Topical; Transermal


Dimethicone Mdx4-4210
Transdermal


Dimethicone Medical Fluid 360
Dental; Intravenous; Topical; Transdermal


Dimethyl Isosorbide
Topical


Dimethyl Sulfoxide
Infusion (IV); Subcutanous; Topical


Dimethylaminoethyl Methacrylate-Butyl
Transdermal


Methacrylate-Methyl Methacrylate



Copolymer



Dimethyldioctadecylammonium Bentonite
Rectal


Dimethylsiloxane/Methylvinylsiloxane
Implantation; Intrauterine


Copolymer



Dinoseb Ammonium Salt
Topical


Dipalmitoylphosphatidylglycerol, Dl-
Inflitration


Dipropylene Glycol
Transdermal


Disodium Cocoamphodiacetate
Topical


Disodium Laureth Sulfosuccinate
Topical


Disodium Lauryl Sulfosuccinate
Topical


Disodium Sulfosalicylate
Topical


Disofenin
Topical


Divinylbenzene Styrene Copolymer
Ophthalmic


Dmdm Hydantoin
Topical


Docosanol
Topical


Docusate Sodium
Intramuscular; Topical


Duro-Tak 280-2516
Transdermal


Duro-Tak 387-2516
Transdermal


Duro-Tak 80-1196
Transdermal


Duro-Tak 87-2070
Transdermal


Duro-Tak 87-2194
Transdermal


Duro-Tak 87-2287
Percutaneous; Transdermal


Duro-Tak 87-2296
Transdermal


Duro-Tak 87-2888
Transdermal


Duro-Tak 87-2979
Transdermal


Edetate Calcium Disodium
Infiltration (AN); Caudal Block; Epidural;



Intramuscular (IM); Infusion (IV); Intra-articular;



Intra-arterial; Intracardiac; Intradiscal;



Intraperitoneal; Intrathecal; Intrauterine;



Intravascular; Intravenous; Intravesical; Nerve



Block; Periarticular; Rectal; Subcutaneous; Ureteral;



Urethral


Edetate Disodium
Infiltration (AN), Auricular (Otic); Caudal Block;



Epidural; Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Inhalation; Intra-arterial; Intra-



articular; Intrabursal; Intracardiac; Intradermal;



Intradiscal; Intralesional; Intrasynovial; Intrauterine;



Intravascular; Intravenous; Iontophoresis; Nasal;



Nerve Block; Ophthalmic; Rectal; Respiratory



(Inhalation); Soft tissue; Topical; Transdermal;



Ureteral; Urethral; Vaginal


Edetate Disodium Anhydrous
Intra-amniotic; Intramuscular; Intravenous; Infusion



(IV); Ophthalmic


Edetate Sodium
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inhalation; Ophthalmic; Topical


Edetic Acid
Auricular (Otic); Rectal; Submucosal; Topical


Egg Phospholipids
Intravenous; Infusion (IV)


Entsufon
Topical


Entsufon Sodium
Topical


Epilactose
Rectal


Epitetracycline Hydrochloride
Topical


Essence Bouquet 9200
Topical


Ethanolamine Hydrochloride
Intravenous


Ethyl Acetate
Intramuscular; Topical; Transdermal


Ethyl Oleate
Transdermal


Ethylcelluloses
Topical; Transdermal; Vaginal


Ethylene Glycol
Topical


Ethylene Vinyl Acetate Copolymer
Implantation; Intrauerine; Ophthalmic; Periodontal;



Subcutaneous; Transdermal


Ethylenediamine
Intravenous; Infusion (IV); Rectal; Topical


Ethylenediamine Dihydrochloride
Topical


Ethylene-Propylene Copolymer
Transdermal


Ethylene-Vinyl Acetate Copolymer
Vaginal


(28% Vinyl Acetate)



Ethylene-Vinyl Acetate Copolymer
Vaginal


(9% Vinylacetate)



Ethylhexyl Hydroxystearate
Topical


Ethylparaben
Topical


Eucalyptol
Dental


Exametazime
Intravenous


Fat, Edible
Rectal


Fat, Hard
Rectal


Fatty Acid Esters
Transdermal


Fatty Acid Pentaerythriol Ester
Topical


Fatty Acids
Topical


Fatty Alcohol Citrate
Topical


Fatty Alcohols
Vaginal


Fd&C Blue No. 1
Dental; Rectal; Topical


Fd&C Green No. 3
Dental; Rectal


Fd&C Red No. 4
Topical


Fd&C Red No. 40
Topical


Fd&C Yellow No. 10 (Delisted)
Topical


Fd&C Yellow No. 5
Topical; Vaginal


Fd&C Yellow No. 6
Inhalation; Rectal; Topical


Ferric Chloride
Intravenous


Ferric Oxide
Topical


Flavor 89-186
Dental


Flavor 89-259
Dental


Flavor Df-119
Dental


Flavor Df-1530
Dental


Flavor Enhancer
Dental


Flavor Fig 827118
Rectal


Flavor Raspberry Pfc-8407
Rectal


Flavor Rhodia Pharmaceutical No. Rf 451
Topical


Fluorochlorohydrocarbons
Inhalation


Formaldehyde
Topical


Formaldehyde Solution
Topical


Fractionated Coconut Oil
Topical


Fragrance 3949-5
Topical


Fragrance 520a
Topical


Fragrance 6.007
Topical


Fragrance 91-122
Topical


Fragrance 9128-Y
Topical


Fragrance 93498g
Topical


Fragrance Balsam Pine No. 5124
Topical


Fragrance Bouquet 10328
Topical


Fragrance Chemoderm 6401-B
Topical


Fragrance Chemoderm 6411
Topical


Fragrance Cream No. 73457
Topical


Fragrance Cs-28197
Topical


Fragrance Felton 066m
Topical


Fragrance Firmenich 47373
Topical


Fragrance Givaudan Ess 9090/1c
Topical


Fragrance H-6540
Topical


Fragrance Herbal 10396
Topical


Fragrance Nj-1085
Topical


Fragrance P O Fl-147
Topical


Fragrance Pa 52805
Topical


Fragrance Pera Derm D
Topical


Fragrance Rbd-9819
Topical


Fragrance Shaw Mudge U-7776
Topical


Fragrance Tf 044078
Topical


Fragrance Ungerer Honeysuckle K 2771
Topical


Fragrance Ungerer N5195
Topical


Fructose
Infusion (IV); Rectal


Gadolinium Oxide
Intravenous


Galactose
Rectal


Gamma Cyclodextrin
Intravenous


Gelatin
Dental; Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intravenous; Respiratory



(Inhalation); Topical; Vaginal


Gelatin, Crosslinked
Dental


Gelfoam Sponge
N/A


GelIan Gum (Low Acyl)
Ophthalmic


Gelva 737
Transdermal


Gentisic Acid
Intravenous


Gentisic Acid Ethanolamide
Infusion (IV)


Gluceptate Sodium
Intravenous


Gluceptate Sodium Dihydrate
Intravenous


Gluconolactone
Intramuscular (IM); Infusion (IV); Intravesou;



Topical


Glucuronic Acid
Intravenous


Glutamic Acid, Dl-
Vaginal


Glutathione
Intramuscular


Glycerin
Auricular (Otic); Dental; Intramuscular; Infusion



(IV); Subcutaneous (SC); Inhalation; Intradermal;



Intravenous; Iontophoresis; Nasal; Ophthalmic;



Perfusion; Biliary; Rectal; Topical; Transdermal;



Vaginal


Glycerol Ester Of Hydrogenated Rosin
Nasal


Glyceryl Citrate
Topical


Glyceryl Isostearate
Topical; Vaginal


Glyceryl Laurate
Transdermal


Glyceryl Monostearate
Topical; Vaginal


Glyceryl Oleate
Topical; Transdermal


Glyceryl Oleate/Propylene Glycol
Topical


Glyceryl Palmitate
Rectal; Topical


Glyceryl Ricinoleate
Topical


Glyceryl Stearate
Auricular (Otic); Dental; Ophthalmic; Rectal;



Topical; Vaginal


Glyceryl Stearate-Laureth-23
Topical


Glyceryl Stearate/Peg Stearate
Rectal


Glyceryl Stearate/Peg-100 Stearate
Topical


Glyceryl Stearate/Peg-40 Stearate
Rectal


Glyceryl Stearate-Stearamidoethyl
Topical


Diethylamine



Glyceryl Trioleate
Epidural


Glycine
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intravenous; Rectal; Respiratory (Inhalation)


Glycine Hydrochloride
Subcutaneous


Glycol Distearate
Topical


Glycol Stearate
Topical


Guanidine Hydrochloride
Intravenous


Guar Gum
Topical; Vaginal


Hair Conditioner (18n195-1m)
Topical


Heptane
Transdermal


Hetastarch
Intravenous


Hexylene Glycol
Topical


High Density Polyethylene
Dental; Intrauterine; Ophthalmic; Topical;



Transdermal; Vaginal


Histidine
Intravenous; Infusion (IV); Subcutaneous


Human Albumin Microspheres
Intravenous


Hyaluronate Sodium
Intra-articular; Intramuscular; Intravitreal; Topical


Hydrocarbon
Rectal


Hydrocarbon Gel, Plasticized
Dental; Ophthalmic; Topical


Hydrochloric Acid
Intrathecal (AN, CNBLK); Inflitration (AN);



Sympathetic (AN, NBLK); Auricular (Otic); Caudal



Block; Dental; Diagnostic; Epidural; Extracorporeal;



Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inflitration; Inhalationi; Interstitial; Intra-



amniotic; Intra-arterial; Intra-articular; Intrabursal;



Intracardiac; Intracaudal; Intracavitary; Intradermal;



Intralesional; Intraocular; Intraperitoneal;



Intrapleural; Intraspinal; Intrasynovial; Intrathecal;



Intratracheal; Intratumor; Intravascular; Intravenous;



Intravesical; Intravitreal; Iontophoresis; Irrigation;



Nasal; Nerve Block, Ophthalmic; Parenteral;



Perfusion, Cardiac; Peridural; Perineural;



Periodontal; Pectal; Respiratory (Inhalation);



Retrobulbar; Soft tissue; Spinal; Subarachnoid;



Subconjunctival; Subcutaneous; Topical;



Transdermal; Ureteral; Urethral


Hydrochloric Acid, Diluted
Infiltration (AN); Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Inhalation; Intra-arterial;



Intravascular; Intravenous; Nerve Block;



Ophthalmic; Topical


Hydrocortisone
Auricular (Otic)


Hydrogel Polymer
Vaginal


Hydrogen Peroxide
Topical


Hydrogenated Castor Oil
Topical


Hydrogenated Palm Oil
Rectal; Vaginal


Hydrogenated Palm/Palm Kernel Oil Peg-6
Topical


Esters



Hydrogenated Polybutene 635-690
Transdermal


Hydroxide Ion
Intramuscular; Infusion (IV)


Hydroxyethyl Cellulose
Auricular (Otic); Ophthalmic; Topical; Transdermal


Hydroxyethylpiperazine Ethane Sulfonic
Intravenous


Acid



Hydroxymethyl Cellulose
Topical


Hydroxyoctacosanyl Hydroxystearate
Topical


Hydroxypropyl Cellulose
Topical


Hydroxypropyl Methylcellulose 2906
Ophthalmic


Hydroxypropyl-Bcyclodextrin
Intravenous; Infusion (IV)


Hypromellose 2208 (15000 Mpa · S)
Vaginal


Hypromellose 2910 (15000 Mpa · S)
Nasal; Ophthalmic


Hypromelloses
Irrigation; Ophthalmic; Rectal; Topical; Vaginal


Imidurea
Topical


Iodine
Intra-arterial; Intra-articular; Intracardiac;



Intradiscal; Intravascular; Intravenous; Periarticular


Iodoxamic Acid
Intravenous


Iofetamine Hydrochloride
Intravenous


Irish Moss Extract
Topical


Isobutane
Topical


Isoceteth-20
Topical


Isoleucine
Infusion (IV)


Isooctyl Acrylate
Topical


Isopropyl Alcohol
Intravenous; Topical


Isopropyl Isostearate
Topical


Isopropyl Myristate
Auricular (Otic); Topical; Transdermal; Vaginal


Isopropyl Myristate-Myristyl Alcohol
Topical


Isopropyl Palmitate
Topical; Transdermal


Isopropyl Stearate
Topical


Isostearic Acid
Topical


Isostearyl Alcohol
Topical


Isotonic Sodium Chloride Solution
Epidural; Intratracheal; Intravenous; Infusion (IV)


Jelene
Ophthalmic; Topical


Kaolin
Topical


Kathon Cg
Topical


Kathon Cg II
Topical


Lactate
Topical


Lactic Acid
Infiltration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Subcutaneous (SC);



Intracardiac; Intravenous; Nerve Block; Topical;



Vaginal


Lactic Acid, Dl-
Intramuscular (IM); Infusion (IV); Intravesou;



Topical; Vaginal


Lactic Acid, L-
Intravenous; Subcutanous


Lactobionic Acid
Intravenous; Infusion (IV)


Lactose
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inhalation; Intracavitary; Intravenous; Rectal;



Transdermal; Vaginal


Lactose Monohydrate
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intracavitary; Intravenous; Respiratory



(Inhalation); Vaginal


Lactose, Hydrous
Intramuscular (IM); Infusion (IV); Intravenous;



Vaginal


Laneth
Topical


Lanolin
Ophthalmic; Rectal; Topical; Vaginal


Lanolin Alcohol-Mineral Oil
Topical


Lanolin Alcohols
Ophthalmic; Topical


Lanolin Anhydrous
Ophthalmic; Topical; Transdermal; Vaginal


Lanolin Cholesterols
Topical


Lanolin Nonionic Derivatives
Ophthalmic


Lanolin, Ethoxylated
Topical


Lanolin, Hydrogenated
Topical


Lauralkonium Chloride
Ophthalmic


Lauramine Oxide
Topical


Laurdimonium Hydrolyzed Animal Collagen
Topical


Laureth Sulfate
Topical


Laureth-2
Topical


Laureth-23
Topical


Laureth-4
Topical


Lauric Diethanolamide
Topical


Lauric Myristic Diethanolamide
Topical


Lauroyl Sarcosine
Ophthalmic


Lauryl Lactate
Transdermal


Lauryl Sulfate
Topical



Lavandula
Angustifolia Flowering Top

Topical


Lecithin
Inhalation; Intramuscular; Rectal; Topical;



Transdermal; Vaginal


Lecithin Unbleached
Topical


Lecithin, Egg
Intravenous


Lecithin, Hydrogenated
Auricular (Otic)


Lecithin, Hydrogenated Soy
Inhalation; Intravenous


Lecithin, Soybean
Inhalation; Vaginal


Lemon Oil
Topical


Leucine
Infusion (IV)


Levulinic Acid
Transdermal


Lidofenin
Intravenous


Light Mineral Oil
Ophthalmic; Rectal; Topical; Vaginal; Transdermal


Light Mineral Oil (85 Ssu)
Topical


Limonene, (+/−)-
Topical


Lipocol Sc-15
Topical


Lysine
Intramuscular (IM); Infusion (IV)


Lysine Acetate
Infusion (IV)


Lysine Monohydrate
Respiratory (Inhalation)


Magnesium Aluminum Silicate
Rectal; Topical; Vaginal


Magnesium Aluminum Silicate Hydrate
Rectal; Topical; Vaginal


Magnesium Chloride
Intramuscular; Intraocular; Intraperitoneal;



Intravitreal; Infusion (IV); Ophthalmic;



Subcutaneous


Magnesium Nitrate
Topical


Magnesium Stearate
Implantation; Intravitreal; Subcutaneous; Topical;



Transmucosal; Vaginal


Maleic Acid
Intramuscular; Infusion (IV)


Mannitol
Intramuscular (IM); Infusion (IV); Subcutanous



(SC); Intravenous; Ophthalmic; Parenteral;



Respiratory (Inhalation); Submucosal; Topical;



Transdermal


Maprofix
Topical


Mebrofenin
Intravenous


Medical Adhesive Modified S-15
Transdermal


Medical Antiform A-F Emulsion
Topical


Medronate Disodium
Intravenous


Medronic Acid
Intravenous


Meglumine
Intra-arterial; Intra-articular; Intracardiac;



Intradiscal; Intramuscular; Intrauterine;



Intravascular; Intravenous; Infusion (IV);



Periarticular; Ureteral; Urethral


Menthol
Detanl; Inhalation; Topical


Metacresol
Intramuscular (IM); Infusion (IV); Subcutanous



(SC); Intradermal


Metaphosphoric Acid
Infusion (IV)


Methanesulfonic Acid
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC)


Methionine
Intramuscular; Intrathecal; Intravenous; Infusion



(IV); Subcutaneous


Methyl Alcohol
Transdermal


Methyl Gluceth-10
Topical


Methyl Gluceth-20
Topical


Methyl Gluceth-20 Sesquistearate
Topical


Methyl Glucose Sesquistearate
Topical


Methyl Laurate
Transdermal


Methyl Pyrrolidone
Periodontal; Subcutaneous


Methyl Salicylate
Topical


Methyl Stearate
Topical; Vaginal


Methylboronic Acid
Intravenous


Methylcellulose (4000 Mpa · S)
Ophthalmic


Methylcelluloses
Intra-articular; Intralesional; Intramuscular;



Intrasynovial; Nasal; Ophthalmic; Soft tissue;



Topical


Methylchloroisothiazolinone
Topical


Methylene Blue
Intravenous


Methylisothiazolinone
Topical


Methylparaben
Infiltration (AN); Auricular (Otic); Caudal Block;



Epidural; Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Inhalation; Intra-arterial; Intra-



articular; Intrabursal; Intradermal; Intralesional;



Intrasynovial; Intravenous; Iontophoresis; Irrigation;



Nasal; Nerve Block; Ophthalmic; Peridural; Rectal;



Soft tissue; Topical; Ureteral; Urethral; Vaginal


Microcrystalline Wax
Topical; Vaginal


Mineral Oil
Auricular (Otic); Dental; Ophthalmic; Topical;



Transdermal; Vaginal


Mono And Diglyceride
Topical


Monostearyl Citrate
Topical


Monothioglycerol
Infiltration (AN); Caudal Block; Epidural;



Intramuscular (IM); Infusion (IV); Subcutanous



(SC); Intravenous; Nerve Block


Multisterol Extract
Topical


Myristyl Alcohol
Topical


Myristyl Lactate
Topical


Myristyl-.Gamma.-Picolinium Chloride
Intra-articular; Intralesional; Intramuscular;



Intrasynovial; Soft tissue


N-(Carbamoyl-Methoxy Peg-40)-1,2-
Intravenous


Distearoyl-Cephalin Sodium



N,N-Dimethylacetamide
Intramuscular; Intravenous; Infusion (IV)


Niacinamide
Intramuscular; Infusion (IV); Intra-articular;



Intralesional; Intrasynovial; Topical


Nioxime
Intravenous


Nitric Acid
Inhalation; Infusion (IV); Ophthalmic; Topical;


Vaginal



Nitrogen
Infiltration (AN); Caudal Block; Dental; Epidural;



Intramuscular; Infusion (IV); Subcutanous (SC);



Inhalation; Intra-arterial; Intracavitary; Intramuscular



(IM); Intrathecal; Intratumor; Intravascular;



Intravenous; Intravesical; Irrigation; Nasal; Nerve



Block; Ophthalmic; Parenteral; Submucosal;



Topical; Transdermal


Nonoxynol Iodine
Topical


Nonoxynol-15
Topical


Nonoxynol-9
Ophthalmic; Topical


Norflurane
Inhalation; Nasal; Respiratory (Inhalation)


Oatmeal
Topical


Octadecene-1/MaleicAcid Copolymer
Topical


Octanoic Acid
Intravenous


Octisalate
Transdermal


Octoxynol-1
Topical


Octoxynol-40
Ophthalmic


Octoxynol-9
Topical


Octyldodecanol
Topical; Transdermal; Vaginal


Octylphenol Polymethylene
Ophthalmic


Oleic Acid
Inhalation; Nasal; Respiratory (Inhalation);



Topical; Transdermal


Oleth-10/Oleth-5
Topical


Oleth-2
Topical


Oleth-20
Topical


Oleyl Alcohol
Topical; Transdermal


Oleyl Oleate
Topical; Transdermal


Olive Oil
Topical


Oxidronate Disodium
Intravenous


Oxyquinoline
Intravenous


Palm Kernel Oil
Rectal


Palmitamine Oxide
Topical


Parabens
Topical


Paraffin
Rectal; Topical


Paraffin, White Soft
Topical


Parfum Creme 45/3
Topical


Peanut Oil
Intramuscular; Intratracheal; Topical; Vaginal


Peanut Oil, Refined
Topical


Pectin
Dental; Topical


Peg 6-32 Stearate/Glycol Stearate
Topical; Vaginal


Peg Vegetable Oil
Intramuscular (IM); Infusion (IV);



Subcutaneous (SC)


Peg-100 Stearate
Topical; Vaginal


Peg-12 Glyceryl Laurate
Topical


Peg-120 Glyceryl Stearate
Topical; Vaginal


Peg-120 Methyl Glucose Dioleate
Topical


Peg-15 Cocamine
Topical


Peg-150 Distearate
Topical


Peg-2 Stearate
Topical; Vaginal


Peg-20 Sorbitan Isostearate
Intramuscular


Peg-22 Methyl Ether/Dodecyl Glycol
Topical


Copolymer



Peg-25 Propylene Glycol Stearate
Topical


Peg-4 Dilaurate
Topical


Peg-4 Laurate
Topical


Peg-40 Castor Oil
Intramuscular (IM); Subcutaneous (SC);



Infusion (IV)


Peg-40 Sorbitan Diisostearate
Dental


Peg-45/Dodecyl Glycol Copolymer
Topical


Peg-5 Oleate
Topical; Vaginal


Peg-50 Stearate
Topical


Peg-54 Hydrogenated Castor Oil
Topical


Peg-6 Isostearate
Topical


Peg-60 Castor Oil
Infusion (IV)


Peg-60 Hydrogenated Castor Oil
Topical


Peg-7 Methyl Ether
Topical


Peg-75 Lanolin
Topical


Peg-8 Laurate
Topical


Peg-8 Stearate
Topical


Pegoxol 7 Stearate
Topical; Vaginal


Pentadecalactone
Transdermal


Pentaerythritol Cocoate
Topical


Pentasodium Pentetate
Intravenous


Pentetate Calcium Trisodium
Intrathecal; Intravenous; Infusion (IV)


Pentetic Acid
Intrathecal; Intravenous


Peppermint Oil
Dental; Topical


Perflutren
Intravenous


Perfume 25677
Topical


Perfume Bouquet
Topical


Perfume E-1991
Topical


Perfume Gd 5604
Topical


Perfume Tana 90/42 Scba
Topical


Perfume W-1952-1
Topical


Petrolatum
Auricular (Otic); Ophthalmic; Topical


Petrolatum, White
Auricular (Otic); Dental; Nasal; Ophthalmic; Rectal;



Topical; Transdermal; Vaginal


Petroleum Distillates
Topical


Phenol
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intra-articular; Intradermal; Intralesional;



Intrasynovial; Intravenous; Soft tissue


Phenol, Liquefied
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intravenous


Phenonip
Iontophoresis; Topical


Phenoxyethanol
Topical


Phenylalanine
Infusion (IV)


Phenylethyl Alcohol
Auricular (Otic); Nasal; Ophthalmic


Phenylmercuric Acetate
Ophthalmic; Topical; Vaginal


Phenylmercuric Nitrate
Intramuscular; Ophthalmic


Phosphatidyl Glycerol, Egg
Intravenous


Phospholipid
Infusion (IV)


Phospholipid, Egg
Intravenous; Infusion (IV)


Phospholipon 90 g
Vagianl


Phosphoric Acid
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Infiltration; Intra-articular; Intralesional;



Intravenous; Ophthalmic; Soft tissue; Topical;



Vaginal


Pine Needle Oil (PinusSylvestris)
Topical


Piperazine Hexahydrate
Vagianl


Plastibase-50w
Dental; Topical


Polacrilin
Iontophoresis; Transdermal


Polidronium Chloride
Ophthalmic; Topical


Poloxamer 124
Topical


Poloxamer 181
Topical


Poloxamer 182
Topical


Poloxamer 188
Intravenous; Ophthalmic; Peridontal; Subcutaneous;



Topical


Poloxamer 237
Topical


Poloxamer 407
Ophthalmic; Peridontal; Topical


Poly(Bis(P-Carboxyphenoxy)Propane
Implantation


Anhydride):Sebacic Acid



Poly(Dimethylsiloxane/Methylvinylsiloxane/
Vagianl


Methylhydrogensiloxane) Dimethylvinyl Or



Dimethylhydroxy Or Trimethyl Endblocked



Poly(Dl-Lactic-Co-Glycolic Acid), (50:50
N/A


Poly(Dl-Lactic-Co-Glycolic Acid), Ethyl
N/A


Ester Terminated, (50:50



Polyacrylic Acid (250000 Mw)
Transdermal


Polybutene (1400 Mw)
Transdermal


Polycarbophil
Ophthalmic; Topical; Vaginal


Polyester
Transdermal; Vaginal


Polyester Polyamine Copolymer
Transdermal


Polyester Rayon
Transdermal


Polyethylene Glycol 1000
Rectal; Respiratory (Inhalation); Topical; Vaginal


Polyethylene Glycol 1450
Topical; Urethral


Polyethylene Glycol 1500
Topical


Polyethylene Glycol 1540
Dental; Rectal; Topical


Polyethylene Glycol 200
Intramuscular; Topical


Polyethylene Glycol 300
Intramuscular (IM); Infusion (IV); Intravenous;



Ophthalmic; Topical


Polyethylene Glycol 300-1600
Topical


Polyethylene Glycol 3350
Intra-articular; Intralesional; Intramuscular;



Intrasynovial; Nasal; Rectal; Soft tissue;



Subcutaneous; Topical; Vaginal


Polyethylene Glycol 400
Intramuscular (IM); Infusion (IV); Intravenous;



Nasal; Ophthalmic; Rectal; Topical; Vaginal


Polyethylene Glycol 4000
Intra-articular; Intralesional; Intramuscular;



Intrasynovial; Rectal; Soft tissue; Topical; Vaginal


Polyethylene Glycol 540
Topical


Polyethylene Glycol 600
Intravenous; Topical


Polyethylene Glycol 6000
Rectal; Topical; Vaginal


Polyethylene Glycol 8000
Ophthalmic; Rectal; Topical; Vaginal


Polyethylene Glycol 900
Topical


Polyethylene High Density Containing
Intrauterine


Ferric Oxide Black (<1%)



Polyethylene Low Density Containing
Initrauterine


Barium Sulfate (20-24%)



Polyethylene T
Initrauterine


Polyethylene Terephthalates
Transdermal


Polyglactin
Dental; Implantation; Intramuscular; Subcutaneous


Polyglyceryl-3 Oleate
Vagianl


Polyglyceryl-4 Oleate
Vagianl


Polyhydroxyethyl Methacrylate
Topical


Polyisobutylene
Topical; Transdermal


Polyisobutylene (1100000 Mw)
Topical; Transdermal


Polyisobutylene (35000 Mw)
Transdermal


Polyisobutylene 178-236
Transdermal


Polyisobutylene 241-294
Transdermal


Polyisobutylene 35-39
Transdermal


Polyisobutylene Low Molecular Weight
Transdermal


Polyisobutylene Medium Molecular Weight
Transdermal


Polyisobutylene/Polybutene Adhesive
Transdermal


Polylactide
Intramuscular; Peridontal


Polyols
Dental


Polyoxyethylene-Polyoxypropylene 1800
Ophthalmic; Topical


Polyoxyethylene Alcohols
Topical


Polyoxyethylene Fatty Acid Esters
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Topical


Polyoxyethylene Propylene
Topical


Polyoxyl 20 Cetostearyl Ether
Topical


Polyoxyl 35 Castor Oil
Intravesical; Infusion (IV); Ophthalmic


Polyoxyl 40 Hydrogenated Castor Oil
Dental; Ophthalmic; Topical


Polyoxyl 40 Stearate
Auricular (Otic); Dental; Ophthalmic; Topical


Polyoxyl 400 Stearate
Nasal; Topical


Polyoxyl 6 And Polyoxyl 32 Palmitostearate
Topical


Polyoxyl Distearate
Topical


Polyoxyl Glyceryl Stearate
Topical


Polyoxyl Lanolin
Topical


Polyoxyl Palmitate
Vagianl


Polyoxyl Stearate
Auricular (Otic); Topical


Polypropylene
Intrauterine; Topical; Transdermal


Polypropylene Glycol
Intramuscular (IM); Infusion (IV); Ophthalmic


Polyquaternium-10
Topical


Polyquaternium-7 (70/30
N/A


Acrylamide/Dadmac



Polysiloxane
Intravenous


Polysorbate 20
Auricular (Otic); Intramuscular (IM); Subcutaneous



(SC); Intravenous; Infusion (IV); Nasal; Ophthalmic;



Topical; Vaginal


Polysorbate 40
Intramuscular (IM); Infusion (IV); Topical


Polysorbate 60
Ophthalmic; Rectal; Topical; Vaginal


Polysorbate 65
Topical


Polysorbate 80
Auricular (Otic); Intra-articular; Intrabursal;



Intradermal; Intralesional; Intramuscular;



Intrasynovial; Intravenous; Infusion (IV); Nasal;



Ophthalmic; Rectal; Soft tissue; Subcutaneous;



Topical; Vaginal


Polyurethane
Vagianl


Polyvinyl Acetate
Transdermal


Polyvinyl Alcohol
Auricular (Otic); Intramuscular; Intraocular;



Intravitreal; Iontophoresis; Ophthalmic; Topical;



Transdermal


Polyvinyl Chloride
Transdermal


Polyvinyl Chloride-Polyvinyl Acetate
Transdermal


Copolymer



Polyvinylpyridine
Transdermal


Poppy Seed Oil
Intralymphatic; Intrauterine


Potash
Topical


Potassium Acetate
Ophthalmic; Rectal


Potassium Alum
Vagianl


Potassium Bicarbonate
Transmucosal


Potassium Bisulfite
Intravenous


Potassium Chloride
Infiltration (AN); Caudal Block; Epidural;



Intraocular; Intravenous; Intravitreal; Infusion (IV);



Nerve Block; Ophthalmic


Potassium Citrate
Topical


Potassium Hydroxide
Intravascular; Intravenous; Infusion (IV); Topical;



Vaginal


Potassium Metabisulfite
Infiltration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Nerve Block; Rectal


Potassium Phosphate, Dibasic
Intra-articular; Intramuscular; Intravenous; Infusion



(IV); Subcutaneous


Potassium Phosphate, Monobasic
Infiltration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Intra-articular; Intramuterine;



Intravenous; Intravesical; Nasal; Nerve Block;



Ophthalmic; Subcutaneous


Potassium Soap
Topical


Potassium Sorbate
Nasal; Ophthalmic; Topical


Povidone Acrylate Copolymer
Topical


Povidone Hydrogel
Iontophoresis; Topical


Povidone K17
Subcutaneous


Povidone K25
Respiratory (Inhalation)


Povidone K29/32
Ophthalmic; Transdermal; Vaginal


Povidone K30
Ophthalmic


Povidone K90
Ophthalmic; Topical


Povidone K90f
Auricular (Otic)


Povidone/Eicosene Copolymer
Topical


Povidones
Auricular (Otic); Intramuscular; Intravenous;



Infusion (IV); Ophthalmic; Subcutaneous; Topical;



Transdermal; Vaginal


Ppg-12/Smdi Copolymer
Topical


Ppg-15 Stearyl Ether
Topical


Ppg-20 Methyl Glucose Ether Distearate
Topical


Ppg-26 Oleate
Topical


Product Wat
Topical


Proline
Infusion (IV)


Promulgen D
Topical; Vaginal


Promulgen G
Topical


Propane
Topical


Propellant A-46
Topical


Propyl Gallate
Topical; Intramuscular


Propylene Carbonate
Topical


Propylene Glycol
Auricular (Otic); Dental; Extracorporeal;



Intramuscular (IM); Infusion (IV); Inhalation;



Intravenous; Nasal; Ophthalmic; Photopheresis;



Rectal; Subcutaneous; Topical; Transdermal;



Vaginal


Propylene Glycol Diacetate
Auricular (Otic); Topical


Propylene Glycol Dicaprylate
Topical


Propylene Glycol Monolaurate
Transdermal


Propylene Glycol Monopalmitostearate
Topical; Vaginal


Propylene Glycol Palmitostearate
Topical


Propylene Glycol Ricinoleate
Topical


Propylene Glycol/Diazolidinyl
Topical


Urea/Methylparaben/Propylparben



Propylparaben
Inflitration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Subcutaneous (SC); Inhalation;



Intra-arterial; Intra-articular; Intrabursal;



Intralesional; Intrasynovial; Intravenous; Nasal;



Nerve Block; Ophthalmic; Rectal; Soft tissue;



Topical; Ureteral; Urethral; Vaginal


Protamine Sulfate
Intramuscular (IM); Subcutaneous (SC); Intradermal


Protein Hydrolysate
Topical


Pvm/Ma Copolymer
Dental


Quaternium-15
Topical


Quaternium-15 Cis-Form
Topical; Vaginal


Quaternium-52
Topical


Ra-2397
Transdermal


Ra-3011
Transdermal


Saccharin
Inhalation; Topical


Saccharin Sodium
Dental; Intramuscular (IM); Infusion (IV);



Inhalation; Intravenous; Rectal; Topical


Saccharin Sodium Anhydrous
Intramuscular (IM); Infusion (IV); Rectal


Safflower Oil
Topical


Sd Alcohol 3a
Topical


Sd Alcohol 40
Topical


Sd Alcohol 40-2
Topical


Sd Alcohol 40b
Topical


Sepineo P 600
Topical


Serine
Infusion (IV)


Sesame Oil
Intramuscular (IM); Subcutaneous (SC)


Shea Butter
Topical


Silastic Brand Medical Grade Tubing
Implantation


Silastic Medical Adhesive, Silicone Type A
Implantation


Silica, Dental
Dental


Silicon
Topical; Transdermal


Silicon Dioxide
Dental; Topical; Vaginal


Silicon Dioxide, Colloidal
Endocervical; Rectal; Respiratory (Inhalation);



Transdermal; Vaginal


Silicone
Intramuscular (IM); Infusion (IV); Intrauterine;



Topical; Transdermal; Vaginal


Silicone Adhesive 4102
Percutaneous; Transdermal


Silicone Adhesive 4502
Transdermal


Silicone Adhesive Bio-Psa Q7-4201
Transdermal; Topical


Silicone Adhesive Bio-Psa Q7-4301
Transdermal; Topical


Silicone Emulsion
Topical


Silicone/Polyester Film Strip
Transdermal


Simethicone
Intramuscular (IM); Infusion (IV); Rectal; Topical


Simethicone Emulsion
Topical


Sipon Ls 20 np
Topical


Soda Ash
Ophthalmic


Sodium Acetate
Auricular (Otic); Extracorporeal; Intramuscular



(IM); Infusion (IV); Subcutaneous (SC); Interstitial;



Intra-articular; Intracavitary; Intradermal;



Intralesional; Intraocular; Intraperitoneal;



Intrapleural; Intrasynovial; Intravenous; Intravitreal;



Nasal; Ophthalmic; Parenteral; Phtotpheresis; Soft



tissue; Submucosal; Topical


Sodium Acetate Anhydrous
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intravenous; Topical


Sodium Alkyl Sulfate
Topical


Sodium Ascorbate
Intravenous


Sodium Benzoate
Dental; Intramuscular (IM); Infusion (IV);



Intravenous; Rectal; Topical


Sodium Bicarbonate
Intramuscular (IM); Infusion (IV); Intraperitoneal;



Intrathecal; Intratracheal; Intravenous; Intravitreal;



Subcutaneous; Vaginal


Sodium Bisulfate
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inhalation; Ophthalmic


Sodium Bisulfite
Inflitration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Subcutaneous (SC); Epidural;



Inhalation; Intra-arterial; Intra-articular; Intrabursal;



Intracardiac; Intradermal; Intradiscal; Intralesional;



Intraperitoneal; Intrasynovial; Iontophoresis;



Irrigation; Intravenous; Nerve Block; Ophthalmic;



soft tissue; Topical


Sodium Borate
Auricular (Otic); Ophthalmic; Topical


Sodium Borate Decahydrate
Ophthalmic


Sodium Carbonate
Infiltration (AN); Intramuscular (IM); Infusion (IV);



Intra-arterial; Intraperitoneal; Intrapleural;



Intratumor; Intravascular; Intravenous; Intravitreal;



Nerve Block; Ophthalmic; Rectal


Sodium Carbonate Decahydrate
Intravenous


Sodium Carbonate Monohydrate
Intra-arterial; Intracardiac; Intravenous; Ophthalmic


Sodium Cetostearyl Sulfate
Topical


Sodium Chlorate
Infiltration (AN); Intramuscular; Infusion (IV);



Nerve Block


Sodium Chloride
Infiltration; Inhalation; Intra-arterial; Intra-articular;



Intrabursal; Intracardiac; Intracaudal; Intracavitary;



Intradermal; Intralesional; Intramuscular;



Intraocular; Intraperitoneal; Intrapleural;



Intrasynovial; Intrathecal; Intratracheal; Intratumor;



Intravascular; Intravenous; Intravenous bolus;



Intravesical; Intravitreal; Iontophoresis; Infusion



(IV); Intramuscular (IM); Subcutaneous (SC); Nasal;



Nerve Block; Ophthalmic; Parenteral; Peridural;



Photopheresis; Rectal; Respiratory (Inhalation); Soft



tissue; Subarachnoid; Submucosal; Topical;



Transermal


Sodium Chloride Injection
Intramuscular


Sodium Chloride Injection, Bacteriostatic
Intraveous


Sodium Cholesteryl Sulfate
Infusion (IV)


Sodium Citrate
Infiltration (AN); Auricular (Otic); Epidural;



Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inhalation; Intra-arterial; Intra-articular;



Intracardiac; Intravacitary; Intralesional; Intraocular;



Iintraperitoneal; Intrapleural; Intrasynovial;



Intrathecal; Intratracheal; Intrauterine; Intravasular;



Intravenous; Iontophoresis; Irrigation; Nasal; Nerve



Block; Ophthalmic; Rectal; Respiratory (Inhalation);



Soft tissue; Topical; Transdermal; Ureteral; Vaginal


Sodium Cocoyl Sarcosinate
Topical


Sodium Desoxycholate
Infusion (IV)


Sodium Dithionite
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Intravenous


Sodium Dodecylbenzenesulfonate
Topical


Sodium Formaldehyde Sulfoxylate
Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Topical


Sodium Gluconate
Intravenous; Infusion (IV)


Sodium Hydroxide
Intrathecal (AN, CNBLK); Inflitration (AN);



Sympathetic (AN, NBLK); Auricular (Otic); Caudal



Block; Dental; Epidural; Extracorporeal;



Intramuscular (IM); Infusion (IV); Subcutaneous



(SC); Inflitration; Inhalationi; Interstitial; Intra-



amniotic; Intra-arterial; Intra-articular; Intrabursal;



Intracardiac; Intracaudl; Intracavitary; Intradermal;



Intradiscal; Intralesional; Intraocular; Intraperioneal;



Intrapleural; Intraspinal; Intrasynovial; Intrathecal;



Intratracheal; Intratumor; Intrauterine; Intravascular;



Intravenous; Intravitreal; Iontophoresis; Irrigation;



Nasal; Nerve Block; Ophthalmic; Parenteral;



Perfusion, cardiac; Peridural; Perineural;



Photopheresis; Rectal; Respiratory (Inhalation);



Retrobular; Soft tissue; Spinal; Subarachnoid;



Subconjunctival; Submucosal; Topical; Transdermal;



Ureteral; Urethral; Vaginal


Sodium Hypochlorite
Infusion (IV)


Sodium Iodide
Intravenous; Topical


Sodium Lactate
Infiltration (AN); Caudal Black; Intramuscular (IM);



Infusion (IV); Subcutaneous (SC); Intracardiac;



Intraperitoneal; Intravenous; Nerve Block; Topical


Sodium Lactate, L-
Epidural; Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intracardiac; Nerve Block


Sodium Laureth-2 Sulfate
Topical


Sodium Laureth-3 Sulfate
Topical


Sodium Laureth-5 Sulfate
Topical


Sodium Lauroyl Sarcosinate
Topical


Sodium Lauryl Sulfate
Dental; Respiratory (Inhalation); Topical; Vaginal


Sodium Lauryl Sulfoacetate
Topical


Sodium Metabisulfite
Intrathecal (AN, CNBLK); Infiltration (AN); Cardal



Block; Dental; Epidural; Intramuscular (IM);



Infusion (IV); Subcutaneous (SC); Inflitration;



Inhalation; Intra-articular; Initrabursal; Intracardiac;



Intramuscular; Intraperitoneal; Intravenous;



Iontophoresis; Nerve Block; Ophthalmic; Peridural;



Rectal; Submucosal; Topical; Vaginal


Sodium Nitrate
Ophthalmic


Sodium Phosphate
Intramuscular (IM); Infusion (IV); Intra-articular;



Intrabursal; Intradermal; Intralesional; Nasal; Nerve



Block; Ophthalmic; Soft tissue; Subcutanesou;



Topical


Sodium Phosphate Dihydrate
Intramuscular (IM); Subcutaneous (SC); Ophthalmic


Sodium Phosphate, Dibasic
Intramuscular (IM); Infusion (IV); Intradermal;



Intralesional; Intrasynovial; Intravenous; Nasal;



Ophthalmic; Soft tissue; Topical; Subcutaneous (SC)


Sodium Phosphate, Dibasic, Anhydrous
Auricular (Otic); Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intra-articular; Intralesional;



Intramuscular; Intravenous; Intravesical; Nasal;



Ophthalmic; Topical; Vaginal


Sodium Phosphate, Dibasic, Dihydrate
Intramuscular (IM); Infusion (IV); Intravenous;



Nasal; Ophthalmic; Subcutaneous; Topical


Sodium Phosphate, Dibasic, Dodecahydrate
Nasal


Sodium Phosphate, Dibasic, Heptahydrate
Infiltration (AN); Auricular (Otic); Intramuscular



(IM); Infusion (IV); Subcutaneous (SC); Iintra-



articular; Intrabursal; Intradermal; Intralesional;



Intramuscular; Intrasynovial; Intravenous;



Intravitreal; Nasal; Nerve Block; Ophthalmic; Soft



tissue; Topical; Urethral


Sodium Phosphate, Monobasic
Intramuscular (IM); Infusion (IV); Intralesional;



Intrasynovial; Iontophoresis; Ophthalmic; Soft



tissue; Subcutaneous; Topical


Sodium Phosphate, Monobasic, Anhydrous
Auricular (Otic); Intramuscular (IM); Infusion (IV);



Intrabursal; Intradermal; Intralesional; Intrasynovial;



Intravascular; Intravenous; Intravesical; Nasal;



Ophthalmic; Soft tissue; Subcutaneous; Topical;



Vaginal


Sodium Phosphate, Monobasic, Dihydrate
Intravenous; Infusion (IV); Nasal; Ophthalmic;



Subcutaneous; Topical


Sodium Phosphate, Monobasic,
Intramuscular (IM); Infusion (IV); Intra-articular;


Monohydrate
Intralesional; Intravascular; Intravenous; Intravitreal;



Ophthalmic; Subcutaneous; Topical


Sodium Polyacrylate (2500000 Mw)
Topical


Sodium Pyrophosphate
Intravenous


Sodium Pyrrolidone Carboxylate
Topical


Sodium Starch Glycolate
Transmucosal


Sodium Succinate Hexahydrate
Intravenous


Sodium Sulfate
Intramuscular (IM); Infusion (IV); Ophthalmic


Sodium Sulfate Anhydrous
Inhalation; Iintramuscular; Ophthalmic


Sodium Sulfate Decahydrate
Ophthalmic


Sodium Sulfite
Auricular (Otic); Epidural; Intramuscular (IM);



Infusion (IV); Inhalation; Intra-articular;



Intralesional; Intravenous; Ophthalmic; Soft tissue;



Subcutaneous; Topical


Sodium Sulfosuccinated Undecyclenic
Topical


Monoalkylolamide



Sodium Tartrate
Intramuscual (IM); Infusion (IV); Intravenous


Sodium Thioglycolate
Subcutaneous


Sodium Thiomalate
Intramuscular (IM); Infusion (IV)


Sodium Thiosulfate
Intravenous; Ophthalmic; Topical


Sodium Thiosulfate Anhydrous
Intravenous


Sodium Trimetaphosphate
Intravenous


Sodium Xylenesulfonate
Topical


Somay 44
Topical


Sorbic Acid
Ophthalmic; Topical; Vaginal


Sorbitan
Topical


Sorbitan Isostearate
Topical


Sorbitan Monolaurate
Ophthalmic; Topical


Sorbitan Monooleate
Rectal; Topical; Transdermal


Sorbitan Monopalmitate
Intramuscular; Topical


Sorbitan Monostearate
Topical; Vaginal


Sorbitan Sesquioleate
Rectal; Topical


Sorbitan Trioleate
Inhalation; Nasal


Sorbitan Tristearate
Topical


Sorbitol
Dental; Intra-articular; Intralesional; Intramuscular;



Intrasynovial; Intravenous; Infusion (IV); Nasal;



Ophthalmic; Rectal; Topical; Vaginal


Sorbitol Solution
Intra-articular; Intralesional; Intramuscular;



Intravenous; Infusion (IV); Nasal; Ophthalmic;


Rectal; Topical; Vaginal



Soybean Flour
Topical


Soybean Oil
Intraveous; Infusion (IV); Topical


Spearmint Oil
Topical


Spermaceti
Topical; Vaginal


Squalane
Topical


Stabilized Oxychloro Complex
Ophthalmic


Stannous 2-Ethylhexanoate
Vagianl


Stannous Chloride
Intravenous; Infusion (IV)


Stannous Chloride Anhydrous
Intravenous; Infusion (IV)


Stannous Fluoride
Intravenous


Stannous Tartrate
Intravenous


Starch
Intramuscular; Rectal; Topical; Vaginal


Starch 1500, Pregelatinized
Vagianl


Starch, Corn
Vagianl


Stearalkonium Chloride
Topical


Stearalkonium Hectorite/Propylene
Transdermal


Carbonate



Stearamidoethyl Diethylamine
Topical; Vaginal


Steareth-10
Rectal; Topical


Steareth-100
Topical


Steareth-2
Topical


Steareth-20
Topical


Steareth-21
Topical


Steareth-40
Topical; Rectal


Stearic Acid
Implantation; Subcutaneous; Topical; Vaginal


Stearic Diethanolamide
Topical


Stearoxytrimethylsilane
Topical


Steartrimonium Hydrolyzed Animal
Topical


Collagen



Stearyl Alcohol
Topical; Vaginal


Sterile Water For Inhalation
Infusion (IV)


Styrene/Isoprene/Styrene Block Copolymer
Topical


Succimer
Intravenous


Succinic Acid
Intramuscular (IM); Infusion (IV); Intravenous


Sucralose
Nasa


Sucrose
Intramuscular; Intravenous; Infusion (IV); Rectal;



Subcutaneous; Topical


Sucrose Distearate
Topical


Sucrose Polyesters
Topical


Sulfacetamide Sodium
Topical


Sulfobutylether.Beta.-Cyclodextrin
Intramuscular; Intravenous; Infusion (IV)


Sulfur Dioxide
Infusion (IV)


Sulfuric Acid
Auricular (Otic); Epidural; Intramuscular (IM);



Infusion (IV); Inhalation; Intraperitoneal;



Intravenous; Irrigation; Nasal; Ophthalmic;



Respiratory (Inhalation); Topical


Sulfurous Acid
Intramuscular


Surfactol Qs
Topical


Tagatose, D-
Rectal


Talc
Topical


Tall Oil
Topical


Tallow Glycerides
Topical


Tartaric Acid
Intramuscular; Intravenous; Infusion (IV); Topical


Tartaric Acid, Dl-
Intramuscular (IM); Infusion (IV); Intravenous;



Rectal; Vaginal


Tenox
Topical


Tenox-2
Topical


Tert-Butyl Alcohol
Intravenous; Infusion (IV); Topical


Tert-Butyl Hydroperoxide
Topical


Tert-Butylhydroquinone
Vagianl


Tetrakis(2-
Intravenous


Methoxyisobutylisocyanide)Copper(I)



Tetrafluoroborate



Tetrapropyl Orthosilicate
Vagianl


Tetrofosmin
Infusion (IV)


Theophylline
Intravenous; Infusion (IV)


Thimerosal
Auricular (Otic); Intramuscular (IM); Infusion (IV);



Subcutaneous (SC); Intravenous; Ophthalmic;



Topical


Threonine
Intravenous; Infusion (IV)


Thymol
Inhalation


Tin
Intravenous


Titanium Dioxide
Dental; Intrauterine; Ophthalmic; Respiratory



(Inhalation); Topical; Transdermal


Tocopherol
Topical


Tocophersolan
Ophthalmic; Topical


Triacetin
Endocervical; Transdermal


Tricaprylin
Epidural; Infiltration


Trichloromonofluoromethane
Inhalation; Nasal; Topical


Trideceth-10
Topical


Triethanolamine Lauryl Sulfate
Topical


Trifluoroacetic Acid
Infusion (IV)


Triglycerides, Medium Chain
Topical


Trihydroxystearin
Topical


Trilaneth-4 Phosphate
Topical


Trilaureth-4 Phosphate
Topical


Trisodium Citrate Dihydrate
Intramuscular (IM); Infusion (IV); Intravenous;



Intravitreal; Nasal; Ophthalmic; Topical


Trisodium Hedta
Topical


Triton 720
Ophthalmic


Triton X-200
Topical


Trolamine
Rectal; Topical; Transdermal; Vaginal


Tromantadine
Intramuscular; Intravenous


Tromethamine
Intramuscular (IM); Infusion (IV); Intra-arterial;



Intrathecal; Intratracheal; Intravasular; Intravenous;



Ophthalmic; Rectal; Respiratory (Inhalation);



Subcutaneous; Topical; Transdermal; Urethral


Tryptophan
Infusion (IV)


Tyloxapol
Ophthalmic; Topical


Tyrosine
Infusion (IV)


Undecylenic Acid
Topical


Union 76 Amsco-Res 6038
Transdermal


Urea
Intramuscular; Vaginal


Valine
Infusion (IV)


Vegetable Oil
Topical


Vegetable Oil Glyceride, Hydrogenated
Rectal


Vegetable Oil, Hydrogenated
Rectal; Topical; Vaginal


Versetamide
Intravenous


Viscarin
Topical


Viscose/Cotton
Transdermal


Vitamin E
Topical


Wax, Emulsifying
Rectal; Topical


Wecobee Fs
Topical; Vaginal


White Ceresin Wax
Vagianl


White Wax
Rectal; Topical; Vaginal


Xanthan Gum
Rectal; Topical


Zinc
Subcutaneous


Zinc Acetate
Subcutaneous, Topical


Zinc Carbonate
Subcutaneous


Zinc Chloride
Intramuscular (IM); Subcutaneous (SC); Intradermal;



Ophthalmic


Zinc Oxide
Intramuscular (IM); Subcutaneous (SC); Rectal;



Respiratory (Inhalation)









Delivery

The present disclosure encompasses the delivery of NAVs for any of therapeutic, pharmaceutical, diagnostic or imaging by any appropriate route taking into consideration likely advances in the sciences of drug delivery. Delivery may be naked or formulated.


Naked Delivery

The NAVs of the present invention may be delivered to a cell naked. As used herein in, “naked” refers to delivering NAVs free from agents which promote transfection. For example, the NAVs delivered to the cell may contain no modifications. The naked NAVs may be delivered to the cell using routes of administration known in the art and described herein.


Formulated Delivery

The NAVs of the present invention may be formulated, using the methods described herein. The formulations may contain polynucleotides which may be modified and/or unmodified. The formulations may further include, but are not limited to, cell penetration agents, a pharmaceutically acceptable carrier, a delivery agent, a bioerodible or biocompatible polymer, a solvent, and a sustained-release delivery depot. The formulated NAVs may be delivered to the cell using routes of administration known in the art and described herein.


The compositions may also be formulated for direct delivery to an organ or tissue in any of several ways in the art including, but not limited to, direct soaking or bathing, via a catheter, by gels, powder, ointments, creams, gels, lotions, and/or drops, by using substrates such as fabric or biodegradable materials coated or impregnated with the compositions, and the like.


Administration

The NAVs of the present invention may be administered by any route which results in a therapeutically effective outcome. These include, but are not limited to enteral (into the intestine), gastroenteral, epidural (into the dura matter), oral (by way of the mouth), transdermal, peridural, intracerebral (into the cerebrum), intracerebroventricular (into the cerebral ventricles), epicutaneous (application onto the skin), intradermal, (into the skin itself), subcutaneous (under the skin), nasal administration (through the nose), intravenous (into a vein), intravenous bolus, intravenous drip, intraarterial (into an artery), intramuscular (into a muscle), intracardiac (into the heart), intraosseous infusion (into the bone marrow), intrathecal (into the spinal canal), intraperitoneal. (infusion or injection into the peritoneum), intravesical infusion, intravitreal, (through the eye), intracavernous injection (into a pathologic cavity) intracavitary (into the base of the penis), intravaginal administration, intrauterine, extra-amniotic administration, transdermal (diffusion through the intact skin for systemic distribution), transmucosal (diffusion through a mucous membrane), transvaginal, insufflation (snorting), sublingual, sublabial, enema, eye drops (onto the conjunctiva), in ear drops, auricular (in or by way of the ear), buccal (directed toward the cheek), conjunctival, cutaneous, dental (to a tooth or teeth), electro-osmosis, endocervical, endosinusial, endotracheal, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra-amniotic, intra-articular, intrabiliary, intrabronchial, intrabursal, intracartilaginous (within a cartilage), intracaudal (within the cauda equine), intracisternal (within the cisterna magna cerebellomedularis), intracorneal (within the cornea), dental intracornal, intracoronary (within the coronary arteries), intracorporus cavernosum (within the dilatable spaces of the corporus cavernosa of the penis), intradiscal (within a disc), intraductal (within a duct of a gland), intraduodenal (within the duodenum), intradural (within or beneath the dura), intraepidermal (to the epidermis), intraesophageal (to the esophagus), intragastric (within the stomach), intragingival (within the gingivae), intraileal (within the distal portion of the small intestine), intralesional (within or introduced directly to a localized lesion), intraluminal (within a lumen of a tube), intralymphatic (within the lymph), intramedullary (within the marrow cavity of a bone), intrameningeal (within the meninges), intraocular (within the eye), intraovarian (within the ovary), intrapericardial (within the pericardium), intrapleural (within the pleura), intraprostatic (within the prostate gland), intrapulmonary (within the lungs or its bronchi), intrasinal (within the nasal or periorbital sinuses), intraspinal (within the vertebral column), intrasynovial (within the synovial cavity of a joint), intratendinous (within a tendon), intratesticular (within the testicle), intrathecal (within the cerebrospinal fluid at any level of the cerebrospinal axis), intrathoracic (within the thorax), intratubular (within the tubules of an organ), intratumor (within a tumor), intratympanic (within the aurus media), intravascular (within a vessel or vessels), intraventricular (within a ventricle), iontophoresis (by means of electric current where ions of soluble salts migrate into the tissues of the body), irrigation (to bathe or flush open wounds or body cavities), laryngeal (directly upon the larynx), nasogastric (through the nose and into the stomach), occlusive dressing technique, ophthalmic (to the external eye), oropharyngeal (directly to the mouth and pharynx), parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (within the respiratory tract by inhaling orally or nasally for local or systemic effect), retrobulbar (behind the pons or behind the eyeball), intramyocardial (entering the myocardium), soft tissue, subarachnoid, subconjunctival, submucosal, transplacental (through or across the placenta), transtracheal (through the wall of the trachea), transtympanic (across or through the tympanic cavity), ureteral (to the ureter), urethral (to the urethra), vaginal, caudal block, diagnostic, nerve block, biliary perfusion, cardiac perfusion, photopheresis or spinal. In specific embodiments, compositions may be administered in a way which allows them cross the blood-brain barrier, vascular barrier, or other epithelial barrier. In one embodiment, a formulation for a route of administration may include at least one inactive ingredient. Non-limiting examples of routes of administration and inactive ingredients which may be included in formulations for the specific route of administration is shown in Table 20. In Table 27, “AN” means anesthetic, “CNBLK” means cervical nerve block, “NBLK” means nerve block, “IV” means intravenous, “IM” means intramuscular and “SC” means subcutaneous.









TABLE 27







Routes of Adminsitration and Inactive Ingredients








Route of Administration
Inactive Ingredient





Intrathecal
Acetone Sodium Bisulfite; Citric Acid; Hydrochloric Acid;


(AN, CNBLK)
Sodium Chloride; Sodium Hydroxide; Sodium Metabisulfite


Infiltration (AN)
Acetic Acid; Acetone Sodium Bisulfite; Ascorbic Acid; Benzyl



Alcohol; Calcium Chloride; Carbon Dioxide; Chlorobutanol; Citric



Acid; Citric Acid Monohydrate; Edetate Calcium Disodium; Edetate



Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid;



Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride;



Potassium Metabisulfite; Potassium Phosphate, Monobasic;



Propylparaben; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate;



Sodium Metabisulfite; Sodium Phosphate, Dibasic, Heptahydrate


Sympathetic NBLK(AN)
Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide


Auricular (Otic)
Acetic Acid; Aluminum Acetate; Aluminum Sulfate Anhydrous;



Benzalkonium Chloride; Benzethonium Chloride; Benzyl Alcohol;



Boric Acid; Calcium Carbonate; Cetyl Alcohol; Chlorobutanol;



Chloroxylenol; Citric Acid; Creatinine; Cupric Sulfate; Cupric Sulfate



Anhydrous; Edetate Disodium; Edetic Acid; Glycerin; Glyceryl



Stearate; Hydrochloric Acid; Hydrocortisone; Hydroxyethyl Cellulose;



Isopropyl Myristate; Lactic Acid; Lecithin, Hydrogenated;



Methylparaben; Mineral Oil; Petrolatum; Petrolatum, White;



Phenylethyl Alcohol; Polyoxyl 40 Stearate; Polyoxyl Stearate;



Polysorbate 20; Polysorbate 80; Polyvinyl Alcohol; Potassium



Metabisulfite; Potassium Phosphate, Monobasic; Povidone K90f;



Povidones; Propylene Glycol; Propylene Glycol Diacetate;



Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Borate;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium



Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous; Sodium



Sulfite; Sulfuric Acid; Thimerosal


Caudal Block
Ascorbic Acid; Calcium Chloride; Citric Acid; Edetate Calcium



Disodium; Edetate Disodium; Hydrochloric Acid; Methylparaben;



Monothioglycerol; Nitrogen; Potassium Chloride; Sodium Chloride;



Sodium Hydroxide; Sodium Lactate; Sodium Metabisulfite


Dental
Acetone Sodium Bisulfite; Alcohol; Alcohol, Dehydrated; Alcohol,



Denatured; Anethole; Benzyl Alcohol; Carboxymethylcellulose



Sodium; Carrageenan; D&C Yellow No. 10; Dimethicone Medical



Fluid 360; Eucalyptol; Fd&C Blue No. 1; Fd&C Green No. 3; Flavor



89-186; Flavor 89-259; Flavor Df-119; Flavor Df-1530; Flavor



Enhancer; Gelatin; Gelatin, Crosslinked; Glycerin; Glyceryl Stearate;



High Density Polyethylene; Hydrocarbon Gel, Plasticized; Hydrochloric



Acid; Menthol; Mineral Oil; Nitrogen; Pectin; Peg-40 Sorbitan



Diisostearate; Peppermint Oil; Petrolatum, White; Plastibase-50w;



Polyethylene Glycol 1540; Polyglactin; Polyols; Polyoxyl 40



Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Propylene Glycol;



Pvm/Ma Copolymer; Saccharin Sodium; Silica, Dental; Silicon



Dioxide; Sodium Benzoate; Sodium Chloride; Sodium Hydroxide;



Sodium Lauryl Sulfate; Sodium Metabisulfite; Sorbitol; Titanium



Dioxide


Diagnostic
Hydrochloric Acid


Endocervical
Colloidal Silicon Dioxide; Triacetin


Epidural
1,2-Dioleoyl-Sn-Glycero-3-Phosphocholine; 1,2-Dipalmitoyl-Sn-



Glycero-3-(Phospho-Rac-(1-Glycerol)); Ascorbic Acid; Benzyl



Alcohol; Calcium Chloride; Cholesterol; Citric Acid; Edetate Calcium



Disodium; Edetate Disodium; Glyceryl Trioleate; Hydrochloric Acid;



Isotonic Sodium Chloride Solution; Methylparaben; Monothioglycerol;



Nitrogen; Potassium Chloride; Sodium Bisulfite; Sodium Chloride;



Sodium Citrate; Sodium Hydroxide; Sodium Lactate, L-; Sodium



Metabisulfite; Sodium Sulfite; Sulfuric Acid; Tricaprylin


Extracorporeal
Acetic Acid; Alcohol, Dehydrated; Benzyl Alcohol; Hydrochloric Acid;



Propylene Glycol; Sodium Acetate; Sodium Chloride; Sodium



Hydroxide


Intramuscular-
Acetic Acid; Alcohol; Alcohol, Dehydrated; Alcohol, Diluted;


Intravenous
Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium



Citrate; Arginine; Ascorbic Acid; Benzethonium Chloride; Benzoic



Acid; Benzyl Alcohol; Calcium Chloride; Carbon Dioxide;



Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Creatinine;



Dextrose; Edetate Calcium Disodium; Edetate Disodium; Edetate



Sodium; Gluconolactone; Glycerin; Hydrochloric Acid; Hydrochloric



Acid, Diluted; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose



Monohydrate; Lactose, Hydrous; Lysine; Mannitol; Methylparaben;



Monothioglycerol; Niacinamide; Nitrogen; Phenol; Phenol, Liquefied;



Phosphoric Acid; Polyethylene Glycol 300; Polyethylene Glycol 400;



Polypropylene Glycol; Polysorbate 40; Potassium Metabisulfite;



Potassium Phosphate, Monobasic; Propylene Glycol; Propylparaben;



Saccharin Sodium; Saccharin Sodium Anhydrous; Silicone;



Simethicone; Sodium Acetate; Sodium Acetate Anhydrous; Sodium



Benzoate; Sodium Bicarbonate; Sodium Bisulfate; Sodium Bisulfite;



Sodium Carbonate; Sodium Chloride; Sodium Citrate; Sodium



Formaldehyde Sulfoxylate; Sodium Hydroxide; Sodium Lactate, L-;



Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic;



Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic,



Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium



Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous;



Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfate; Sodium



Sulfite; Sodium Tartrate; Sodium Thiomalate; Succinic Acid; Sulfuric



Acid; Tartaric Acid, Dl-; Thimerosal; Trisodium Citrate Dihydrate;



Tromethamine


Intramuscular-
Acetic Acid; Alcohol; Alcohol, Dehydrated; Benzyl Alcohol;


Intravenous-
Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Citric Acid,


Subcutaneous
Hydrous; Creatinine; Dextrose; Edetate Disodium; Edetate Sodium;



Gelatin; Glycerin; Glycine; Hydrochloric Acid; Hydrochloric Acid,



Diluted; Lactic Acid; Lactose; Lactose Monohydrate; Metacresol;



Methanesulfonic Acid; Methylparaben; Monothioglycerol; Nitrogen;



Phenol; Phosphoric Acid; Polyoxyethylene Fatty Acid Esters;



Propylparaben; Sodium Acetate; Sodium Bisulfate; Sodium Bisulfite;



Sodium Chloride; Sodium Citrate; Sodium Dithionite; Sodium



Hydroxide; Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite;



Sodium Phosphate, Dibasic, Heptahydrate; Thimerosal


Intramuscular-
Acetic Acid; Anhydrous Dextrose; Benzyl Alcohol; Chlorobutanol;


Subcutaneous
Citric Acid; Cysteine; Edetate Disodium; Gelatin; Glycerin; Glycine;



Hydrochloric Acid; Lactose Monohydrate; Mannitol; Metacresol;



Methylparaben; Nitrogen; Peg Vegetable Oil; Peg-40 Castor Oil;



Phenol; Phenol, Liquefied; Phosphoric Acid; Polyoxyethylene Fatty



Acid Esters; Polysorbate 20; Propylparaben; Protamine Sulfate; Sesame



Oil; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Chloride;



Sodium Citrate; Sodium Formaldehyde Sulfoxylate; Sodium Hydroxide;



Sodium Phosphate Dihydrate; Sodium Phosphate, Dibasic,



Heptahydrate; Sulfuric Acid; Thimerosal; Zinc Chloride; Zinc Oxide


Implantation
Acetone; Crospovidone; Dimethylsiloxane/Methylvinylsiloxane



Copolymer; Ethylene Vinyl Acetate Copolymer; Magnesium Stearate;



Poly(Bis(P-Carboxyphenoxy)Propane Anhydride):Sebacic Acid;



Polyglactin; Silastic Brand Medical Grade Tubing; Silastic Medical



Adhesive, Silicone Type A; Stearic Acid


Infiltration
Cholesterol; Citric Acid; Diethyl Pyrocarbonate;



Dipalmitoylphosphatidylglycerol, Dl-; Hydrochloric Acid; Nitrogen;



Phosphoric Acid; Sodium Chloride; Sodium Hydroxide; Sodium



Metabisulfite; Tricaprylin


Inhalation
Acetone Sodium Bisulfite; Acetylcysteine; Alcohol; Alcohol,



Dehydrated; Ammonia; Ascorbic Acid; Benzalkonium Chloride;



Carbon Dioxide; Cetylpyridinium Chloride; Chlorobutanol; Citric Acid;



D&C Yellow No. 10; Dichlorodifluoromethane;



Dichlorotetrafluoroethane; Edetate Disodium; Edetate Sodium; Fd&C



Yellow No. 6; Fluorochlorohydrocarbons; Glycerin; Hydrochloric Acid;



Hydrochloric Acid, Diluted; Lactose; Lecithin; Lecithin, Hydrogenated



Soy; Lecithin, Soybean; Menthol; Methylparaben; Nitric Acid;



Nitrogen; Norflurane; Oleic Acid; Propylene Glycol; Propylparaben;



Saccharin; Saccharin Sodium; Sodium Bisulfate; Sodium Bisulfite;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium



Metabisulfite; Sodium Sulfate Anhydrous; Sodium Sulfite; Sorbitan



Trioleate; Sulfuric Acid; Thymol; Trichloromonofluoromethane


Interstitial
Benzyl Alcohol; Dextrose; Hydrochloric Acid; Sodium Acetate;



Sodium Hydroxide


Intra-amniotic
Citric Acid; Edetate Disodium Anhydrous; Hydrochloric Acid; Sodium



Hydroxide


Intra-arterial
Anhydrous Trisodium Citrate; Benzyl Alcohol; Carbon Dioxide; Citric



Acid; Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium;



Hydrochloric Acid; Hydrochloric Acid, Diluted; Iodine; Meglumine;



Methylparaben; Nitrogen; Propylparaben; Sodium Bisulfite; Sodium



Carbonate; Sodium Carbonate Monohydrate; Sodium Chloride; Sodium



Citrate; Sodium Hydroxide; Tromethamine


Intra-articular
Acetic Acid; Anhydrous Trisodium Citrate; Benzalkonium Chloride;



Benzyl Alcohol; Carboxymethylcellulose; Carboxymethylcellulose



Sodium; Cellulose, Microcrystalline; Citric Acid; Creatine; Creatinine;



Crospovidone; Diatrizoic Acid; Edetate Calcium Disodium; Edetate



Disodium; Hyaluronate Sodium; Hydrochloric Acid; Iodine;



Meglumine; Methylcelluloses; Methylparaben; Myristyl-.Gamma.-



Picolinium Chloride; Niacinamide; Phenol; Phosphoric Acid;



Polyethylene Glycol 3350; Polyethylene Glycol 4000; Polysorbate 80;



Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic;



Propylparaben; Sodium Acetate; Sodium Bisulfite; Sodium Chloride;



Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium



Phosphate; Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate,



Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Anhydrous;



Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sorbitol;



Sorbitol Solution


Intrabursal
Anhydrous Trisodium Citrate; Benzalkonium Chloride; Benzyl Alcohol;



Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid;



Creatinine; Edetate Disodium; Hydrochloric Acid; Methylparaben;



Polysorbate 80; Propylparaben; Sodium Bisulfite; Sodium Chloride;



Sodium Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium



Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic,



Anhydrous


Intracardiac
Carbon Dioxide; Citric Acid; Citric Acid Monohydrate; Diatrizoic Acid;



Edetate Calcium Disodium; Edetate Disodium; Hydrochloric Acid;



Iodine; Lactic Acid; Meglumine; Sodium Bisulfite; Sodium Carbonate



Monohydrate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide;



Sodium Lactate; Sodium Lactate, L-; Sodium Metabisulfite


Intracaudal
Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide


Intracavitary
Alcohol, Dehydrated; Alfadex; Anhydrous Lactose; Benzyl Alcohol;



Dextrose; Hydrochloric Acid; Lactose; Lactose Monohydrate; Nitrogen;



Sodium Acetate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide


Intradermal
Benzalkonium Chloride; Benzyl Alcohol; Carboxymethylcellulose



Sodium; Creatinine; Edetate Disodium; Glycerin; Hydrochloric Acid;



Metacresol; Methylparaben; Phenol; Polysorbate 80; Protamine Sulfate;



Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium



Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium



Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic,



Anhydrous; Zinc Chloride


Intradiscal
Cysteine Hydrochloride Anhydrous; Cysteine, Dl-; Diatrizoic Acid;



Edetate Calcium Disodium; Edetate Disodium; Iodine; Meglumine;



Sodium Bisulfite; Sodium Hydroxide


Intralesional
Acetic Acid; Benzalkonium Chloride; Benzyl Alcohol;



Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid;



Creatine; Creatinine; Edetate Disodium; Hydrochloric Acid;



Methylcelluloses; Methylparaben; Myristyl-.Gamma.-Picolinium



Chloride; Niacinamide; Phenol; Phosphoric Acid; Polyethylene Glycol



3350; Polyethylene Glycol 4000; Polysorbate 80; Propylparaben;



Sodium Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate;



Sodium Hydroxide; Sodium Phosphate; Sodium Phosphate, Dibasic;



Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate,



Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Monohydrate;



Sodium Sulfite; Sorbitol; Sorbitol Solution


Intralymphatic
Poppy Seed Oil


Intramuscular
Acetic Acid; Activated Charcoal; Adipic Acid; Alcohol; Alcohol,



Dehydrated; Ammonium Acetate; Anhydrous Dextrose; Ascorbic Acid;



Benzalkonium Chloride; Benzethonium Chloride; Benzoic Acid; Benzyl



Alcohol; Benzyl Benzoate; Butylated Hydroxyanisole; Butylated



Hydroxytoluene; Butylparaben; Calcium; Calcium Chloride; Carbon



Dioxide; Carboxymethylcellulose; Carboxymethylcellulose Sodium;



Castor Oil; Cellulose, Microcrystalline; Chlorobutanol; Chlorobutanol



Hemihydrate; Chlorobutanol, Anhydrous; Citric Acid; Citric Acid



Monohydrate; Corn Oil; Cottonseed Oil; Creatine; Creatinine;



Croscarmellose Sodium; Crospovidone; Dextrose; Diatrizoic Acid;



Docusate Sodium; Edetate Calcium Disodium; Edetate Disodium;



Edetate Disodium Anhydrous; Edetate Sodium; Ethyl Acetate; Gelatin;



Glutathione; Glycerin; Glycine; Hyaluronate Sodium; Hydrochloric



Acid; Hydroxide Ion; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose



Monohydrate; Lactose, Hydrous; Lecithin; Magnesium Chloride;



Maleic Acid; Mannitol; Meglumine; Metacresol; Methionine;



Methylcelluloses; Methylparaben; Monothioglycerol; Myristyl-



.Gamma.-Picolinium Chloride; N,N-Dimethylacetamide; Niacinamide;



Nitrogen; Peanut Oil; Peg-20 Sorbitan Isostearate; Phenol;



Phenylmercuric Nitrate; Phosphoric Acid; Polyethylene Glycol 200;



Polyethylene Glycol 300; Polyethylene Glycol 3350; Polyethylene



Glycol 4000; Polyglactin; Polylactide; Polysorbate 20; Polysorbate 40;



Polysorbate 80; Polyvinyl Alcohol; Potassium Phosphate, Dibasic;



Potassium Phosphate, Monobasic; Povidones; Propyl Gallate; Propylene



Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium



Anhydrous; Sesame Oil; Sodium Acetate; Sodium Acetate Anhydrous;



Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium



Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Chloride



Injection; Sodium Citrate; Sodium Formaldehyde Sulfoxylate; Sodium



Hydroxide; Sodium Metabisulfite; Sodium Phosphate; Sodium



Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium



Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic;



Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate,



Monobasic, Monohydrate; Sodium Sulfate Anhydrous; Sodium Sulfite;



Sodium Tartrate; Sorbitan Monopalmitate; Sorbitol; Sorbitol Solution;



Starch; Sucrose; Sulfobutylether .Beta.-Cyclodextrin; Sulfuric Acid;



Sulfurous Acid; Tartaric Acid; Thimerosal; Tromantadine;



Tromethamine; Urea


Intraocular
Benzalkonium Chloride; Calcium Chloride; Citric Acid Monohydrate;



Hydrochloric Acid; Magnesium Chloride; Polyvinyl Alcohol; Potassium



Chloride; Sodium Acetate; Sodium Chloride; Sodium Citrate; Sodium



Hydroxide


Intraperitoneal
Benzyl Alcohol; Calcium Chloride; Dextrose; Edetate Calcium



Disodium; Hydrochloric Acid; Magnesium Chloride; Sodium Acetate;



Sodium Bicarbonate; Sodium Bisulfite; Sodium Carbonate; Sodium



Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate; Sodium



Metabisulfite; Sulfuric Acid


Intrapleural
Benzyl Alcohol; Citric Acid; Dextrose; Dichlorodifluoromethane;



Hydrochloric Acid; Sodium Acetate; Sodium Carbonate; Sodium



Chloride; Sodium Citrate; Sodium Hydroxide


Intraspinal
Dextrose; Hydrochloric Acid; Sodium Hydroxide


Intrasynovial
Acetic Acid; Benzyl Alcohol; Carboxymethylcellulose Sodium; Citric



Acid; Creatinine; Edetate Disodium; Hydrochloric Acid;



Methylcelluloses; Methylparaben; Myristyl-.Gamma-Picolinium



Chloride; Niacinamide; Phenol; Polyethylene Glycol 3350;



Polyethylene Glycol 4000; Polysorbate 80; Propylparaben; Sodium



Acetate; Sodium Bisulfite; Sodium Chloride; Sodium Citrate; Sodium



Hydroxide; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate,



Monobasic, Anhydrous; Sorbitol


Intrathecal
Benzyl Alcohol; Carbon Dioxide; Citric Acid; Edetate Calcium



Disodium; Hydrochloric Acid; Methionine; Nitrogen; Pentetate Calcium



Trisodium; Pentetic Acid; Sodium Bicarbonate; Sodium Chloride;



Sodium Citrate; Sodium Hydroxide; Sulfuric Acid; Tromethamine


Intratracheal
Acetic Acid; Benzyl Alcohol; Carboxymethylcellulose Sodium;



Hydrochloric Acid; Isotonic Sodium Chloride Solution; Peanut Oil;



Sodium Bicarbonate; Sodium Chloride; Sodium Citrate; Sodium



Hydroxide; Tromethamine


Intratumor
Benzyl Alcohol; Hydrochloric Acid; Nitrogen; Sodium Carbonate;



Sodium Chloride; Sodium Hydroxide


Intrauterine
Barium Sulfate; Crospovidone; Diatrizoic Acid;



Dimethylsiloxane/Methylvinylsiloxane Copolymer; Edetate Calcium



Disodium; Edetate Disodium; Ethylene Vinyl Acetate Copolymer; High



Density Polyethylene; Meglumine; Polyethylene High Density



Containing Ferric Oxide Black (<1%); Polyethylene Low Density



Containing Barium Sulfate (20-24%); Polyethylene T; Polypropylene;



Poppy Seed Oil; Potassium Phosphate, Monobasic; Silicone; Sodium



Citrate; Sodium Hydroxide; Titanium Dioxide


Intravascular
Alcohol; Alcohol, Dehydrated; Calcium Chloride; Carbon Dioxide;



Citric Acid; Diatrizoic Acid; Edetate Calcium Disodium; Edetate



Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Iodine;



Meglumine; Nitrogen; Potassium Hydroxide; Sodium Carbonate;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium



Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic,



Monohydrate; Tromethamine


Intravenous
Alpha-Tocopherol; Alpha-Tocopherol, Dl-; 1,2-Dimyristoyl-Sn-



Glycero-3-Phosphocholine; 1,2-Distearoyl-Sn-Glycero-3-(Phospho-



Rac-(1-Glycerol)); 1,2-Distearoyl-Sn-Glycero-3-Phosphocholine;



Acetic Acid; Acetic Acid, Glacial; Acetic Anhydride; Acetylated



Monoglycerides; Acetyltryptophan, Dl-; Activated Charcoal; Albumin



Aggregated; Albumin Colloidal; Albumin Human; Alcohol; Alcohol,



Dehydrated; Alcohol, Denatured; Ammonium Acetate; Ammonium



Hydroxide; Ammonium Sulfate; Anhydrous Citric Acid; Anhydrous



Dextrose; Anhydrous Lactose; Anhydrous Trisodium Citrate; Arginine;



Ascorbic Acid; Benzenesulfonic Acid; Benzethonium Chloride;



Benzoic Acid; Benzyl Alcohol; Benzyl Chloride; Bibapcitide; Boric



Acid; Butylated Hydroxytoluene; Calcium Chloride; Calcium



Gluceptate; Calcium Hydroxide; Calcobutrol; Caldiamide Sodium;



Caloxetate Trisodium; Calteridol Calcium; Captisol; Carbon Dioxide;



Cellulose, Microcrystalline; Chlorobutanol; Chlorobutanol



Hemihydrate; Chlorobutanol, Anhydrous; Cholesterol; Citrate; Citric



Acid; Citric Acid Monohydrate; Citric Acid, Hydrous; Cysteine;



Cysteine Hydrochloride; Dalfampridine; Dextran; Dextran 40;



Dextrose; Dextrose Monohydrate; Dextrose Solution; Diatrizoic Acid;



Dimethicone Medical Fluid 360; Edetate Calcium Disodium; Edetate



Disodium; Edetate Disodium Anhydrous; Egg Phospholipids;



Ethanolamine Hydrochloride; Ethylenediamine; Exametazime; Ferric



Chloride; Gadolinium Oxide; Gamma Cyclodextrin; Gelatin; Gentisic



Acid; Gluceptate Sodium; Gluceptate Sodium Dihydrate;



Gluconolactone; Glucuronic Acid; Glycerin; Glycine; Guanidine



Hydrochloride; Hetastarch; Histidine; Human Albumin Microspheres;



Hydrochloric Acid; Hydrochloric Acid, Diluted;



Hydroxyethylpiperazine Ethane Sulfonic Acid; Hydroxypropyl-



Bcyclodextrin; Iodine; Iodoxamic Acid; Iofetamine Hydrochloride;



Isopropyl Alcohol; Isotonic Sodium Chloride Solution; Lactic Acid;



Lactic Acid, Dl-; Lactic Acid, L-; Lactobionic Acid; Lactose; Lactose



Monohydrate; Lactose, Hydrous; Lecithin, Egg; Lecithin, Hydrogenated



Soy; Lidofenin; Mannitol; Mebrofenin; Medronate Disodium; Medronic



Acid; Meglumine; Methionine; Methylboronic Acid; Methylene Blue;



Methylparaben; Monothioglycerol; N-(Carbamoyl-Methoxy Peg-40)-



1,2-Distearoyl-Cephalin Sodium; N,N-Dimethylacetamide; Nioxime;



Nitrogen; Octanoic Acid; Oxidronate Disodium; Oxyquinoline;



Pentasodium Pentetate; Pentetate Calcium Trisodium; Pentetic Acid;



Perflutren; Phenol; Phenol, Liquefied; Phosphatidyl Glycerol, Egg;



Phospholipid, Egg; Phosphoric Acid; Poloxamer 188; Polyethylene



Glycol 300; Polyethylene Glycol 400; Polyethylene Glycol 600;



Polysiloxane; Polysorbate 20; Polysorbate 80; Potassium Bisulfite;



Potassium Chloride; Potassium Hydroxide; Potassium Metabisulfite;



Potassium Phosphate, Dibasic; Potassium Phosphate, Monobasic;



Povidones; Propylene Glycol; Propylparaben; Saccharin Sodium;



Sodium Acetate; Sodium Acetate Anhydrous; Sodium Ascorbate;



Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium



Carbonate; Sodium Carbonate Decahydrate; Sodium Carbonate



Monohydrate; Sodium Chloride; Sodium Chloride Injection,



Bacteriostatic; Sodium Citrate; Sodium Dithionite; Sodium Gluconate;



Sodium Hydroxide; Sodium Iodide; Sodium Lactate; Sodium



Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic; Sodium



Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate;



Sodium Phosphate, Dibasic, Heptahydrate; Sodium Phosphate,



Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate;



Sodium Phosphate, Monobasic, Monohydrate; Sodium Pyrophosphate;



Sodium Succinate Hexahydrate; Sodium Sulfite; Sodium Tartrate;



Sodium Thiosulfate; Sodium Thiosulfate Anhydrous; Sodium



Trimetaphosphate; Sorbitol; Sorbitol Solution; Soybean Oil; Stannous



Chloride; Stannous Chloride Anhydrous; Stannous Fluoride; Stannous



Tartrate; Succimer; Succinic Acid; Sucrose; Sulfobutylether .Beta.-



Cyclodextrin; Sulfuric Acid; Tartaric Acid; Tartaric Acid, Dl-; Tert-



Butyl Alcohol; Tetrakis(2-Methoxyisobutylisocyanide)Copper(I)



Tetrafluoroborate; Theophylline; Thimerosal; Threonine; Tin;



Trisodium Citrate Dihydrate; Tromantadine; Tromethamine;



Versetamide


Intravenous Bolus
Sodium Chloride


Intravesical
Alcohol, Dehydrated; Edetate Calcium Disodium; Hydrochloric Acid;



Nitrogen; Polyoxyl 35 Castor Oil; Potassium Phosphate, Monobasic;



Sodium Chloride; Sodium Hydroxide; Sodium Phosphate, Dibasic,



Anhydrous; Sodium Phosphate, Monobasic, Anhydrous


Intravitreal
Calcium Chloride; Carboxymethylcellulose Sodium; Cellulose,



Microcrystalline; Hyaluronate Sodium; Hydrochloric Acid; Magnesium



Chloride; Magnesium Stearate; Polysorbate 80; Polyvinyl Alcohol;



Potassium Chloride; Sodium Acetate; Sodium Bicarbonate; Sodium



Carbonate; Sodium Chloride; Sodium Hydroxide; Sodium Phosphate,



Dibasic, Heptahydrate; Sodium Phosphate, Monobasic, Monohydrate;



Trisodium Citrate Dihydrate


Iontophoresis
Cetylpyridinium Chloride; Citric Acid; Edetate Disodium; Glycerin;



Hydrochloric Acid; Methylparaben; Phenonip; Polacrilin; Polyvinyl



Alcohol; Povidone Hydrogel; Sodium Bisulfite; Sodium Chloride;



Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite; Sodium



Phosphate, Monobasic


Irrigation
Acetic Acid; Activated Charcoal; Benzoic Acid; Hydrochloric Acid;



Hypromelloses; Methylparaben; Nitrogen; Sodium Bisulfite; Sodium



Citrate; Sodium Hydroxide; Sulfuric Acid


Intravenous-
Acetic Acid; Alcohol; Benzyl Alcohol; Calcium Hydroxide;


Subcutaneous
Chlorobutanol; Glycerin; Hydrochloric Acid; Lactose Monohydrate;



Methylparaben; Nitrogen; Phenol; Phenol, Liquefied; Phosphoric Acid;



Propylparaben; Sodium Acetate; Sodium Carbonate; Sodium Chloride;



Sodium Hydroxide


Intravenous
1,2-Dimyristoyl-Sn-Glycero-3-(Phospho-S-(1-Glycerol)); 1,2-


(Infusion)
Dimyristoyl-Sn-Glycero-3-Phosphocholine; Acetic Acid; Acetic Acid,



Glacial; Activated Charcoal; Alanine; Albumin Human; Alcohol;



Alcohol, Dehydrated; Ammonium Acetate; Anhydrous Citric Acid;



Anhydrous Dextrose; Anhydrous Lactose; Anhydrous Trisodium



Citrate; Arginine; Ascorbic Acid; Aspartic Acid; Benzenesulfonic Acid;



Benzethonium Chloride; Benzoic Acid; Benzyl Alcohol; Brocrinat;



Butylated Hydroxyanisole; Butylated Hydroxytoluene; Carbon Dioxide;



Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Citric Acid,



Hydrous; Cysteine; Cysteine Hydrochloride; Deoxycholic Acid;



Dextrose; Dextrose Solution; Diatrizoic Acid; Diethanolamine;



Dimethyl Sulfoxide; Disodium Sulfosalicylate; Disofenin; Edetate



Calcium Disodium; Edetate Disodium; Edetate Disodium Anhydrous;



Edetate Sodium; Egg Phospholipids; Ethylenediamine; Fructose;



Gelatin; Gentisic Acid Ethanolamide; Glycerin; Glycine; Histidine;



Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydroxide Ion;



Hydroxypropyl-Bcyclodextrin; Isoleucine; Isotonic Sodium Chloride



Solution; Lactic Acid; Lactic Acid, Dl-; Lactobionic Acid; Lactose;



Lactose Monohydrate; Lactose, Hydrous; Leucine; Lysine; Lysine



Acetate; Magnesium Chloride; Maleic Acid; Mannitol; Meglumine;



Metacresol; Metaphosphoric Acid; Methanesulfonic Acid; Methionine;



Methylparaben; Monothioglycerol; N,N-Dimethylacetamide; Nitric



Acid; Nitrogen; Peg Vegetable Oil; Peg-40 Castor Oil; Peg-60 Castor



Oil; Pentetate Calcium Trisodium; Phenol; Phenylalanine;



Phospholipid; Phospholipid, Egg; Phosphoric Acid; Polyethylene



Glycol 300; Polyethylene Glycol 400; Polyoxyl 35 Castor Oil;



Polysorbate 20; Polysorbate 80; Potassium Chloride; Potassium



Hydroxide; Potassium Metabisulfite; Potassium Phosphate, Dibasic;



Potassium Phosphate, Monobasic; Povidones; Proline; Propylene



Glycol; Propylparaben; Saccharin Sodium; Saccharin Sodium



Anhydrous; Serine; Sodium Acetate; Sodium Acetate Anhydrous;



Sodium Benzoate; Sodium Bicarbonate; Sodium Bisulfite; Sodium



Carbonate; Sodium Chlorate; Sodium Chloride; Sodium Cholesteryl



Sulfate; Sodium Citrate; Sodium Desoxycholate; Sodium Dithionite;



Sodium Formaldehyde Sulfoxylate; Sodium Gluconate; Sodium



Hydroxide; Sodium Hypochlorite; Sodium Lactate; Sodium Lactate, L-;



Sodium Metabisulfite; Sodium Phosphate; Sodium Phosphate, Dibasic;



Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate, Dibasic,



Dihydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium



Phosphate, Monobasic; Sodium Phosphate, Monobasic, Anhydrous;



Sodium Phosphate, Monobasic, Dihydrate; Sodium Phosphate,



Monobasic, Monohydrate; Sodium Sulfite; Sodium Tartrate; Sorbitol;



Sorbitol Solution; Soybean Oil; Stannous Chloride; Stannous Chloride



Anhydrous; Sterile Water For Inhalation; Sucrose; Sulfobutylether



.Beta.-Cyclodextrin; Sulfur Dioxide; Sulfuric Acid; Tartaric Acid;



Tartaric Acid, Dl-; Tert-Butyl Alcohol; Tetrofosmin; Theophylline;



Threonine; Trifluoroacetic Acid; Trisodium Citrate Dihydrate;



Tromethamine; Tryptophan; Tyrosine; Valine


Any Delivery Route
Alcohol; Benzyl Alcohol; Citric Acid Monohydrate; Gelfoam Sponge;



Hydrochloric Acid; Methylparaben; Poly(Dl-Lactic-Co-Glycolic Acid),



(50:50; Poly(Dl-Lactic-Co-Glycolic Acid), Ethyl Ester Terminated,



(50:50; Polyquaternium-7 (70/30 Acrylamide/Dadmac; Propylene



Glycol; Propylparaben; Sodium Chloride; Sodium Citrate; Sodium



Hydroxide; Sodium Lactate; Sodium Phosphate, Monobasic,



Monohydrate


Nasal
Acetic Acid; Alcohol, Dehydrated; Allyl .Alpha.-Ionone; Anhydrous



Dextrose; Anhydrous Trisodium Citrate; Benzalkonium Chloride;



Benzethonium Chloride; Benzyl Alcohol; Butylated Hydroxyanisole;



Butylated Hydroxytoluene; Caffeine; Carbon Dioxide;



Carboxymethylcellulose Sodium; Cellulose, Microcrystalline;



Chlorobutanol; Citric Acid; Citric Acid Monohydrate; Dextrose;



Dichlorodifluoromethane; Dichlorotetrafluoroethane; Edetate



Disodium; Glycerin; Glycerol Ester Of Hydrogenated Rosin;



Hydrochloric Acid; Hypromellose 2910 (15000 Mpa · S);



Methylcelluloses; Methylparaben; Nitrogen; Norflurane; Oleic Acid;



Petrolatum, White; Phenylethyl Alcohol; Polyethylene Glycol 3350;



Polyethylene Glycol 400; Polyoxyl 400 Stearate; Polysorbate 20;



Polysorbate 80; Potassium Phosphate, Monobasic; Potassium Sorbate;



Propylene Glycol; Propylparaben; Sodium Acetate; Sodium Chloride;



Sodium Citrate; Sodium Hydroxide; Sodium Phosphate; Sodium



Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium



Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic,



Dodecahydrate; Sodium Phosphate, Dibasic, Heptahydrate; Sodium



Phosphate, Monobasic, Anhydrous; Sodium Phosphate, Monobasic,



Dihydrate; Sorbitan Trioleate; Sorbitol; Sorbitol Solution; Sucralose;



Sulfuric Acid; Trichloromonofluoromethane; Trisodium Citrate



Dihydrate


Nerve Block
Acetic Acid; Acetone Sodium Bisulfite; Ascorbic Acid; Benzyl



Alcohol; Calcium Chloride; Carbon Dioxide; Chlorobutanol; Citric



Acid; Citric Acid Monohydrate; Edetate Calcium Disodium; Edetate



Disodium; Hydrochloric Acid; Hydrochloric Acid, Diluted; Lactic Acid;



Methylparaben; Monothioglycerol; Nitrogen; Potassium Chloride;



Potassium Metabisulfite; Potassium Phosphate, Monobasic;



Propylparaben; Sodium Bisulfite; Sodium Carbonate; Sodium Chlorate;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Lactate;



Sodium Lactate, L-; Sodium Metabisulfite; Sodium Phosphate; Sodium



Phosphate, Dibasic, Heptahydrate


Ophthalmic
Acetic Acid; Alcohol; Alcohol, Dehydrated; Alginic Acid; Amerchol-



Cab; Ammonium Hydroxide; Anhydrous Trisodium Citrate; Antipyrine;



Benzalkonium Chloride; Benzethonium Chloride; Benzododecinium



Bromide; Boric Acid; Caffeine; Calcium Chloride; Carbomer 1342;



Carbomer 934p; Carbomer 940; Carbomer Homopolymer Type B (Allyl



Pentaerythritol Crosslinked); Carboxymethylcellulose Sodium; Castor



Oil; Cetyl Alcohol; Chlorobutanol; Chlorobutanol, Anhydrous;



Cholesterol; Citric Acid; Citric Acid Monohydrate; Creatinine;



Diethanolamine; Diethylhexyl Phthalate **See Cder Guidance:



Limiting The Use Of Certain Phthalates As Excipients In Cder-



Regulated Products; Divinylbenzene Styrene Copolymer; Edetate



Disodium; Edetate Disodium Anhydrous; Edetate Sodium; Ethylene



Vinyl Acetate Copolymer; Gellan Gum (Low Acyl); Glycerin; Glyceryl



Stearate; High Density Polyethylene; Hydrocarbon Gel, Plasticized;



Hydrochloric Acid; Hydrochloric Acid, Diluted; Hydroxyethyl



Cellulose; Hydroxypropyl Methylcellulose 2906; Hypromellose 2910



(15000 Mpa · S); Hypromelloses; Jelene; Lanolin; Lanolin Alcohols;



Lanolin Anhydrous; Lanolin Nonionic Derivatives; Lauralkonium



Chloride; Lauroyl Sarcosine; Light Mineral Oil; Magnesium Chloride;



Mannitol; Methylcellulose (4000 Mpa · S); Methylcelluloses;



Methylparaben; Mineral Oil; Nitric Acid; Nitrogen; Nonoxynol-9;



Octoxynol-40; Octylphenol Polymethylene; Petrolatum; Petrolatum,



White; Phenylethyl Alcohol; Phenylmercuric Acetate; Phenylmercuric



Nitrate; Phosphoric Acid; Polidronium Chloride; Poloxamer 188;



Poloxamer 407; Polycarbophil; Polyethylene Glycol 300; Polyethylene



Glycol 400; Polyethylene Glycol 8000; Polyoxyethylene-



Polyoxypropylene 1800; Polyoxyl 35 Castor Oil; Polyoxyl 40



Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polypropylene Glycol;



Polysorbate 20; Polysorbate 60; Polysorbate 80; Polyvinyl Alcohol;



Potassium Acetate; Potassium Chloride; Potassium Phosphate,



Monobasic; Potassium Sorbate; Povidone K29/32; Povidone K30;



Povidone K90; Povidones; Propylene Glycol; Propylparaben; Soda Ash;



Sodium Acetate; Sodium Bisulfate; Sodium Bisulfite; Sodium Borate;



Sodium Borate Decahydrate; Sodium Carbonate; Sodium Carbonate



Monohydrate; Sodium Chloride; Sodium Citrate; Sodium Hydroxide;



Sodium Metabisulfite; Sodium Nitrate; Sodium Phosphate; Sodium



Phosphate Dihydrate; Sodium Phosphate, Dibasic; Sodium Phosphate,



Dibasic, Anhydrous; Sodium Phosphate, Dibasic, Dihydrate; Sodium



Phosphate, Dibasic, Heptahydrate; Sodium Phosphate, Monobasic;



Sodium Phosphate, Monobasic, Anhydrous; Sodium Phosphate,



Monobasic, Dihydrate; Sodium Phosphate, Monobasic, Monohydrate;



Sodium Sulfate; Sodium Sulfate Anhydrous; Sodium Sulfate



Decahydrate; Sodium Sulfite; Sodium Thiosulfate; Sorbic Acid;



Sorbitan Monolaurate; Sorbitol; Sorbitol Solution; Stabilized Oxychloro



Complex; Sulfuric Acid; Thimerosal; Titanium Dioxide;



Tocophersolan; Trisodium Citrate Dihydrate; Triton 720;



Tromethamine; Tyloxapol; Zinc Chloride


Parenteral
Hydrochloric Acid; Mannitol; Nitrogen; Sodium Acetate; Sodium



Chloride; Sodium Hydroxide


Percutaneous
Duro-Tak 87-2287; Silicone Adhesive 4102


Perfusion, Biliary
Glycerin


Perfusion, Cardiac
Hydrochloric Acid; Sodium Hydroxide


Periarticular
Diatrizoic Acid; Edetate Calcium Disodium; Iodine; Meglumine


Peridural
Citric Acid; Hydrochloric Acid; Methylparaben; Sodium Chloride;



Sodium Hydroxide; Sodium Metabisulfite


Perineural
Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide


Periodontal
Ethylene Vinyl Acetate Copolymer; Hydrochloric Acid; Methyl



Pyrrolidone; Poloxamer 188; Poloxamer 407; Polylactide


Photopheresis
Acetic Acid; Alcohol, Dehydrated; Propylene Glycol; Sodium Acetate;



Sodium Chloride; Sodium Hydroxide


Rectal
Alcohol; Alcohol, Dehydrated; Aluminum Subacetate; Anhydrous



Citric Acid; Aniseed Oil; Ascorbic Acid; Ascorbyl Palmitate; Balsam



Peru; Benzoic Acid; Benzyl Alcohol; Bismuth Subgallate; Butylated



Hydroxyanisole; Butylated Hydroxytoluene; Butylparaben; Caramel;



Carbomer 934; Carbomer 934p; Carboxypolymethylene; Cerasynt-Se;



Cetyl Alcohol; Cocoa Butter; Coconut Oil, Hydrogenated; Coconut



Oil/Palm Kernel Oil Glycerides, Hydrogenated; Cola Nitida Seed



Extract; D&C Yellow No. 10; Dichlorodifluoromethane;



Dichlorotetrafluoroethane; Dimethyldioctadecylammonium Bentonite;



Edetate Calcium Disodium; Edetate Disodium; Edetic Acid; Epilactose;



Ethylenediamine; Fat, Edible; Fat, Hard; Fd&C Blue No. 1; Fd&C



Green No. 3; Fd&C Yellow No. 6; Flavor Fig 827118; Flavor



Raspberry Pfc-8407; Fructose; Galactose; Glycerin; Glyceryl Palmitate;



Glyceryl Stearate; Glyceryl Stearate/Peg Stearate; Glyceryl



Stearate/Peg-40 Stearate; Glycine; Hydrocarbon; Hydrochloric Acid;



Hydrogenated Palm Oil; Hypromelloses; Lactose; Lanolin; Lecithin;



Light Mineral Oil; Magnesium Aluminum Silicate; Magnesium



Aluminum Silicate Hydrate; Methylparaben; Nitrogen; Palm Kernel



Oil; Paraffin; Petrolatum, White; Polyethylene Glycol 1000;



Polyethylene Glycol 1540; Polyethylene Glycol 3350; Polyethylene



Glycol 400; Polyethylene Glycol 4000; Polyethylene Glycol 6000;



Polyethylene Glycol 8000; Polysorbate 60; Polysorbate 80; Potassium



Acetate; Potassium Metabisulfite; Propylene Glycol; Propylparaben;



Saccharin Sodium; Saccharin Sodium Anhydrous; Silicon Dioxide,



Colloidal; Simethicone; Sodium Benzoate; Sodium Carbonate; Sodium



Chloride; Sodium Citrate; Sodium Hydroxide; Sodium Metabisulfite;



Sorbitan Monooleate; Sorbitan Sesquioleate; Sorbitol; Sorbitol Solution;



Starch; Steareth-10; Steareth-40; Sucrose; Tagatose, D-; Tartaric Acid,



Dl-; Trolamine; Tromethamine; Vegetable Oil Glyceride,



Hydrogenated; Vegetable Oil, Hydrogenated; Wax, Emulsifying; White



Wax; Xanthan Gum; Zinc Oxide


Respiratory
Alcohol; Alcohol, Dehydrated; Apaflurane; Benzalkonium Chloride;


(Inhalation)
Calcium Carbonate; Edetate Disodium; Gelatin; Glycine; Hydrochloric



Acid; Lactose Monohydrate; Lysine Monohydrate; Mannitol;



Norflurane; Oleic Acid; Polyethylene Glycol 1000; Povidone K25;



Silicon Dioxide, Colloidal; Sodium Chloride; Sodium Citrate; Sodium



Hydroxide; Sodium Lauryl Sulfate; Sulfuric Acid; Titanium Dioxide;



Tromethamine; Zinc Oxide


Retrobulbar
Hydrochloric Acid; Sodium Hydroxide


Soft Tissue
Acetic Acid; Anhydrous Trisodium Citrate; Benzyl Alcohol;



Carboxymethylcellulose; Carboxymethylcellulose Sodium; Citric Acid;



Creatinine; Edetate Disodium; Hydrochloric Acid; Methylcelluloses;



Methylparaben; Myristyl-.Gamma.-Picolinium Chloride; Phenol;



Phosphoric Acid; Polyethylene Glycol 3350; Polyethylene Glycol 4000;



Polysorbate 80; Propylparaben; Sodium Acetate; Sodium Bisulfite;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium



Phosphate; Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate,



Monobasic, Anhydrous; Sodium Sulfite


Spinal
Anhydrous Dextrose; Dextrose; Hydrochloric Acid; Sodium Hydroxide


Subarachnoid
Hydrochloric Acid; Sodium Chloride; Sodium Hydroxide


Subconjunctival
Benzyl Alcohol; Hydrochloric Acid; Sodium Hydroxide


Subcutaneous
Acetic Acid; Acetic Acid, Glacial; Albumin Human; Ammonium



Hydroxide; Ascorbic Acid; Benzyl Alcohol; Calcium Chloride;



Carboxymethylcellulose Sodium; Chlorobutanol; Cresol; Diatrizoic



Acid; Dimethyl Sulfoxide; Edetate Calcium Disodium; Edetate



Disodium; Ethylene Vinyl Acetate Copolymer; Glycerin; Glycine;



Glycine Hydrochloride; Histidine; Hydrochloric Acid; Lactic Acid;



Lactic Acid, L-; Lactose; Magnesium Chloride; Magnesium Stearate;



Mannitol; Metacresol; Methanesulfonic Acid; Methionine; Methyl



Pyrrolidone; Methylparaben; Nitrogen; Phenol; Phenol, Liquefied;



Phosphoric Acid; Poloxamer 188; Polyethylene Glycol 3350;



Polyglactin; Polysorbate 20; Polysorbate 80; Potassium Phosphate,



Dibasic; Potassium Phosphate, Monobasic; Povidone K17; Povidones;



Propylene Glycol; Propylparaben; Protamine Sulfate; Sodium Acetate;



Sodium Acetate Anhydrous; Sodium Bicarbonate; Sodium Bisulfite;



Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sodium



Metabisulfite; Sodium Phosphate; Sodium Phosphate Dihydrate;



Sodium Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous;



Sodium Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate,



Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate;



Sodium Phosphate, Monobasic, Monohydrate; Sodium Sulfite; Sodium



Thioglycolate; Stearic Acid; Sucrose; Thimerosal; Tromethamine; Zinc;



Zinc Acetate; Zinc Carbonate; Zinc Chloride; Zinc Oxide


Sublingual
Alcohol, Dehydrated


Submucosal
Acetic Acid; Edetic Acid; Mannitol; Nitrogen; Sodium Acetate; Sodium



Chloride; Sodium Hydroxide; Sodium Metabisulfite


Topical
.Alpha.-Terpineol; .Alpha.-Tocopherol; .Alpha.-Tocopherol Acetate,



Dl-; .Alpha.-Tocopherol, Dl-; 1,2,6-Hexanetriol; 1-O-Tolylbiguanide;



2-Ethyl-1,6-Hexanediol; Acetic Acid; Acetone; Acetylated Lanolin



Alcohols; Acrylates Copolymer; Adhesive Tape; Alcohol; Alcohol,



Dehydrated; Alcohol, Denatured; Alcohol, Diluted; Alkyl Ammonium



Sulfonic Acid Betaine; Alkyl Aryl Sodium Sulfonate; Allantoin;



Almond Oil; Aluminum Acetate; Aluminum Chlorhydroxy



Allantoinate; Aluminum Hydroxide; Aluminum Hydroxide-Sucrose,



Hydrated; Aluminum Hydroxide Gel; Aluminum Hydroxide Gel F 500;



Aluminum Hydroxide Gel F 5000; Aluminum Monostearate; Aluminum



Oxide; Aluminum Silicate; Aluminum Starch Octenylsuccinate;



Aluminum Stearate; Aluminum Sulfate Anhydrous; Amerchol C;



Amerchol-Cab; Aminomethylpropanol; Ammonia Solution; Ammonia



Solution, Strong; Ammonium Hydroxide; Ammonium Lauryl Sulfate;



Ammonium Nonoxynol-4 Sulfate; Ammonium Salt Of C-12-C-15



Linear Primary Alcohol Ethoxylate; Ammonyx; Amphoteric-2;



Amphoteric-9; Anhydrous Citric Acid; Anhydrous Trisodium Citrate;



Anoxid Sbn; Antifoam; Apricot Kernel Oil Peg-6 Esters; Aquaphor;



Arlacel; Ascorbic Acid; Ascorbyl Palmitate; Beeswax; Beeswax,



Synthetic; Beheneth-10; Bentonite; Benzalkonium Chloride; Benzoic



Acid; Benzyl Alcohol; Betadex; Boric Acid; Butane; Butyl Alcohol;



Butyl Ester Of Vinyl Methyl Ether/Maleic Anhydride Copolymer



(125000 Mw); Butyl Stearate; Butylated Hydroxyanisole; Butylated



Hydroxytoluene; Butylene Glycol; Butylparaben; C20-40 Pareth-24;



Calcium Chloride; Calcium Hydroxide; Canada Balsam;



Caprylic/Capric Triglyceride; Caprylic/Capric/Stearic Triglyceride;



Captan; Caramel; Carbomer 1342; Carbomer 1382; Carbomer 934;



Carbomer 934p; Carbomer 940; Carbomer 941; Carbomer 980;



Carbomer 981; Carbomer Homopolymer Type B (Allyl Pentaerythritol



Crosslinked); Carbomer Homopolymer Type C (Allyl Pentaerythritol



Crosslinked); Carboxy Vinyl Copolymer; Carboxymethylcellulose;



Carboxymethylcellulose Sodium; Carboxypolymethylene; Carrageenan;



Carrageenan Salt; Castor Oil; Cedar Leaf Oil; Cellulose; Cerasynt-Se;



Ceresin; Ceteareth-12; Ceteareth-15; Ceteareth-30; Cetearyl



Alcohol/Ceteareth-20; Cetearyl Ethylhexanoate; Ceteth-10; Ceteth-2;



Ceteth-20; Ceteth-23; Cetostearyl Alcohol; Cetrimonium Chloride;



Cetyl Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Chlorobutanol;



Chlorocresol; Chloroxylenol; Cholesterol; Choleth-24; Citric Acid;



Citric Acid Monohydrate; Cocamide Ether Sulfate; Cocamine Oxide;



Coco Betaine; Coco Diethanolamide; Coco Monoethanolamide; Cocoa



Butter; Coco-Glycerides; Coconut Oil; Cocoyl Caprylocaprate;



Collagen; Coloring Suspension; Cream Base; Creatinine; Crospovidone;



Cyclomethicone; Cyclomethicone/Dimethicone Copolyol; D&C Red



No. 28; D&C Red No. 33; D&C Red No. 36; D&C Red No. 39; D&C



Yellow No. 10; Decyl Methyl Sulfoxide; Dehydag Wax Sx;



Dehydroacetic Acid; Dehymuls E; Denatonium Benzoate; Dextrin;



Diazolidinyl Urea; Dichlorobenzyl Alcohol; Dichlorodifluoromethane;



Dichlorotetrafluoroethane; Diethanolamine; Diethyl Sebacate;



Diethylene Glycol Monoethyl Ether; Dihydroxyaluminum



Aminoacetate; Diisopropanolamine; Diisopropyl Adipate; Diisopropyl



Dilinoleate; Dimethicone 350; Dimethicone Copolyol; Dimethicone



Medical Fluid 360; Dimethyl Isosorbide; Dimethyl Sulfoxide; Dinoseb



Ammonium Salt; Disodium Cocoamphodiacetate; Disodium Laureth



Sulfosuccinate; Disodium Lauryl Sulfosuccinate; Dmdm Hydantoin;



Docosanol; Docusate Sodium; Edetate Disodium; Edetate Sodium;



Edetic Acid; Entsufon; Entsufon Sodium; Epitetracycline



Hydrochloride; Essence Bouquet 9200; Ethyl Acetate; Ethylcelluloses;



Ethylene Glycol; Ethylenediamine; Ethylenediamine Dihydrochloride;



Ethylhexyl Hydroxystearate; Ethylparaben; Fatty Acid Pentaerythriol



Ester; Fatty Acids; Fatty Alcohol Citrate; Fd&C Blue No. 1; Fd&C Red



No. 4; Fd&C Red No. 40; Fd&C Yellow No. 10 (Delisted); Fd&C



Yellow No. 5; Fd&C Yellow No. 6; Ferric Oxide; Flavor Rhodia



Pharmaceutical No. Rf 451; Formaldehyde; Formaldehyde Solution;



Fractionated Coconut Oil; Fragrance 3949-5; Fragrance 520a; Fragrance



6.007; Fragrance 91-122; Fragrance 9128-Y; Fragrance 93498g;



Fragrance Balsam Pine No. 5124; Fragrance Bouquet 10328; Fragrance



Chemoderm 6401-B; Fragrance Chemoderm 6411; Fragrance Cream



No. 73457; Fragrance Cs-28197; Fragrance Felton 066m; Fragrance



Firmenich 47373; Fragrance Givaudan Ess 9090/1c; Fragrance H-6540;



Fragrance Herbal 10396; Fragrance Nj-1085; Fragrance P O Fl-147;



Fragrance Pa 52805; Fragrance Pera Derm D; Fragrance Rbd-9819;



Fragrance Shaw Mudge U-7776; Fragrance Tf 044078; Fragrance



Ungerer Honeysuckle K 2771; Fragrance Ungerer N5195; Gelatin;



Gluconolactone; Glycerin; Glyceryl Citrate; Glyceryl Isostearate;



Glyceryl Monostearate; Glyceryl Oleate; Glyceryl Oleate/Propylene



Glycol; Glyceryl Palmitate; Glyceryl Ricinoleate; Glyceryl Stearate;



Glyceryl Stearate-Laureth-23; Glyceryl Stearate/Peg-100 Stearate;



Glyceryl Stearate-Stearamidoethyl Diethylamine; Glycol Distearate;



Glycol Stearate; Guar Gum; Hair Conditioner (18n195-1m); Hexylene



Glycol; High Density Polyethylene; Hyaluronate Sodium; Hydrocarbon



Gel, Plasticized; Hydrochloric Acid; Hydrochloric Acid, Diluted;



Hydrogen Peroxide; Hydrogenated Castor Oil; Hydrogenated



Palm/Palm Kernel Oil Peg-6 Esters; Hydroxyethyl Cellulose;



Hydroxymethyl Cellulose; Hydroxyoctacosanyl Hydroxystearate;



Hydroxypropyl Cellulose; Hypromelloses; Imidurea; Irish Moss



Extract; Isobutane; Isoceteth-20; Isooctyl Acrylate; Isopropyl Alcohol;



Isopropyl Isostearate; Isopropyl Myristate; Isopropyl Myristate-



Myristyl Alcohol; Isopropyl Palmitate; Isopropyl Stearate; Isostearic



Acid; Isostearyl Alcohol; Jelene; Kaolin; Kathon Cg; Kathon Cg Ii;



Lactate; Lactic Acid; Lactic Acid, Dl-; Laneth; Lanolin; Lanolin



Alcohol-Mineral Oil; Lanolin Alcohols; Lanolin Anhydrous; Lanolin



Cholesterols; Lanolin, Ethoxylated; Lanolin, Hydrogenated; Lauramine



Oxide; Laurdimonium Hydrolyzed Animal Collagen; Laureth Sulfate;



Laureth-2; Laureth-23; Laureth-4; Lauric Diethanolamide; Lauric



Myristic Diethanolamide; Lauryl Sulfate; Lavandula Angustifolia



Flowering Top; Lecithin; Lecithin Unbleached; Lemon Oil; Light



Mineral Oil; Light Mineral Oil (85 Ssu); Limonene, (+/−)-; Lipocol Sc-



15; Magnesium Aluminum Silicate; Magnesium Aluminum Silicate



Hydrate; Magnesium Nitrate; Magnesium Stearate; Mannitol; Maprofix;



Medical Antiform A-F Emulsion; Menthol; Methyl Gluceth-10; Methyl



Gluceth-20; Methyl Gluceth-20 Sesquistearate; Methyl Glucose



Sesquistearate; Methyl Salicylate; Methyl Stearate; Methylcelluloses;



Methylchloroisothiazolinone; Methylisothiazolinone; Methylparaben;



Microcrystalline Wax; Mineral Oil; Mono And Diglyceride;



Monostearyl Citrate; Multisterol Extract; Myristyl Alcohol; Myristyl



Lactate; Niacinamide; Nitric Acid; Nitrogen; Nonoxynol Iodine;



Nonoxynol-15; Nonoxynol-9; Oatmeal; Octadecene-1/Maleic Acid



Copolymer; Octoxynol-1; Octoxynol-9; Octyldodecanol; Oleic Acid;



Oleth-10/Oleth-5; Oleth-2; Oleth-20; Oleyl Alcohol; Oleyl Oleate;



Olive Oil; Palmitamine Oxide; Parabens; Paraffin; Paraffin, White Soft;



Parfum Creme 45/3; Peanut Oil; Peanut Oil, Refined; Pectin; Peg 6-32



Stearate/Glycol Stearate; Peg-100 Stearate; Peg-12 Glyceryl Laurate;



Peg-120 Glyceryl Stearate; Peg-120 Methyl Glucose Dioleate; Peg-15



Cocamine; Peg-150 Distearate; Peg-2 Stearate; Peg-22 Methyl



Ether/Dodecyl Glycol Copolymer; Peg-25 Propylene Glycol Stearate;



Peg-4 Dilaurate; Peg-4 Laurate; Peg-45/Dodecyl Glycol Copolymer;



Peg-5 Oleate; Peg-50 Stearate; Peg-54 Hydrogenated Castor Oil; Peg-6



Isostearate; Peg-60 Hydrogenated Castor Oil; Peg-7 Methyl Ether; Peg-



75 Lanolin; Peg-8 Laurate; Peg-8 Stearate; Pegoxol 7 Stearate;



Pentaerythritol Cocoate; Peppermint Oil; Perfume 25677; Perfume



Bouquet; Perfume E-1991; Perfume Gd 5604; Perfume Tana 90/42



Scba; Perfume W-1952-1; Petrolatum; Petrolatum, White; Petroleum



Distillates; Phenonip; Phenoxyethanol; Phenylmercuric Acetate;



Phosphoric Acid; Pine Needle Oil (Pinus Sylvestris); Plastibase-50w;



Polidronium Chloride; Poloxamer 124; Poloxamer 181; Poloxamer 182;



Poloxamer 188; Poloxamer 237; Poloxamer 407; Polycarbophil;



Polyethylene Glycol 1000; Polyethylene Glycol 1450; Polyethylene



Glycol 1500; Polyethylene Glycol 1540; Polyethylene Glycol 200;



Polyethylene Glycol 300; Polyethylene Glycol 300-1600; Polyethylene



Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000;



Polyethylene Glycol 540; Polyethylene Glycol 600; Polyethylene



Glycol 6000; Polyethylene Glycol 8000; Polyethylene Glycol 900;



Polyhydroxyethyl Methacrylate; Polyisobutylene; Polyisobutylene



(1100000 Mw); Polyoxyethylene-Polyoxypropylene 1800;



Polyoxyethylene Alcohols; Polyoxyethylene Fatty Acid Esters;



Polyoxyethylene Propylene; Polyoxyl 20 Cetostearyl Ether; Polyoxyl 40



Hydrogenated Castor Oil; Polyoxyl 40 Stearate; Polyoxyl 400 Stearate;



Polyoxyl 6 And Polyoxyl 32 Palmitostearate; Polyoxyl Distearate;



Polyoxyl Glyceryl Stearate; Polyoxyl Lanolin; Polyoxyl Stearate;



Polypropylene; Polyquaternium-10; Polysorbate 20; Polysorbate 40;



Polysorbate 60; Polysorbate 65; Polysorbate 80; Polyvinyl Alcohol;



Potash; Potassium Citrate; Potassium Hydroxide; Potassium Soap;



Potassium Sorbate; Povidone Acrylate Copolymer; Povidone Hydrogel;



Povidone K90; Povidone/Eicosene Copolymer; Povidones; Ppg-



12/Smdi Copolymer; Ppg-15 Stearyl Ether; Ppg-20 Methyl Glucose



Ether Distearate; Ppg-26 Oleate; Product Wat; Promulgen D;



Promulgen G; Propane; Propellant A-46; Propyl Gallate; Propylene



Carbonate; Propylene Glycol; Propylene Glycol Diacetate; Propylene



Glycol Dicaprylate; Propylene Glycol Monopalmitostearate; Propylene



Glycol Palmitostearate; Propylene Glycol Ricinoleate; Propylene



Glycol/Diazolidinyl Urea/Methylparaben/Propylparben; Propylparaben;



Protein Hydrolysate; Quaternium-15; Quaternium-15 Cis-Form;



Quaternium-52; Saccharin; Saccharin Sodium; Safflower Oil; Sd



Alcohol 3a; Sd Alcohol 40; Sd Alcohol 40-2; Sd Alcohol 40b; Sepineo



P 600; Shea Butter; Silicon; Silicon Dioxide; Silicone; Silicone



Adhesive Bio-Psa Q7-4201; Silicone Adhesive Bio-Psa Q7-4301;



Silicone Emulsion; Simethicone; Simethicone Emulsion; Sipon Ls



20 np; Sodium Acetate; Sodium Acetate Anhydrous; Sodium Alkyl



Sulfate; Sodium Benzoate; Sodium Bisulfite; Sodium Borate; Sodium



Cetostearyl Sulfate; Sodium Chloride; Sodium Citrate; Sodium Cocoyl



Sarcosinate; Sodium Dodecylbenzenesulfonate; Sodium Formaldehyde



Sulfoxylate; Sodium Hydroxide; Sodium Iodide; Sodium Lactate;



Sodium Laureth-2 Sulfate; Sodium Laureth-3 Sulfate; Sodium Laureth-5



Sulfate; Sodium Lauroyl Sarcosinate; Sodium Lauryl Sulfate; Sodium



Lauryl Sulfoacetate; Sodium Metabisulfite; Sodium Phosphate; Sodium



Phosphate, Dibasic; Sodium Phosphate, Dibasic, Anhydrous; Sodium



Phosphate, Dibasic, Dihydrate; Sodium Phosphate, Dibasic,



Heptahydrate; Sodium Phosphate, Monobasic; Sodium Phosphate,



Monobasic, Anhydrous; Sodium Phosphate, Monobasic, Dihydrate;



Sodium Phosphate, Monobasic, Monohydrate; Sodium Polyacrylate



(2500000 Mw); Sodium Pyrrolidone Carboxylate; Sodium Sulfite;



Sodium Sulfosuccinated Undecyclenic Monoalkylolamide; Sodium



Thiosulfate; Sodium Xylenesulfonate; Somay 44; Sorbic Acid;



Sorbitan; Sorbitan Isostearate; Sorbitan Monolaurate; Sorbitan



Monooleate; Sorbitan Monopalmitate; Sorbitan Monostearate; Sorbitan



Sesquioleate; Sorbitan Tristearate; Sorbitol; Sorbitol Solution; Soybean



Flour; Soybean Oil; Spearmint Oil; Spermaceti; Squalane; Starch;



Stearalkonium Chloride; Stearamidoethyl Diethylamine; Steareth-10;



Steareth-100; Steareth-2; Steareth-20; Steareth-21; Steareth-40; Stearic



Acid; Stearic Diethanolamide; Stearoxytrimethylsilane; Steartrimonium



Hydrolyzed Animal Collagen; Stearyl Alcohol;



Styrene/Isoprene/Styrene Block Copolymer; Sucrose; Sucrose



Distearate; Sucrose Polyesters; Sulfacetamide Sodium; Sulfuric Acid;



Surfactol Qs; Talc; Tall Oil; Tallow Glycerides; Tartaric Acid; Tenox;



Tenox-2; Tert-Butyl Alcohol; Tert-Butyl Hydroperoxide; Thimerosal;



Titanium Dioxide; Tocopherol; Tocophersolan;



Trichloromonofluoromethane; Trideceth-10; Triethanolamine Lauryl



Sulfate; Triglycerides, Medium Chain; Trihydroxystearin; Trilaneth-4



Phosphate; Trilaureth-4 Phosphate; Trisodium Citrate Dihydrate;



Trisodium Hedta; Triton X-200; Trolamine; Tromethamine; Tyloxapol;



Undecylenic Acid; Vegetable Oil; Vegetable Oil, Hydrogenated;



Viscarin; Vitamin E; Wax, Emulsifying; Wecobee Fs; White Wax;



Xanthan Gum; Zinc Acetate


Transdermal
Acrylates Copolymer; Acrylic Acid-Isooctyl Acrylate Copolymer;



Acrylic Adhesive 788; Adcote 72a103; Aerotex Resin 3730; Alcohol;



Alcohol, Dehydrated; Aluminum Polyester; Bentonite; Butylated



Hydroxytoluene; Butylene Glycol; Butyric Acid; Caprylic/Capric



Triglyceride; Carbomer 1342; Carbomer 940; Carbomer 980;



Carrageenan; Cetylpyridinium Chloride; Citric Acid; Crospovidone;



Daubert 1-5 Pestr (Matte) 164z; Diethylene Glycol Monoethyl Ether;



Diethylhexyl Phthalate **See Cder Guidance: Limiting The Use Of



Certain Phthalates As Excipients In Cder-Regulated Products;



Dimethicone Copolyol; Dimethicone Mdx4-4210; Dimethicone Medical



Fluid 360; Dimethylaminoethyl Methacrylate-Butyl Methacrylate-



Methyl Methacrylate Copolymer; Dipropylene Glycol; Duro-Tak 280-



2516; Duro-Tak 387-2516; Duro-Tak 80-1196; Duro-Tak 87-2070;



Duro-Tak 87-2194; Duro-Tak 87-2287; Duro-Tak 87-2296; Duro-Tak



87-2888; Duro-Tak 87-2979; Edetate Disodium; Ethyl Acetate; Ethyl



Oleate; Ethylcelluloses; Ethylene Vinyl Acetate Copolymer; Ethylene-



Propylene Copolymer; Fatty Acid Esters; Gelva 737; Glycerin; Glyceryl



Laurate; Glyceryl Oleate; Heptane; High Density Polyethylene;



Hydrochloric Acid; Hydrogenated Polybutene 635-690; Hydroxyethyl



Cellulose; Hydroxypropyl Cellulose; Isopropyl Myristate; Isopropyl



Palmitate; Lactose; Lanolin Anhydrous; Lauryl Lactate; Lecithin;



Levulinic Acid; Light Mineral Oil; Medical Adhesive Modified S-15;



Methyl Alcohol; Methyl Laurate; Mineral Oil; Nitrogen; Octisalate;



Octyldodecanol; Oleic Acid; Oleyl Alcohol; Oleyl Oleate;



Pentadecalactone; Petrolatum, White; Polacrilin; Polyacrylic Acid



(250000 Mw); Polybutene (1400 Mw); Polyester; Polyester Polyamine



Copolymer; Polyester Rayon; Polyethylene Terephthalates;



Polyisobutylene; Polyisobutylene (1100000 Mw); Polyisobutylene



(35000 Mw); Polyisobutylene 178-236; Polyisobutylene 241-294;



Polyisobutylene 35-39; Polyisobutylene Low Molecular Weight;



Polyisobutylene Medium Molecular Weight;



Polyisobutylene/Polybutene Adhesive; Polypropylene; Polyvinyl



Acetate; Polyvinyl Alcohol; Polyvinyl Chloride; Polyvinyl Chloride-



Polyvinyl Acetate Copolymer; Polyvinylpyridine; Povidone K29/32;



Povidones; Propylene Glycol; Propylene Glycol Monolaurate; Ra-2397;



Ra-3011; Silicon; Silicon Dioxide, Colloidal; Silicone; Silicone



Adhesive 4102; Silicone Adhesive 4502; Silicone Adhesive Bio-Psa



Q7-4201; Silicone Adhesive Bio-Psa Q7-4301; Silicone/Polyester Film



Strip; Sodium Chloride; Sodium Citrate; Sodium Hydroxide; Sorbitan



Monooleate; Stearalkonium Hectorite/Propylene Carbonate; Titanium



Dioxide; Triacetin; Trolamine; Tromethamine; Union 76 Amsco-Res



6038; Viscose/Cotton


Transmucosal
Magnesium Stearate; Mannitol; Potassium Bicarbonate; Sodium Starch



Glycolate


Ureteral
Benzyl Alcohol; Diatrizoic Acid; Edetate Calcium Disodium; Edetate



Disodium; Hydrochloric Acid; Meglumine; Methylparaben;



Propylparaben; Sodium Citrate; Sodium Hydroxide


Urethral
Diatrizoic Acid; Edetate Calcium Disodium; Edetate Disodium;



Hydrochloric Acid; Meglumine; Methylparaben; Polyethylene Glycol



1450; Propylparaben; Sodium Hydroxide; Sodium Phosphate, Dibasic,



Heptahydrate; Tromethamine


Vaginal
Adipic Acid; Alcohol, Denatured; Allantoin; Anhydrous Lactose;



Apricot Kernel Oil Peg-6 Esters; Barium Sulfate; Beeswax; Bentonite;



Benzoic Acid; Benzyl Alcohol; Butylated Hydroxyanisole; Butylated



Hydroxytoluene; Calcium Lactate; Carbomer 934; Carbomer 934p;



Cellulose, Microcrystalline; Ceteth-20; Cetostearyl Alcohol; Cetyl



Alcohol; Cetyl Esters Wax; Cetyl Palmitate; Cholesterol; Choleth;



Citric Acid; Citric Acid Monohydrate; Coconut Oil/Palm Kernel Oil



Glycerides, Hydrogenated; Crospovidone; Edetate Disodium;



Ethylcelluloses; Ethylene-Vinyl Acetate Copolymer (28% Vinyl



Acetate); Ethylene-Vinyl Acetate Copolymer (9% Vinylacetate); Fatty



Alcohols; Fd&C Yellow No. 5; Gelatin; Glutamic Acid, Dl-; Glycerin;



Glyceryl Isostearate; Glyceryl Monostearate; Glyceryl Stearate; Guar



Gum; High Density Polyethylene; Hydrogel Polymer; Hydrogenated



Palm Oil; Hypromellose 2208 (15000 Mpa · S); Hypromelloses;



Isopropyl Myristate; Lactic Acid; Lactic Acid, Dl-; Lactose; Lactose



Monohydrate; Lactose, Hydrous; Lanolin; Lanolin Anhydrous;



Lecithin; Lecithin, Soybean; Light Mineral Oil; Magnesium Aluminum



Silicate; Magnesium Aluminum Silicate Hydrate; Magnesium Stearate;



Methyl Stearate; Methylparaben; Microcrystalline Wax; Mineral Oil;



Nitric Acid; Octyldodecanol; Peanut Oil; Peg 6-32 Stearate/Glycol



Stearate; Peg-100 Stearate; Peg-120 Glyceryl Stearate; Peg-2 Stearate;



Peg-5 Oleate; Pegoxol 7 Stearate; Petrolatum, White; Phenylmercuric



Acetate; Phospholipon 90 g; Phosphoric Acid; Piperazine Hexahydrate;



Poly(Dimethylsiloxane/Methylvinylsiloxane/Methylhydrogensiloxane)



Dimethylvinyl Or Dimethylhydroxy Or Trimethyl Endblocked;



Polycarbophil; Polyester; Polyethylene Glycol 1000; Polyethylene



Glycol 3350; Polyethylene Glycol 400; Polyethylene Glycol 4000;



Polyethylene Glycol 6000; Polyethylene Glycol 8000; Polyglyceryl-3



Oleate; Polyglyceryl-4 Oleate; Polyoxyl Palmitate; Polysorbate 20;



Polysorbate 60; Polysorbate 80; Polyurethane; Potassium Alum;



Potassium Hydroxide; Povidone K29/32; Povidones; Promulgen D;



Propylene Glycol; Propylene Glycol Monopalmitostearate;



Propylparaben; Quaternium-15 Cis-Form; Silicon Dioxide; Silicon



Dioxide, Colloidal; Silicone; Sodium Bicarbonate; Sodium Citrate;



Sodium Hydroxide; Sodium Lauryl Sulfate; Sodium Metabisulfite;



Sodium Phosphate, Dibasic, Anhydrous; Sodium Phosphate,



Monobasic, Anhydrous; Sorbic Acid; Sorbitan Monostearate; Sorbitol;



Sorbitol Solution; Spermaceti; Stannous 2-Ethylhexanoate; Starch;



Starch 1500, Pregelatinized; Starch, Corn; Stearamidoethyl



Diethylamine; Stearic Acid; Stearyl Alcohol; Tartaric Acid, Dl-; Tert-



Butylhydroquinone; Tetrapropyl Orthosilicate; Trolamine; Urea;



Vegetable Oil, Hydrogenated; Wecobee Fs; White Ceresin Wax; White



Wax









Non-limiting routes of administration for the NAVs of the present invention are described below.


Parenteral and Injectable Administration

Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as CREMOPHOR*, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.


A pharmaceutical composition for parenteral administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for parenteral administration includes hydrochloric acid, mannitol, nitrogen, sodium acetate, sodium chloride and sodium hydroxide.


Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables. The sterile formulation may also comprise adjuvants such as local anesthetics, preservatives and buffering agents.


Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.


Injectable formulations may be for direct injection into a region of a tissue, organ and/or subject. As a non-limiting example, a tissue, organ and/or subject may be directly injected a formulation by intramyocardial injection into the ischemic region. (See e.g., Zangi et al. Nature Biotechnology 2013; the contents of which are herein incorporated by reference in its entirety).


In order to prolong the effect of an active ingredient, it is often desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.


Rectal and Vaginal Administration

Compositions for rectal or vaginal (e.g., transvaginal) administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.


As a non-limiting example, the formulations for rectal and/or vaginal administration may be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and/or vagina to release the drug. Such materials include cocoa butter and polyethylene glycols.


A pharmaceutical composition for rectal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for rectal administration includes alcohol, alcohol, dehydrated, aluminum subacetate, anhydrous citric acid, aniseed oil, ascorbic acid, ascorbyl palmitate, balsam peru, benzoic acid, benzyl alcohol, bismuth subgallate, butylated hydroxyanisole, butylated hydroxytoluene, butylparaben, caramel, carbomer 934, carbomer 934p, carboxypolymethylene, cerasynt-se, cetyl alcohol, cocoa butter, coconut oil, hydrogenated, coconut oil/palm kernel oil glycerides, hydrogenated, cola nitida seed extract, d&c yellow no. 10, dichlorodifluoromethane, dichlorotetrafluoroethane, dimethyldioctadecylammonium bentonite, edetate calcium disodium, edetate disodium, edetic acid, epilactose, ethylenediamine, fat, edible, fat, hard, fd&c blue no. 1, fd&c green no. 3, fd&c yellow no. 6, flavor fig 827118, flavor raspberry pfc-8407, fructose, galactose, glycerin, glyceryl palmitate, glyceryl stearate, glyceryl stearate/peg stearate, glyceryl stearate/peg-40 stearate, glycine, hydrocarbon, hydrochloric acid, hydrogenated palm oil, hypromelloses, lactose, lanolin, lecithin, light mineral oil, magnesium aluminum silicate, magnesium aluminum silicate hydrate, methylparaben, nitrogen, palm kernel oil, paraffin, petrolatum, white, polyethylene glycol 1000, polyethylene glycol 1540, polyethylene glycol 3350, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polysorbate 60, polysorbate 80, potassium acetate, potassium metabisultite, propylene glycol, propylparaben, saccharin sodium, saccharin sodium anhydrous, silicon dioxide, colloidal, simethicone, sodium benzoate, sodium carbonate, sodium chloride, sodium citrate, sodium hydroxide, sodium metabisulfite, sorbitan monooleate, sorbitan sesquioleate, sorbitol, sorbitol solution, starch, steareth-10, steareth-40, sucrose, tagatose, d-, tartaric acid, dl-, trolamine, tromethamine, vegetable oil glyceride, hydrogenated, vegetable oil, hydrogenated, wax, emulsifying, white wax, xanthan gum and zinc oxide.


A pharmaceutical composition for vaginal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for vaginal administration includes adipic acid, alcohol, denatured, allantoin, anhydrous lactose, apricot kernel oil peg-6 esters, barium sulfate, beeswax, bentonite, benzoic acid, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, calcium lactate, carbomer 934, carbomer 934p, cellulose, microcrystalline, ceteth-20, cetostearyl alcohol, cetyl alcohol, cetyl esters wax, cetyl palmitate, cholesterol, choleth, citric acid, citric acid monohydrate, coconut oil/palm kernel oil glycerides, hydrogenated, crospovidone, edetate disodium, ethylcelluloses, ethylene-vinyl acetate copolymer (28% vinyl acetate), ethylene-vinyl acetate copolymer (9% vinylacetate), fatty alcohols, fd&c yellow no. 5, gelatin, glutamic acid, dl-, glycerin, glyceryl isostearate, glyceryl monostearate, glyceryl stearate, guar gum, high density polyethylene, hydrogel polymer, hydrogenated palm oil, hypromellose 2208 (15000 mpa·s), hypromelloses, isopropyl myristate, lactic acid, lactic acid, dl-, lactose, lactose monohydrate, lactose, hydrous, lanolin, lanolin anhydrous, lecithin, lecithin, soybean, light mineral oil, magnesium aluminum silicate, magnesium aluminum silicate hydrate, magnesium stearate, methyl stearate, methylparaben, microcrystalline wax, mineral oil, nitric acid, octyldodecanol, peanut oil, peg 6-32 stearate/glycol stearate, peg-100 stearate, peg-120 glyceryl stearate, peg-2 stearate, peg-5 oleate, pegoxol 7 stearate, petrolatum, white, phenylmercuric acetate, phospholipon 90 g, phosphoric acid, piperazine hexahydrate, poly(dimethylsiloxane/methylvinylsiloxanelmethylhydrogensiloxane) dimethylvinyl or dimethylhydroxy or trimethyl endblocked, polycarbophil, polyester, polyethylene glycol 1000, polyethylene glycol 3350, polyethylene glycol 400, polyethylene glycol 4000, polyethylene glycol 6000, polyethylene glycol 8000, polyglyceryl-3 oleate, polyglyceryl-4 oleate, polyoxyl palmitate, polysorbate 20, polysorbate 60, polysorbate 80, polyurethane, potassium alum, potassium hydroxide, povidone k29/32, povidones, promulgen d, propylene glycol, propylene glycol monopalmitostearate, propylparaben, quaternium-15 cis-form, silicon dioxide, silicon dioxide, colloidal, silicone, sodium bicarbonate, sodium citrate, sodium hydroxide, sodium lauryl sulfate, sodium metabisulfite, sodium phosphate, dibasic, anhydrous, sodium phosphate, monobasic, anhydrous, sorbic acid, sorbitan monostearate, sorbitol, sorbitol solution, spermaceti, stannous 2-ethylhexanoate, starch, starch 1500, pregelatinized, starch, corn, stearamidoethyl diethylamine, stearic acid, stearyl alcohol, tartaric acid, dl-, tert-butylhydroquinone, tetrapropyl orthosilicate, trolamine, urea, vegetable oil, hydrogenated, wecobee fs, white ceresin wax and white wax.


Oral Administration

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents and/or excipients commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as CREMOPHOR*, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.


Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.


Suspensions for oral dosage may contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients may be suspending agents, as a non-limiting example the suspending agents may be sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate; or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.


Oily suspensions for oral dosage can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid


The oral dosage may also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.


Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g. starches, lactose, sucrose, glucose, mannitol, and silicic acid), binders (e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia), humectants (e.g. glycerol), disintegrating agents (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g. paraffin), absorption accelerators (e.g. quaternary ammonium compounds), wetting agents (e.g. cetyl alcohol and glycerol monostearate), absorbents (e.g. kaolin and bentonite clay), and lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate), and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents. The solid dosage forms may also dissolve once they come in contact with liquid such as, but not limited to, salvia and bile.


Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations.


Solid dosage forms may be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.


Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.


Dosage forms for oral delivery may also be chewable or may be suckable (e.g., lozenge form). The chewable dosages forms may be sustained release formulations such as, but not limited to, the sustained release compositions described in International Publication No WO2013082470 and US Publication No US20130142876, each of which is herein incorporated by reference in its entirety. The chewable dosage forms may comprise amphipathic lipids such as, but not limited to, those described in International Publication No WO2013082470 and US Publication No US20130142876, each of which is herein incorporated by reference in its entirety.


Topical or Transdermal Administration

As described herein, compositions containing the NAVs of the invention may be formulated for administration transdermally. The skin may be an ideal target site for delivery as it is readily accessible. Gene expression may be restricted not only to the skin, potentially avoiding nonspecific toxicity, but also to specific layers and cell types within the skin.


The site of cutaneous expression of the delivered compositions will depend on the route of nucleic acid delivery. Two routes are commonly considered to deliver NAVs to the skin: (ii) intradermal injection; and (iii) systemic delivery (e.g. for treatment of dermatologic diseases that affect both cutaneous and extracutaneous regions). NAVs can be delivered to the skin by several different approaches known in the art. After delivery of the nucleic acid, gene products have been detected in a number of different skin cell types, including, but not limited to, basal keratinocytes, sebaceous gland cells, dermal fibroblasts and dermal macrophages.


In one embodiment, the invention provides for the NAV compositions to be delivered in more than one injection.


In one embodiment, before transdermal administration at least one area of tissue, such as skin, may be subjected to a device and/or solution which may increase permeability. In one embodiment, the tissue may be subjected to an abrasion device to increase the permeability of the skin (see U.S. Patent Publication No. 20080275468, herein incorporated by reference in its entirety). In another embodiment, the tissue may be subjected to an ultrasound enhancement device. An ultrasound enhancement device may include, but is not limited to, the devices described in U.S. Publication No. 20040236268 and U.S. Pat. Nos. 6,491,657 and 6,234,990; each of which are herein incorporated by reference in their entireties. Methods of enhancing the permeability of tissue are described in U.S. Publication Nos. 20040171980 and 20040236268 and U.S. Pat. No. 6,190,315; each of which are herein incorporated by reference in their entireties.


In one embodiment, a device may be used to increase permeability of tissue before delivering formulations of modified mRNA described herein. The permeability of skin may be measured by methods known in the art and/or described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety. As a non-limiting example, a modified mRNA formulation may be delivered by the drug delivery methods described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety.


In another non-limiting example tissue may be treated with a eutectic mixture of local anesthetics (EMLA) cream before, during and/or after the tissue may be subjected to a device which may increase permeability. Katz et al. (Anesth Analg (2004); 98:371-76; herein incorporated by reference in its entirety) showed that using the EMLA cream in combination with a low energy, an onset of superficial cutaneous analgesia was seen as fast as 5 minutes after a pretreatment with a low energy ultrasound.


In one embodiment, enhancers may be applied to the tissue before, during, and/or after the tissue has been treated to increase permeability. Enhancers include, but are not limited to, transport enhancers, physical enhancers, and cavitation enhancers. Non-limiting examples of enhancers are described in U.S. Pat. No. 6,190,315, herein incorporated by reference in its entirety.


In one embodiment, a device may be used to increase permeability of tissue before delivering formulations of NAVs described herein, which may further contain a substance that invokes an immune response. In another non-limiting example, a formulation containing a substance to invoke an immune response may be delivered by the methods described in U.S. Publication Nos. 20040171980 and 20040236268; each of which are herein incorporated by reference in their entireties.


Dosage forms for transdermal administration of a composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, an active ingredient is admixed under sterile conditions with a pharmaceutically acceptable excipient and/or any needed preservatives and/or buffers as may be required.


Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms may be prepared, for example, by dissolving and/or dispensing the compound in the proper medium. Alternatively or additionally, rate may be controlled by either providing a rate controlling membrane and/or by dispersing the compound in a polymer matrix and/or gel.


A pharmaceutical NAV composition for transdermal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for transdermal administration includes acrylates copolymer, acrylic acid-isooctyl acrylate copolymer, acrylic adhesive 788, adcote 72a103, aerotex resin 3730, alcohol, alcohol, dehydrated, aluminum polyester, bentonite, butylated hydroxytoluene, butylene glycol, butyric acid, caprylic/capric triglyceride, carbomer 1342, carbomer 940, carbomer 980, carrageenan, cetylpyridinium chloride, citric acid, crospovidone, daubert 1-5 pestr (matte) 164z, diethylene glycol monoethyl ether, diethylhexyl phthalate, dimethicone copolyol, dimethicone mdx4-4210, dimethicone medical fluid 360, dimethylaminoethyl methacrylate-butyl methacrylate-methyl methacrylate copolymer, dipropylene glycol, duro-tak 280-2516, duro-tak 387-2516, duro-tak 80-1196, duro-tak 87-2070, duro-tak 87-2194, duro-tak 87-2287, duro-tak 87-2296, duro-tak 87-2888, duro-tak 87-2979, edetate disodium, ethyl acetate, ethyl oleate, ethylcelluloses, ethylene vinyl acetate copolymer, ethylene-propylene copolymer, fatty acid esters, gelva 737, glycerin, glyceryl laurate, glyceryl oleate, heptane, high density polyethylene, hydrochloric acid, hydrogenated polybutene 635-690, hydroxyethyl cellulose, hydroxypropyl cellulose, isopropyl myristate, isopropyl palmitate, lactose, lanolin anhydrous, lauryl lactate, lecithin, levulinic acid, light mineral oil, medical adhesive modified s-15, methyl alcohol, methyl laurate, mineral oil, nitrogen, octisalate, octyldodecanol, oleic acid, oleyl alcohol, oleyl oleate, pentadecalactone, petrolatum, white, polacrilin, polyacrylic acid (250000 mw), polybutene (1400 mw), polyester, polyester polyamine copolymer, polyester rayon, polyethylene terephthalates, polyisobutylene, polyisobutylene (1100000 mw), polyisobutylene (35000 mw), polyisobutylene 178-236, polyisobutylene 241-294, polyisobutylene 35-39, polyisobutylene low molecular weight, polyisobutylene medium molecular weight, polyisobutylene/polybutene adhesive, polypropylene, polyvinyl acetate, polyvinyl alcohol, polyvinyl chloride, polyvinyl chloride-polyvinyl acetate copolymer, polyvinylpyridine, povidone k29/32, povidones, propylene glycol, propylene glycol monolaurate, ra-2397, ra-3011, silicon, silicon dioxide, colloidal, silicone, silicone adhesive 4102, silicone adhesive 4502, silicone adhesive bio-psa q7-4201, silicone adhesive bio-psa q7-4301, silicone/polyester tilm strip, sodium chloride, sodium citrate, sodium hydroxide, sorbitan monooleate, stearalkonium hectorite/propylene carbonate, titanium dioxide, triacetin, trolamine, tromethamine, union 76 amsco-res 6038 and viscose/cotton.


A pharmaceutical NAV composition for intradermal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intradermal administration includes benzalkonium chloride, benzyl alcohol, carboxymethylcellulose sodium, creatinine, edetate disodium, glycerin, hydrochloric acid, metacresol, methylparaben, phenol, polysorbate 80, protamine sulfate, sodium acetate, sodium bisulfite, sodium chloride, sodium hydroxide, sodium phosphate, sodium phosphate, dibasic, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous and zinc chloride.


Depot Administration

As described herein, in some embodiments, the composition is formulated in depots for extended release. Generally, a specific organ or tissue (a “target tissue”) is targeted for administration.


In some aspects of the invention, the NAVs are spatially retained within or proximal to a target tissue. Provided are method of providing a composition to a target tissue of a mammalian subject by contacting the target tissue (which contains one or more target cells) with the composition under conditions such that the composition, in particular the nucleic acid component(s) of the composition, is substantially retained in the target tissue, meaning that at least 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the composition is retained in the target tissue. Advantageously, retention is determined by measuring the amount of the nucleic acid present in the composition that enters one or more target cells. For example, at least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the nucleic acids administered to the subject are present intracellularly at a period of time following administration. For example, intramuscular injection to a mammalian subject is performed using an aqueous composition containing a ribonucleic acid and a transfection reagent, and retention of the composition is determined by measuring the amount of the ribonucleic acid present in the muscle cells.


Aspects of the invention are directed to methods of providing a composition to a target tissue of a mammalian subject, by contacting the target tissue (containing one or more target cells) with the composition under conditions such that the composition is substantially retained in the target tissue. The composition contains an effective amount of a polynucleotides such that the polypeptide of interest is produced in at least one target cell. The compositions generally contain a cell penetration agent, although “naked” NAV (such as nucleic acids without a cell penetration agent or other agent) is also contemplated, and a pharmaceutically acceptable carrier.


In some circumstances, the amount of a protein produced by cells in a tissue is desirably increased. Preferably, this increase in protein production is spatially restricted to cells within the target tissue. Thus, provided are methods of increasing production of a protein of interest in a tissue of a mammalian subject. A composition is provided that contains polynucleotides characterized in that a unit quantity of composition has been determined to produce the polypeptide of interest in a substantial percentage of cells contained within a predetermined volume of the target tissue.


In some embodiments, the NAV composition includes a plurality of different polynucleotides, where one or more than one of the polynucleotides encodes a polypeptide of interest. Optionally, the composition also contains a cell penetration agent to assist in the intracellular delivery of the composition. A determination is made of the dose of the composition required to produce the polypeptide of interest in a substantial percentage of cells contained within the predetermined volume of the target tissue (generally, without inducing significant production of the polypeptide of interest in tissue adjacent to the predetermined volume, or distally to the target tissue). Subsequent to this determination, the determined dose is introduced directly into the tissue of the mammalian subject.


In one embodiment, the invention provides for the NAVs to be delivered in more than one injection or by split dose injections.


In one embodiment, the invention may be retained near target tissue using a small disposable drug reservoir, patch pump or osmotic pump. Non-limiting examples of patch pumps include those manufactured and/or sold by BD® (Franklin Lakes, NJ), Insulet Corporation (Bedford, MA), SteadyMed Therapeutics (San Francisco, CA), Medtronic (Minneapolis, MN) (e.g., MiniMed), UniLife (York, PA), Valeritas (Bridgewater, NJ), and SpringLeaf Therapeutics (Boston, MA). A non-limiting example of an osmotic pump include those manufactured by DURECT® (Cupertino, CA) (e.g., DUROS® and ALZET®).


Pulmonary Administration

A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 nm to about 7 nm or from about 1 nm to about 6 nm. Such compositions are suitably in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nm and at least 95% of the particles by number have a diameter less than 7 nm. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nm and at least 90% of the particles by number have a diameter less than 6 nm. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.


Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50% to 99.9% (w/w) of the composition, and active ingredient may constitute 0.1% to 20% (w/w) of the composition. A propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).


As a non-limiting example, the NAVs described herein may be formulated for pulmonary delivery by the methods described in U.S. Pat. No. 8,257,685; herein incorporated by reference in its entirety.


Pharmaceutical NAV compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 0.1 nm to about 200 nm.


The compositions and formulations provided herein which may be used for pulmonary delivery may further comprise one or more surfactants. Suitable surfactants or surfactant components for enhancing the uptake of the compositions of the invention include synthetic and natural as well as full and truncated forms of surfactant protein A, surfactant protein B, surfactant protein C, surfactant protein D and surfactant Protein E, di-saturated phosphatidylcholine (other than dipalmitoyl), dipalmitoylphosphatidylcholine, phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, phosphatidylethanolamine, phosphatidylserine; phosphatidic acid, ubiquinones, lysophosphatidylethanolamine, lysophosphatidylcholine, palmitoyl-lysophosphatidylcholine, dehydroepiandrosterone, dolichols, sulfatidic acid, glycerol-3-phosphate, dihydroxyacetone phosphate, glycerol, glycero-3-phosphocholine, dihydroxyacetone, palmitate, cytidine diphosphate (CDP) diacylglycerol, CDP choline, choline, choline phosphate; as well as natural and artificial lamellar bodies which are the natural carrier vehicles for the components of surfactant, omega-3 fatty acids, polyenic acid, polyenoic acid, lecithin, palmitinic acid, non-ionic block copolymers of ethylene or propylene oxides, polyoxypropylene, monomeric and polymeric, polyoxyethylene, monomeric and polymeric, poly(vinyl amine) with dextran and/or alkanoyl side chains, Brij 35. Triton X-100 and synthetic surfactants ALEC, Exosurf, Survan and Atovaquone, among others. These surfactants can be used either as single or part of a multiple component surfactant in a formulation, or as covalently bound additions to the 5′ and/or 3′ ends of the nucleic acid component of a pharmaceutical composition herein.


Intranasal, Nasal and Buccal Administration

Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a NAV pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 sm to 500 μm. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.


Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods and may, for example, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.


A pharmaceutical NAV composition for inhalation (respiratory) administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for inhalation (respiratory) administration includes acetone sodium bisulfite, acetylcysteine, alcohol, alcohol, dehydrated, ammonia, apaflurane, ascorbic acid, benzalkonium chloride, calcium carbonate, carbon dioxide, cetylpyridinium chloride, chlorobutanol, citric acid, d&c yellow no. 10, dichlorodifluoromethane, dichlorotetrafluoroethane, edetate disodium, edetate sodium, fd&c yellow no. 6, fluorochlorohydrocarbons, gelatin, glycerin, glycine, hydrochloric acid, hydrochloric acid, diluted, lactose, lactose monohydrate, lecithin, lecithin, hydrogenated soy, lecithin, soybean, lysine monohydrate, mannitol, menthol, methylparaben, nitric acid, nitrogen, norflurane, oleic acid, polyethylene glycol 1000, povidone k25, propylene glycol, propylparaben, saccharin, saccharin sodium, silicon dioxide, colloidal, sodium bisulfate, sodium bisulfite, sodium chloride, sodium citrate, sodium hydroxide, sodium lauryl sulfate, sodium metabisulfite, sodium sulfate anhydrous, sodium sulfite, sorbitan trioleate, sulfuric acid, thymol, titanium dioxide, trichloromonofluoromethane, tromethamine and zinc oxide.


A pharmaceutical NAV composition for nasal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for nasal administration includes acetic acid, alcohol, dehydrated, allyl .alpha.-ionone, anhydrous dextrose, anhydrous trisodium citrate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, caffeine, carbon dioxide, carboxymethylcellulose sodium, cellulose, microcrystalline, chlorobutanol, citric acid, citric acid monohydrate, dextrose, dichlorodifluoromethane, dichlorotetrafluoroethane, edetate disodium, glycerin, glycerol ester of hydrogenated rosin, hydrochloric acid, hypromellose 2910 (15000 mpa·s), methylcelluloses, methylparaben, nitrogen, norflurane, oleic acid, petrolatum, white, phenylethyl alcohol, polyethylene glycol 3350, polyethylene glycol 400, polyoxyl 400 stearate, polysorbate 20, polysorbate 80, potassium phosphate, monobasic, potassium sorbate, propylene glycol, propylparaben, sodium acetate, sodium chloride, sodium citrate, sodium hydroxide, sodium phosphate, sodium phosphate, dibasic, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, dihydrate, sodium phosphate, dibasic, dodecahydrate, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous, sodium phosphate, monobasic, dihydrate, sorbitan trioleate, sorbitol, sorbitol solution, sucralose, sulfuric acid, trichloromonofluoromethane and trisodium citrate dihydrate.


Ophthalmic and Auricular (Otic) Administration

A pharmaceutical NAV composition may be prepared, packaged, and/or sold in a formulation suitable for delivery to and/or around the eye and/or delivery to the ear (e.g., auricular (otic) administration). Non-limiting examples of route of administration for delivery to and/or around the eye include retrobulbar, conjuctival, intracorneal, intraocular, intravitreal, ophthlamic and subconjuctiva. Such formulations may, for example, be in the form of eye drops or ear drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of any additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention. A multilayer thin film device may be prepared to contain a pharmaceutical composition for delivery to the eye and/or surrounding tissue.


A pharmaceutical NAV composition for ophthalmic administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for ophthalmic administration includes acetic acid, alcohol, alcohol, dehydrated, alginic acid, amerchol-cab, ammonium hydroxide, anhydrous trisodium citrate, antipyrine, benzalkonium chloride, benzethonium chloride, benzododecinium bromide, boric acid, caffeine, calcium chloride, carbomer 1342, carbomer 934p, carbomer 940, carbomer homopolymer type b (allyl pentaerythritol crosslinked), carboxymethylcellulose sodium, castor oil, cetyl alcohol, chlorobutanol, chlorobutanol, anhydrous, cholesterol, citric acid, citric acid monohydrate, creatinine, diethanolamine, diethylhexyl phthalate, divinylbenzene styrene copolymer, edetate disodium, edetate disodium anhydrous, edetate sodium, ethylene vinyl acetate copolymer, gellan gum (low acyl), glycerin, glyceryl stearate, high density polyethylene, hydrocarbon gel, plasticized, hydrochloric acid, hydrochloric acid, diluted, hydroxyethyl cellulose, hydroxypropyl methylcellulose 2906, hypromellose 2910 (15000 mpa·s), hypromelloses, jelene, lanolin, lanolin alcohols, lanolin anhydrous, lanolin nonionic derivatives, lauralkonium chloride, lauroyl sarcosine, light mineral oil, magnesium chloride, mannitol, methylcellulose (4000 mpa·s), methylcelluloses, methylparaben, mineral oil, nitric acid, nitrogen, nonoxynol-9, octoxynol-40, octylphenol polymethylene, petrolatum, petrolatum, white, phenylethyl alcohol, phenylmercuric acetate, phenylmercuric nitrate, phosphoric acid, polidronium chloride, poloxamer 188, poloxamer 407, polycarbophil, polyethylene glycol 300, polyethylene glycol 400, polyethylene glycol 8000, polyoxyethylene-polyoxypropylene 1800, polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 40 stearate, polypropylene glycol, polysorbate 20, polysorbate 60, polysorbate 80, polyvinyl alcohol, potassium acetate, potassium chloride, potassium phosphate, monobasic, potassium sorbate, povidone k29/32, povidone k30, povidone k90, povidones, propylene glycol, propylparaben, soda ash, sodium acetate, sodium bisulfate, sodium bisulfite, sodium borate, sodium borate decahydrate, sodium carbonate, sodium carbonate monohydrate, sodium chloride, sodium citrate, sodium hydroxide, sodium metabisulfite, sodium nitrate, sodium phosphate, sodium phosphate dihydrate, sodium phosphate, dibasic, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, dihydrate, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, sodium phosphate, monobasic, anhydrous, sodium phosphate, monobasic, dihydrate, sodium phosphate, monobasic, monohydrate, sodium sulfate, sodium sulfate anhydrous, sodium sulfate decahydrate, sodium sulfite, sodium thiosulfate, sorbic acid, sorbitan monolaurate, sorbitol, sorbitol solution, stabilized oxychloro complex, sulfuric acid, thimerosal, titanium dioxide, tocophersolan, trisodium citrate dihydrate, triton 720, tromethamine, tyloxapol and zinc chloride.


A pharmaceutical NAV composition for retrobulbar administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for retrobulbar administration includes hydrochloric acid and sodium hydroxide.


A pharmaceutical NAV composition for intraocular administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intraocular administration includes benzalkonium chloride, calcium chloride, citric acid monohydrate, hydrochloric acid, magnesium chloride, polyvinyl alcohol, potassium chloride, sodium acetate, sodium chloride, sodium citrate and sodium hydroxide.


A pharmaceutical NAV composition for intravitreal administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for intravitreal administration includes calcium chloride, carboxymethylcellulose sodium, cellulose, microcrystalline, hyaluronate sodium, hydrochloric acid, magnesium chloride, magnesium stearate, polysorbate 80, polyvinyl alcohol, potassium chloride, sodium acetate, sodium bicarbonate, sodium carbonate, sodium chloride, sodium hydroxide, sodium phosphate dibasic heptahydrate, sodium phosphate monobasic monohydrate and trisodium citrate dehydrate.


A pharmaceutical NAV composition for subconjunctival administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for subconjunctival administration includes benzyl alcohol, hydrochloric acid and sodium hydroxide.


A pharmaceutical NAV composition for auricular administration may comprise at least one inactive ingredient. Any or none of the inactive ingredients used may have been approved by the US Food and Drug Administration (FDA). A non-exhaustive list of inactive ingredients for use in pharmaceutical compositions for auricular administration includes acetic acid, aluminum acetate, aluminum sulfate anhydrous, benzalkonium chloride, benzethonium chloride, benzyl alcohol, boric acid, calcium carbonate, cetyl alcohol, chlorobutanol, chloroxylenol, citric acid, creatinine, cupric sulfate, cupric sulfate anhydrous, edetate disodium, edetic acid, glycerin, glyceryl stearate, hydrochloric acid, hydrocortisone, hydroxyethyl cellulose, isopropyl myristate, lactic acid, lecithin, hydrogenated, methylparaben, mineral oil, petrolatum, petrolatum, white, phenylethyl alcohol, polyoxyl 40 stearate, polyoxyl stearate, polysorbate 20, polysorbate 80, polyvinyl alcohol, potassium metabisulfite, potassium phosphate, monobasic, povidone k90f, povidones, propylene glycol, propylene glycol diacetate, propylparaben, sodium acetate, sodium bisulfite, sodium borate, sodium chloride, sodium citrate, sodium hydroxide, sodium phosphate, dibasic, anhydrous, sodium phosphate, dibasic, heptahydrate, sodium phosphate, monobasic, anhydrous, sodium sulfite, sulfuric acid and thimerosal.


Payload Administration: Detectable Agents and Therapeutic Agents

The NAVs described herein can be used in a number of different scenarios in which delivery of a substance (the “payload”) to a biological target is desired, for example delivery of detectable substances for detection of the target, or delivery of a therapeutic agent. Detection methods can include, but are not limited to, both imaging in vitro and in vivo imaging methods, e.g., immunohistochemistry, bioluminescence imaging (BLI), Magnetic Resonance Imaging (MRI), positron emission tomography (PET), electron microscopy, X-ray computed tomography, Raman imaging, optical coherence tomography, absorption imaging, thermal imaging, fluorescence reflectance imaging, fluorescence microscopy, fluorescence molecular tomographic imaging, nuclear magnetic resonance imaging, X-ray imaging, ultrasound imaging, photoacoustic imaging, lab assays, or in any situation where tagging/staining/imaging is required.


NAVs described herein can be used in intracellular targeting of a payload, e.g., detectable or therapeutic agent, to specific organelle. Exemplary intracellular targets can include, but are not limited to, the nuclear localization for advanced mRNA processing, or a nuclear localization sequence (NLS) linked to the mRNA containing an inhibitor.


In addition, the NAVs described herein can be used to deliver therapeutic agents to cells or tissues, e.g., in living animals. For example, the NAVs described herein can be used to deliver highly polar chemotherapeutics agents to kill cancer cells. The NAVs attached to the therapeutic agent through a linker can facilitate member permeation allowing the therapeutic agent to travel into a cell to reach an intracellular target.


In some embodiments, the payload may be a therapeutic agent such as a cytotoxin, radioactive ion, chemotherapeutic, or other therapeutic agent. A cytotoxin or cytotoxic agent includes any agent that may be detrimental to cells. Examples include, but are not limited to, taxol, cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin, etoposide, teniposide, vincristine, vinblastine, colchicine, doxorubicin, daunorubicin, dihydroxyanthracinedione, mitoxantrone, mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids, procaine, tetracaine, lidocaine, propranolol, puromycin, maytansinoids, e.g., maytansinol (see U.S. Pat. No. 5,208,020 incorporated herein in its entirety), rachelmycin (CC-1065, see U.S. Pat. Nos. 5,475,092, 5,585,499, and 5,846,545, all of which are incorporated herein by reference), and analogs or homologs thereof. Radioactive ions include, but are not limited to iodine (e.g., iodine 125 or iodine 131), strontium 89, phosphorous, palladium, cesium, iridium, phosphate, cobalt, yttrium 90, samarium 153, and praseodymium. Other therapeutic agents include, but are not limited to, antimetabolites (e.g., methotrexate, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-fluorouracil decarbazine), alkylating agents (e.g., mechlorethamine, thiotepa chlorambucil, rachelmycin (CC-1065), melphalan, carmustine (BSNU), lomustine (CCNU), cyclophosphamide, busulfan, dibromomannitol, streptozotocin, mitomycin C, and cis-dichlorodiamine platinum (11) (DDP) cisplatin), anthracyclines (e.g., daunorubicin (formerly daunomycin) and doxorubicin), antibiotics (e.g., dactinomycin (formerly actinomycin), bleomycin, mithramycin, and anthramycin (AMC)), and anti-mitotic agents (e.g., vincristine, vinblastine, taxol and maytansinoids).


In some embodiments, the payload may be a detectable agent, such as various organic small molecules, inorganic compounds, nanoparticles, enzymes or enzyme substrates, fluorescent materials, luminescent materials (e.g., luminol), bioluminescent materials (e.g., luciferase, luciferin, and aequorin), chemiluminescent materials, radioactive materials (e.g., 18F, 67Ga, 81mKr, 82Rb, 111In, 123I, 33Xe, 201Tl, 125I, 35S, 14C, 3H, or 99mTc (e.g., as pertechnetate (technetate(VII), TcO4), and contrast agents (e.g., gold (e.g., gold nanoparticles), gadolinium (e.g., chelated Gd), iron oxides (e.g., superparamagnetic iron oxide (SPIO), monocrystalline iron oxide nanoparticles (MIONs), and ultrasmall superparamagnetic iron oxide (USPIO)), manganese chelates (e.g., Mn-DPDP), barium sulfate, iodinated contrast media (iohexol), microbubbles, or perfluorocarbons). Such optically-detectable labels include for example, without limitation, 4-acetamido-4′-isothiocyanatostilbene-2,2′disulfonic acid; acridine and derivatives (e.g., acridine and acridine isothiocyanate); 5-(2′-aminoethyl)aminonaphthalene-1-sulfonic acid (EDANS); 4-amino-N-[3-vinylsulfonyl)phenyl]naphthalimide-3,5 disulfonate; N-(4-anilino-1-naphthyl)maleimide; anthranilamide; BODIPY; Brilliant Yellow; coumarin and derivatives (e.g., coumarin, 7-amino-4-methylcoumarin (AMC, Coumarin 120), and 7-amino-4-trifluoromethylcoumarin (Coumarin 151)); cyanine dyes; cyanosine; 4′,6-diaminidino-2-phenylindole (DAPI); 5′ 5″-dibromopyrogallol-sulfonaphthalein (Bromopyrogallol Red); 7-diethylamino-3-(4′-isothiocyanatophenyl)-4-methylcoumarin; diethylenetriamine pentaacetate; 4,4′-diisothiocyanatodihydro-stilbene-2,2′-disulfonic acid; 4,4′-diisothiocyanatostilbene-2,2′-disulfonic acid; 5-[dimethylamino]-naphthalene-1-sulfonyl chloride (DNS, dansylchloride); 4-dimethylaminophenylazophenyl-4′-isothiocyanate (DABITC); eosin and derivatives (e.g., eosin and eosin isothiocyanate); erythrosin and derivatives (e.g., erythrosin B and erythrosin isothiocyanate); ethidium; fluorescein and derivatives (e.g., 5-carboxyfluorescein (FAM), 5-(4,6-dichlorotriazin-2-yl)aminofluorescein (DTAF), 2′,7′-dimethoxy-4′5′-dichloro-6-carboxyfluorescein, fluorescein, fluorescein isothiocyanate, X-rhodamine-5-(and-6)-isothiocyanate (QFITC or XRITC), and fluorescamine); 2-[2-[3-[[1,3-dihydro-1,1-dimethyl-3-(3-sulfopropyl)-2H-benz[e]indol-2-ylidene]ethylidene]-2-[4-(ethoxycarbonyl)-1-piperazinyl]-1-cyclopenten-1-yl]ethenyl]-1,1-dimethyl-3-(3-sulforpropyl)-1H-benz[e]indolium hydroxide, inner salt, compound with n,n-diethylethanamine(1:1) (IR144); 5-chloro-2-[2-[3-[(5-chloro-3-ethyl-2(3H)-benzothiazol-ylidene)ethylidene]-2-(diphenylamino)-1-cyclopenten-1-yl]ethenyl]-3-ethyl benzothiazolium perchlorate (IR140); Malachite Green isothiocyanate; 4-methylumbelliferone orthocresolphthalein; nitrotyrosine; pararosaniline; Phenol Red; B-phycoerythrin; o-phthaldialdehyde; pyrene and derivatives (e.g., pyrene, pyrene butyrate, and succinimidyl 1-pyrene); butyrate quantum dots; Reactive Red 4 (CIBACRON™ Brilliant Red 3B-A); rhodamine and derivatives (e.g., 6-carboxy-X-rhodamine (ROX), 6-carboxyrhodamine (R6G), lissamine rhodamine B sulfonyl chloride rhodarnine (Rhod), rhodamine B, rhodamine 123, rhodamine X isothiocyanate, sulforhodamine B, sulforhodamine 101, sulfonyl chloride derivative of sulforhodamine 101 (Texas Red), N,N,N′,N′tetramethyl-6-carboxyrhodamine (TAMRA) tetramethyl rhodamine, and tetramethyl rhodamine isothiocyanate (TRITC)); riboflavin; rosolic acid; terbium chelate derivatives; Cyanine-3 (Cy3); Cyanine-5 (Cy5); cyanine-5.5 (Cy5.5), Cyanine-7 (Cy7); IRD 700; IRD 800; Alexa 647; La Jolta Blue; phthalo cyanine; and naphthalo cyanine.


In some embodiments, the detectable agent may be a non-detectable precursor that becomes detectable upon activation (e.g., fluorogenic tetrazine-fluorophore constructs (e.g., tetrazine-BODIPY FL, tetrazine-Oregon Green 488, or tetrazine-BODIPY TMR-X) or enzyme activatable fluorogenic agents (e.g., PROSENSE® (VisEn Medical))). In vitro assays in which the enzyme labeled compositions can be used include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), immunoprecipitation assays, immunofluorescence, enzyme immunoassays (EIA), radioimmunoassays (RIA), and Western blot analysis.


Combinations

The NAVs may be used in combination with one or more other therapeutic, prophylactic, diagnostic, or imaging agents. By “in combination with,” it is not intended to imply that the agents must be administered at the same time and/or formulated for delivery together, although these methods of delivery are within the scope of the present disclosure. Compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. In general, each agent will be administered at a dose and/or on a time schedule determined for that agent. In some embodiments, the present disclosure encompasses the delivery of pharmaceutical, prophylactic, diagnostic, or imaging compositions in combination with agents that may improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body.


The combinations can conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical compositions comprising a combination as defined above together with a pharmaceutically acceptable diluent or carrier represent a further aspect of the invention.


The individual compounds of such combinations can be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. In one embodiment, the individual compounds will be administered simultaneously in a combined pharmaceutical formulation.


It will further be appreciated that therapeutically, prophylactically, diagnostically, or imaging active agents utilized in combination may be administered together in a single composition or administered separately in different compositions. In general, it is expected that agents utilized in combination with be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. In one embodiment, the combinations, each or together may be administered according to the split dosing regimens described herein.


Dosing

The present invention provides methods comprising administering NAVs and in accordance with the invention to a subject in need thereof. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like. Compositions in accordance with the invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention may be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective, prophylactically effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.


In certain embodiments, compositions in accordance with the present invention may be administered at dosage levels sufficient to deliver from about 0.0001 mg/kg to about 100 mg/kg, from about 0.001 mg/kg to about 0.05 mg/kg, from about 0.005 mg/kg to about 0.05 mg/kg, from about 0.001 mg/kg to about 0.005 mg/kg, from about 0.05 mg/kg to about 0.5 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, or from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic, diagnostic, prophylactic, or imaging effect (see e.g., the range of unit doses described in International Publication No WO2013078199, herein incorporated by reference in its entirety). The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). When multiple administrations are employed, split dosing regimens such as those described herein may be used.


According to the present invention, NAVs may be administered in split-dose regimens. As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses, e.g, two or more administrations of the single unit dose. As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event. As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose. In one embodiment, the NAVs of the present invention are administered to a subject in split doses. The NAVs may be formulated in buffer only or in a formulation described herein.


Dosage Forms

A NAV pharmaceutical composition described herein can be formulated into a dosage form described herein, such as an intranasal, intratracheal, or injectable (e.g., intravenous, intraocular, intravitreal, intramuscular, intracardiac, intraperitoneal, subcutaneous).


Liquid Dosage Forms

Liquid dosage forms for parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art including, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In certain embodiments for parenteral administration, compositions may be mixed with solubilizing agents such as CREMOPHOR*, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and/or combinations thereof.


Injectable

Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art and may include suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed include, but are not limited to, water, Ringer's solution. U.S.P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables.


Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.


In order to prolong the effect of an active ingredient, it may be desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the NAVs then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered NAV may be accomplished by dissolving or suspending the NAVs in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the NAVs in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of NAVs to polymer and the nature of the particular polymer employed, the rate of polynucleotides release can be controlled. Examples of other biodegradable polymers include, but are not limited to, poly(orthoesters) and poly(anhydrides). Depot injectable formulations may be prepared by entrapping the NAVs in liposomes or microemulsions which are compatible with body tissues.


Pulmonary

Formulations described herein as being useful for pulmonary delivery may also be used for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration may be a coarse powder comprising the active ingredient and having an average particle from about 0.2 μm to 500 μm. Such a formulation may be administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose.


Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may, for example, contain about 0.1% to 20% (w/w) active ingredient, where the balance may comprise an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 nm, and may further comprise one or more of any additional ingredients described herein.


General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference in its entirety).


Coatings or Shells

Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.


Multi-Dose and Repeat-Dose Administration

In some embodiments, NAV compounds and/or compositions of the present invention may be administered in two or more doses (referred to herein as “multi-dose administration”). Such doses may comprise the same components or may comprise components not included in a previous dose. Such doses may comprise the same mass and/or volume of components or an altered mass and/or volume of components in comparison to a previous dose. In some embodiments, multi-dose administration may comprise repeat-dose administration. As used herein, the term “repeat-dose administration” refers to two or more doses administered consecutively or within a regimen of repeat doses comprising substantially the same components provided at substantially the same mass and/or volume. In some embodiments, subjects may display a repeat-dose response. As used herein, the term “repeat-dose response” refers to a response in a subject to a repeat-dose that differs from that of another dose administered within a repeat-dose administration regimen. In some embodiments, such a response may be the expression of a protein in response to a repeat-dose comprising NAV. In such embodiments, protein expression may be elevated in comparison to another dose administered within a repeat-dose administration regimen or protein expression may be reduced in comparison to another dose administered within a repeat-dose administration regimen. Alteration of protein expression may be from about 1% to about 20%, from about 5% to about 50% from about 10% to about 60%, from about 25% to about 75%, from about 40% to about 100% and/or at least 100%. A reduction in expression of mRNA administered as part of a repeat-dose regimen, wherein the level of protein translated from the administered RNA is reduced by more than 40% in comparison to another dose within the repeat-dose regimen is referred to herein as “repeat-dose resistance.”


Properties of the Pharmaceutical Compositions

The NAV pharmaceutical compositions described herein can be characterized by one or more of the following properties:


Bioavailability

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an increase in bioavailability as compared to a composition lacking a delivery agent as described herein. As used herein, the term “bioavailability” refers to the systemic availability of a given amount of NAVs administered to a mammal. Bioavailability can be assessed by measuring the area under the curve (AUC) or the maximum serum or plasma concentration (Cmax) of the unchanged form of a compound following administration of the compound to a mammal. AUC is a determination of the area under the curve plotting the serum or plasma concentration of a compound along the ordinate (Y-axis) against time along the abscissa (X-axis). Generally, the AUC for a particular compound can be calculated using methods known to those of ordinary skill in the art and as described in G. S. Banker, Modern Pharmaceutics, Drugs and the Pharmaceutical Sciences, v. 72, Marcel Dekker, New York, Inc., 1996, herein incorporated by reference in its entirety.


The Cmax value is the maximum concentration of the compound achieved in the serum or plasma of a mammal following administration of the compound to the mammal. The Cam value of a particular compound can be measured using methods known to those of ordinary skill in the art. The phrases “increasing bioavailability” or “improving the pharmacokinetics,” as used herein mean that the systemic availability of a first NAV, measured as AUC, Cmax, or Cmin in a mammal is greater, when co-administered with a delivery agent as described herein, than when such co-administration does not take place. In some embodiments, the bioavailability of the NAVs can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.


In some embodiments, liquid formulations of NAVs may have varying in vivo half-life, requiring modulation of doses to yield a therapeutic effect. To address this, in some embodiments of the present invention, NAV formulations may be designed to improve bioavailability and/or therapeutic effect during repeat administrations. Such formulations may enable sustained release of NAVs and/or reduce NAV degradation rates by nucleases. In some embodiments, suspension formulations are provided comprising NAVs, water immiscible oil depots, surfactants and/or co-surfactants and/or co-solvents. Combinations of oils and surfactants may enable suspension formulation with NAVs. Delivery of NAVs in a water immiscible depot may be used to improve bioavailability through sustained release of polynucleotides from the depot to the surrounding physiologic environment and/or prevent polynucleotide degradation by nucleases.


In some embodiments, cationic nanoparticles comprising combinations of divalent and monovalent cations may be formulated with NAVs. Such nanoparticles may form spontaneously in solution over a given period (e.g. hours, days, etc). Such nanoparticles do not form in the presence of divalent cations alone or in the presence of monovalent cations alone. The delivery of NAVs in cationic nanoparticles or in one or more depot comprising cationic nanoparticles may improve NAV bioavailability by acting as a long-acting depot and/or reducing the rate of degradation by nucleases.


Therapeutic Window

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an increase in the therapeutic window of the administered NAV composition as compared to the therapeutic window of the administered NAV composition lacking a delivery agent as described herein. As used herein “therapeutic window” refers to the range of plasma concentrations, or the range of levels of therapeutically active substance at the site of action, with a high probability of eliciting a therapeutic effect. In some embodiments, the therapeutic window of the NAVs when co-administered with a delivery agent as described herein can increase by at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%.


Volume of Distribution

The NAVs, when formulated into a composition with a delivery agent as described herein, can exhibit an improved volume of distribution (Vdist), e.g., reduced or targeted, relative to a composition lacking a delivery agent as described herein. The volume of distribution (Vdist) relates the amount of the drug in the body to the concentration of the drug in the blood or plasma. As used herein, the term “volume of distribution” refers to the fluid volume that would be required to contain the total amount of the drug in the body at the same concentration as in the blood or plasma: Vdist equals the amount of drug in the body/concentration of drug in blood or plasma. For example, for a 10 mg dose and a plasma concentration of 10 mg/L, the volume of distribution would be 1 liter. The volume of distribution reflects the extent to which the drug is present in the extravascular tissue. A large volume of distribution reflects the tendency of a compound to bind to the tissue components compared with plasma protein binding. In a clinical setting, Vdist can be used to determine a loading dose to achieve a steady state concentration. In some embodiments, the volume of distribution of the NAVs when co-administered with a delivery agent as described herein can decrease at least about 2%, at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%.


Biological Effect

In one embodiment, the biological effect of the NAV delivered to the animals may be categorized by analyzing the protein expression in the animals. The protein expression may be determined from analyzing a biological sample collected from a mammal administered the NAV of the present invention


Detection of Polynucleotides by Mass Spectrometry

Mass spectrometry (MS) is an analytical technique that can provide structural and molecular mass/concentration information on molecules after their conversion to ions. The molecules are first ionized to acquire positive or negative charges and then they travel through the mass analyzer to arrive at different areas of the detector according to their mass/charge (m/z) ratio.


Mass spectrometry is performed using a mass spectrometer which includes an ion source for ionizing the fractionated sample and creating charged molecules for further analysis. For example ionization of the sample may be performed by electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), photoionization, electron ionization, fast atom bombardment (FAB)/liquid secondary ionization (LSIMS), matrix assisted laser desorption/ionization (MALDI), field ionization, field desorption, thermospray/plasmaspray ionization, and particle beam ionization. The skilled artisan will understand that the choice of ionization method can be determined based on the analyte to be measured, type of sample, the type of detector, the choice of positive versus negative mode, etc.


After the sample has been ionized, the positively charged or negatively charged ions thereby created may be analyzed to determine a mass-to-charge ratio (i.e., m/z). Suitable analyzers for determining mass-to-charge ratios include quadropole analyzers, ion traps analyzers, and time-of-flight analyzers. The ions may be detected using several detection modes. For example, selected ions may be detected (i.e., using a selective ion monitoring mode (SIM)), or alternatively, ions may be detected using a scanning mode, e.g., multiple reaction monitoring (MRM) or selected reaction monitoring (SRM).


Liquid chromatography-multiple reaction monitoring (LC-MS/MRM) coupled with stable isotope labeled dilution of peptide standards has been shown to be an effective method for protein verification (e.g., Keshishian et al., Mol Cell Proteomics 2009 8: 2339-2349; Kuhn et al., Clin Chem 2009 55:1108-1117; Lopez et al., Clin Chem 2010 56:281-290; each of which are herein incorporated by reference in its entirety). Unlike untargeted mass spectrometry frequently used in biomarker discovery studies, targeted MS methods are peptide sequence-based modes of MS that focus the full analytical capacity of the instrument on tens to hundreds of selected peptides in a complex mixture. By restricting detection and fragmentation to only those peptides derived from proteins of interest, sensitivity and reproducibility are improved dramatically compared to discovery-mode MS methods. This method of mass spectrometry-based multiple reaction monitoring (MRM) quantitation of proteins can dramatically impact the discovery and quantitation of biomarkers via rapid, targeted, multiplexed protein expression profiling of clinical samples.


In one embodiment, a biological sample which may contain at least one protein encoded by at least one modified mRNA of the present invention may be analyzed by the method of MRM-MS. The quantification of the biological sample may further include, but is not limited to, isotopically labeled peptides or proteins as internal standards.


According to the present invention, the biological sample, once obtained from the subject, may be subjected to enzyme digestion. As used herein, the term “digest” means to break apart into shorter peptides. As used herein, the phrase “treating a sample to digest proteins” means manipulating a sample in such a way as to break down proteins in a sample. These enzymes include, but are not limited to, trypsin, endoproteinase Glu-C and chymotrypsin. In one embodiment, a biological sample which may contain at least one protein encoded by at least one modified mRNA of the present invention may be digested using enzymes.


In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed for protein using electrospray ionization. Electrospray ionization (ESI) mass spectrometry (ESIMS) uses electrical energy to aid in the transfer of ions from the solution to the gaseous phase before they are analyzed by mass spectrometry. Samples may be analyzed using methods known in the art (e.g., Ho et al., Clin Biochem Rev. 2003 24(1):3-12; herein incorporated by reference in its entirety). The ionic species contained in solution may be transferred into the gas phase by dispersing a fine spray of charge droplets, evaporating the solvent and ejecting the ions from the charged droplets to generate a mist of highly charged droplets. The mist of highly charged droplets may be analyzed using at least 1, at least 2, at least 3 or at least 4 mass analyzers such as, but not limited to, a quadropole mass analyzer. Further, the mass spectrometry method may include a purification step. As a non-limiting example, the first quadrapole may be set to select a single m/z ratio so it may filter out other molecular ions having a different m/z ratio which may eliminate complicated and time-consuming sample purification procedures prior to MS analysis.


In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed for protein in a tandem ESIMS system (e.g., MS/MS). As non-limiting examples, the droplets may be analyzed using a product scan (or daughter scan) a precursor scan (parent scan) a neutral loss or a multiple reaction monitoring.


In one embodiment, a biological sample which may contain protein encoded by modified mRNA of the present invention may be analyzed using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry (MALDIMS). MALDI provides for the nondestructive vaporization and ionization of both large and small molecules, such as proteins. In MALDI analysis, the analyte is first co-crystallized with a large molar excess of a matrix compound, which may also include, but is not limited to, an ultraviolet absorbing weak organic acid. Non-limiting examples of matrices used in MALDI are α-cyano-4-hydroxycinnamic acid, 3,5-dimethoxy-4-hydroxycinnamic acid and 2,5-dihydroxybenzoic acid. Laser radiation of the analyte-matrix mixture may result in the vaporization of the matrix and the analyte. The laser induced desorption provides high ion yields of the intact analyte and allows for measurement of compounds with high accuracy. Samples may be analyzed using methods known in the art (e.g., Lewis, Wei and Siuzdak, Encyclopedia of Analytical Chemistry 2000:5880-5894; herein incorporated by reference in its entirety). As non-limiting examples, mass analyzers used in the MALDI analysis may include a linear time-of-flight (TOF), a TOF reflectron or a Fourier transform mass analyzer.


In one embodiment, the analyte-matrix mixture may be formed using the dried-droplet method. A biologic sample is mixed with a matrix to create a saturated matrix solution where the matrix-to-sample ratio is approximately 5000:1. An aliquot (approximately 0.5-2.0 uL) of the saturated matrix solution is then allowed to dry to form the analyte-matrix mixture.


In one embodiment, the analyte-matrix mixture may be formed using the thin-layer method. A matrix homogeneous film is first formed and then the sample is then applied and may be absorbed by the matrix to form the analyte-matrix mixture.


In one embodiment, the analyte-matrix mixture may be formed using the thick-layer method. A matrix homogeneous film is formed with a nitro-cellulose matrix additive. Once the uniform nitro-cellulose matrix layer is obtained the sample is applied and absorbed into the matrix to form the analyte-matrix mixture.


In one embodiment, the analyte-matrix mixture may be formed using the sandwich method. A thin layer of matrix crystals is prepared as in the thin-layer method followed by the addition of droplets of aqueous trifluoroacetic acid, the sample and matrix. The sample is then absorbed into the matrix to form the analyte-matrix mixture.


VI. Kits and Devices
Kits

The invention provides a variety of kits for conveniently and/or effectively carrying out methods of the present invention. Typically kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.


In one aspect, the present invention provides kits comprising the NAV molecules (including any proteins or polynucleotides) of the invention. In one embodiment, the kit comprises one or more functional antigens or function fragments thereof.


The kits can be for protein production, comprising a first polynucleotides comprising a translatable region of an antigen. The kit may further comprise packaging and instructions and/or a delivery agent to form a formulation composition. The delivery agent may comprise a saline, a buffered solution, a lipidoid or any delivery agent disclosed herein.


In one embodiment, the buffer solution may include sodium chloride, calcium chloride, phosphate and/or EDTA. In another embodiment, the buffer solution may include, but is not limited to, saline, saline with 2 mM calcium, 5% sucrose, 5% sucrose with 2 mM calcium, 5% Mannitol, 5% Mannitol with 2 mM calcium, Ringer's lactate, sodium chloride, sodium chloride with 2 mM calcium and mannose (See e.g., U.S. Pub. No. 20120258046; herein incorporated by reference in its entirety). In a further embodiment, the buffer solutions may be precipitated or it may be lyophilized. The amount of each component may be varied to enable consistent, reproducible higher concentration saline or simple buffer formulations.


The components may also be varied in order to increase the stability of polynucleotides in the buffer solution over a period of time and/or under a variety of conditions.


In one aspect, the present invention provides kits for protein production, comprising: a polynucleotide comprising a translatable region, provided in an amount effective to produce a desired amount of a protein encoded by the translatable region when introduced into a target cell; a second polynucleotide comprising an inhibitory nucleic acid, provided in an amount effective to substantially inhibit the innate immune response of the cell; and packaging and instructions.


In one aspect, the present invention provides kits for protein production, comprising a polynucleotide comprising a translatable region, wherein the polynucleotide exhibits reduced degradation by a cellular nuclease, and packaging and instructions.


In one aspect, the present invention provides kits for protein production, comprising a polynucleotide comprising a translatable region, wherein the polynucleotide exhibits reduced degradation by a cellular nuclease, and a mammalian cell suitable for translation of the translatable region of the first nucleic acid.


Devices

The present invention provides for devices which may incorporate RNAVs comprising polynucleotides that encode polypeptides of interest, e.g., encode antigenic polypeptides. These devices contain in a stable formulation the reagents to synthesize a polynucleotide in a formulation available to be immediately delivered to a subject in need thereof, such as a human patient.


Devices for administration may be employed to deliver the NAVs of the present invention according to single, multi- or split-dosing regimens taught herein. Such devices are taught in, for example, International Application PCT/US2013/30062 filed Mar. 9, 2013 (Attorney Docket Number M300), the contents of which are incorporated herein by reference in their entirety.


Method and devices known in the art for multi-administration to cells, organs and tissues are contemplated for use in conjunction with the methods and compositions disclosed herein as embodiments of the present invention. These include, for example, those methods and devices having multiple needles, hybrid devices employing for example lumens or catheters as well as devices utilizing heat, electric current or radiation driven mechanisms.


According to the present invention, these multi-administration devices may be utilized to deliver the single, multi- or split doses contemplated herein. Such devices are taught for example in, International Application PCT/US2013/30062 filed Mar. 9, 2013 (Attorney Docket Number M300), the contents of which are incorporated herein by reference in their entirety.


In one embodiment, the NAV is administered subcutaneously or intramuscularly via at least 3 needles to three different, optionally adjacent, sites simultaneously, or within a 60 minutes period (e.g., administration to 4, 5, 6, 7, 8, 9, or 10 sites simultaneously or within a 60 minute period).


Methods and Devices Utilizing Catheters and/or Lumens


Methods and devices using catheters and lumens may be employed to administer the NAVs of the present invention on a single, multi- or split dosing schedule. Such methods and devices are described in International Application PCT/US2013/30062 filed Mar. 9, 2013 (Attorney Docket Number M300), the contents of which are incorporated herein by reference in their entirety.


Methods and Devices Utilizing Electrical Current

Methods and devices utilizing electric current may be employed to deliver the NAVs of the present invention according to the single, multi- or split dosing regimens taught herein. Such methods and devices are described in International Application PCT/US2013/30062 filed Mar. 9, 2013 (Attorney Docket Number M300), the contents of which are incorporated herein by reference in their entirety.


VII. Definitions

At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, Cs alkyl, and C6 alkyl. Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional.


About: As used herein, the term “about” means+/−10% of the recited value.


Administered in combination: As used herein, the term “administered in combination” or “combined administration” means that two or more agents are administered to a subject at the same time or within an interval such that there may be an overlap of an effect of each agent on the patient. In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently closely together such that a combinatorial (e.g., a synergistic) effect is achieved.


Adjuvant: As used herein, the term “adjuvant” means a substance that enhances a subject's immune response to an antigen. The NAVs of the present invention may optionally comprise one or more adjuvants.


Animal: As used herein, the term “animal” refers to any member of the animal kingdom. In some embodiments, “animal” refers to humans at any stage of development. In some embodiments, “animal” refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone.


Antigen: As defined herein, the term “antigen” or “antibody generator” (“Ag”) refers to a composition, for example, a substance or agent which causes an immune response in an organism, e.g., causes the immune response of the organism to produce antibodies against the substance or agent in particular, which provokes an adaptive immune response in an organism. Antigens can be any immunogenic substance including, in particular, proteins, polypeptides, polysaccharides, nucleic acids, lipids and the like. Exemplary antigens are derived from infectious agents. Such agents can include parts or subunits of infectious agents, for example, coats, coat components, e.g., coat protein or polypeptides, surface components, e.g., surface proteins or polypeptides, capsule components, cell wall components, flagella, fimbrae, and/or toxins or toxoids) of infectious agents, for example, bacteria, viruses, and other microorganisms. Certain antigens, for example, lipids and/or nucleic acids are antigenic, preferably, when combined with proteins and/or polysaccharides.


Antigens of interest or desired antigens: As used herein, the terms “antigens of interest” or “desired antigens” include those proteins and other biomolecules provided herein that are components of or encoded by polynucleotides which are components of one or more NAVs.


Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).


Associated with: As used herein, the terms “associated with,” “conjugated,” “linked,” “attached,” and “tethered,” when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stable so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. An “association” need not be strictly through direct covalent chemical bonding. It may also suggest ionic or hydrogen bonding or a hybridization based connectivity sufficiently stable such that the “associated” entities remain physically associated.


Bifunctional: As used herein, the term “bifunctional” refers to any substance, molecule or moiety which is capable of or maintains at least two functions. The functions may effect the same outcome or a different outcome. The structure that produces the function may be the same or different. For example, bifunctional modified RNAs of the present invention may encode a cytotoxic peptide (a first function) while those nucleosides which comprise the encoding RNA are, in and of themselves, cytotoxic (second function). In this example, delivery of the bifunctional modified RNA to a cancer cell would produce not only a peptide or protein molecule which may ameliorate or treat the cancer but would also deliver a cytotoxic payload of nucleosides to the cell should degradation, instead of translation of the modified RNA, occur.


Biocompatible: As used herein, the term “biocompatible” means compatible with living cells, tissues, organs or systems posing little to no risk of injury, toxicity or rejection by the immune system.


Biodegradable: As used herein, the term “biodegradable” means capable of being broken down into innocuous products by the action of living things.


Biologically active: As used herein, the phrase “biologically active” refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, a polynucleotide of the present invention may be considered biologically active if even a portion of the polynucleotides is biologically active or mimics an activity considered biologically relevant.


Cancer stem cells: As used herein, “cancer stem cells” are cells that can undergo self-renewal and/or abnormal proliferation and differentiation to form a tumor.


Chemical terms: The following provides the definition of various chemical terms from “acyl” to “thiol.”


The term “acyl,” as used herein, represents a hydrogen or an alkyl group (e.g., a haloalkyl group), as defined herein, that is attached to the parent molecular group through a carbonyl group, as defined herein, and is exemplified by formyl (i.e., a carboxyaldehyde group), acetyl, trifluoroacetyl, propionyl, butanoyl and the like. Exemplary unsubstituted acyl groups include from 1 to 7, from 1 to 11, or from 1 to 21 carbons. In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.


Non-limiting examples of optionally substituted acyl groups include, alkoxycarbonyl, alkoxycarbonylacyl, arylalkoxycarbonyl, aryloyl, carbamoyl, carboxyaldehyde, (heterocyclyl) imino, and (heterocyclyl)oyl:


The “alkoxycarbonyl” group, which as used herein, represents an alkoxy, as defined herein, attached to the parent molecular group through a carbonyl atom (e.g., —C(O)—OR, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group). Exemplary unsubstituted alkoxycarbonyl include from 1 to 21 carbons (e.g., from 1 to 11 or from 1 to 7 carbons). In some embodiments, the alkoxy group is further substituted with 1, 2, 3, or 4 substituents as described herein.


The “alkoxycarbonylacyl” group, which as used herein, represents an acyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., —C(O)-alkyl-C(O)—OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group). Exemplary unsubstituted alkoxycarbonylacyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 acyl, C1-10 alkoxycarbonyl-C1-10 acyl, or C1-20 alkoxycarbonyl-C1-20 acyl). In some embodiments, each alkoxy and alkyl group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group) for each group.


The “arylalkoxycarbonyl” group, which as used herein, represents an arylalkoxy group, as defined herein, attached to the parent molecular group through a carbonyl (e.g., —C(O)—O-alkyl-aryl). Exemplary unsubstituted arylalkoxy groups include from 8 to 31 carbons (e.g., from 8 to 17 or from 8 to 21 carbons, such as C6-10 aryl-C1-6 alkoxy-carbonyl, C6-10 aryl-C1-10 alkoxy-carbonyl, or C6-10 aryl-C1-20 alkoxy-carbonyl). In some embodiments, the arylalkoxycarbonyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.


The “aryloyl” group, which as used herein, represents an aryl group, as defined herein, that is attached to the parent molecular group through a carbonyl group. Exemplary unsubstituted aryloyl groups are of 7 to 11 carbons. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.


The “carbamoyl” group, which as used herein, represents —C(O)—N(RN1)2, where the meaning of each RN1 is found in the definition of “amino” provided herein.


The “carboxyaldehyde” group, which as used herein, represents an acyl group having the structure —CHO.


The “(heterocyclyl) imino” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an imino group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The “(heterocyclyl)oyl” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through a carbonyl group. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The term “alkyl,” as used herein, is inclusive of both straight chain and branched chain saturated groups from 1 to 20 carbons (e.g., from 1 to 10 or from 1 to 6), unless otherwise specified. Alkyl groups are exemplified by methyl, ethyl, n- and iso-propyl, n-, sec-, iso- and tert-butyl, neopentyl, and the like, and may be optionally substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH2) or a substituted amino (i.e., —N(RN1)2, where RN1 is as defined for amino); (4) C6-10 aryl-C1-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy, optionally substituted with an O-protecting group; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl): (11) C1-7 spirocyclyl: (12) thioalkoxy; (13) thiol; (14) —CO2RA′, optionally substituted with an O-protecting group and where RA′ is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C6-10 aryl, (d) hydrogen, (e) C1-6 alk-C6-10 aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl;

    • (15) —C(O)NRB′RC′, where each of RB′ and RC′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (16) —SO2RD′, where RD′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) C1-6 alk-C6-10 aryl, and (d) hydroxy; (17) —SO2NRE′RF′, where each of RE′ and RF′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl and (d) C1-6 alk-C6-10 aryl; (18) —C(O)RG′, where RG′ is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C6-10, aryl, (d) hydrogen. (e) C1-6 alk-C(Oo aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (19) —NRH′C(O)RI′, wherein RH′ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and RI′ is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C6-10 aryl, (d2) hydrogen, (e2) C1-6 alk-C6-10 aryl, (12) amino-C1-20 alkyl, (g2) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (20) —NRJ′C(O)ORK′, wherein RJ′ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and RK′ is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C6-10 aryl, (d2) hydrogen, (e2) C1-6 alk-C6-10 aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C1-alkaryl can be further substituted with an oxo group to afford the respective aryloyl substituent.


The term “alkylene,” as used herein, represent a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms, and is exemplified by methylene, ethylene, isopropylene, and the like. The term “Cx-y alkylene” and the prefix “Cx-y alk-” represent alkylene groups having between x and y carbons. Exemplary values for x are 1, 2, 3, 4, 5, and 6, and exemplary values for y are 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, or 20 (e.g., C1-6, C1-10, C2-20, C2-6, C2-10, or C2-20 alkylene). In some embodiments, the alkylene can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for an alkyl group. Similarly, the suffix “-ene” appended to any group indicates that the group is a divalent group.


Non-limiting examples of optionally substituted alkyl and alkylene groups include acylaminoalkyl, acyloxyalkyl, alkoxyalkyl, alkoxycarbonylalkyl, alkylsulfinyl, alkylsulfinylalkyl, aminoalkyl, carbamoylalkyl, carboxyalkyl, carboxyaminoalkyl, haloalkyl, hydroxyalkyl, pertluoroalkyl, and sulfoalkyl:


The “acylaminoalkyl” group, which as used herein, represents an acyl group, as defined herein, attached to an amino group that is in turn attached to the parent molecular group through an alkylene group, as defined herein (i.e., -alkyl-N(RN1)—C(O)—R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group (e.g., haloalkyl) and RN1 is as defined herein). Exemplary unsubstituted acylaminoalkyl groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons). In some embodiments, the alkylene group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is —NH2 or —NHRN1, wherein RN1 is, independently, OH, NO2, NH2, NRN22, SO2ORN2, SO2RN2, SORN2, alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each RN2 can be H, alkyl, or aryl.


The “acyloxyalkyl” group, which as used herein, represents an acyl group, as defined herein, attached to an oxygen atom that in turn is attached to the parent molecular group though an alkylene group (i.e., -alkyl-O—C(O)—R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group). Exemplary unsubstituted acyloxyalkyl groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons). In some embodiments, the alkylene group is, independently, further substituted with 1, 2, 3, or 4 substituents as described herein.


The “alkoxyalkyl” group, which as used herein, represents an alkyl group that is substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkyl groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C1-6 alkoxy-C1-6 alkyl, C1-10 alkoxy-C1-10 alkyl, or C1-20 alkoxy-C1-20 alkyl). In some embodiments, the alkyl and the alkoxy each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.


The “alkoxycarbonylalkyl” group, which as used herein, represents an alkyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkyl-C(O)—OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group). Exemplary unsubstituted alkoxycarbonylalkyl include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 alkyl, C1-10 alkoxycarbonyl-C1-10 alkyl, or C1-20 alkoxycarbonyl-C1-20 alkyl). In some embodiments, each alkyl and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).


The “alkylsulfinylalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with an alkylsulfinyl group. Exemplary unsubstituted alkylsulfinylalkyl groups are from 2 to 12, from 2 to 20, or from 2 to 40 carbons. In some embodiments, each alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The “aminoalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2RA′, where RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).


The “carbamoylalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a carbamoyl group, as defined herein. The alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.


The “carboxyalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a carboxy group, as defined herein. The alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the carboxy group can be optionally substituted with one or more 0-protecting groups.


The “carboxyaminoalkyl” group, which as used herein, represents an aminoalkyl group, as defined herein, substituted with a carboxy, as defined herein. The carboxy, alkyl, and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2RA′, where RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C4, alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group, and/or an O-protecting group).


The “haloalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or 1). A haloalkyl may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens. Haloalkyl groups include perfluoroalkyls (e.g., —CF3), —CHF2, —CH2F, —CCl3, —CH2CH2Br, —CH2CH(CH2CH2Br)CH3, and —CHICH3. In some embodiments, the haloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.


The “hydroxyalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by hydroxymethyl, dihydroxypropyl, and the like. In some embodiments, the hydroxyalkyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.


The “perfluoroalkyl” group, which as used herein, represents an alkyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. Perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.


The “sulfoalkyl” group, which as used herein, represents an alkyl group, as defined herein, substituted with a sulfo group of —SO3H. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein, and the sulfo group can be further substituted with one or more O-protecting groups (e.g., as described herein).


The term “alkenyl,” as used herein, represents monovalent straight or branched chain groups of, unless otherwise specified, from 2 to 20 carbons (e.g., from 2 to 6 or from 2 to 10 carbons) containing one or more carbon-carbon double bonds and is exemplified by ethenyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, and the like. Alkenyls include both cis and trans isomers. Alkenyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from amino, aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.


Non-limiting examples of optionally substituted alkenyl groups include, alkoxycarbonylalkenyl, aminoalkenyl, and hydroxyalkenyl:


The “alkoxycarbonylalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkenyl-C(O)—OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group). Exemplary unsubstituted alkoxycarbonylalkenyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C1-6 alkoxycarbonyl-C2-6 alkenyl, C1-10 alkoxycarbonyl-C2-10 alkenyl, or C1-20 alkoxycarbonyl-C2-20 alkenyl). In some embodiments, each alkyl, alkenyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).


The “aminoalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, substituted with an amino group, as defined herein. The alkenyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2RA′, where RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).


The “hydroxyalkenyl” group, which as used herein, represents an alkenyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group, and is exemplified by dihydroxypropenyl, hydroxyisopentenyl, and the like. In some embodiments, the hydroxyalkenyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.


The term “alkynyl,” as used herein, represents monovalent straight or branched chain groups from 2 to 20 carbon atoms (e.g., from 2 to 4, from 2 to 6, or from 2 to 10 carbons) containing a carbon-carbon triple bond and is exemplified by ethynyl, I-propynyl, and the like. Alkynyl groups may be optionally substituted with 1, 2, 3, or 4 substituent groups that are selected, independently, from aryl, cycloalkyl, or heterocyclyl (e.g., heteroaryl), as defined herein, or any of the exemplary alkyl substituent groups described herein.


Non-limiting examples of optionally substituted alkynyl groups include alkoxycarbonylalkynyl, aminoalkynyl, and hydroxyalkynyl:


The “alkoxycarbonylalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., -alkynyl-C(O)—OR, where R is an optionally substituted C1-20, C1-10, or C1-6 alkyl group). Exemplary unsubstituted alkoxycarbonylalkynyl include from 4 to 41 carbons (e.g., from 4 to 10, from 4 to 13, from 4 to 17, from 4 to 21, or from 4 to 31 carbons, such as C1-6 alkoxycarbonyl-C2-6 alkynyl, C1-10 alkoxycarbonyl-C2-10 alkynyl, or C1-20 alkoxycarbonyl-C2-20 alkynyl). In some embodiments, each alkyl, alkynyl, and alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents as described herein (e.g., a hydroxy group).


The “aminoalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, substituted with an amino group, as defined herein. The alkynyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2RA′, where RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy, and/or an N-protecting group).


The “hydroxyalkynyl” group, which as used herein, represents an alkynyl group, as defined herein, substituted with one to three hydroxy groups, with the proviso that no more than one hydroxy group may be attached to a single carbon atom of the alkyl group. In some embodiments, the hydroxyalkynyl group can be substituted with 1, 2, 3, or 4 substituent groups (e.g., O-protecting groups) as defined herein for an alkyl.


The term “amino,” as used herein, represents —N(RN1)2, wherein each RN1 is, independently, H, OH, NO2, N(RN2)2, SO2ORN2, SO2RN2, SORN2, an N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl groups or any described herein), heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), wherein each of these recited RN1 groups can be optionally substituted, as defined herein for each group; or two RN1 combine to form a heterocyclyl or an N-protecting group, and wherein each RN2 is, independently, H, alkyl, or aryl. The amino groups of the invention can be an unsubstituted amino (i.e., —NH2) or a substituted amino (i.e., —N(RN1)2). In a preferred embodiment, amino is —NH2 or —NHRN1, wherein RN1 is, independently, OH, NO2, NH2, NRN22, SO2ORN2, SO2RN2, SORN2, alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), alkoxycarbonylalkyl (e.g., t-butoxycarbonylalkyl) or aryl, and each RN2 can be H, C1-20 alkyl (e.g., C1-6 alkyl), or C6-10 aryl.


Non-limiting examples of optionally substituted amino groups include acylamino and carbamyl:


The “acylamino” group, which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an amino group, as defined herein (i.e., —N(RN1)—C(O)—R, where R is H or an optionally substituted C1-6, C1-10, or C1-2 alkyl group (e.g., haloalkyl) and RN1 is as defined herein). Exemplary unsubstituted acylamino groups include from 1 to 41 carbons (e.g., from 1 to 7, from 1 to 13, from 1 to 21, from 2 to 7, from 2 to 13, from 2 to 21, or from 2 to 41 carbons). In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein, and/or the amino group is —NH2 or —NHRN1, wherein RN1 is, independently, OH, NO2, NH2, NRN22, SO2ORN2, SO2RN2, SORN2, alkyl, aryl, acyl (e.g., acetyl, trifluoroacetyl, or others described herein), or alkoxycarbonylalkyl, and each RN2 can be H, alkyl, or aryl.


The “carbamyl” group, which as used herein, refers to a carbamate group having the structure —NRN1C(═O)OR or —OC(═O)N(RN1)2, where the meaning of each RN1 is found in the definition of “amino” provided herein, and R is alkyl, cycloalkyl, alkcycloalkyl, aryl, alkaryl, heterocyclyl (e.g., heteroaryl), or alkheterocyclyl (e.g., alkheteroaryl), as defined herein.


The term “amino acid,” as described herein, refers to a molecule having a side chain, an amino group, and an acid group (e.g., a carboxy group of —CO2H or a sulfo group of —SO3H), wherein the amino acid is attached to the parent molecular group by the side chain, amino group, or acid group (e.g., the side chain). In some embodiments, the amino acid is attached to the parent molecular group by a carbonyl group, where the side chain or amino group is attached to the carbonyl group. Exemplary side chains include an optionally substituted alkyl, aryl, heterocyclyl, alkaryl, alkheterocyclyl, aminoalkyl, carbamoylalkyl, and carboxyalkyl. Exemplary amino acids include alanine, arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, histidine, hydroxynorvaline, isoleucine, leucine, lysine, methionine, norvaline, ornithine, phenylalanine, proline, pyrrolysine, selenocysteine, serine, taurine, threonine, tryptophan, tyrosine, and valine. Amino acid groups may be optionally substituted with one, two, three, or, in the case of amino acid groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy; (2) C1-6 alkylsulfinyl; (3) amino, as defined herein (e.g., unsubstituted amino (i.e., —NH2) or a substituted amino (i.e., —N(RN1)2, where RN1 is as defined for amino); (4) C6-10 aryl-C1-6 alkoxy; (5) azido; (6) halo; (7) (C2-9 heterocyclyl)oxy; (8) hydroxy; (9) nitro; (10) oxo (e.g., carboxyaldehyde or acyl); (11) C1-7 spirocyclyl; (12) thioalkoxy; (13) thiol; (14) —CO2RA′, where RA′ is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C6-10 aryl, (d) hydrogen, (e) C1-6 alk-C6-10 aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (15) —C(O)NRB′RC′, where each of RB′ and RC′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (16) —SO2RD′, where RD′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) C1-6 alk-C6-10 aryl, and (d) hydroxy; (17) —SO2NRE′RF′, where each of RE′ and RF′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl and (d) C1-6 alk-C6-10 aryl; (18) —C(O)RG′—, where RG′ is selected from the group consisting of (a) C1-20 alkyl (e.g., C1-6 alkyl), (b) C2-20 alkenyl (e.g., C2-6 alkenyl), (c) C6-10 aryl, (d) hydrogen, (e) C1-6 alk-C6-10 aryl, (f) amino-C1-20 alkyl, (g) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (19) —NRH′C(O)RI′, wherein RH′ is selected from the group consisting of (al) hydrogen and (b1) C1-6 alkyl, and RH′ is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C6-10 aryl, (d2) hydrogen, (e2) C1-6 alk-C6-10 aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; (20) —NRJ′C(O)ORK′, wherein RJ′ is selected from the group consisting of (a1) hydrogen and (b1) C1-6 alkyl, and RK′ is selected from the group consisting of (a2) C1-20 alkyl (e.g., C1-6 alkyl), (b2) C2-20 alkenyl (e.g., C2-6 alkenyl), (c2) C6-10 aryl, (d2) hydrogen, (e2) C1-6 alk-C6-10 aryl, (f2) amino-C1-20 alkyl, (g2) polyethylene glycol of —(CH2)s2(OCH2CH2)s1(CH2)s3OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C1-20 alkyl, and (h2) amino-polyethylene glycol of —NRN1(CH2)s2(CH2CH2O)s1(CH2)s3NRN1, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and each RN1 is, independently, hydrogen or optionally substituted C1-6 alkyl; and (21) amidine. In some embodiments, each of these groups can be further substituted as described herein.


The term “aryl,” as used herein, represents a mono-, bicyclic, or multicyclic carbocyclic ring system having one or two aromatic rings and is exemplified by phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, anthracenyl, phenanthrenyl, fluorenyl, indanyl, indenyl, and the like, and may be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., pertluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) C6-10 aryl; (6) amino; (7) C1-6 alk-C6-10 aryl; (8) azido; (9) C3-8 cycloalkyl; (10) C1-6 alk-C3-8 cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C1-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C1-20 thioalkoxy (e.g., C1-6 thioalkoxy); (17) —(CH2)qCO2RA′, where q is an integer from zero to four, and RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl; (18) —(CH2)qCONRB′RC′, where q is an integer from zero to four and where RB′ and RC′ are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (19) —(CH2)qSO2RD′, where q is an integer from zero to four and where RD′ is selected from the group consisting of (a) alkyl, (b) C6-10 aryl, and (c) alk-C6-10 aryl; (20) —(CH2)qSO2NRE′RF′, where q is an integer from zero to four and where each of RE′ and RF′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (21) thiol; (22) C6-10 aryloxy; (23) C3-8 cycloalkoxy; (24) C6-10 aryl-C1-6 alkoxy; (25) C1-6 alk-C1-12 heterocyclyl (e.g., C1-6 alk-C1-12 heteroaryl): (26) C2-20 alkenyl; and (27) C2-20 alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.


The “arylalkyl” group, which as used herein, represents an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted arylalkyl groups are from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C1-6 alk-C6-10 aryl, C1-10 alk-C6-10 aryl, or C1-20 alk-C6-10 aryl). In some embodiments, the alkylene and the aryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective groups. Other groups preceded by the prefix “alk-” are defined in the same manner, where “alk” refers to a C1-6 alkylene, unless otherwise noted, and the attached chemical structure is as defined herein.


The term “azido” represents an —N3 group, which can also be represented as —N═N═N.


The term “bicyclic,” as used herein, refer to a structure having two rings, which may be aromatic or non-aromatic. Bicyclic structures include spirocyclyl groups, as defined herein, and two rings that share one or more bridges, where such bridges can include one atom or a chain including two, three, or more atoms. Exemplary bicyclic groups include a bicyclic carbocyclyl group, where the first and second rings are carbocyclyl groups, as defined herein; a bicyclic aryl groups, where the first and second rings are aryl groups, as defined herein; bicyclic heterocyclyl groups, where the first ring is a heterocyclyl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group; and bicyclic heteroaryl groups, where the first ring is a heteroaryl group and the second ring is a carbocyclyl (e.g., aryl) or heterocyclyl (e.g., heteroaryl) group. In some embodiments, the bicyclic group can be substituted with 1, 2, 3, or 4 substituents as defined herein for cycloalkyl, heterocyclyl, and aryl groups.


The term “boranyl,” as used herein, represents —B(RB1)3, where each RB1 is, independently, selected from the group consisting of H and optionally substituted alkyl. In some embodiments, the boranyl group can be substituted with 1, 2, 3, or 4 substituents as defined herein for alkyl.


The terms “carbocyclic” and “carbocyclyl,” as used herein, refer to an optionally substituted C3-12 monocyclic, bicyclic, or tricyclic structure in which the rings, which may be aromatic or non-aromatic, are formed by carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, cycloalkynyl, and aryl groups.


The term “carbonyl,” as used herein, represents a C(O) group, which can also be represented as C═O.


The term “carboxy,” as used herein, means —CO2H.


The term “cyano,” as used herein, represents an —CN group.


The term “cycloalkyl,” as used herein represents a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicycle heptyl, and the like. When what would otherwise be a cycloalkyl group includes one or more carbon-carbon double bonds, the group is referred to as a “cycloalkenyl” group. For the purposes of this invention, cycloalkenyl excludes aryl groups. When what would otherwise be a cycloalkyl group includes one or more carbon-carbon triple bonds, the group is referred to as a “cycloalkynyl” group. Exemplary cycloalkenyl groups include cyclopentenyl, cyclohexenyl, and the like. The cycloalkyl groups of this invention can be optionally substituted with: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6 alkyl, azido-C1-6 alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) C6-10 aryl; (6) amino; (7) C1-6 alk-C6-10 aryl; (8) azido; (9) C3-8 cycloalkyl; (10) C1-6 alk-C3-8 cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C1-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C1-20 thioalkoxy (e.g., C1-6 thioalkoxy); (17) —(CH2)qCO2RA′, where q is an integer from zero to four, and RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl; (18) —(CH2)qCONRB′RC′, where q is an integer from zero to four and where RB′ and RC′ are independently selected from the group consisting of (a) hydrogen, (b) C6-10 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (19) —(CH2)qSO2RD′, where q is an integer from zero to four and where RD′ is selected from the group consisting of (a) C6-10 alkyl, (b) C6-10 aryl, and (c) C1-6 alk-C6-10 aryl; (20) —(CH2)qSO2NRE′RF′, where q is an integer from zero to four and where each of RE′ and RF′ is, independently, selected from the group consisting of (a) hydrogen, (b) C6-10 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (21) thiol; (22) C6-10 aryloxy; (23) C3-8 cycloalkoxy; (24) C6-10 aryl-C1-6 alkoxy; (25) C1-6 alk-C1-12 heterocyclyl (e.g., C1-6 alk-C1-12 heteroaryl); (26) oxo; (27) C2-20 alkenyl; and (28) C2-20 alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.


The “cycloalkylalkyl” group, which as used herein, represents a cycloalkyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein (e.g., an alkylene group of from 1 to 4, from 1 to 6, from 1 to 10, or form 1 to 20 carbons). In some embodiments, the alkylene and the cycloalkyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.


The term “halo,” as used herein, represents a halogen selected from bromine, chlorine, iodine, or fluorine.


The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups. The terms “heteroalkenyl” and heteroalkynyl,” as used herein refer to alkenyl and alkynyl groups, as defined herein, respectively, in which one or two of the constituent carbon atoms have each been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkenyl and heteroalkynyl groups can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.


Non-limiting examples of optionally substituted heteroalkyl, heteroalkenyl, and heteroalkynyl groups include acyloxy, alkenyloxy, alkoxy, alkoxyalkoxy, alkoxycarbonylalkoxy, alkynyloxy, aminoalkoxy, arylalkoxy, carboxyalkoxy, cycloalkoxy, haloalkoxy, (heterocyclyl)oxy, perfluoroalkoxy, thioalkoxy, and thioheterocyclylalkyl:


The “acyloxy” group, which as used herein, represents an acyl group, as defined herein, attached to the parent molecular group though an oxygen atom (i.e., —O—C(O)—R, where R is H or an optionally substituted C1-6, C1-10, or C1-20 alkyl group). Exemplary unsubstituted acyloxy groups include from 1 to 21 carbons (e.g., from 1 to 7 or from 1 to 11 carbons). In some embodiments, the alkyl group is further substituted with 1, 2, 3, or 4 substituents as described herein.


The “alkenyloxy” group, which as used here, represents a chemical substituent of formula —OR, where R is a C2-20 alkenyl group (e.g., C2-6 or C2-10 alkenyl), unless otherwise specified. Exemplary alkenyloxy groups include ethenyloxy, propenyloxy, and the like. In some embodiments, the alkenyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).


The “alkoxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C1-20 alkyl group (e.g., C1-6 or C1-10 alkyl), unless otherwise specified. Exemplary alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy, and the like. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., hydroxy or alkoxy).


The “alkoxyalkoxy” group, which as used herein, represents an alkoxy group that is substituted with an alkoxy group. Exemplary unsubstituted alkoxyalkoxy groups include between 2 to 40 carbons (e.g., from 2 to 12 or from 2 to 20 carbons, such as C2-6 alkoxy-C1-6 alkoxy, C1-10 alkoxy-C1-10 alkoxy, or C1-20 alkoxy-C1-20 alkoxy). In some embodiments, the each alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The “alkoxycarbonylalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, that is substituted with an alkoxycarbonyl group, as defined herein (e.g., —O-alkyl-C(O)—OR, where R is an optionally substituted C1-6, C1-10, or C1-20 alkyl group). Exemplary unsubstituted alkoxycarbonylalkoxy include from 3 to 41 carbons (e.g., from 3 to 10, from 3 to 13, from 3 to 17, from 3 to 21, or from 3 to 31 carbons, such as C1-6 alkoxycarbonyl-C1-6 alkoxy, C1-10 alkoxycarbonyl-C1-10 alkoxy, or C1-20 alkoxycarbonyl-C1-20 alkoxy). In some embodiments, each alkoxy group is further independently substituted with 1, 2, 3, or 4 substituents, as described herein (e.g., a hydroxy group).


The “alkynyloxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C2-20 alkynyl group (e.g., C2-6 or C2-10 alkynyl), unless otherwise specified. Exemplary alkynyloxy groups include ethynyloxy, propynyloxy, and the like. In some embodiments, the alkynyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein (e.g., a hydroxy group).


The “aminoalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with an amino group, as defined herein. The alkyl and amino each can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the respective group (e.g., CO2RA′, where RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl, e.g., carboxy).


The “arylalkoxy” group, which as used herein, represents an alkaryl group, as defined herein, attached to the parent molecular group through an oxygen atom. Exemplary unsubstituted arylalkoxy groups include from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as C6-10 aryl-C1-6 alkoxy, C6-10 aryl-C1-10 alkoxy, or C6-10 aryl-C1-20 alkoxy). In some embodiments, the arylalkoxy group can be substituted with 1, 2, 3, or 4 substituents as defined herein.


The “aryloxy” group, which as used herein, represents a chemical substituent of formula —OR′, where R′ is an aryl group of 6 to 18 carbons, unless otherwise specified. In some embodiments, the aryl group can be substituted with 1, 2, 3, or 4 substituents as defined herein.


The “carboxyalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with a carboxy group, as defined herein. The alkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for the alkyl group, and the carboxy group can be optionally substituted with one or more 0-protecting groups.


The “cycloalkoxy” group, which as used herein, represents a chemical substituent of formula —OR, where R is a C3-8 cycloalkyl group, as defined herein, unless otherwise specified. The cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein. Exemplary unsubstituted cycloalkoxy groups are from 3 to 8 carbons. In some embodiment, the cycloalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.


The “haloalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, substituted with a halogen group (i.e., F, Cl, Br, or I). A haloalkoxy may be substituted with one, two, three, or, in the case of alkyl groups of two carbons or more, four halogens. Haloalkoxy groups include perfluoroalkoxys (e.g., —OCF3), —OCHF2, —OCH2F, —OCCl3, —OCH2CH2Br, —OCH2CH(CH2CH2Br)CH3, and —OCHICH3. In some embodiments, the haloalkoxy group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein for alkyl groups.


The “(heterocyclyl)oxy” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an oxygen atom. In some embodiments, the heterocyclyl group can be substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The “perfluoroalkoxy” group, which as used herein, represents an alkoxy group, as defined herein, where each hydrogen radical bound to the alkoxy group has been replaced by a fluoride radical. Perfluoroalkoxy groups are exemplified by trifluoromethoxy, pentafluoroethoxy, and the like.


The “alkylsulfinyl” group, which as used herein, represents an alkyl group attached to the parent molecular group through an —S(O)—group. Exemplary unsubstituted alkylsulfinyl groups are from 1 to 6, from 1 to 10, or from 1 to 20 carbons. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein.


The “thioarylalkyl” group, which as used herein, represents a chemical substituent of formula —SR, where R is an arylalkyl group. In some embodiments, the arylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.


The “thioalkoxy” group as used herein, represents a chemical substituent of formula —SR, where R is an alkyl group, as defined herein. In some embodiments, the alkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.


The “thioheterocyclylalkyl” group, which as used herein, represents a chemical substituent of formula —SR, where R is an heterocyclylalkyl group. In some embodiments, the heterocyclylalkyl group can be further substituted with 1, 2, 3, or 4 substituent groups as described herein.


The term “heteroaryl,” as used herein, represents that subset of heterocyclyls, as defined herein, which are aromatic: i.e., they contain 4n+2 pi electrons within the mono- or multicyclic ring system. Exemplary unsubstituted heteroaryl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 11, 2 to 10, or 2 to 9) carbons. In some embodiment, the heteroaryl is substituted with 1, 2, 3, or 4 substituents groups as defined for a heterocyclyl group.


The term “heteroarylalkyl” refers to a heteroaryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted heteroarylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-C1-12 heteroaryl, C1-10 alk-C1-12 heteroaryl, or C1-20 alk-C1-12 heteroaryl). In some embodiments, the alkylene and the heteroaryl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group. Heteroarylalkyl groups are a subset of heterocyclylalkyl groups.


The term “heterocyclyl,” as used herein represents a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. The 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. Exemplary unsubstituted heterocyclyl groups are of 1 to 12 (e.g., 1 to 11, 1 to 10, 1 to 9, 2 to 12, 2 to 10, or 2 to 9) carbons. The term “heterocyclyl” also represents a heterocyclic compound having a bridged multicyclic structure in which one or more carbons and/or heteroatoms bridges two non-adjacent members of a monocyclic ring, e.g., a quinuclidinyl group. The term “heterocyclyl” includes bicyclic, tricyclic, and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three carbocyclic rings, e.g., an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, or another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Examples of fused heterocyclyls include tropanes and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclics include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidiniyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, quinoxalinyl, dihydroquinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzothiadiazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, triazolyl, tetrazolyl, oxadiazolyl (e.g., 1,2,3-oxadiazolyl), purinyl, thiadiazolyl (e.g., 1,2,3-thiadiazolyl), tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, dihydroquinolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, dihydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, isobenzofuranyl, benzothienyl, and the like, including dihydro and tetrahydro forms thereof, where one or more double bonds are reduced and replaced with hydrogens. Still other exemplary heterocyclyls include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (e.g., 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (e.g., 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (e.g., 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1H-triazolyl (e.g., 4,5-dihydro-3-methyl-4-amino 5-oxo-1H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl); 2,6-dioxo-piperidinyl (e.g., 2,6-dioxo-3-ethyl-3-phenylpiperidinyl); 1,6-dihydro-6-oxopyridiminyl; 1,6-dihydro-4-oxopyrimidinyl (e.g., 2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl); 1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (e.g., 1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl); 1,6-dihydro-6-oxo-pyridazinyl (e.g., 1,6-dihydro-6-oxo-3-ethylpyridazinyl): 1,6-dihydro-6-oxo-1,2,4-triazinyl (e.g., 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl); 2,3-dihydro-2-oxo-1H-indolyl (e.g., 3,3-dimethyl-2,3-dihydro-2-oxo-1H-indolyl and 2,3-dihydro-2-oxo-3,3′-spiropropane-1H-indol-1-yl); 1,3-dihydro-1-oxo-2H-iso-indolyl; 1,3-dihydro-1,3-dioxo-2H-iso-indolyl; 1H-benzopyrazolyl (e.g., 1-(ethoxycarbonyl)-1H-benzopyrazolyl); 2,3-dihydro-2-oxo-1H-benzimidazolyl (e.g., 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl); 2,3-dihydro-2-oxo-benzoxazolyl (e.g., 5-chloro-2,3-dihydro-2-oxo-benzoxazolyl); 2,3-dihydro-2-oxo-benzoxazolyl: 2-oxo-2H-benzopyranyl; 1,4-benzodioxanyl; 1,3-benzodioxanyl; 2,3-dihydro-3-oxo,4H-1,3-benzothiazinyl; 3,4-dihydro-4-oxo-3H-quinazolinyl (e.g., 2-methyl-3,4-dihydro-4-oxo-3H-quinazolinyl); 1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl (e.g., 1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3H-quinazolyl); 1,2,3,6-tetrahydro-2,6-dioxo-7H-purinyl (e.g., 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purinyl); 1,2,3,6-tetrahydro-2,6-dioxo-1H-purinyl (e.g., 1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1H-purinyl); 2-oxobenz[c,d]indolyl; 1,1-dioxo-2H-naphth[1,8-c,d]isothiazolyl; and 1,8-naphthylenedicarboxamido. Additional heterocyclics include 3,3a,4,5,6,6a-hexahydro-pyrrolo[3,4-b]pyrrol-(2H)-yl, and 2,5-diazabicyclo[2.2.1]heptan-2-yl, homopiperazinyl (or diazepanyl), tetrahydropyranyl, dithiazolyl, benzofuranyl, benzothienyl, oxepanyl, thiepanyl, azocanyl, oxecanyl, and thiocanyl. Heterocyclic groups also include groups of the formula




embedded image


where

    • E′ is selected from the group consisting of —N— and —CH—; F′ is selected from the group consisting of —N═CH—, —NH—CH2—, —NH—C(O)—, —NH—, —CH═N—, —CH2—NH—. —C(O)—NH—, —CH═CH—, —CH2—, —CH2CH2—, —CH2O—, —OCH2—, —O—, and —S—; and G′ is selected from the group consisting of —CH— and —N—. Any of the heterocyclyl groups mentioned herein may be optionally substituted with one, two, three, four or five substituents independently selected from the group consisting of: (1) C1-7 acyl (e.g., carboxyaldehyde); (2) C1-20 alkyl (e.g., C1-6 alkyl, C1-6 alkoxy-C1-6 alkyl, C1-6 alkylsulfinyl-C1-6 alkyl, amino-C1-6, alkyl, azido-C1-6, alkyl, (carboxyaldehyde)-C1-6 alkyl, halo-C1-6 alkyl (e.g., perfluoroalkyl), hydroxy-C1-6 alkyl, nitro-C1-6 alkyl, or C1-6 thioalkoxy-C1-6 alkyl); (3) C1-20 alkoxy (e.g., C1-6 alkoxy, such as perfluoroalkoxy); (4) C1-6 alkylsulfinyl; (5) C1-10 aryl; (6) amino; (7) C1-6 alk-C1-10 aryl; (8) azido; (9) C3-8 cycloalkyl; (10) C1-6 alk-C3-8 cycloalkyl; (11) halo; (12) C1-12 heterocyclyl (e.g., C2-12 heteroaryl); (13) (C1-12 heterocyclyl)oxy; (14) hydroxy; (15) nitro; (16) C1-20 thioalkoxy (e.g., C1-6 thioalkoxy); (17) —(CH2)qCO2RA′, where q is an integer from zero to four, and RA′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, (c) hydrogen, and (d) C1-6 alk-C6-10 aryl; (18) —(CH2)qCONRB′RC′, where q is an integer from zero to four and where RB′ and RC′ are independently selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (19) —(CH2)qSO2RD′, where q is an integer from zero to four and where RD′ is selected from the group consisting of (a) C1-6 alkyl, (b) C6-10 aryl, and (c) C1-6 alk-C6-10 aryl; (20) —(CH2)qSO2NRE′RF′, where q is an integer from zero to four and where each of RE′ and RF′ is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C6-10 aryl, and (d) C1-6 alk-C6-10 aryl; (21) thiol; (22) C6-10 aryloxy; (23) C3-8 cycloalkoxy; (24) arylalkoxy; (25) C1-6 alk-C1-12 heterocyclyl (e.g., C1-6 alk-C1-12 heteroaryl); (26) oxo; (27) (C1-12 heterocyclyl)imino; (28) C2-20 alkenyl; and (29) C2-20 alkynyl. In some embodiments, each of these groups can be further substituted as described herein. For example, the alkylene group of a C1-alkaryl or a C1-alkheterocyclyl can be further substituted with an oxo group to afford the respective aryloyl and (heterocyclyl)oyl substituent group.


The “heterocyclylalkyl” group, which as used herein, represents a heterocyclyl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted heterocyclylalkyl groups are from 2 to 32 carbons (e.g., from 2 to 22, from 2 to 18, from 2 to 17, from 2 to 16, from 3 to 15, from 2 to 14, from 2 to 13, or from 2 to 12 carbons, such as C1-6 alk-C1-12 heterocyclyl, C1-10 alk-C1-12 heterocyclyl, or C1-20 alk-C1-12 heterocyclyl). In some embodiments, the alkylene and the heterocyclyl each can be further substituted with 1, 2, 3, or 4 substituent groups as defined herein for the respective group.


The term “hydrocarbon,” as used herein, represents a group consisting only of carbon and hydrogen atoms.


The term “hydroxy,” as used herein, represents an —OH group.


The term “N-protected amino,” as used herein, refers to an amino group, as defined herein, to which is attached one or two N-protecting groups, as defined herein.


The term “N-protecting group,” as used herein, represents those groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis,” 3rd Edition (John Wiley & Sons, New York, 1999), which is incorporated herein by reference. N-protecting groups include acyl, aryloyl, or carbamyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and chiral auxiliaries such as protected or unprotected D, L or D. L-amino acids such as alanine, leucine, phenylalanine, and the like; sulfonyl-containing groups such as benzenesulfonyl, p-toluenesulfonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxy carbonyl, t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like, alkaryl groups such as benzyl, uiphenylmethyl, benzyloxymethyl, and the like and silyl groups, such as trimethylsilyl, and the like. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).


The term “nitro,” as used herein, represents an —NO2 group.


The term “O-protecting group,” as used herein, represents those groups intended to protect an oxygen containing (e.g., phenol, hydroxyl, or carbonyl) group against undesirable reactions during synthetic procedures. Commonly used 0-protecting groups are disclosed in Greene, “Protective Groups in Organic Synthesis.” 3rd Edition (John Wiley & Sons. New York, 1999), which is incorporated herein by reference. Exemplary 0-protecting groups include acyl, aryloyl, or carbamyl groups, such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, t-butyldimethylsilyl, tri-iso-propylsilyloxymethyl, 4,4′-dimethoxytrityl, isobutyryl, phenoxyacetyl, 4-isopropylpehenoxyacetyl, dimethylformamidino, and 4-nitrobenzoyl; alkylcarbonyl groups, such as acyl, acetyl, propionyl, pivaloyl, and the like; optionally substituted arylcarbonyl groups, such as benzoyl; silyl groups, such as trimethylsilyl (TMS), tert-butyldimethylsilyl (TBDMS), tri-iso-propylsilyloxymethyl (TOM), triisopropylsilyl (TIPS), and the like; ether-forming groups with the hydroxyl, such methyl, methoxymethyl, tetrahydropyranyl, benzyl, p-methoxybenzyl, trityl, and the like; alkoxycarbonyls, such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, n-isopropoxycarbonyl, n-butyloxycarbonyl, isobutyloxycarbonyl, sec-butyloxycarbonyl, t-butyloxycarbonyl, 2-ethylhexyloxycarbonyl, cyclohexyloxycarbonyl, methyloxycarbonyl, and the like; alkoxyalkoxycarbonyl groups, such as methoxymethoxycarbonyl, ethoxymethoxycarbonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, 2-butoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, allyloxycarbonyl, propargyloxycarbonyl, 2-butenoxycarbonyl, 3-methyl-2-butenoxycarbonyl, and the like; haloalkoxycarbonyls, such as 2-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, and the like; optionally substituted arylalkoxycarbonyl groups, such as benzyloxycarbonyl, p-methylbenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dinitrobenzyloxycarbonyl, 3,5-dimethylbenzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, fluorenylmethyloxycarbonyl, and the like; and optionally substituted aryloxycarbonyl groups, such as phenoxycarbonyl, p-nitrophenoxycarbonyl, o-nitrophenoxycarbonyl, 2,4-dinitrophenoxycarbonyl, p-methyl-phenoxycarbonyl, m-methylphenoxycarbonyl, o-bromophenoxycarbonyl, 3,5-dimethylphenoxycarbonyl, p-chlorophenoxycarbonyl, 2-chloro-4-nitrophenoxy-carbonyl, and the like); substituted alkyl, aryl, and alkaryl ethers (e.g., uityl; methylthiomethyl; methoxymethyl; benzyloxymethyl; siloxymethyl; 2,2,2,-trichloroethoxymethyl; tetrahydropyranyl; tetrahydrofuranyl; ethoxyethyl; 1-[2-(trimethylsilyl)ethoxy]ethyl; 2-trimethylsilylethyl; t-butyl ether; p-chlorophenyl, p-methoxyphenyl, p-nitrophenyl, benzyl, p-methoxybenzyl, and nitrobenzyl); silyl ethers (e.g., trimethylsilyl; triethylsilyl; triisopropylsilyl; dimethylisopropylsilyl; t-butyldimethylsilyl; t-butyldiphenylsilyl; tribenzylsilyl; triphenylsilyl; and diphenymethylsilyl); carbonates (e.g., methyl, methoxymethyl, 9-fluorenylmethyl; ethyl; 2,2,2-trichloroethyl; 2-(trimethylsilyl)ethyl; vinyl, allyl, nitrophenyl; benzyl; methoxybenzyl; 3,4-dimethoxybenzyl; and nitrobenzyl); carbonyl-protecting groups (e.g., acetal and ketal groups, such as dimethyl acetal, 1,3-dioxolane, and the like; acylal groups; and dithiane groups, such as 1,3-dithianes, 1,3-dithiolane, and the like); carboxylic acid-protecting groups (e.g., ester groups, such as methyl ester, benzyl ester, t-butyl ester, orthoesters, and the like; and oxazoline groups.


The term “oxo” as used herein, represents ═O.


The prefix “perfluoro,” as used herein, represents anyl group, as defined herein, where each hydrogen radical bound to the alkyl group has been replaced by a fluoride radical. For example, perfluoroalkyl groups are exemplified by trifluoromethyl, pentafluoroethyl, and the like.


The term “protected hydroxyl,” as used herein, refers to an oxygen atom bound to an O-protecting group.


The term “spirocyclyl,” as used herein, represents a C20.7 alkylene diradical, both ends of which are bonded to the same carbon atom of the parent group to form a spirocyclic group, and also a C1-6 heteroalkylene diradical, both ends of which are bonded to the same atom. The heteroalkylene radical forming the spirocyclyl group can containing one, two, three, or four heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the spirocyclyl group includes one to seven carbons, excluding the carbon atom to which the diradical is attached. The spirocyclyl groups of the invention may be optionally substituted with 1, 2, 3, or 4 substituents provided herein as optional substituents for cycloalkyl and/or heterocyclyl groups.


The term “sulfonyl,” as used herein, represents an —S(O)2—group.


The term “thiol,” as used herein represents an —SH group.


Chimera: As used herein, “chimera” is an entity having two or more incongruous or heterogeneous parts or regions.


Chimeric polynucleotide: As used herein, “chimeric polynucleotides” are those nucleic acid polymers having portions or regions which differ in size and/or chemical modification pattern, chemical modification position, chemical modification percent or chemical modification population and combinations of the foregoing.


Compound: As used herein, the term “compound,” is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted.


The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms.


Compounds of the present disclosure also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples prototropic tautomers include ketone—enol pairs, amide—imidic acid pairs, lactam—lactim pairs, amide—imidic acid pairs, enamine—imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.


Compounds of the present disclosure also include all of the isotopes of the atoms occurring in the intermediate or final compounds. “Isotopes” refers to atoms having the same atomic number but different mass numbers resulting from a different number of neutrons in the nuclei. For example, isotopes of hydrogen include tritium and deuterium.


The compounds and salts of the present disclosure can be prepared in combination with solvent or water molecules to form solvates and hydrates by routine methods.


Conserved: As used herein, the term “conserved” refers to nucleotides or amino acid residues of a polynucleotide sequence or polypeptide sequence, respectively, that are those that occur unaltered in the same position of two or more sequences being compared. Nucleotides or amino acids that are relatively conserved are those that are conserved amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences.


In some embodiments, two or more sequences are said to be “completely conserved” if they are 100% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “highly conserved” if they are about 70% identical, about 80% identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are at least 30% identical, at least 40% identical, at least 50% identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be “conserved” if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80% identical, about 90% identical, about 95% identical, about 98% identical, or about 99% identical to one another. Conservation of sequence may apply to the entire length of an polynucleotide or polypeptide or may apply to a portion, region or feature thereof.


Controlled Release: As used herein, the term “controlled release” refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome.


Cyclic or Cyclized: As used herein, the term “cyclic” refers to the presence of a continuous loop. Cyclic molecules need not be circular, only joined to form an unbroken chain of subunits. Cyclic molecules such as the engineered RNA or mRNA of the present invention may be single units or multimers or comprise one or more components of a complex or higher order structure.


Cytostatic: As used herein, “cytostatic” refers to inhibiting, reducing, suppressing the growth, division, or multiplication of a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.


Cytotoxic: As used herein, “cytotoxic” refers to killing or causing injurious, toxic, or deadly effect on a cell (e.g., a mammalian cell (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.


Delivery: As used herein, “delivery” refers to the act or manner of delivering a compound, substance, entity, moiety, cargo or payload.


Delivery Agent: As used herein, “delivery agent” refers to any substance which facilitates, at least in part, the in vivo delivery of a polynucleotide to targeted cells.


Destabilized: As used herein, the term “destable,” “destabilize,” or “destabilizing region” means a region or molecule that is less stable than a starting, wild-type or native form of the same region or molecule.


Detectable label: As used herein, “detectable label” refers to one or more markers, signals, or moieties which are attached, incorporated or associated with another entity that is readily detected by methods known in the art including radiography, fluorescence, chemiluminescence, enzymatic activity, absorbance and the like. Detectable labels include radioisotopes, fluorophores, chromophores, enzymes, dyes, metal ions, ligands such as biotin, avidin, streptavidin and haptens, quantum dots, and the like. Detectable labels may be located at any position in the peptides or proteins disclosed herein. They may be within the amino acids, the peptides, or proteins, or located at the N- or C—termini.


Diastereomer: As used herein, the term “diastereomer,” means stereoisomers that are not mirror images of one another and are non-superimposable on one another.


Digest: As used herein, the term “digest” means to break apart into smaller pieces or components. When referring to polypeptides or proteins, digestion results in the production of peptides.


Differentiated cell: As used herein, the term “differentiated cell” refers to any somatic cell that is not, in its native form, pluripotent. Differentiated cell also encompasses cells that are partially differentiated.


Differentiation: As used herein, the term “differentiation factor” refers to a developmental potential altering factor such as a protein, RNA or small molecule that can induce a cell to differentiate to a desired cell-type.


Differentiate: As used herein, “differentiate” refers to the process where an uncommitted or less committed cell acquires the features of a committed cell.


Distal: As used herein, the term “distal” means situated away from the center or away from a point or region of interest.


Dosing regimen: As used herein, a “dosing regimen” is a schedule of administration or physician determined regimen of treatment, prophylaxis, or palliative care.


Dose splitting factor (DSF)-ratio of PUD of dose split treatment divided by PUD of total daily dose or single unit dose. The value is derived from comparison of dosing regimens groups.


Enantiomer: As used herein, the term “enantiomer” means each individual optically active form of a compound of the invention, having an optical purity or enantiomeric excess (as determined by methods standard in the art) of at least 80% (i.e., at least 90% of one enantiomer and at most 10% of the other enantiomer), preferably at least 90% and more preferably at least 98%.


Encapsulate: As used herein, the term “encapsulate” means to enclose, surround or encase.


Encoded protein cleavage signal: As used herein, “encoded protein cleavage signal” refers to the nucleotide sequence which encodes a protein cleavage signal.


Engineered: As used herein, embodiments of the invention are “engineered” when they are designed to have a feature or property, whether structural or chemical, that varies from a starting point, wild type or native molecule.


Effective Amount: As used herein, the term “effective amount” of an agents that amount sufficient to effect beneficial or desired results, for example, clinical results, and, as such, an “effective amount” depends upon the context in which it is being applied. For example, in the context of administering an agent that treats cancer, an effective amount of an agent is, for example, an amount sufficient to achieve treatment, as defined herein, of cancer, as compared to the response obtained without administration of the agent.


Exosome: As used herein, “exosome” is a vesicle secreted by mammalian cells or a complex involved in RNA degradation.


Expression: As used herein, “expression” of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g., by splicing, editing, 5′ cap formation, and/or 3′ end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.


Feature: As used herein, a “feature” refers to a characteristic, a property, or a distinctive element.


Formulation: As used herein, a “formulation” includes at least a polynucleotide of a NAV and a delivery agent.


Fragment: A “fragment,” as used herein, refers to a portion. For example, fragments of proteins may comprise polypeptides obtained by digesting full-length protein isolated from cultured cells.


Functional: As used herein, a “functional” biological molecule is a biological molecule in a form in which it exhibits a property and/or activity by which it is characterized.


Homology: As used herein, the term “homology” refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be “homologous” to one another if their sequences are at least 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% identical or similar. The term “homologous” necessarily refers to a comparison between at least two sequences (polynucleotide or polypeptide sequences). In accordance with the invention, two polynucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50%, 60%, 70%, 80%, 90%, 95%, or even 99% for at least one stretch of at least about 20 amino acids. In some embodiments, homologous polynucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. For polynucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the invention, two protein sequences are considered to be homologous if the proteins are at least about 50%, 60%, 70%, 80%, or 90% identical for at least one stretch of at least about 20 amino acids.


Identity: As used herein, the term “identity” refers to the overall relatedness between polymeric molecules, e.g., between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two polynucleotide sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M Stockton Press, New York, 1991; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989. 4:11-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, H., and Lipman, D., SIAM J Applied Math., 48:1073 (1988); incorporated herein by reference. Techniques for determining identity are codified in publicly available computer programs. Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J., et al., Nucleic Acids Research, 12(1), 387 (1984)), BLASTP, BLASTN, and FASTA Altschul, S. F. et al., J. Molec. Biol., 215, 403 (1990)).


Infectious Agent: As used herein, the phrase “infectious agent” means an agent capable of producing an infection in an organism, for example, in an animal. An infectious agent may refer to any microorganism, virus, infectious substance, or biological product that may be engineered as a result of biotechnology, or any naturally occurring or bioengineered component of any such microorganism, virus, infectious substance, or biological product, can cause emerging and contagious disease, death or other biological malfunction in a human, an animal, a plant or another living organism.


Inhibit expression of a gene: As used herein, the phrase “inhibit expression of a gene” means to cause a reduction in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically a reduction in the level of an mRNA results in a reduction in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein.


Influenza: As used herein, “influenza” or “flu” is an infectious disease of birds and mammals caused by RNA viruses of the family Orthomyxoviridae, the influenza viruses.


Isomer: As used herein, the term “isomer” means any tautomer, stereoisomer, enantiomer, or diastereomer of any compound of the invention. It is recognized that the compounds of the invention can have one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric E/Z isomers) or diastereomers (e.g., enantiomers (i.e., (+) or (−)) or cis/trans isomers). According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures, e.g., racemates. Enantiomeric and stereoisomeric mixtures of compounds of the invention can typically be resolved into their component enantiomers or stereoisomers by well-known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Enantiomers and stereoisomers can also be obtained from stereomerically or enantiomerically pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.


In vitro: As used herein, the term “in vitro” refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).


In vivo: As used herein, the term “in vivo” refers to events that occur within an organism (e.g., animal, plant, or microbe or cell or tissue thereof).


Isolated: As used herein, the term “isolated” refers to a substance or entity that has been separated from at least some of the components with which it was associated (whether in nature or in an experimental setting). Isolated substances may have varying levels of purity in reference to the substances from which they have been associated. Isolated substances and/or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated agents are more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is “pure” if it is substantially free of other components. Substantially isolated: By “substantially isolated” is meant that the compound is substantially separated from the environment in which it was formed or detected. Partial separation can include, for example, a composition enriched in the compound of the present disclosure. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the present disclosure, or salt thereof. Methods for isolating compounds and their salts are routine in the art.


IVT Polynucleotide: As used herein, an “IVT polynucleotide” is a linear polynucleotide which may be made using in vitro transcription (IVT) enzymatic synthesis methods.


Linker: As used herein, a “linker” refers to a group of atoms, e.g., 10-1,000 atoms, and can be comprised of the atoms or groups such as, but not limited to, carbon, amino, alkylamino, oxygen, sulfur, sulfoxide, sulfonyl, carbonyl, and imine. The linker can be attached to a modified nucleoside or nucleotide on the nucleobase or sugar moiety at a first end, and to a payload, e.g., a detectable or therapeutic agent, at a second end. The linker may be of sufficient length as to not interfere with incorporation into a nucleic acid sequence. The linker can be used for any useful purpose, such as to form polynucleotide multimers (e.g., through linkage of two or more chimeric polynucleotides molecules or IVT polynucleotides) or polynucleotides conjugates, as well as to administer a payload, as described herein. Examples of chemical groups that can be incorporated into the linker include, but are not limited to, alkyl, alkenyl, alkynyl, amido, amino, ether, thioether, ester, alkylene, heteroalkylene, aryl, or heterocyclyl, each of which can be optionally substituted, as described herein. Examples of linkers include, but are not limited to, unsaturated alkanes, polyethylene glycols (e.g., ethylene or propylene glycol monomeric units. e.g., diethylene glycol, dipropylene glycol, triethylene glycol, tripropylene glycol, tetraethylene glycol, or tetraethylene glycol), and dextran polymers and derivatives thereof. Other examples include, but are not limited to, cleavable moieties within the linker, such as, for example, a disulfide bond (—S—S—) or an azo bond (—N═N—), which can be cleaved using a reducing agent or photolysis. Non-limiting examples of a selectively cleavable bond include an amido bond can be cleaved for example by the use of tris(2-carboxyethyl)phosphine (TCEP), or other reducing agents, and/or photolysis, as well as an ester bond can be cleaved for example by acidic or basic hydrolysis.


MicroRNA (miRNA) binding site: As used herein, a microRNA (miRNA) binding site represents a nucleotide location or region of a nucleic acid transcript to which at least the “seed” region of a miRNA binds.


Modified: As used herein “modified” refers to a changed state or structure of a molecule of the invention. Molecules may be modified in many ways including chemically, structurally, and functionally. In one embodiment, the polynucleotide molecules of the present invention are modified by the introduction of non-natural nucleosides and/or nucleotides, e.g., as it relates to the natural ribonucleotides A, U, G, and C. Noncanonical nucleotides such as the cap structures are not considered “modified” although they differ from the chemical structure of the A, C, G, U ribonucleotides.


Mucus: As used herein, “mucus” refers to the natural substance that is viscous and comprises mucin glycoproteins.


Naturally occurring: As used herein, “naturally occurring” means existing in nature without artificial aid.


Neutralizing antibody: As used herein, a “neutralizing antibody” refers to an antibody which binds to its antigen and defends a cell from an antigen or infectious agent by neutralizing or abolishing any biological activity it has.


Non-human vertebrate: As used herein, a “non human vertebrate” includes all vertebrates except Homo sapiens, including wild and domesticated species. Examples of non-human vertebrates include, but are not limited to, mammals, such as alpaca, banteng, bison, camel, cat, cattle, deer, dog, donkey, gayal, goat, guinea pig, horse, llama, mule, pig, rabbit, reindeer, sheep water buffalo, and yak.


Nucleic Acid Vaccine: As used herein, “nucleic acid vaccine” or “NAV” or “NAV composition” refers to a vaccine or vaccine composition which includes a nucleic acid or nucleic acid molecule (e.g., a polynucleotide) encoding an antigen (e.g., an antigenic protein or polypeptide.) in exemplary embodiments, a nucleic acid vaccine or NAV includes a ribonucleic (“RNA”) polynucleotide, ribonucleic acid (“RNA”) or ribonucleic acid (“RNA”) molecule. Such embodiments can be referred to as ribonucleic acid (“RNA”) vaccines (RNAVs). In preferred embodiments, a nucleic acid vaccine or NAV includes a messenger RNA (“mRNA”) polynucleotide, messenger RNA (“mRNA”) or messenger RNA (“mRNA”) molecule as described in detail herein. Such embodiments can be referred to as messenger RNA (“mRNA”) vaccines (mRNAVs).


Off-target: As used herein, “off target” refers to any unintended effect on any one or more target, gene, or cellular transcript.


Open reading frame: As used herein, the term “open reading frame” or “ORF” refers to a continuous polynucleotide sequence, for example, a DNA sequence or RNA sequence (e.g., an mRNA sequence), comprising a start codon, a subsequent region comprising a plurality of amino acid-encoding codons, and a terminal stop codon, wherein the region comprising the plurality of amino acid-encoding codons contains no stop codons.


Operably linked: As used herein, the phrase “operably linked” refers to a functional connection between two or more molecules, constructs, transcripts, entities, moieties or the like.


Optionally substituted: Herein a phrase of the form “optionally substituted X” (e.g., optionally substituted alkyl) is intended to be equivalent to “X, wherein X is optionally substituted” (e.g., “alkyl, wherein said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional.


Part: As used herein, a “part” or “region” of a polynucleotide is defined as any portion of the polynucleotide which is less than the entire length of the polynucleotide.


Peptide: As used herein, “peptide” is less than or equal to 50 amino acids long, e.g., about 5, 10, 15, 20, 25, 30, 35, 40, 45, or 50 amino acids long.


Paratope: As used herein, a “paratope” refers to the antigen-binding site of an antibody.


Patient: As used herein, “patient” refers to a subject who may seek or be in need of treatment, requires treatment, is receiving treatment, will receive treatment, or a subject who is under care by a trained professional for a particular disease or condition.


Pharmaceutically acceptable: The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.


Pharmaceutically acceptable excipients: The phrase “pharmaceutically acceptable excipient,” as used herein, refers any ingredient other than the compounds described herein (for example, a vehicle capable of suspending or dissolving the active compound) and having the properties of being substantially nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors), emollients, emulsifiers, fillers (diluents), film formers or coatings, flavors, fragrances, glidants (flow enhancers), lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, and waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.


Pharmaceutically acceptable salts: The present disclosure also includes pharmaceutically acceptable salts of the compounds described herein. As used herein, “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form (e.g., by reacting the free base group with a suitable organic acid). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Representative acid addition salts include acetate, acetic acid, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzene sulfonic acid, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. The pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two: generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, Pharmaceutical Salts: Properties, Selection, and Use, P. H. Stahl and C. G. Wermuth (eds.), Wiley-VCH, 2008, and Berge et al., Journal of Pharmaceutical Science, 66, 1-19 (1977), each of which is incorporated herein by reference in its entirety.


Pharmaceutically acceptable solvate: The term “pharmaceutically acceptable solvate,” as used herein, means a compound of the invention wherein molecules of a suitable solvent are incorporated in the crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered. For example, solvates may be prepared by crystallization, recrystallization, or precipitation from a solution that includes organic solvents, water, or a mixture thereof. Examples of suitable solvents are ethanol, water (for example, mono-, di-, and tri-hydrates), N-methylpyrrolidinone (NMP), dimethyl sulfoxide (DMSO), N,N′-dimethylformamide (DMF), N,N′-dimethylacetamide (DMAC), 1,3-dimethyl-2-imidazolidinone (DMEU), 1,3-dimethyl-3,4,5,6-tetrahydro-2-(1H)-pyrimidinone (DMPU), acetonitrile (ACN), propylene glycol, ethyl acetate, benzyl alcohol, 2-pyrrolidone, benzyl benzoate, and the like. When water is the solvent, the solvate is referred to as a “hydrate.”


Pharmacokinetic: As used herein, “pharmacokinetic” refers to any one or more properties of a molecule or compound as it relates to the determination of the fate of substances administered to a living organism. Pharmacokinetics is divided into several areas including the extent and rate of absorption, distribution, metabolism and excretion. This is commonly referred to as ADME where: (A) Absorption is the process of a substance entering the blood circulation; (D) Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body; (M) Metabolism (or Biotransformation) is the irreversible transformation of parent compounds into daughter metabolites; and (E) Excretion (or Elimination) refers to the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in body tissue.


Physicochemical: As used herein, “physicochemical” means of or relating to a physical and/or chemical property.


Polypeptide per unit drug (PUD): As used herein, a PUD or product per unit drug, is defined as a subdivided portion of total daily dose, usually 1 mg, pg, kg, etc., of a product (such as a polypeptide) as measured in body fluid or tissue, usually defined in concentration such as pmol/mL, mmol/mL, etc divided by the measure in the body fluid.


Preventing: As used herein, the term “preventing” refers to partially or completely delaying onset of an infection, disease, disorder and/or condition; partially or completely delaying onset of one or more symptoms, features, or clinical manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular infection, disease, disorder, and/or condition; partially or completely delaying progression from an infection, a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the infection, the disease, disorder, and/or condition.


Prodrug: The present disclosure also includes prodrugs of the compounds described herein. As used herein, “prodrugs” refer to any substance, molecule or entity which is in a form predicate for that substance, molecule or entity to act as a therapeutic upon chemical or physical alteration. Prodrugs may by covalently bonded or sequestered in some way and which release or are converted into the active drug moiety prior to, upon or after administered to a mammalian subject. Prodrugs can be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Preparation and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.


Proliferate: As used herein, the term “proliferate” means to grow, expand or increase or cause to grow, expand or increase rapidly. “Proliferative” means having the ability to proliferate. “Anti-proliferative” means having properties counter to or inapposite to proliferative properties.


Prophylactic: As used herein, “prophylactic” refers to a therapeutic or course of action used to prevent the spread of disease.


Prophylaxis: As used herein, a “prophylaxis” refers to a measure taken to maintain health and prevent the spread of disease. An “immune prophylaxis” refers to a measure to produce active or passive immunity to prevent the spread of disease.


Protein cleavage site: As used herein, “protein cleavage site” refers to a site where controlled cleavage of the amino acid chain can be accomplished by chemical, enzymatic or photochemical means.


Protein cleavage signal: As used herein “protein cleavage signal” refers to at least one amino acid that flags or marks a polypeptide for cleavage.


Protein of interest: As used herein, the terms “proteins of interest” or “desired proteins” include those provided herein and fragments, mutants, variants, and alterations thereof.


Proximal: As used herein, the term “proximal” means situated nearer to the center or to a point or region of interest.


Pseudouridine: As used herein, pseudouridine refers to the C-glycoside isomer of the nucleoside uridine. A “pseudouridine analog” is any modification, variant, isoform or derivative of pseudouridine. For example, pseudouridine analogs include but are not limited to 1-carboxymethyl-pseudouridine, 1-propynyl-pseudouridine, 1-taurinomethyl-pseudouridine, 1-taurinomethyl-4-thio-pseudouridine, 1-methylpseudouridine (m1ψ), 1-methyl-4-thio-pseudouridine (m1s4ψ), 4-thio-1-methyl-pseudouridine, 3-methyl-pseudouridine (m3ψ), 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydropseudouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, N1-methyl-pseudouridine, 1-methyl-3-(3-amino-3-carboxypropyl)pseudouridine (acp3 ψ), and 2′-O-methyl-pseudouridine (Wm).


Purified: As used herein, “purify,” “purified,” “purification” means to make substantially pure or clear from unwanted components, material defilement, admixture or imperfection.


Repeated transfection: As used herein, the term “repeated transfection” refers to transfection of the same cell culture with a polynucleotide a plurality of times. The cell culture can be transfected at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, at least 7 times, at least 8 times, at least 9 times, at least 10 times, at least 11 times, at least 12 times, at least 13 times, at least 14 times, at least 15 times, at least 16 times, at least 17 times at least 18 times, at least 19 times, at least 20 times, at least 25 times, at least 30 times, at least 35 times, at least 40 times, at least 45 times, at least 50 times or more.


Sample: As used herein, the term “sample” or “biological sample” refers to a subset of its tissues, cells or component parts (e.g. body fluids, including but not limited to blood, mucus, lymphatic fluid, synovial fluid, cerebrospinal fluid, saliva, amniotic fluid, amniotic cord blood, urine, vaginal fluid and semen). A sample further may include a homogenate, lysate or extract prepared from a whole organism or a subset of its tissues, cells or component parts, or a fraction or portion thereof, including but not limited to, for example, plasma, serum, spinal fluid, lymph fluid, the external sections of the skin, respiratory, intestinal, and genitourinary tracts, tears, saliva, milk, blood cells, tumors, organs. A sample further refers to a medium, such as a nutrient broth or gel, which may contain cellular components, such as proteins or nucleic acid molecule.


Signal Sequences: As used herein, the phrase “signal sequences” refers to a sequence which can direct the transport or localization of a protein.


Single unit dose: As used herein, a “single unit dose” is a dose of any therapeutic administered in one dose/at one time/single route/single point of contact, i.e., single administration event.


Similarity: As used herein, the term “similarity” refers to the overall relatedness between polymeric molecules, e.g. between polynucleotide molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art.


Split dose: As used herein, a “split dose” is the division of single unit dose or total daily dose into two or more doses.


Stable: As used herein “stable” refers to a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and preferably capable of formulation into an efficacious therapeutic agent.


Stabilized: As used herein, the term “stabilize”, “stabilized,” “stabilized region” means to make or become stable.


Stereoisomer: As used herein, the term “stereoisomer” refers to all possible different isomeric as well as conformational forms which a compound may possess (e.g., a compound of any formula described herein), in particular all possible stereochemically and conformationally isomeric forms, all diastereomers, enantiomers and/or conformers of the basic molecular structure. Some compounds of the present invention may exist in different tautomeric forms, all of the latter being included within the scope of the present invention.


Subject: As used herein, the term “subject” or “patient” refers to any organism to which a composition in accordance with the invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.


Substantially: As used herein, the term “substantially” refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term “substantially” is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena.


Substantially equal: As used herein as it relates to time differences between doses, the term means plus/minus 2%.


Substantially simultaneously: As used herein and as it relates to plurality of doses, the term means within 2 seconds.


Suffering from: An individual who is “suffering from” a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.


Susceptible to: An individual who is “susceptible to” a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition but harbors a propensity to develop a disease or its symptoms. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition (for example, cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and/or condition.


Sustained release: As used herein, the term “sustained release” refers to a pharmaceutical composition or compound release profile that conforms to a release rate over a specific period of time.


Synthetic: The term “synthetic” means produced, prepared, and/or manufactured by the hand of man. Synthesis of polynucleotides or polypeptides or other molecules of the present invention may be chemical or enzymatic.


Vaccine: As used herein, a vaccine is a compound or composition which comprises at least one polynucleotide encoding at least one antigen.


Targeted Cells: As used herein, “targeted cells” refers to any one or more cells of interest. The cells may be found in vitro, in vivo, in situ or in the tissue or organ of an organism. The organism may be an animal, preferably a mammal, more preferably a human and most preferably a patient.


Therapeutic Agent: The term “therapeutic agent” refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.


Therapeutically effective amount: As used herein, the term “therapeutically effective amount” means an amount of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.


Therapeutically effective outcome: As used herein, the term “therapeutically effective outcome” means an outcome that is sufficient in a subject suffering from or susceptible to an infection, disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the infection, disease, disorder, and/or condition.


Total daily dose: As used herein, a “total daily dose” is an amount given or prescribed in 24 hr period. It may be administered as a single unit dose.


Transcription factor: As used herein, the term “transcription factor” refers to a DNA-binding protein that regulates transcription of DNA into RNA, for example, by activation or repression of transcription. Some transcription factors effect regulation of transcription alone, while others act in concert with other proteins. Some transcription factor can both activate and repress transcription under certain conditions. In general, transcription factors bind a specific target sequence or sequences highly similar to a specific consensus sequence in a regulatory region of a target gene. Transcription factors may regulate transcription of a target gene alone or in a complex with other molecules.


Transfection: As used herein, the term “transfection” refers to methods to introduce exogenous nucleic acids into a cell. Methods of transfection include, but are not limited to, chemical methods, physical treatments and cationic lipids or mixtures.


Translation: As used herein “translation” is the process by which a polynucleotide molecule is processed by a ribosome or ribosomal-like machinery, e.g., cellular or artificial, to produce a peptide or polypeptide.


Transcription: As used herein “transcription” is the process by which a polynucleotide molecule is processed by a polymerase or other enzyme to produce a polynucleotide, e.g., an RNA polynucleotide.


Treating: As used herein, the term “treating” refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms or features of a particular infection, disease, disorder, and/or condition. Treatment may be administered to a subject who does not exhibit signs of a disease, infection, disorder, and/or condition and/or to a subject who exhibits only early signs of a disease, infection, disorder, and/or condition for the purpose of decreasing the risk of developing pathology associated with the disease, infection, disorder, and/or condition.


Unmodified: As used herein, “unmodified” refers to any substance, compound or molecule prior to being changed in any way. Unmodified may, but does not always, refer to the wild type or native form of a biomolecule. Molecules may undergo a series of modifications whereby each modified molecule may serve as the “unmodified” starting molecule for a subsequent modification.


Vaccine: As used herein, the phrase “vaccine” refers to a biological preparation that improves immunity in the context of a particular disease, disorder or condition.


Viral protein: As used herein, the pharse “viral protein” means any protein originating from a virus.


EQUIVALENTS AND SCOPE

Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims.


In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.


It is also noted that the term “comprising” is intended to be open and permits but does not require the inclusion of additional elements or steps. When the term “comprising” is used herein, the term “consisting of” is thus also encompassed and disclosed.


Where ranges are given, endpoints are included. Furthermore, it is to be understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.


In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc.) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.


All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control.


Section and table headings are not intended to be limiting.


EXAMPLES
Example 1. Manufacture of Polynucleotides

According to the present invention, the manufacture of polynucleotides and or parts or regions thereof may be accomplished utilizing the methods taught in U.S. Ser. No. 61/800,049 filed Mar. 15, 2013 entitled “Manufacturing Methods for Production of RNA Transcripts” (Attorney Docket number M500), the contents of which is incorporated herein by reference in its entirety.


Purification methods may include those taught in U.S. Provisional Patent Application No. 61/799,872, U.S. Provisional Patent Application No. 61/794,842, U.S. Provisional Patent Application 61/800,326, each of which is incorporated herein by reference in its entirety.


Detection and characterization methods of the polynucleotides may be performed as taught in US Provisional Patent Application No. 61n99,780 and U.S. Provisional Patent Application No. 61/798,945, each of which is incorporated herein by reference in its entirety.


Characterization of the polynucleotides of the invention may be accomplished using a procedure selected from the group consisting of polynucleotide mapping, reverse transcriptase sequencing, charge distribution analysis, and detection of RNA impurities, wherein characterizing comprises determining the RNA transcript sequence, determining the purity of the RNA transcript, or determining the charge heterogeneity of the RNA transcript. Such methods are taught in, for example, U.S. Provisional Patent Application No. 61/799,905 and US Provisional Patent Application No. 61/800,110, the contents of each of which is incorporated herein by reference in its entirety.


Example 2. Chimeric Polynucleotide Synthesis
Introduction

According to the present invention, two regions or parts of a chimeric polynucleotide may be joined or ligated using triphosphate chemistry.


According to this method, a first region or part of 100 nucleotides or less is chemically synthesized with a 5′ monophosphate and terminal 3′desOH or blocked OH. If the region is longer than 80 nucleotides, it may be synthesized as two strands for ligation.


If the first region or part is synthesized as a non-positionally modified region or part using in vitro transcription (IVT), conversion the 5′monophosphate with subsequent capping of the 3′ terminus may follow.


Monophosphate protecting groups may be selected from any of those known in the art.


The second region or part of the chimeric polynucleotide may be synthesized using either chemical synthesis or IVT methods. IVT methods may include an RNA polymerase that can utilize a primer with a modified cap. Alternatively, a cap of up to 130 nucleotides may be chemically synthesized and coupled to the IVT region or part.


It is noted that for ligation methods, ligation with DNA T4 ligase, followed by treatment with DNAse should readily avoid concatenation.


The entire chimeric polynucleotide need not be manufactured with a phosphate-sugar backbone. If one of the regions or parts encodes a polypeptide, then it is preferable that such region or part comprise a phosphate-sugar backbone.


Ligation is then performed using any known click chemistry, orthoclick chemistry, solulink, or other bioconjugate chemistries known to those in the art.


Synthetic Route

The chimeric polynucleotide is made using a series of starting segments. Such segments include:

    • (a) Capped and protected 5′ segment comprising a normal 3′OH (SEG. 1)
    • (b) 5′ triphosphate segment which may include the coding region of a polypeptide and comprising a normal 3′OH (SEG. 2)
    • (c) 5′ monophosphate segment for the 3′ end of the chimeric polynucleotide (e.g., the tail) comprising cordycepin or no 3′OH (SEG. 3)


After synthesis (chemical or IVT), segment 3 (SEG. 3) is treated with cordycepin and then with pyrophosphatase to create the 5′monophosphate.


Segment 2 (SEG. 2) is then ligated to SEG. 3 using RNA ligase. The ligated polynucleotide is then purified and treated with pyrophosphatase to cleave the diphosphate. The treated SEG.2-SEG. 3 construct is then purified and SEG. 1 is ligated to the 5′ terminus. A further purification step of the chimeric polynucleotide may be performed.


Where the chimeric polynucleotide encodes a polypeptide, the ligated or joined segments may be represented as: 5′UTR (SEG. 1), open reading frame or ORF (SEG. 2) and 3′UTR+PolyA (SEG. 3).


The yields of each step may be as much as 90-95%.


Example 3: PCR for cDNA Production

PCR procedures for the preparation of cDNA are performed using 2×KAPA HIFI™ HotStart ReadyMix by Kapa Biosystems (Woburn, MA). This system includes 2×KAPA ReadyMix12.5 μl; Forward Primer (10 uM) 0.75 μl; Reverse Primer (10 uM) 0.75 μl; Template cDNA −100 ng; and dH20 diluted to 25.0 μl. The reaction conditions are at 95° C. for 5 min. and 25 cycles of 98° C. for 20 sec, then 58° C. for 15 sec, then 72° C. for 45 sec, then 72° C. for 5 min. then 4° C. to termination.


The reverse primer of the instant invention incorporates a poly-T120 for a poly-A120 in the mRNA. Other reverse primers with longer or shorter poly(T) tracts can be used to adjust the length of the poly(A) tail in the polynucleotide mRNA.


The reaction is cleaned up using Invitrogen's PURELINK™ PCR Micro Kit (Carlsbad, CA) per manufacturer's instructions (up to 5 μg). Larger reactions will require a cleanup using a product with a larger capacity. Following the cleanup, the cDNA is quantified using the NANODROP™ and analyzed by agarose gel electrophoresis to confirm the cDNA is the expected size. The cDNA is then submitted for sequencing analysis before proceeding to the in vitro transcription reaction.


Example 4. In Vitro Transcription (IVT)

The in vitro transcription reaction generates polynucleotides containing uniformly modified polynucleotides. Such uniformly modified polynucleotides may comprise a region or part of the polynucleotides of the invention. The input nucleotide triphosphate (NTP) mix is made in-house using natural and un-natural NTPs.


A typical in vitro transcription reaction includes the following:



















1
Template cDNA
1.0
μg



2
10× transcription buffer (400 mM Tris-
2.0
μl




HCl pH 8.0, 190 mM MgCl2, 50






mM DTT, 10 mM Spermidine)





3
Custom NTPs (25 mM each)
7.2
μl



4
RNase Inhibitor
20
U



5
T7 RNA polymerase
3000
U











6
dH20
Up to 20.0 μl. and



7
Incubation at 37° C. for 3 hr-5 hrs.









The crude IVT mix may be stored at 4° C. overnight for cleanup the next day. 1 U of RNase-free DNase is then used to digest the original template. After 15 minutes of incubation at 37° C., the mRNA is purified using Ambion's MEGACLEAR™ Kit (Austin, TX) following the manufacturer's instructions. This kit can purify up to 500 μg of RNA. Following the cleanup, the RNA is quantified using the NanoDrop and analyzed by agarose gel electrophoresis to confirm the RNA is the proper size and that no degradation of the RNA has occurred.


Example 5. Enzymatic Capping

Capping of a polynucleotide is performed as follows where the mixture includes: IVT RNA 60 μg-180 μg and dH20 up to 72 μl. The mixture is incubated at 65° C. for 5 minutes to denature RNA, and then is transferred immediately to ice.


The protocol then involves the mixing of 10× Capping Buffer (0.5 M Tris-HCl (pH 8.0), 60 mM KCl, 12.5 mM MgCl2) (10.0 μl); 20 mM GTP (5.0 μl); 20 mM S-Adenosyl Methionine (2.5 μl); RNase Inhibitor (100 U); 2′-O-Methyltransferase (400 U); Vaccinia capping enzyme (Guanylyl transferase) (40 U); dH20 (Up to 28 μl); and incubation at 37° C. for 30 minutes for 60 μg RNA or up to 2 hours for 180 μg of RNA.


The polynucleotide is then purified using Ambion's MEGACLEAR™ Kit (Austin, TX) following the manufacturer's instructions. Following the cleanup, the RNA is quantified using the NANODROI™ (ThermoFisher, Waltham, MA) and analyzed by agarose gel electrophoresis to confirm the RNA is the proper size and that no degradation of the RNA has occurred. The RNA product may also be sequenced by running a reverse-transcription-PCR to generate the cDNA for sequencing.


Example 6. PolyA Tailing Reaction

Without a poly-T in the cDNA, a poly-A tailing reaction must be performed before cleaning the final product. This is done by mixing Capped IVT RNA (100 μl); RNase Inhibitor (20 U); 10× Tailing Buffer (0.5 M Tris-HCl (pH 8.0), 2.5 M NaCl, 100 mM MgCl2)(12.0 μl); 20 mM ATP (6.0 μl); Poly-A Polymerase (20 U); dH20 up to 123.5 μl and incubation at 37° C. for 30 min. If the poly-A tail is already in the transcript, then the tailing reaction may be skipped and proceed directly to cleanup with Ambion's MEGACLEAR™ kit (Austin, TX) (up to 500 μg). Poly-A Polymerase is preferably a recombinant enzyme expressed in yeast.


It should be understood that the processivity or integrity of the polyA tailing reaction may not always result in an exact size polyA tail. Hence polyA tails of approximately between 40-200 nucleotides, e.g, about 40, 50, 60, 70, 80, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 150-165, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164 or 165 are within the scope of the invention.


Example 7. Natural 5′ Caps and 5′ Cap Analogues

5′-capping of polynucleotides may be completed concomitantly during the in vitro-transcription reaction using the following chemical RNA cap analogs to generate the 5′-guanosine cap structure according to manufacturer protocols: 3′-O-Me-m7G(5′)ppp(5′) G [the ARCA cap];G(5′)ppp(5′)A; G(5′)ppp(5′)G; m7G(5′)ppp(5′)A; m7G(5′)ppp(5′)G (New England BioLabs. Ipswich, MA). 5′-capping of modified RNA may be completed post-transcriptionally using a Vaccinia Virus Capping Enzyme to generate the “Cap 0” structure: m7G(5′)ppp(5′)G (New England BioLabs, Ipswich, MA). Cap 1 structure may be generated using both Vaccinia Virus Capping Enzyme and a 2′-O methyl-transferase to generate: m7G(5′)ppp(5′)G-2′-O-methyl. Cap 2 structure may be generated from the Cap 1 structure followed by the 2′-O-methylation of the 5′-antepenultimate nucleotide using a 2′-0 methyl-transferase. Cap 3 structure may be generated from the Cap 2 structure followed by the 2′-O-methylation of the 5′-preantepenultimate nucleotide using a 2′-O methyl-transferase. Enzymes are preferably derived from a recombinant source.


When transfected into mammalian cells, the modified mRNAs have a stability of between 12-18 hours or more than 18 hours, e.g., 24, 36, 48, 60, 72 or greater than 72 hours.


Example 8. Capping Assays
A. Protein Expression Assay

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be transfected into cells at equal concentrations. 6, 12, 24 and 36 hours post-transfection the amount of protein secreted into the culture medium can be assayed by ELISA. Synthetic polynucleotides that secrete higher levels of protein into the medium would correspond to a synthetic polynucleotide with a higher translationally-competent Cap structure.


B. Purity Analysis Synthesis

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be compared for purity using denaturing Agarose-Urea gel electrophoresis or HPLC analysis. Polynucleotides with a single, consolidated band by electrophoresis correspond to the higher purity product compared to polynucleotides with multiple bands or streaking bands. Synthetic polynucleotides with a single HPLC peak would also correspond to a higher purity product. The capping reaction with a higher efficiency would provide a more pure polynucleotide population.


C. Cytokine Analysis

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be transfected into cells at multiple concentrations. 6, 12, 24 and 36 hours post-transfection the amount of pro-inflammatory cytokines such as TNF-alpha and IFN-beta secreted into the culture medium can be assayed by ELISA. Polynucleotides resulting in the secretion of higher levels of pro-inflammatory cytokines into the medium would correspond to a polynucleotides containing an immune-activating cap structure.


D. Capping Reaction Efficiency

Polynucleotides encoding a polypeptide, containing any of the caps taught herein can be analyzed for capping reaction efficiency by LC-MS after nuclease treatment. Nuclease treatment of capped polynucleotides would yield a mixture of free nucleotides and the capped 5′-5-triphosphate cap structure detectable by LC-MS. The amount of capped product on the LC-MS spectra can be expressed as a percent of total polynucleotide from the reaction and would correspond to capping reaction efficiency. The cap structure with higher capping reaction efficiency would have a higher amount of capped product by LC-MS.


Example 9. Agarose Gel Electrophoresis of Modified RNA or RT PCR Products

Individual polynucleotides (200-400 ng in a 20 μl volume) or reverse transcribed PCR products (200-400 ng) are loaded into a well on a non-denaturing 1.2% Agarose E-Gel (Invitrogen, Carlsbad, CA) and run for 12-15 minutes according to the manufacturer protocol.


Example 10. Nanodrop Modified RNA Quantification and UV Spectral Data

Modified polynucleotides in TE buffer (1 μl) are used for Nanodrop UV absorbance readings to quantitate the yield of each polynucleotide from an chemical synthesis or in vitro transcription reaction.


Example 11. Formulation of Modified mRNA Using Lipidoids

Polynucleotides are formulated for in vitro experiments by mixing the polynucleotides with the lipidoid at a set ratio prior to addition to cells. In vivo formulation may require the addition of extra ingredients to facilitate circulation throughout the body. To test the ability of these lipidoids to form particles suitable for in vivo work, a standard formulation process used for siRNA-lipidoid formulations may used as a starting point. After formation of the particle, polynucleotide is added and allowed to integrate with the complex. The encapsulation efficiency is determined using a standard dye exclusion assays.


Example 12. Method of Screening for Protein Expression
A. Electrospray Ionization

A biological sample which may contain proteins encoded by a polynucleotide administered to the subject is prepared and analyzed according to the manufacturer protocol for electrospray ionization (ESI) using 1, 2, 3 or 4 mass analyzers. A biologic sample may also be analyzed using a tandem ESI mass spectrometry system.


Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.


B. Matrix-Assisted Laser Desorption/Ionization

A biological sample which may contain proteins encoded by one or more polynucleotides administered to the subject is prepared and analyzed according to the manufacturer protocol for matrix-assisted laser desorption/ionization (MALDI).


Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.


C. Liquid Chromatography-Mass Spectrometry-Mass Spectrometry

A biological sample, which may contain proteins encoded by one or more polynucleotides, may be treated with a trypsin enzyme to digest the proteins contained within. The resulting peptides are analyzed by liquid chromatography-mass spectrometry-mass spectrometry (LC/MS/MS). The peptides are fragmented in the mass spectrometer to yield diagnostic patterns that can be matched to protein sequence databases via computer algorithms. The digested sample may be diluted to achieve 1 ng or less starting material for a given protein. Biological samples containing a simple buffer background (e.g. water or volatile salts) are amenable to direct in-solution digest; more complex backgrounds (e.g. detergent, non-volatile salts, glycerol) require an additional clean-up step to facilitate the sample analysis.


Patterns of protein fragments, or whole proteins, are compared to known controls for a given protein and identity is determined by comparison.


Example 13. Cyclization and/or Concatemerization

According to the present invention, a polynucleotide may be cyclized, or concatemerized, to generate a translation competent molecule to assist interactions between poly-A binding proteins and 5′-end binding proteins. The mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1) chemical, 2) enzymatic, and 3) ribozyme catalyzed. The newly formed 5′-/3′-linkage may be intramolecular or intermolecular.


In the first route, the 5′-end and the 3′-end of the nucleic acid contain chemically reactive groups that, when close together, form a new covalent linkage between the 5′-end and the 3′-end of the molecule. The 5′-end may contain an NHS-ester reactive group and the 3′-end may contain a 3′-amino-terminated nucleotide such that in an organic solvent the 3′-amino-terminated nucleotide on the 3′-end of a synthetic mRNA molecule will undergo a nucleophilic attack on the 5′-NHS-ester moiety forming a new 5′-/3′-amide bond.


In the second route, T4 RNA ligase may be used to enzymatically link a 5′-phosphorylated nucleic acid molecule to the 3′-hydroxyl group of a nucleic acid forming a new phosphorodiester linkage. In an example reaction, 1 μg of a nucleic acid molecule is incubated at 37° C. for 1 hour with 1-10 units of T4 RNA ligase (New England Biolabs, Ipswich, MA) according to the manufacturer's protocol. The ligation reaction may occur in the presence of a split polynucleotide capable of base-pairing with both the 5′- and 3′-region in juxtaposition to assist the enzymatic ligation reaction.


In the third route, either the 5′- or 3′-end of the cDNA template encodes a ligase ribozyme sequence such that during in vitro transcription, the resultant nucleic acid molecule can contain an active ribozyme sequence capable of ligating the 5′-end of a nucleic acid molecule to the 3′-end of a nucleic acid molecule. The ligase ribozyme may be derived from the Group I Intron, Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment). The ribozyme ligase reaction may take 1 to 24 hours at temperatures between 0 and 37° C.


Example 14. Antigen Polynucleotides

Polynucleotides used in the studies herein which encode certain infectious agent antigens or variants thereof are shown in Table 28.









TABLE 28







Antigen polynucleotides (RNA vaccine)










Construct





Number
Gene ID
Description
Construct













 1
120552
Flu PR8 HA
HAPR8_Ferritin_Hs3




ferritin



 2
120553
flu 1999NC HA
HA1999NC_Ferritin_




ferritin
Hs3


 3
125387
H5N1 HA antigen
H5N1_HA_NIBRG-





14


 4
125388
H1N1 PR8 HA
CurevacPR8HA_




antigen with MT
MT5U_Hs3U




5U/3U



 5
135929
Influenza HA
HA_A/Mallard/




antigen
Netherlands/12/2000_





H7N3_Hs3U


 6
135930
Influenza HA
HA_A/Puerto




antigen
Rico/8/1934_H1N1_





Hs3U


 7
135931
Influenza HA
HA_A/Viet




antigen
Nam/850/2009_





H1N1_Hs3U


 8
135932
Influenza HA
HA_A/New




antigen
Calcedonia/20/99_H1N1_





Hs3U


 9
135933
Influenza HA
HA_A/Vietnam/1203/




antigen
2004_H5N1_Hs3U


10
135934
Influenza HA
HA_A/Hong




antigen
Kong/1073/99_H9N2_





Hs3U


11
135935
Influenza HA
HA_A/Wisconsin/67/




antigen
2005_H3N2_Hs3U


12
135936
Influenza HA
HA_A/Hong




antigen
Kong/1/1968_H3N2_





Hs3U


13
136473
flu HA antigen
A/duck/Anhui/SC702/





2013(H7N9)_Hs3U


14
136754
C diff antigen
Cdiff_toxinA.truc_





nMyc.cFLAG_Hs3U


15
136755
C diff antigen
Cdiff_toxinB.truc_





nMyc.cFLAG_Hs3U


16
136756
C diff antigen
Cdiff_cdtA.truc_nMyc.





cFLAG_Hs3U


17
136757
C diff antigen
Cdiff_cdtB.truc_nMyc.





cFLAG_Hs3U


18
120554
Dengue strain 2
DEN2_DIII_Ferritin_




domain 3 ferritin
Hs3


19
120555
Dengue strain 3
DEN3_DIII_Ferritin_




domain 3 ferritin
Hs3


20
120556
Dengue strain 4
DEN4_DIII_Ferritin_




domain 3 ferritin
Hs3


21
120557
dengue strain 1-4
Dengue_TDIII_Hs3




Domain 3



22
121542
Dengue strain 1
DEN1_DIII_Ferritin_




domain 3 ferritin
Corr_Hs3


23
131502
Dengue 2,
DEN2_D2Y98P_




D2Y98P strain,
PrME_Hs3




PrME





transmembrane





antigen



24
131503
Dengue 2,
DEN2_D2Y98P_




D2Y98P strain,
PrME80_Hs3




PrME secreted





antigen



25
131507
Dengue 2,
DEN2_D2Y98P_




D2Y98P strain,
PrME80_ScFv.aDEC205.




PrME secreted
FLAG_Hs3




antigen with





dendritic targeting





ScFv against





mouse DEC205



26
136358

Staph aureus

SpA_sec.D. wt.nXpress.




antigen
cHA_VKsp_Hs3U


27
136359

Staph aureus

SpA_intra.D.kkaa.




antigen
nFLAG.cMyc_Hs3U


28
136360

Staph aureus

SpA_mem.D.kkaa.




antigen
nFLAG.cMyc_





CD28mem_Hs3U


29
136361

Staph aureus

SpA_sec.D.kkaa.




antigen
nFLAG.cMyc_VKsp_





Hs3U


30
136362

Staph aureus

SpA_intra.D.wt.nXpress.




antigen
cHA_Hs3U


31
136363

Staph aureus

SpA_mem.D.wt.




antigen
nXpress.cHA_CD28mem_





Hs3U


32
136364

Staph aureus

SpA_sec.D.wt_VKsp




antigen



33
136758
MRSA IsdA
MRSA_IsdA.truc_




antigen
nMyc.cFLAG_Hs3U


34
136759
MRSA IsdB
MRSA_IsdB.truc_




antigen
nMyc.cFLAG_Hs3U


35
136763
MRSA SDRD
MRSA_sdrd.truc_




antigen
nMyc.cFLAG_Hs3U


36
136764
MRSA SDRE
MRSA_sdre.truc




antigen
nMyc.cFLAG_Hs3U


37
136765
MRSA MECA
MRSA_mecA.truc_




antigen
nMyc.cFLAG_Hs3U


38
139325
MRSA SDRD
MRSA_sdrd.contig1._




antigen
FLAG_Hs3U


39
139326
MRSA SDRD
MRSA_sdrd.Contig2._




antigen
FLAG_Hs3U


40
139327
MRSA SDRE
MRSA_sdre.Contig1._




antigen
FLAG_Hs3U


41
139328
MRSA SDRE
MRSA_sdre.Contig2._




antigen
FLAG_Hs3U


42
140470
MRSA ISDA
MRSA_IsdA.fl_




antigen
FLAG_Hs3U


43
139277
MRSA MECA
MRSA_mecA.fl._




antigen
FLAG_Hs3U


44
136747
ETEC antigen
ETEC.eltA(S63K/





R192G/L211A)_nMyc.





cFLAG_Hs3U


45
136748
ETEC antigen
ETEC.eltB_nMyc.





cFLAG_Hs3U


46
136749
ETEC antigen
ETEC.Sta3(A14Q)_





nMyc.cFLAG_Hs3U


47
136750
ETEC antigen
ETEC.etpA._nMyc.





cFLAG_Hs3U


48
136751
ETEC antigen
ETEC.etpB._nMyc.





cFLAG_Hs3U


49
136752
ETEC antigen
ETEC.EatA_nMyc.





cFLAG_Hs3U


50
136753
ETEC antigen
ETEC_cssA_nMyc.





cFLAG_Hs3U


51
136747
ETEC antigen
ETEC.eltA(S63K/





R192G/L211A)_nMyc.





cFLAG_Hs3U


52
142544
ETEC antigen
ETEC.etpB.fl_FLAG_





Hs3U


53
136749
ETEC antigen
ETEC.Sta3(A14Q)_





nMyc.cFLAG_Hs3U


54
136753
ETEC CSSA
ETEC_cssA_nMyc.




antigen
cFLAG_Hs3U


55
139323
ETEC EATA
ETEC_EatA.contig1._




antigen
FLAG_Hs3U


56
139324
ETEC EATA
ETEC_EatA.contig2._




antigen
FLAG_Hs3U


57
139321
ETEC EPTA
ETEC_eptA.contig1._




antigen
FLAG_Hs3U


58
139322
ETEC ETPA
ETEC_etpA.contig2._




antigen
FLAG_Hs3U


59
136760
Tuberculosis
TB_Ag85A_nMyc.




antigen
cFLAG_Hs3U


60
136761
Tuberculosis
TB_Ag85B_nMyc.




antigen
cFLAG_Hs3U


61
136762
Tuberculosis
TB_TB10.4_nMyc.




antigen
cFLAG_Hs3U


62
136335
Cholera toxin B
CholeraToxB.H78A.





FLAG_VKsp_Hs3U


63
144097
vaccine Influenza
PR8HA.Stalk.




HA antigen
pscaffold_Hs3U




(nanoscaffold)



64
144094
vaccine Influenza
PR8HA.stalk.HbCore.




HA antigen
monoRNA_Hs3U




(splitcore)



65
144095
vaccine Influenza
PR8HA.stalk.HbCoreC.




HA antigen
RKR_Hs3U




(splitcore)



66
144096
vaccine Influenza
PR8HA.stalk.HbCoreN.




HA antigen
RKR_Hs3U




(splitcore)



67
144098
vaccine Influenza
PR8HA.headless.




HA antigen;
Stalk.ugly(N76D/N270D)_




aglycosylated
Hs3U


68
144099
vaccine Influenza
PR8HA.headless.




HA antigen;
Stalk.ugly(N27D/N28D/




aglycosylated
N40D/N76D/N270D)_





Hs3U


69
150088
Vaccine MERS
MERS-




CoV spike protein
CoV_ProteinS/EMC/




(V5 epitope
2012.V5_Hs3U




tagged)



70
139276
vaccine MRSA
MRSA_IsdB.fl._




IsdB antigen
FLAG_Hs3U


71
149385
MERS-CoV
DPPIV.Fc_HS3U




passive immunity



72
150092
Vaccine HEV71
HEV71.VP1.2.3.VP5_




(polycistronic
HS3U




antigen containing





VP1 VP2 & VP3)





each separated by





a furin cleavage





site RKR



73
144093
vaccine Influenza
PR8HA.Stalk_Hs3U




HA antigen



74

Vaccine Klebsiella
Beta-lactamase





pneumoniae:

SHV-2




cefotaxime,





ceftazidime and





other broad





spectrum





cephalosporins.



75

Vaccine PsaA SP
Pneumococcal





Streptococcus

surface adhesin A





pneumoniae






surface adhesin A





Fragment (22-





309)



76

Vaccine

Pseudomonas type 2






Pseudomonas

Cephalosporinase





aeruginosa ampC






beta-lactamase



77

Vaccine
Beta-lactamase class





Pseudomonas

B VIM-2





aeruginosa VIM-2,






a carbapenem-





hydrolyzing





metallo-beta-





lactamase



78

Vaccine
Beta-lactamase





Pseudomonas

LCR-1





aeruginosa, LCR-1






hydrolyzes





methicillin.



79

Vaccine Staph

Staph aureus





aureus Toxic
TSST1




shock syndrome





toxin-1



80

Vaccine Staph

Staph aureus PVL






aureus PVL toxin

toxin


81

vaccine
Pneumolysin toxoid





Streptococcus







pneumoniae






Pneumolysin





toxoid



82

Full length with

Streptococcus





mutations of

pneumoniae ppaC





W433F, D385N,





and C428G









Additional antigens including wild type and engineered antigens are taught in Tables 29 and 30.


Pan-Flu NAVs

In one embodiment the “HA head” region of one or more influenza virus strains is removed leaving only the stem or transmembrane region. This region or multiple regions if selected, is then used as the immunogen to screen for optimal response to a viral challenge. As such broad neutralization could be achieved against multiple strains or a multi-response to one strain. The resultant vaccine would represent a pan-influenza vaccine.


Further, a pan-influenza vaccine could also be combined with any immune potentiator disclosed herein.


Polynucleotides used in the studies herein which encode certain infectious agent antigens or variants thereof may be formulated in any of the formulations described herein including LNPs and may be administered intradermally (ID) or intramuscularly (IM) or by any suitable route.


Disclosed in Table 29 are the HA regions, transmembrane and cytoplasmic regions of several influenza strains to be used in the stem vaccination generation protocol just described.









TABLE 29







Wild type antigens encoded by NAV polynucleotides















Full length HA AA






Virus
Strain
Sequence
HA1
HA2
TM
CY





H1N1
A/PR8/34
(SEQ ID NO: 931)
(SEQ ID NO:
(SEQ ID NO:
(SEQ
(SEQ




MKANLLVLLCALAAA
932)
933)
ID
ID




DADTICIGYHANNSTD
MKANLLVLL
GLFGAIAG
NO:
NO:




TVDTVLEKNVTVTHS
CALAAADAD
FIEGGWTG
934)
935)




VNLLEDSHNGKLCRL
TICIGYHANN
MIDGWYG
ILAI
SFW




KGIAPLQLGKCNIAGW
STDTVDTVLE
YHHQNEQ
YST
MCSN




LLGNPECDPLLPVRSW
KNVTVTHSV
GSGYAADQ
VAS
GSLQ




SYIVETPNSENGICYPG
NLLEDSHNG
KSTQNAIN
SLVL
CRICI




DFIDYEELREQLSSVSS
KLCRLKGIAP
GITNKVNT
LVSL





PERFEIFPKESSWPNHN
LQLGKCNIAG
VIEKMNIQF
GAI





TNGVTAACSHEGKSSF
WLLGNPECD
TAVGKEFN






YRNLLWLTEKEGSYP
PLLPVRSWSY
KLEKRMEN






KLKNSYVNKKGKEVL
IVETPNSENGI
LNKKVDD






VLWGIHHPPNSKEQQ
CYPGDFIDYE
GFLDIWTY






NLYQNENAYVSVVTS
ELREQLSSVS
NAELLVLL






NYNRRFTPEIAERPKV
SFERFEIFPKE
ENERTLDF






RDQAGRMNYYWTLL
SSWPNHNTN
HDSNVKNL






KPGDTIIFEANGNLIAP
GVTAACSHE
YEKVKSQL






MYAFALSRGFGSGIITS
GKSSFYRNLL
KNNAKEIG






NASMHECNTKCQTPL
WLTEKEGSY
NGCFEFYH






GAINSSLPYQNIHPVTI
PKLKNSYVN
KCDNECME






GECPKYVRSAKLRMV
KKGKEVLVL
SVRNGTYD






TGLRNNPSIQSRGLFG
WGIHHPPNSK
YPKYSEES






AIAGFIEGGWTGMIDG
EQQNLYQNE
KLNREKVD






WYGYHHQNEQGSGY
NAYVSVVTS
GVKLESMG






AADQKSTQNAINGITN
NYNRRFTPEI
IYQ






KVNTVIEKMNIQFTAV
AERPKVRDQ







GKEFNKLEKRMENLN
AGRMNYYW







KKVDDGFLDIWTYNA
TLLKPGDTIIF







ELLVLLENERTLDFHD
EANGNLIAPM







SNVKNLYEKVKSQLK
YAFALSRGFG







NNAKEIGNGCFEFYHK
SGIITSNASM







CDNECMESVRNGTYD
HECNTKCQTP







YPKYSEESKLNREKVD
LGAINSSLPY







GVKLESMGIYQILAIYS
QNIHPVTIGE







TVASSLVLLVSLGAISF
CPKYVRSAK







WMCSNGSLQCRICI
LRMVTGLRN







NPSIQSR









H1N1
A/New
(SEQ ID NO: 936)
(SEQ ID NO:
(SEQ ID NO:
(SEQ
(SEQ



Caledonia/
MKAKLLVLLCTFTAT
937)
938)
ID
ID



20/1999
YADTICIGYHANNSTD
MKAKLLVLL
GLFGAIAG
NO:
NO:




TVDTVLEKNVTVTHS
CTFTATYADT
FIEGGWTG
939)
940)




VNLLEDSHNGKLCLL
ICIGYHANNS
MVDGWYG
ILAI
SFW




KGIAPLQLGNCSVAG
TDTVDTVLE
YHHQNEQ
YST
MCSN




WILGNPECELLISKES
KNVTVTHSV
GSGYAADQ
VAS
GSLQ




WSYIVETPNPENGTCY
NLLEDSHNG
KSTQNAIN
SLVL
CRICI




PGYFADYEELREQLSS
KLCLLKGIAP
GITNKVNS
LVSL





VSSFERFEIFPKESSWP
LQLGNCSVA
VIEKMNTQ
GAI





NHTVTGVSASCSHNG
GWILGNPECE
FTAVGKEF






KSSFYRNLLWLTGKN
LLISKESWSYI
NKLERRME






GLYPNLSKSYVNNKE
VETPNPENGT
NLNKKVD






KEVLVLWGVHHPPNI
CYPGYFADY
DGFLDIWT






GNQRALYHTENAYVS
EELREQLSSV
YNAELLVL






VVSSHYSRRFTPEIAK
SSFERFEIFPK
LENERTLD






RPKVRDQEGRINYYW
ESSWPNHTVT
FHDSNVKN






TLLEPGDTIIFEANGNL
GVSASCSHN
LYEKVKSQ






IAPWYAFALSRGFGSG
GKSSFYRNLL
LKNNAKEI






IITSNAPMDECDAKCQ
WLTGKNGLY
GNGCFEFY






TPQGAINSSLPFQNVH
PNLSKSYVNN
HKCNNEC






PVTIGECPKYVRSAKL
KEKEVLVLW
MESVKNGT






RMVTGLRNIPSIQSRG
GVHHPPNIGN
YDYPKYSE






LFGAIAGFIEGGWTGM
QRALYHTEN
ESKLNREKI






VDGWYGYHHQNEQG
AYVSVVSSH
DGVKLESM






SGYAADQKSTQNAIN
YSRRFTPEIA
GVYQ






GITNKVNSVIEKMNTQ
KRPKVRDQE







FTAVGKEFNKLERRM
GRINYYWTL







ENLNKKVDDGFLDIW
LEPGDTIIFEA







TYNAELLVLLENERTL
NGNLIAPWY







DFHDSNVKNLYEKVK
AFALSRGFGS







SQLKNNAKEIGNGCFE
GIITSNAPMD







FYHKCNNECMESVKN
ECDAKCQTP







GTYDYPKYSEESKLNR
QGAINSSLPF







EKIDGVKLESMGVYQI
QNVHPVTIGE







LAIYSTVASSLVLLVSL
CPKYVRSAK







GAISFWMCSNGSLQCR
LRMVTGLRNI







ICI
PSIQSR








H10N8
A/JX346/
(SEQ ID NO: 941)
(SEQ ID NO:
(SEQ ID NO:
(SEQ
(SEQ



2013
MYKIVVIIALLGAVKG
942)
943)
ID
ID




LDKICLGHHAVANGTI
MYKIVVIIAL
RGLFGAIA
NO:
NO:




VKTLTNEQEEVTNATE
LGAVKGLDKI
GFLENGWE
944)
945)




TVESTGINRLCMKGRK
CLGHHAVAN
GMVDGWY
WFS
CLKN




HKDLGNCHPIGMLIGT
GTIVKTLTNE
GFRHQNAQ
FGA
GNM




PACDLHLTGMWDTLI
QEEVTNATET
GTGQAAD
SCFV
RCTIC




ERENAIAYCYPGATVN
VESTGINRLC
YKSTQAAI
LLA
I




VEALRQKIMESGGINK
MKGRKHKDL
DQITGKLN
VVM





ISTGFTYGSSINSAGTT
GNCHPIGMLI
RLVEKTNT
GLFF





RACMRNGGNSFYAEL
GTPACDLHLT
EFESIESEFS
F





KWLVSKSKGQNFPQT
GMWDTLIER
EIEHQIGNV






TNTYRNTDTAEHLIM
ENAIAYCYPG
INWTKDSIT






WGIHHPSSTQEKNDLY
ATVNVEALR
DIWTYQAE






GTQSLSISVGSSTYRN
QKIMESGGIN
LLVAMENQ






NFVPVVGARPQVNGQ
KISTGFTYGS
HTIDMADS






SGRIDFHWTLVQPGDN
SINSAGTTRA
EMLNLYER






ITFSHNGGLIAPSRVSK
CMRNGGNSF
VRKQLRQN






LIGRGLGIQSDAPIDNN
YAELKWLVS
AEEDGKGC






CESKCFWRGGSINTRL
KSKGQNFPQT
FEIYHACD






PFQNLSPRTVGQCPKY
TNTYRNTDT
DSCMESIR






VNRRSLMLATGMRNV
AEHLIMWGIH
NNTYDHSQ






PELIQGRGLFGAIAGFL
HPSSTQEKND
YREEALLN






ENGWEGMVDGWYGF
LYGTQSLSIS
RLNINPVTL






RHQNAQGTGQAADY
VGSSTYRNNF
SSGYKDIIL






KS TQAAIDQITGKLNR
VPVVGARPQ







LVEKTNTEFESIESEFS
VNGQSGRIDF







EIEHQIGNVINWTKDSI
HWTLVQPGD







TDIWTYQAELLVAME
NITFSHNGGLI







NQHTIDMADSEMLNL
APSRVSKLIG







YERVRKQLRQNAEED
RGLGIQSDAP







GKGCFEIYHACDDSC
IDNNCESKCF







MESIRNNTYDHSQYRE
WRGGSINTRL







EALLNRLNINPVTLSS
PFQNLSPRTV







GYKDIILWFSFGASCF
GQCPKYVNR







VLLAVVMGLFFFCLK
RSLMLATGM







NGNMRCTICI
RNVPELIQG








H7N9
A/Anhui/1/
(SEQ ID NO: 946)
(SEQ ID NO:
(SEQ ID NO:
(SEQ
(SEQ



2013
MNTQILVFALIAIIPTN
947)
948)
ID
ID




ADKICLGHHAVSNGT
MNTQILVFAL
RGLFGAIA
NO:
NO:




KVNTLTERGVEVVNA
IAIIPTNADKI
GFIENGWE
949)
950)




TETVERTNIPRICSKGK
CLGHHAVSN
GLIDGWYG
WFS
CVKN




KTVDLGQCGLLGTITG
GTKVNTLTER
FRHQNAQG
FGA
GNM




PPQCDQFLEFSADLIIE
GVEVVNATE
EGTAADYK
SCFI
RCTIC




RREGSDVCYPGKFVN
TVERTNIPRIC
STQSAIDQI
LLAI
I




EEALRQILRESGGIDKE
SKGKKTVDL
TGKLNRLIE
VMG





AMGFTYSGIRTNGATS
GQCGLLGTIT
KTNQQFELI
LVFI





ACRRSGSSFYAEMKW
GPPQCDQFLE
DNEFNEVE






LLSNTDNAAFPQMTKS
FSADLIIERRE
KQIGNVIN






YKNTRKSPALIVWGIH
GSDVCYPGK
WTRDSITE






HSVSTAEQTKLYGSGN
FVNEEALRQI
VWSYNAEL






KLVTVGSSNYQQSFVP
LRESGGIDKE
LVAMENQ






SPGARPQVNGQSGRID
AMGFTYSGIR
HTIDLADSE






FHWLMLNPNDTVTFS
TNGATSACR
MDKLYER






FNGAFIAPDRASFLRG
RSGSSFYAEM
VKRQLREN






KSMGIQSGVQVDANC
KWLLSNTDN
AEEDGTGC






EGDCYHSGGTIISNLPF
AAFPQMTKS
FEIFHKCDD






QNIDSRAVGKCPRYV
YKNTRKSPAL
DCMASIRN






KQRSLLLATGMKNVP
IVWGIHHSVS
NTYDHSKY






EIPKGRGLFGAIAGFIE
TAEQTKLYGS
REEAMQNR






NGWEGLIDGWYGFRH
GNKLVTVGS
IQIDPVKLS






QNAQGEGTAADYKST
SNYQQSFVPS
SGYKDVIL






QSAIDQITGKLNRLIEK
PGARPQVNG







TNQQFELIDNEFNEVE
QSGRIDFHWL







KQIGNVINWTRDSITE
MLNPNDTVT







VWSYNAELLVAMENQ 
FSFNGAFIAP







HTIDLADSEMDKLYER
DRASFLRGKS







VKRQLRENAEEDGTG
MGIQSGVQV







CFEIFHKCDDDCMASI
DANCEGDCY







RNNTYDHSKYREEAM
HSGGTIISNLP







QNRIQIDPVKLSSGYK
FQNIDSRAVG







DVILWFSFGASCFILLA
KCPRYVKQR







IVMGLVFICVKNGNM
SLLLATGMK







RCTICI
NVPEIPKG








H7N9
.A/Jiangsu/
(SEQ ID NO: 951)
(SEQ ID NO:
(SEQ ID NO:
(SEQ
(SEQ



2/2013(H
MNTQILVFALIAIIPTN
952)
953)
ID
ID



242)
ADKICLGHHAVSNGT
MNTQILVFAL
RGLFGAIA
NO:
NO:




KVNTLTERGVEVVNA
IAIIPTNADKI
GFIENGWE
954)
955)




TETVERTNIPRICSKGK
CLGHHAVSN
GLIDGWYG
WFS
CVKN




MTVDLGQCGLLGTITG
GTKVNTLTER
FRHQNAQG
FGA
GNM




PPQCDQFLEFSADLIIE
GVEVVNATE
EGTAADYK
SCFI
RCTIC




RREGSDVCYPGKFVN
TVERTNIPRIC
STQSAIDQI
LLAI
I




EEALRQILRESGGIDKE
SKGKMTVDL
TGKLNRLIE
VMG





AMGFTYSGIRTNGATS
GQCGLLGTIT
KTNQQFELI
LVFI





ACRRSGSSFYAEMKW
GPPQCDQFLE
DNEFNEVE






LLSNTDNAAFPQMTKS
FSADLIIERRE
KQIGNVIN






YKNTRKSPALIVWGIH
GSDVCYPGK
WTRDSITE






HSVSTAEQTKLYGSGN
FVNEEALRQI
VWSYNAEL






KLVTVGSSNYQQSFVP
LRESGGIDKE
LVAMENQ






SPGARPQVNGLSGRID
AMGFTYSGIR
HTIDLADSE






FHWLMLNPNDTVTFS
TNGATSACR
MDKLYER






FNGAFIAPDRASFLRG
RSGSSFYAEM
VKRQLREN






KSMGIQSGVQVDANC
KWLLSNTDN
AEEDGTGC






EGDCYHSGGTIISNLPF
AAFPQMTKS
FEIFHKCDD






QNIDSRAVGKCPRYV
YKNTRKSPAL
DCMASIRN






KQRSLLLATGMKNVP
IVWGIHHSVS
NTYDHSKY






EIPKGRGLFGAIAGFIE
TAEQTKLYGS
ReEAMQNR






NGWEGLIDGWYGFRH
GNKLVTVGS
IQIDPVKLS






QNAQGEGTAADYKST
SNYQQSFVPS
SGYKDVIL






QSAIDQITGKLNRLIEK
PGARPQVNG







TNQQFELIDNEFNEVE
LSGRIDFHWL







KQIGNVINWTRDSITE
MLNPNDTVT







VWSYNAELLVAMENQ
FSFNGAFIAP







HTIDLADSEMDKLYER
DRASFLRGKS







VKRQLRENAEEDGTG
MGIQSGVQV







CFEIFHKCDDDCMASI
DANCEGDCY







RNNTYDHSKYReEAM
HSGGTIISNLP







QNRIQIDPVKLSSGYK
FQNIDSRAVG







DVILWFSFGASCFILLA
KCPRYVKQR







IVMGLVFICVKNGNM
SLLLATGMK







RCTICI
NVPEIPKG









In the Table, TM stands for transmembrane and CY stands for cytoplasmic.


Following the vaccine generation strategy above, engineered antigens may also be used to develop pan-flu vaccines. Such constructs are shown in Table 30.









TABLE 30







Engineered antigens encoded by NAV polynucleotides













Configur-
Protein


SEQ ID


Virus
Strain
ation
engineering
Full length Sequence
NO.





H1N1
PR8/34
HA(PR8)-
fusion protein
MKANLLVLLCALAAADADTICIGY
956




Ferritin
of HA
HANNSTDTVDTVLEKNVTVTHSV






antigen with
NLLEDSHNGKLCRLKGIAPLQLGK






ferritin (H
CNIAGWLLGNPECDPLLPVRSWSY







pylori) to

IVETPNSENGICYPGDFIDYEELRE






form
QLSSVSSFERFEIFPKESSWPNHNT






nanoscaffold,
NGVTAACSHEGKSSFYRNLLWLTE






secreted
KEGSYPKLKNSYVNKKGKEVLVL







WGIHHPPNSKEQQNLYQNENAYV







SVVTSNYNRRFTPEIAERPKVRDQ







AGRMNYYWTLLKPGDTIIFEANGN







LIAPMYAFALSRGFGSGIITSNASM







HECNTKCQTPLGAINSSLPYQNIHP







VTIGECPKYVRSAKLRMVTGLRNN







PSIQSRGLFGAIAGFIEGGWTGMID







GWYGYHHQNEQGSGYAADQKST







QNAINGITNKVNTVIEKMNIQFTA







VGKEFNKLEKRMENLNKKVDDGF







LDIWTYNAELLVLLENERTLDFHD







SNVKNLYEKVKSQLKNNAKEIGN







GCFEFYHKCDNECMESVRNGTYD







YPKYSEESKLNREKVDSGGDIIKLL







NEQVNKEMQSSNLYMSMSSWCYT







HSLDGAGLFLFDHAAEEYEHAKK







LIIFLNENNVPVQLTSISAPEHKFEG







LTQIFQKAYEHEQHISESINNIVDH







AIKSKDHATFNFLQWYVAEQHEEE







VLFKDILDKIELIGNENHGLYLADQ







YVKGIAKSRKS






H1N1
A/New
HA(NC19
fusion protein
MKAKLLVLLCTFTATYADTICIGY
957



Caledonia/
99)-
of HA
HANNSTDTVDTVLEKNVTVTHSV




20/1999
Ferritin
antigen with
NLLEDSHNGKLCLLKGIAPLQLGN




(1999

ferritin (H
CSVAGWILGNPECELLISKESWSYI




NC)

pylori) to
VETPNPENGTCYPGYFADYEELRE






form
QLSSVSSFERFEIFPKESSWPNHTV






nanoscaffold,
TGVSASCSHNGKSSFYRNLLWLTG






secreted
KNGLYPNLSKSYVNNKEKEVLVL







WGVHHPPNIGNQRALYHTENAYV







SVVSSHYSRRFTPEIAKRPKVRDQE







GRINYYWTLLEPGDTIIFEANGNLI







APWYAFALSRGFGSGIITSNAPMD







ECDAKCQTPQGAINSSLPFQNVHP







VTIGECPKYVRSAKLRMVTGLRNI







PQRETRGLFGAIAGFIEGGWTGMV







DGWYGYHHQNEQGSGYAADQKS







TQNAINGITNKVNSVIEKMNTQFT







AVGKEFNKLERRMENLNKKVDDG







FLDIWTYNAELLVLLENERTLDFH







DSNVKNLYEKVKSQLKNNAKEIG







NGCFEFYHKCNNECMESVKNGTY







DYPKYSEESKLNREKIDSGGDIIKL







LNEQVNKEMQSSNLYMSMSSWCY







THSLDGAGLFLFDHAAEEYEHAK







KLIIFLNENNVPVQLTSISAPEHKFE







GLTQIFQKAYEHEQHISESINNIVD







HAIKSKDHATFNFLQWYVAEQHE







EEVLFKDILDKIELIGNENHGLYLA







DQYVKGIAKSRKSGS






H1N1
PR8/34
HA1(-)
Headless HA
MKANLLVLLCALAAADADTICIGY
958




stem only
antigen (Stem
HANNSTDTVDTVLEKNVTVTHSV





HA
only),
NLLEDSHNGKLCGGGGCNTKCQT





antigen
transmembrane,
PLGAINSSLPYQNIHPVTIGECPKY







VRSAKLRMVTGLRNIPSIQSRGLFG







AIAGFIEGGWTGMIDGWYGYHHQ







NEQGSGYAADQKSTQNAINGITNK







VNTVIEKMNIQFTAVGKEFNKLEK







RMENLNKKVDDGFLDIWTYNAEL







LVLLENERTLDFHDSNVKNLYEKV







KSQLKNNAKEIGNGCFEFYHKCDN







ECMESVRNGTYDYPKYSEESKLNR







EKVDGVKLESMGIYQILAIYSTVAS







SLVLLVSLGAISFWMCSNGSLQCRI







CI






H1N1
PR8/34
Mono-
Headless HA
MKANLLVLLCALAAADADTICIGY
959




glycosyl-
antigen (Stem
HANNSTDTVDTVLEKNVTVTHSV





ated
only),
NLLEDSHNGKLCGGGGCNTKCQT





HA 1(-)
transmembrane,
PLGAIDSSLPYQNIHPVTIGECPKY





stem only
mongly-
VRSAKLRMVTGLRNIPSIQSRGLFG





HA
cosylated
AIAGFIEGGWTGMIDGWYGYHHQ





antigen
by N76D,
NEQGSGYAADQKSTQNAINGITNK






N270D
VNTVIEKMNIQFTAVGKEFNKLEK







RMENLNKKVDDGFLDIWTYNAEL







LVLLENERTLDFHDSNVKNLYEKV







KSQLKNNAKEIGNGCFEFYHKCDN







ECMESVRDGTYDYPKYSEESKLNR







EKVDGVKLESMGIYQILAIYSTVAS







SLVLLVSLGAISFWMCSNGSLQCRI







CI






H1N1
PR8/34
agly-
Headless HA
MKANLLVLLCALAAADADTICIGY
960




cosylated
antigen (Stem
HADDSTDTVDTVLEKDVTVTHSV





HA 1(-)
only),
NLLEDSHNGKLCGGGGCNTKCQT





Stem
transmembrane,
PLGAIDSSLPYQNIHPVTIGECPKY





only HA
agly-
VRSAKLRMVTGLRNIPSIQSRGLFG





antigen
cosylated
AIAGFIEGGWTGMIDGWYGYHHQ






by
NEQGSGYAADQKSTQNAINGITNK






N27D,N28D,
VNTVIEKMNIQFTAVGKEFNKLEK






N40D, N76D,
RMENLNKKVDDGFLDIWTYNAEL






N279D
LVLLENERTLDFHDSNVKNLYEKV







KSQLKNNAKEIGNGCFEFYHKCDN







ECMESVRDGTYDYPKYSEESKLNR







EKVDGVKLESMGIYQILAIYSTVAS







SLVLLVSLGAISFWMCSNGSLQCRI







CI






H1N1
PR8/34
HA1(-)
Headless HA
MKANLLVLLCALAAADADTICIGY
961




stem HA-
antigen (stem
HANNSTDTVDTVLEKNVTVTHSV





ferritin
only) fused to
NLLEDSHNGKLCGGGGCNTKCQT






ferritin
PLGAINSSLPYQNIHPVTIGECPKY






nanoscaffold,
VRSAKLRMVTGLRNIPSIQSRGLFG






secreted
AIAGFIEGGWTGMIDGWYGYHHQ







NEQGSGYAADQKSTQNAINGITNK







VNTVIEKMNIQFTAVGKEFNKLEK







RMENLNKKVDDGFLDIWTYNAEL







LVLLENERTLDFHDSNVKNLYEKV







KSQLKNNAKEIGNGCFEFYHKCDN







ECMESVRNGTYDYPKYSEESKLNR







EKVDSGGDIIKLLNEQVNKEMQSS







NLY







MSMSSWCYTHSLDGAGLFLFDHA







AEEYEHAKKLIIFLNENNVPVQLTS







ISAPEHKFEGLT







QIFQKAYEHEQHISESINNIVDHAIK







SKDHATFNFLQWYVAEQHEEEVL







FKDILDKIELI







GNENHGLYLADQYVKGIAKSRKS







GS









Example 15. Influenza Study—H1N1 Hemagglutinin (HA) Antigen

The instant study was designed in two phases, first to test the the immunogenicity of mRNA vaccines encoding HA from influenza A/PR/8 (HiNi1) in mice and second to test the efficacy of candidate influenza vaccines in mice against a lethal challenge with influenza (INFV) A/PR/8/34 (HIN1). The study design is outlined in Table 31. The NAV polynucleotide used in the study was construct 4 from Table 28.


In phase I of this study, mice were vaccinated on week 0 and 3 via intravenous (IV), intramuscular (IM), or intradermal (ID) routes. One group remained unvaccinated and one was administered inactivated PR8 antigen. Serum was collected from each mouse on weeks 1, 3 (pre-dose), and 5. Individual bleeds were tested for anti-HA activity via virus neutralization assay and HA inhibition (HAI) from all three time points and pooled samples from week 5 only were tested by Western blot using A/PR/8/34 (H1N1).


Phase II

Since the desired immune response was achieved (HAI titer >40), phase II of the study was performed. In phase II, mice were challenged with a lethal dose (10×LD90; ˜100 plaque-forming units; PFU) of A/PR/8/34 (H1N1) via intranasal (IN) instillation. Mice were monitored for weights, health, and survival for 14 days.


This study tested the immunogenicity of mRNA vaccines encoding HA from Influenza A/PR/8 (H1N1) in mice. The study utilized 12 groups of five BALB/c female mice. Mice were vaccinated on week 0 and 3 via intranasal (positive control), intravenous, intramuscular, or intradermal routes. One group was unvaccinated and one administered inactivated PR8 antigen via intranasal vaccination.


This study tested whether candidate ribonucleic acid vaccines and formulations could protect mice from lethal influenza A/PR/8/34 (H1N1) infection. The mice used were 6-8 week old female BALB/c mice in groups of 10. Mice were vaccinated on weeks 0 and 3 via IM, ID, or IV route. Mouse serum was tested for microneutralization and HAI. Mice were then challenged with ˜1 LD90 of influenza A/PR/8/34 (H1N1) on week 7 administered intranasally (IN). Endpoint was day 13 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis were euthanized. Temperature and weights were taken daily.


The LNP formulation consisted of a cationic lipid, non-cationic lipid, PEG lipid and structural lipid in the ratios 50:10:1.5:38.5. The cationic lipid was DLin-KC2-DMA (50 mol %), the non-cationic lipid was DSPC (10 mol %), the PEG lipid was PEG-DOMG (1.5 mol %) and the structural lipid was cholesterol (38.5 mol %).


Serum was collected from each mouse on weeks 1, 3 (pre-dose), and 5. Individual bleeds were tested for anti-HA activity via virus neutralization assay and HA inhibition (HAI) from all three time points (individual animals) and pooled samples from week 5 only were tested by Western blot using inactivated Influenza A/PR/8 (H1N1).


Standard Protocol for Intranasal Infection of Mice

Female 6-8 week old BALB/c mice were housed in groups of 5 mice. Mice were quarantined at the study site (Noble Life Sciences, Gaithersburg, MD) for at least 3 days prior to the start of the study. Food and water was provided ad libitum.


The groups of mice challenged with INFV were infected via intranasal (IN) inoculation with ˜10×LD90 in 100 μL of INFV in PBS under light anesthesia (Isoflurane). After the infection, mice were placed back into their cages for observation and subsequent dosing.


Microneutralization

The microneutralization protocol was the standard protocol for microneutralization of influenza as published by the World Health Organization, 6 December, 2010 and outlined by the WHO Collaborating Center for Surveillance, Epidemiology and Control of Influenza, Centers for Disease Control and Prevention, Atlanta, USA, the contents of which are incorporated herein by reference in their entirety.


Serologic Diagnosis of Influenza Virus Infections by Hemagglutination Inhibition.

The standard protocol for inhibition of hemagglutination can be found in publication WHO Influenza Manual, WHO/CDS/CSR/NCS/2002.5 Rev. 1, at page 37, the contents of which are incorporated by reference in their entirety.


Briefly, the protocol is as follows.


Procedure
I. Treatment of Sera





    • 1. Identification of Influenza Isolates by Hemagglutination.

    • 2. Adsorb sera to remove nonspecific agglutinins as described above.





II. Standardization of RBCs

Standardize RBCs according to the procedure in art recognized procedures.


III. HA Titration of Control Antigens

Following the procedure for titration of the control antigens given above. IV. Preparation of standardized antigens for HAT test and “Back Titration” Each control antigen must be standardized to contain 4 HA units/25 μl, 8 HA units/50 μl.


Note: Four HA units are added to the test in 25 μl because the HA unit calculations are based on a volume of 50 μl.


V. HAI Test for Serologic Diagnosis





    • 1. Label appropriate microtiter plates.

    • 2. Add 25 μl of PBS to wells B through H (B1-H12) of each numbered column.

    • 3. Add 50 μl of each treated serum (1:10) to the appropriate first well (A1-A 12) of the numbered column.

    • 4. Prepare serial twofold dilutions of the treated sera by transferring 25 μl from the first well of the numbered columns 1-12 to successive wells.





Discard the final 25 μl after row H.

    • 5. Add 25 μl of standardized antigen to all wells (A 1-H12) in a set of treated sera.
    • 6. Add 25 μl of PBS instead of antigen to the set of treated sera for serum controls (A1-H12).
    • 7. Mix the contents of the plates by shaking on a mechanical vibrator for 10 sec or by agitating the plates manually.
    • 8. Cover the plates and incubate at room temperature (22 to 25° C.) for 30-45 min.
    • 9. Add 50 μl of standardized RBCs to all wells. Mix as before.
    • 10. Cover the plates and allow the RBCs to settle at room temperature (22 to 25C) for the appropriate time according to RBCs being used.
    • 11. Record the HAI titers.


The positive control antigens and corresponding antisera should give consistent results when compared with previous tests. A fourfold titer increase between the acute and convalescent serum is considered diagnostically positive for that influenza type/subtype.


Western Blots

Serum from bleeds performed on vaccinated mice on week 5 was pooled and diluted 1:1000 for analysis in Western blots. Inactivated PR8 antigen was separated via SDS-PAGE and probed with the pooled sera. Positive signals were observed in groups 2-7 and 12, with the highest signals observed in groups 4-7 and 12.


500 ng per lane of inactivated PR8 antigen was separated via SDS- on 10% bis-tris gels. Protein was transferred to Polyvinylidene Difluoride (PVDF) membranes and membranes were blocked with milk and probed with a 1:1000 dilution of pooled sera from each group from week 5 bleeds.


Antibody was detected with 1:3000 dilution of goat anti-mouse alkaline phosphatase (AP)


Observation of Mice

Mice were observed through 13 days post infection (14 days total, 0-13 days post infection).


Mice were weighed daily on an Ohause scale and the weights were recorded.


All animals had chips implanted at least 3 days prior to virus challenge that monitored the body temperature. The temperatures were recorded daily.


Survival and health of each mouse was evaluated once Lime a day.









TABLE 31







Study Design













Vaccine (n = 5






mice/group)





Mouse
Delivered




Group
Strain
week 0, 3
Dosage/Route
Readouts














1
Female
N/A
N/A
Animals displaying


2
BALB/
Unmodified
LNP IV,
severe illness will


3
c, 6-8
N1-methyl
0.4 mg/kg
be euthanized.



weeks
pseudouridine/5-

Serum samples



of age
methyl cytosine

collected on weeks


4

Unmodified
IM, LNP
1, 3, and 5.


5

N1-methyl
0.4 mg/kg
Serum analyzed via




pseudouridine/5-

Western blot (week




methyl cytosine

5 pooled samples),


6

Unmodified
ID, LNP
virus neutralization


7

N1-methyl
0.4 mg/kg
assay (all




pseudouridine/5-

individuals), and




methyl cytosine

HAI (all


8

Unmodified
ID, 80 ug w/
individuals).


9

N1-methyl
lipoplex





pseudouridine/5-
(Lipofectamine





methyl cytosine
2000)



10 

Unmodified
ID, 80 ug



11 

N1-methyl
naked mRNA





pseudouridine/5-






methyl cytosine




12 

Control
IN, Inactivated






PR8 virus










In the Table the following abbreviations apply; IM, intramuscular; ID, intradermal; IN, intranasal; IV, intravenous; LNP, lipid nanoparticle









TABLE 32







Mean HAI Titers










Sample ID
Week 1
Week 3
Week 5













Naïve
8
7
7


Unmodified; LNP IV, 0.4 mg/kg
8
28
635


N1-methyl pseudouridine/5-methyl
25
139
2004


cytosine; LNP IV, 0.4 mg/kg





Unmodified; LNP IM, 0.4 mg/kg
22
63
2560


N1-methyl pseudouridine/5-methyl
60
482
2803


cytosine; LNP IM, 0.4 mg/kg





Unmodified; LNP ID, 0.4 mg/kg
39
279
3796


N1-methyl pseudouridine/5-methyl
114
965
10152


cytosine; LNP ID, 0.4 mg/kg





Unmodified; 80 ug w/lipoplex
7
17
197


(Lipofectamine 2000)





N1-methyl pseudouridine/5-methyl
7
20
28


cytosine; 80 ug w/lipoplex





(Lipofectamine 2000)





Unmodified; ID, 80 ug naked mRNA
7
7
61


N1-methyl pseudouridine/5-methyl
7
16
133


cytosine; ID, 80 ug naked mRNA





Control PR8 Antigen
14
14
441









Inhibition of Hemagglutination

Inhibition of hemagglutination (HAI) was measured in mouse sera samples on weeks 1, 3, and 5 post-vaccination. After week 1, both groups 5 and 7 displayed HAI titers over 40, at 60 and 114, respectively. On week 3, groups 3-7 displayed HAI activity over 40, with the highest being group 7 at 965. On week 5, all groups except 1 (naïve) and 9 displayed HAI activity over 40, with group 7>10,000.


It is noted that 1:40 is predictive of efficacy. An HAI titer of >40 is deemed necessary to protect from a lethal challenge of influenza.


The data showed that there was 100% rescue from lethal influenza challenge with rapid onset of protective antibody titers after 1 week and high antibody titers, i.e., 50 fold over unmodified mRNA and 20 fold over the protein vaccine. Furthermore, it was shown that for ribonucleic acid vaccines of the invention a much lower effective mRNA dose is required, i.e., ten fold less than unmodified mRNA. (FIG. 10).


Microneutralization

Two-fold dilutions of mouse sera were added to 100 TCID50/ml of virus in 96-well plates. After 24-hours of incubation, 1.5×104 Madin-Darby Canine-Kidney cells were added to each well. After a −20 hour incubation at 37° C., virus was detected and scored with an anti-NP antibody and read at 490 nm. No neutralization activity was detected with week 1 samples (signal <50; lower limit of detection). By week 3, mice in groups 5 and 7 displayed neutralizing activity between 79 and 250 (group 5) and 250 (group 7). Neither of the other groups displayed any neutralizing activity. On week 5, groups 2-4 showed high neutralizing activity between 789 and 2493, with group 7 displaying neutralizing activity 2494 and ˜25,000. The control group of mice, vaccinated with inactivated PR8, displayed neutralizing activity in 3 of 5 mice and ranged between 79 and 250. The data are shown in Tables 33-35.









TABLE 33







Week 1 Microneutralization













Mouse
Mouse
Mouse
Mouse
Mouse


Sample ID
1
2
3
4
5





Naïve
 <50*
<50
<50
<50
<50


Unmodified; LNP IV,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; LNP







IV, 0.4 mg/kg







Unmodified; LNP IM,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; LNP







IM, 0.4 mg/kg







Unmodified; LNP ID,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; LNP







ID, 0.4 mg/kg







Unmodified; 80 ug w/
<50
<50
<50
<50
<50


lipoplex







(Lipofectamine 2000)







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; 80 ug







w/lipoplex







(Lipofectamine 2000)







Unmodified; ID, 80 ug
<50
<50
<50
<50
<50


naked mRNA







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; ID,







80 ug naked mRNA







Control PR8 Antigen
<50
<50
<50
<50
<50





*Titers of ‘<50’ indicate titers below Limit of detection (1:50)













TABLE 34







Week 3 Microneutralization













Mouse
Mouse
Mouse
Mouse
Mouse


Sample ID
1
2
3
4
5















Naïve
 <50*
<50
<50
<50
<50


Unmodified; LNP IV,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; LNP







IV, 0.4 mg/kg







Unmodified; LNP IM,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
  79
79
79
250
250


pseudouridine/5-







methyl cytosine; LNP







IM, 0.4 mg/kg







Unmodified; LNP ID,
<50
<50
<50
<50
<50


0.4 mg/kg







N1-methyl
250 
250
250
250
250


pseudouridine/5-







methyl cytosine; LNP







ID, 0.4 mg/kg







Unmodified; 80 ug w/
<50
<50
<50
<50
<50


lipoplex







(Lipofectamine 2000)







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; 80 ug







w/lipoplex







(Lipofectamine 2000)







Unmodified; ID, 80 ug
<50
<50
<50
<50
<50


naked mRNA







N1-methyl
<50
<50
<50
<50
<50


pseudouridine/5-







methyl cytosine; ID,







80 ug naked mRNA







Control PR8 Antigen
<50
<50
<50
<50
<50





*Titers of ‘<50’ indicate titers below Limit of detection (1:50)













TABLE 35







Week 5 Microneutralization













Mouse
Mouse
Mouse
Mouse
Mouse


Sample ID
1
2
3
4
5















Naïve
<50*
<50
<50
<50
<50


Unmodified; LNP IV, 0.4
  2493 
789
789
<50
250


mg/kg







N1-methyl pseudouridine/5-
  789
789
2493
789
2493


methyl cytosine; LNP IV,







0.4 mg/kg







Unmodified; LNP IM, 0.4
  789
789
2493
789
2493


mg/kg







N1-methyl pseudouridine/5-
  789
2493
2493
789
789


methyl cytosine; LNP IM,







0.4 mg/kg







Unmodified; LNP ID, 0.4
 <50
<50
<50
<50
<50


mg/kg







N1-methyl pseudouridine/5-
  7877 
7877
24892
2493
7877


methyl cytosine; LNP ID,







0.4 mg/kg







Unmodified; 80 ug w/
 <50
<50
<50
<50
79


lipoplex (Lipofectamine







2000)







N1-methyl pseudouridine/5-
 <50
<50
<50
<50
<50


methyl cytosine; 80 ug w/







lipoplex (Lipofectamine







2000)







Unmodified; ID, 80 ug
 <50
79
<50
<50
<50


naked mRNA







N1-methyl pseudouridine/5-
 <50
<50
<50
<50
<50


methyl cytosine; ID, 80 ug







naked mRNA







Control PR8 Antigen
  250
79
<50
<50
250





*Titers of ‘<50’ indicate titers below Limit of detection (1:50)






Survival

All mice were challenged with a lethal dose (10×LD90) of INFV A/PR/8/34 on week 7 post-vaccination. Mice were observed for morbidity and mortality for up to 14 days. All vaccinated mice displayed 100% survival, compared to the naïve group (group 1), which was not vaccinated. 12 groups of 5 mice were challenged via IN instillation with ˜100 PFU of INFV A/PR/8/34 (H1N1). Mice were observed daily for 14 days for health, morbidity, and mortality. All animals except for unvaccinated, which died at approximately day 7, survived the 14 day study.


Weight Loss Data

Weight loss and health of mice challenged with A/PR/8/34. 12 groups of 5 mice were challenged via IN instillation with ˜100 PFU of INFV A/PR/8/34 (H1N1). Mice were observed daily for 14 days for health, morbidity, and mortality.


All vaccinated mice displayed 100% survival, although some groups displayed weight loss. The unvaccinated group displayed 0% survival and died on days 6 and 7, post-infection. While differences in weight-loss were observed in challenged vaccinated mice, no conclusion can be drawn as to its significance. The group vaccinated with NAVs having N1 methylpseudouridine/5-methyl cytosine with naked mRNA displayed health scores of ‘2’ on days 2 and 3 post-infection, but made a recovery to ‘healthy’ for the rest of the study. The groups vaccinated with NAVs having N1 methylpseudouridine/5-methyl cytosine ID 80 ug w/ lipofecatmine 2000 (LF2000) and N1 methylpseudouridine and 5-methylcytosine LNP ID both displayed health scores of ‘2’ on days 5 and 6 post-infection which continued through the duration of the study. The LNP formulation consisted of a cationic lipid, non-cationic lipid, PEG lipid and structural lipid in the ratios 50:10:1.5:38.5. The cationic lipid was DLin-KC2-DMA (50 mol %), the non-cationic lipid was DSPC (10 mol %), the PEG lipid was PEG-DOMG (1.5 mol %) and the structural lipid was cholesterol (38.5 mol %).


All groups generally maintained weight between 90-110% of original weight with the exception of the unvaccinated group. These animals were at approximately 70% of their original weight by day 6. Health scoring was per Table 36.









TABLE 36







Health score chart












Score
Initial
Description
Appearance
Mobility
Attitude





1
H
Healthy
Smooth coat, bright eyes
Active, scurrying,
Alert






burrowing



2
SR
Slighly
Slightly ruffled coat
Active, scurrying,
Alert




Ruffled
(usually only around heand
burrowing






and neck




3
R
Ruffled
Ruffled coat throughout
Active, scurrying,
Alert





body. A “wet” appearance
burrowing



4
S
Sick
Verr ruffled coat. Slightly
Walking, but not
Mildly





closed, inset eyes
scurrying
lethargic


5
VS
Very Sick
Very ruffled coat, closed,
Slow to no movement;
Extremely




(euthanized)
inset eyes
will return upright
lethargic






position if put on side



6
E
Euthanize
Very ruffled coat, closed
No movement or
Completely





inset eyes; moribund
uncontrollable; spastic
unaware or





requires human euthenasia
movement. Will not
in noticeable






return to upright
distress


7
D
Deceased












Example 16. MRSA Study

Antigens of MRSA which may be encoded by the ribonucleic acid vaccines include, SpA, SpAKKAA, IsdA, IsdB, SDRD, SDRE, TSST-1, PVL, a-HL, NMD-1 and SCCmec. The study design is shown in Table 37. In these studies, construct number 27 from Table 28 was used.


A. Test for Efficacy of Modified Ribonucleic Acid Vaccines in Staph. Aureus Pneumonia Challenge Model in Mice


This study will test the efficacy of ribonucleic acid vaccine encoding MRSA Ag808 in BALB/c mice. The study utilizes 15 groups of 15 BALB/c female mice (225 total. Mice are vaccinated on week 0 and 3 via intradermal (ID) or intramuscular (IM) route with either an LNP Formulation comprising DLin-KC2-DMA (“KC2”) or DLin-MC3-DMA (“MC3”). The KC2 LNP formulation consisted of a cationic lipid (DLin-KC2-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMO 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). One group is unvaccinated and one administered a positive control antigen. Prior to challenge, mice will be bled by tail vein on weeks 1, 3 and 5 and serum samples will be retained for later analysis. The mice will be challenged with MRSA (strain Newman) at ˜1×LD90 via intranasal (IN) inoculation on week 5. Mice will be monitored for morbidity using a health score assigned based on a standard scoring system, weight loss, and mortality and the endpoint is day 14 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis will be euthanized. Mice will be held until week 7, to perform additional work with the animals (ex. further vaccinations, bleed or infectious challenge).


B. Test for Efficacy of N1-Methylpseudouridine Modified Ribonucleic Acid

Vaccines in Staphylococcus aureus Peritonitis Challenge This study tested the efficacy of a ribonucleic acid vaccine encoding MRSA Ag808 in BALB/c mice. The study utilized 15 groups of 15 BALB/c female mice (270 total. Mice were vaccinated on week 0 and 3 via intradermal (ID) or intramuscular (IM) route with either an LNP Formulation comprising DLin-KC2-DMA (“KC2”) or DLin-MC3-DMA (“MC3”). The KC2 LNP formulation consisted of a cationic lipid (DLin-KC2-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %). One group was unvaccinated and one administered a positive control antigen. Prior to challenge, mice were bled by tail vein on weeks 1, 3 and 5 and serum samples were retained for later analysis. The mice that were challenged via intranasal instillation received a predicted challenge dose of 2e8 CFU/mouse (actual upon back-titration was 3.3e8/mouse) and the mice that were challenged via IP infection received a predicted 1e7 CFU/mouse (actual upon back-titration 6.7e6 CFU/mouse). Mice were monitored for morbidity using a heahh score assigned based on a standard scoring system, weight loss, and mortality and the endpoint is day 14 post infection, death, or euthanasia. Animals displaying severe illness as determined by >30% weight loss, extreme lethargy, or paralysis were euthanized.









TABLE 37







Study Design














Group









(n = 15)
Antigen
Dosage
Route
Chemistry
Formulation
Administration
Samples





 1
N/A
N/A
N/A
N/A
NaCl
Vaccination on
Bled by


 2
MRSA
 0.4 mg/kg
ID
N1methyl-
LNP; KC2
weeks 0 and 3
tail vein


 3
Ag808
 0.08 mg/kg

pseudoruridine


on weeks


 4

0.016 mg/kg




1, 3, and 5;


 5

 0.4 mg/kg
IM



retained


 6

 0.08 mg/kg




for future


 7

0.016 mg/kg




analysis


 8

 0.4 mg/kg
ID

LNP; MC3




 9

 0.08 mg/kg







10

0.016 mg/kg







11

 0.4 mg/kg
IM






12

 0.08 mg/kg







13

0.016 mg/kg







14
Inactivated
TBD
TBD
N/A
TBD





bacteria








15
Inactivated
TBD
TBD
N/A
TBD





bacteria









Mice that were vaccinated and challenged via IP route with 3% hog mucin all displayed 0% survival within 24 hours of challenge. Mice that were vaccinated and challenged via IN instillation displayed between 6 and 33% survival and median survival times between 2 and 3 days. Efficacy was not shown with either the tested RNA vaccine construct or the controls (inactivated bacteria and protein control) in either challenge model, suggesting that the model was not adequate for testing the constructs. The vehicle-vaccinated group displayed 20% survival and a median survival time of 3 days. Without being bound in theory, is is believed that the severity of the MRSA infection model precluded detection of vaccine efficacy. Other models can be tested to determine efficacy.


Example 17. Dengue Study: Dengue Virus RNA Vaccine Immunogenicity in Mice

This study provides a preliminary analysis of the immunogenicity of a nucleic acid mRNA vaccine using a dengue virus (DENV) serotype 2 antigen in BALB/c mice. The study utilizes 44 groups of 10 BALB/c female (5) and male (5) mice (440 total, 6-8 weeks of age at study initiation, see Table 38 for design summary). In this study, construct numbers used are referenced and found in Table 28.


Mice were vaccinated on weeks 0 and 3 via intramuscular (M) or intradermal (ID) routes. One group remained unvaccinated and one was administered 105 plaque-forming units (PFU) live DENV2, D2Y98P isolate via intravenous ( ) injection as a positive control. Serum was collected from each mouse on weeks 1, 3, and 5; bleeds on weeks 1 and 3 were in-life samples (tail vein or submandibular bleeds) and week 5 will be a terminal (intracardiac) bleed. Individual serum samples were stored at −80° C. until analysis by neutralization or microneutralization assay. Pooled samples from each group at the week 5 time points were tested by Western blot for reactivity with viral lysate.









TABLE 38







Detailed experimental design (treatment, readouts)















Vaccine








(n = 10,








female)








mice/group)








Delivered







Mouse
week 0

Formulation/




Group
Strain
and 3
Chemistry
Route
Dose
Readouts





 1
Female
N/A

N/A
N/A
Serum samples


 2
BALB/c,
DEN2Y98—PrME
N1-methylpseudouridine/
ID
0.4 mg/kg
collected on


 3
6-8 weeks
(construct 23 from
5-methyl cytosine
IM
in LNP
weeks 1, 3, and


 4
of age
Table 28)

ID
0.08 mg/kg
5. Serum


 5



IM
in LNP
analyzed via


 6



ID
0.016 mg/kg
Western blot


 7



IM
in LNP



 8


N1-methylpseudouridine
ID
0.4 mg/kg



 9



IM
in LNP



10



ID
0.08 mg/kg



11



IM
in LNP



11



ID
0.016 mg/kg



12



IM
in LNP



13

DEN2Y98—PrME80
N1-methylpseudouridine/
ID
0.4 mg/kg



14

(construct 24 from
5-methyl cytosine
IM
in LNP



15

Table 28)

ID
0.08 mg/kg



16



IM
in LNP



17



ID
0.016 mg/kg



18



IM
in LNP



19


N1-methylpseudouridine
ID
0.4 mg/kg



20



IM
in LNP



21



ID
0.08 mg/kg



22



IM
in LNP



23



ID
0.016 mg/kg



24



IM
in LNP



25

DEN2Y98—PrME80-
N1-methylpseudouridine/
ID
0.4 mg/kg



26

DC (construct 25
5-methyl cytosine
IM
in LNP



27

from Table 28)

ID
0.08 mg/kg



28



IM
in LNP



29



ID
0.016 mg/kg



30



IM
in LNP



31


N1-methylpseudouridine
ID
0.4 mg/kg



32



IM
in LNP



33



ID
0.08 mg/kg



34



IM
in LNP



35



ID
0.016 mg/kg



36



IM
in LNP



37

DEN2-DIII-Ferritin
N1-methylpseudouridine
ID
0.4 mg/kg in



38

(construct 18 from

IM
LNP



39

Table 28)

ID
0.08 mg/kg



40



IM
in LNP



41



ID
0.016 mg/kg



42



IM
in LNP



43

Control,

IV
105 PFU





D2Y98P








live virus









Signal was detected in groups 5, 15, 39, and 44 (live virus control) by a band that appeared between 50 and 60 kDa in the Western blot data. The data suggests that a mRNA vaccine to a single dengue viral antigen can produce antibody in preliminary studies.


Example 18. Tuberculosis Ribonucleic Acid Vaccine: Combinatorial Approach of Adjuvants and Antigens

The objective of the study is to identify a multi-valent, multi-adjuvant vaccine effective in different diseases stages of tuberculosis. Initial experiment assesses 12 antigens with 8 cytokine adjuvants in three disease stage models. The antigens encoded by the polynucleotides of the invention include Ag85A (Rv3804c), Ag85B (Rv1886c), TB10.4 (Rv0288), ESAT6 (Rv3785), Rv2660L, Rv3619, Rv1813c, Rv3620c, Rv2608. Rv1196, Rv0125 and/or MT401. Target cytokine adjuvants include GM-CSF, TL-17, IFNg, IL-15, IL-2, IL-21, Anti-PD1/2 and/or Lactoferrin.


Example 19. Human Enterovirus (HEV68 and HEV71) Study

Several key antigens for use in generating vaccines have been identified. These include: (i) VP1 BC/DE loop of all three HEV68 lineages and (ii) VP1+VP2 of HEV71. The RNAV polynucleotide for use in generating vaccines from the HEV71 antigen is construct 72 from Table 28).


Example 20. MERS-CoV Study

As MERS-CoV binds cells via DPP4Fc, treatment for MERS-CoV can include an mRNA encoding DPP4-Fc with or without MERS-CoA binding site and mutant binding sites for diabetes signaling and truncated receptor binding domain of MERS-CoV Spike protein. See PLoS One. 2013; 8(12): e81587). This vaccine would act as a decoy for the virus as it will attract the MERS-CoV.


Another key vaccine for MERS-CoV is identified as an mRNA encoding MERS-CoV Spike Glucoprotein as an antigen. The protein sequence is given here (SEQ ID NO: 962).









SEQ ID NO. 962:


mihsvfllmflltptesyvdvgpdsiksacievdiqqtffdktwprpid





vskadgiiypqgrtysnitityqglfpyqgdhgdmyvysaghatgttpq





klfvanysqdvkqfangfvvrigaaanstgtviispstsatirkiypaf





mlgssvgnfsdgkmgrffnhtlvllpdgcgtllrafycileprsgnhcp





agnsytsfatyhtpatdcsdgnynrnaslnsfkeyfnlrnctfmytyni





tedeilewfgitqtaqgvhlfssryvdlyggnmfqfatlpvydtikyys





iiphsirsiqsdrkawaafyvyklqpltflldfsvdgyirraidcgfnd





lsqlhcsyesfdvesgvysyssfeakpsgsvveqaegvecdfspllsgt





ppqvynfkrlvftncnynltkllslfsvndftcsqispaaiasncyssl





ildyfsyplsmksdlsyssagpisqfnykqsfsnptclilatvphnltt





itkplkysyinkcsrllsddrtevpqlvnanqyspcvsivpstvwedgd





yyrkqlsplegggwlvasgstvamteqlqmgfgitvqygtdtnsvcpkl





efandtkiasqlgncveyslygvsgrgvfqnctavgvrqqrfvydayqn





lvgyysddgnyyclracvsvpvsviydketkthatlfgsvacehisstm





sqysrstrsmlkrrdstygplqtpvgcvlglynsslfvedcklplgqsl





calpdtpstltprsvrsvpgemrlasiafnhpiqvdqlnssyfklsipt





nfsfgvtqeyiqttiqkvtvdckqyvcngfqkceqllreygqfcskinq





alhganlrqddsvrnlfasvkssqsspiipgfggdfnitllepvsistg





srsarsaiedllfdkvtiadpgymqgyddcmqqgpasardlicaqyvag





ykvlpplmdvnmeaaytssllgsiagvgwtaglssfaaipfaqsifyri





ngvgitqqvlsenqkliankfnqalgamqtgftttneafhkvqdavnnn





agalsklaselsntfgaisasigdiiqrldvleqdaqidrlingrlttl





nafvaqqlvrsesaalsaqlakdkvnecvkaqskrsgfcgqgthivsfv





vnapnglyfmhvgyypsnhievvsayglcdaanptnciapvngyfiktn





ntrivdewsytgssfyapepitslntkyvapqvtyqnistnlpppllgn





stgidfqdeldeffknvstsipnfgsltqinttlldltyemlslqqvvk





alnesyidlkelgnytyynkwpwyiwlgfiaglvalalcvffilcctgc





gtncmgklkcnrccdryeeydlephkvhvh






Example 21: H10N8 In Vitro Studies

In vitro studies on the translatability of H10 hemagglutinin mRNA were performed in HeLa cells.


Western blot analysis revealed that HA is expressed in HeLa cells following transfection with the mRNA NAV encoding the HA protein of the H10N8 strain of influenza virus.


Example 22: Influenza Study—Dosing and Formulations

A mRNA vaccine encoding the HA protein of the H1N1 strain of influenza virus was tested at various doses and in various formulations for the ability ti illicit an immune response in mice.


The efficacy of different doses and formulations were evaluated in mice. HAI titers of mice determined on Day 35 after vaccination on Day 0 and Day 21 with mRNA encoding HA of the H1N1 virus are shown in FIG. 11. Titers were highest at doses of 10 μg mRNA/mouse (400 μg mRNA/kg) with both the KC2 and MC3 formulations administered ID or IM (Table 39).









TABLE 39







Hemagglutinin inhibition titers in mice following vaccination with


different doses and formulations of mRNA encoding the


hemagglutinin protein of the H1N1 virus vaccine












Group No.
Route of






(n = 10
Vaccination


Dose



per
on days 0

Formula-
(μg/
Mean HAI


group)
and 21
Vaccine
tion
mouse)
titer ± SD















 1
N/A
None
PBS
0
0


 2
ID
H1N1/C1
KC2
10
1792 ± 661 


 3



2
1088 ± 309 


 4



0.4
272 ± 152


 5



0.08
52 ± 44


 6
ID
H1N1/C0
KC2
10
992 ± 648


 7



2
692 ± 743


 8



0.4
140 ± 78 


 9



0.08
35 ± 31


10
ID
H1N1/C0
MC3
10
1600 ± 867 


11



2
1152 ± 588 


12



0.4
290 ± 254


13



0.08
37 ± 25


14
IM
H1N1/C0
MC3
10
1664 ± 1422


15



2
1056 ± 641 


16



0.4
800 ± 346


17



0.08
180 ± 105


18
IN
Inactivated
PBS
20 μL
96 ± 47




PR8 virus





19
ID
H1N1/
PBS
50
11 ± 3 




G2/C1





G0 = generation 0, i.e. canonical unmodified nucleotides;


G2 = Generation 2 of the modified nucleotides;


G5 = Generation 5 of the modified nucleotides (intended for clinical development).


C0 = CAP0;


C1 = CAP1 (intended for clinical development)


N/A: Not applicable.


IN: intranasal:


ID: intradermal;


IM: intramuscular






Example 23: Influenza Study—Onset of Immunity—Survival and HAI

This study evaluated the efficacy of an mRNA vaccine encoding influenza A/PR/8 (H1 N1) in female BALB/c mice following lethal challenge with influenza A/PR/8 virus. Groups of animals were vaccinated and challenged after week 1, 2, 3, or 4. Serum was collected from each mouse one day prior to challenge. Individual bleeds were tested for hemagglutination inhibition using Influenza A/PR/8 (H1N1). Control groups included unvaccinated mice and mice vaccinated with inactivated PR8 virus as a positive control. These animals were challenged in parallel with groups that were vaccinated with the mRNA vaccine. Challenge was performed with a lethal dose (100 PFU) of A/PR/8/34 (H1N1) via intranasal instillation. Animals were monitored for morbidity using a health score assigned based on a standard scoring system, weight loss and mortality. All mice receiving the mRNA vaccine showed 100% survival and minimal body weight loss (FIG. 12A-12D). At week 1 post vaccination, hemagglutination inhibition titers of mice receiving the mRNA vaccine and mice receiving the positive control vaccine were similar. However, at weeks 2, 3 and 4 post vaccination, mice receiving the mRNA vaccine showed higher mean titers compared with mice receiving the positive control vaccine (FIG. 13).


Groups of 15 female BALB/c mice (6-8 weeks of age) were vaccinated in week 0 with: mRNA encapsulated in LNP at a dose of 0.4 mg/kg by ID injection; inactivated PR8 virus given IN: or vehicle.


In weeks 1, 2, 3 and 4 after vaccination, animals were inoculated with influenza A/PR/8/34 virus under light anesthesia. The animals received 100 μL of the virus diluted in PBS to a final concentration of 1×103 PFU/mL via IN instillation.


Health assessments were performed and weights were recorded daily for 14 days (days 0-13 post infection). Survival and health was evaluated using the scoring system shown in Table 36.


All animals had chips implanted at least 3 days prior to virus challenge that monitored the body temperature. The temperatures were recorded daily. One day prior to each challenge, serum samples were collected and the serum was analyzed in an HAI assay.


Survival curves are presented in FIG. 15. The animals were monitored for survival for 14 days. Log-rank analysis was performed in GraphPad Prism v6.


Mice vaccinated with mRNA vaccine or inactivated PR8 all displayed 100% survival, while mice that were unvaccinated displayed between 0 and 40% survival (Table 40.) No significant decreases in body weight of treated mice were detected.









TABLE 40







Percent and mean survival of mice after vaccination and challenge


with influenza A/PR/8/34 virus













Significance to




Mean
Relative Vehicle




Survival
Control (p


Group (n = 15 per group)
% Survival
(Days)
values)














Vehicle
Week 1
10
8
N/A



Week 2
40
10
N/A



Week 3
0
9
N/A



Week 4
6.67
9
N/A


Inactivated PR8
Week 1
100
Undefined
<0.0001


virus
Week 2
100
Undefined
0.0004



Week 3
100
Undefined
<0.0001



Week 4
100
Undefined
<0.0001


mRNA vaccine
Week 1
100
Undefined
<0.0001


encapsulated in
Week 2
100
Undefined
0.0004


LNP
Week 3
100
Undefined
<0.0001



Week 4
100
Undefined
<0.0001









Mean HA titers are shown in FIG. 13 and Table 41.









TABLE 41







Mean hemaglutination inhibition (±SD) titers of mice


after vaccination and challenge with influenza A/PR/8/34 virus








Vaccination
Challenge with influenza A/PR/8/34 virus











in week 0
Week 1
Week 2
Week 3
Week 4





Vehicle
0
0
0
0


Inactivated PR8 virus
25 ± 47
19 ± 26
37 ± 39
43 ± 30


mRNA vaccine
25 ± 17
203 ± 138
379 ± 178
363 ± 154





Values are mean ± SD (standard deviation)






These data demonstrate that mice vaccinated with mRNA vaccine at a dose of 0.4 mg/kg ID or inactivated PR8 virus showed 100% survival after challenge with influenza A/PR/8/34 virus in weeks 1, 2, 3, or 4 indicating that the vaccine conveyed protection against infection with influenza A/PR/8/34 virus under the conditions of this study. HAT activity remained low in weeks 1 through 4 for animals vaccinated with inactivated PR8 virus. Mice vaccinated with mRNA showed low mean HAI titers in week 1 after challenge, but increased titers in weeks 2, 3 and 4, respectively.


Example 24: Evaluation of H1 and H7-Specific T Cell Responses in Influenza Vaccine

Mice were immunized ID at week 0 and 3 with mRNA vaccine encoding the HA protein of influenza H1N1 or H7N9 virus and splenocytes were collected in week 5. T cells were stimulated for 16-18 hours with an HA peptide library (15mers of a full length protein)


that reproduce the H1 or H7 sequence. Non-specific stimulation of T cells was performed using PMA+ionomycin. IFNγ ELISpot was used to identify staining for IFNγ. B cells were stimulated with either a peptide library (15mers of a full length protein) that reproduce the H1 or H7 sequence. Polyclonal B cell stimulation was performed using R848+rIL-2. B cell ELISpot was used to identify staining for antigen-specific IgG.


IFNγ ELISpot results demonstrated increased IFNγ secretion by T cells after stimulation with H1 or H7 peptides (FIGS. 14A and 14B). No increased IFNγ secretion was observed in T cells stimulated with PMA+ionomycin (FIG. 14C). The results demonstrated that T cell responses are antigen specific.


B cell ELISpot results demonstrated IgG secretion upon stimulation of B cells with full antigen, but not with H1/H7 peptides (FIGS. 15A-15D). The lack of stimulation with the peptide library was to be expected because an IgG response is stimulated via MHCII antigens, which tend to be longer than MHCI antigen needed for stimulation of a T cell response.


Example 25: Evaluation of H1, H7, and H10-Specific T and B Cell Response Against Influenza Vaccines in Mouse Splenocytes

Influenza-specific T and B cell responses were evaluated following administration of mRNA vaccines (NAVs) encoding the H1, H10, and H7 hemagglutinin proteins. Briefly, 36 groups of 5 female 6-8 week old BALB/c mice were vaccinated with various doses via the intradermal route (ID) on day 0. Seven-week post vaccination, animals were sacrificed and spleens were harvested. The splenocytes were assessed by IFNγ ELISpot; Intracellular Cytokine Staining (ICS) for CD3, CD4, CD8, CD45, CCR7, CD44, CD25. IL-2 IFNγ, and TNFα markers; and by B-cell ELISpot.


IFNγ ELISpot Analyses

Splenocytes from groups of mice that had been administered H10N8/N1-methyl pseudouridine /C0 were assessed for H1, H7 and H10-specific IFNγ production by IFNγ ELISpot. Naïve mice did not yield measurable IFNγ cytokine response, whereas H10 peptide-specific IFNγ ELISpot responses were detected in mice vaccinated intradermally with H10N8/N1-methyl pseudouridine /C0. The magnitude of these responses was found to be dependent on the dose of the vaccine administered. Peptide-stimulated splenocytes did not yield detectable H1- or H7-specific IFNγ ELISpot responses. All groups produced IFNγ ELISpot responses following stimulation with PMA+ionomycin (positive control).


H1 peptide-specific IFNγ ELISpot responses were detected from splenocytes isolated from mice that had been administered H1N1/G2/C1, H1N1/G2/C0 (MC3 formulation), or H1N1/G2/C0 (KC2 formulation) intradermally, as well as from splenocytes from mice that had been administered H1N1/G2/C0 (MC3 formulation) intramuscularly.


H7 peptide-specific IFNγ ELISpot responses were detected from splenocytes isolated from mice that had been administered H7N9/G2/C0 either intradermally or intramuscularly.


Splenocytes from control mice that had received H1N1/G2/C1/PBS showed no response to peptide stimulation.


B Cell ELISpot Analyses

Briefly, H1-specific IgG and IgM responses were detected in several groups of mice vaccinated with different H1 vaccine formulations. H7- and H10-specific IgG and IgM responses were also elicited in the H7N9/N1-methyl pseudouridine /C0- and H10N8/N1-methyl pseudouridine /C0-vaccinated mice, respectively.


Intracellular Cytokine Staining Results

Intracellular Cytokine Staining and flow cytometric analysis indicated that H1-specific Th1 (IFNγ, TNFα, IL-2) cytokine responses were induced at both 16-18 hrs and 48 hrs in CD4+ T cells and CD8+ T cells following stimulation of splenocytes from H1-vaccinated mice with corresponding peptide or protein.


Additionally, H7- and H-10 peptide and protein-specific Th1 (IFNγ, TNFα, IL-2) responses were also detected in CD4+ and CD8+ T cells. H7-specific responses were noted in groups vaccinated with H7 vaccine formulations, and H10-specific responses were seen in groups vaccinated with H10 vaccine formulations.


Example 26: Evaluation of H7- and H10-Specific T and B Cell Response Against Influenza Vaccines in Mouse Splenocytes—Time Course

Influenza-specific T and B cell responses were evaluated following administration of mRNA vaccines (NAVs) encoding the H10 and H7 hemagglutinin proteins. Briefly, 27 groups of 5 female 6-8 week old BALB/c mice (135 mice total) were vaccinated with various doses via the intradermal route (ID) on day 0 shown in Table 42. On days 7, 21, and 84 groups of 5 animals were sacrificed and blood samples and spleens were harvested.


The mouse spleens were analyzed using IFNγ ELISPOT, IgG ELISPOT (for B cell responses), and Intracellular Cytokine Staining (ICS). Serum samples were analyzed for inhibition of hemagglutinin (HAI) by first treating with Receptor Destroying Enzyme (RDE) to inactivate non-specific inhibitors of hemagglutination (false positives) present in the sera. Next, RDE-treated sera were adsorbed using red blood cells (RBCs) to remove non-specific agglutinin (false negatives). Serially-diluted treated sera (2-fold dilutions) were pre-incubated with a standardized quantity of recombinant influenza antigen before RBCs were added to the mixture. Inhibition of hemagglutination indicates the presence of HA-specific antibodies. Pooled anti-H10 mouse serum was used as a positive control and showed HAI titers within range of previously-observed data.


After receiving a single dose of the mRNA NAVs on day 0, HAI titers were not detected at day 7 (Table 42) but were detected at day 21 (Table 43) and continued to increase through day 84 (Table 44). Day 84 titers were 2-fold to 15-fold higher than those from day 21 (FIGS. 15 and 16).


Administration of the H10N8/N1-methyl pseudouridine /C1 formulation MC3 resulted in higher HAI titers as compared to the HAI titers induced by the H10N8/N1-methyl pseudouridine/C0 formulation MC3 (FIG. 17). The MC3 LNP formulation consisted of a cationic lipid (DLin-MC3-DMA, 50 mol %), non-cationic lipid (DSPC, 10 mol %), PEG lipid (PEG-DOMG 1.5 mol %) and a structural lipid (cholesterol, 38.5 mol %).


Administration of the H10N8/N1-methyl pseudouridine/C1 formulation MC3 at 10 μg/dose achieved the highest HAI titers, whereas the HAI titers following administration of the 2.0 μg/dose and 0.4 μg/dose are similar to each other (FIG. 16).









TABLE 42







HAI Titers against H10 and H7 at Day 7












Dose

HAI titers of mouse sera



mRNA vaccine
per

Day 0 (Nov. 10, 2014) = vaccination day 0



once at day 0
mouse
Group
Day 7 (Nov. 17, 2014) = terminal bleeds groups 1-9


















via ID injection
(μg)
(N = 5)
M1
M2
M3
M4
M5
Mean
Stdev






















H10N8/N1-methyl
10
1
<10
<10
<10
<10
<10
<
10
N/A
HAI titers


pseudouridine/C1,
2
2
<10
<10
<10
<10
<10
<
10
N/A
against H10


formulation MC3
0.4
3
<10
<10
<10
<10
<10
<
10
N/A
protein


H10N8/N1-methyl
10
4
<10
<10
<10
<10
<10
<
10
N/A



pseudouridine/C0,
2
5
<10
<10
<10
<10
<10
<
10
N/A



formulation MC3
0.4
6
<10
<10
<10
<10
<10
<
10
N/A



PBS
0
7
<10
<10
<10
<10
<10
<
10
N/A



PBS
0
7
<10
<10
<10
<10
<10
<
10
N/A
HAI titers


H7N9/C0
10
8
<10
<10
<10
<10
<10
<
10
N/A
against H7


H7N9/C1
10
9
<10
<10
<10
<10
<10
<
10
N/A
protein
















TABLE 43







HAI Titers against H10 and H7 at Day 21












Dose

HAI titers of mouse sera



mRNAna vaccine
per

Day 0 (Nov. 10, 2014) = vaccination day 0



once at day 0 via
mouse
Group
Day 21 (Dec. 1, 2014) = terminal bleeds group 10-18


















ID injection
(μg)
(N = 5)
M1
M2
M3
M4
M5
Mean
Stdev






















H10N8/N1-methyl
10
10
160
320
640
80
160

272
223
HAI


pseudouridine/C1,
2
11
40
80
40
80
160

80
49
titers


formulation MC3
0.4
12
80
160
40
80
80

88
44
against


H10N8/N1-methyl
10
13
160
40
80
20
40

68
56
H10


pseudouridine/C0,
2
14
20
20
10
10
20

16
5
protein


formulation MC3
0.4
15
20
10
40
20
80

34
28



PBS
0
16
<10
<10
<10
<10
<10
<
10
N/A



PBS
0
16
<10
<10
<10
<10
<10
<
10
0
HAI


H7N9/C0
10
17
40
10
10
20
20

26
13
titers


H7N9C1
10
18
160
160
160
320
80

176
88
against













H7













protein
















TABLE 44







HAI Titers against H10 and H7 at Day 84












Dose

HAI titers of mouse sera



mRNA vaccine
per

Day 0 Nov. 10, 2014) = vaccination day 0



once at day 0
mouse
Group
Day 84 (Feb. 2, 2015) = terminal bleeds groups 19-27


















via ID injection
(μg)
(N = 5)
M1
M2
M3
M4
M5
Mean
Stdev






















H10N8/N1-methyl
10
19
160
320
320
1280
640

544
447
HAI titers


pseudouridine/C1,
2
20
320
320
640
160
320

352
175
against


formulation MC3
0.4
21
640
320
160
320
640

416
215
H10


H10N8/N1-methyl
10
22
160
320
320
320
320

288
72
protein


pseudouridine/C0,
2
23
320
320
160
80
320

240
113



formulation MC3
0.4
24
40
320
320
320
80

216
143



PBS
0
25
<10
<10
<10
<10
<10
<
10
N/A



PBS
0
25
<10
<10
<10
<10
<10
<
10
N/A
HAI titers


H7N9/C0
10
26
20
40
80
20
<10
5
40
28
against H7


H7N9/C1
10
27
640
320
320
160
80

304
215
protein









Example 27: Anti-H10 Hemagglutinin Analysis in Non-Human Primates—Dose Range Study

Groups of cynomolgus monkeys were vaccinated with various doses of NAV encoding H10 HA/LNP formulations (50 μg/dose, 200 μg/dose, 400 μg/dose), NAV encoding H10 HA/LNP delivered with 3M device, or control NAV encoding H10 HA/PBS. Serum samples were taken from the monkeys weekly and evaluated for inhibition of hemagglutinin (Table 45, FIG. 19).









TABLE 45







HAI titers against H10 protein









HAI titers against H10 protein (A/Jiangxi-Donghu/346/2013)

















Cynomolgus
Pre-
Week
Week
Week
Week
Week
Week
Week



monkey ID
treatment
1
2
3
4
5
6
9



















Group 1
1001
10
40
20
20
320
1280
1280
5120


(50 μg)
1002
20
20
40
40
640
2560
2560
10240



1003
<10
<10
40
80
640
2560
2560
10240



Mean
<13
<23
33
47
533
2133
2133
8533


Group 2
2001
<10
<10
10
40
640
5120
2560
10240


(200 μg)
2002
20
20
20
40
640
2560
2560
10240



2003
<10
40
20
40
320
5120
5120
10240



Mean
<13
<23
17
40
533
4267
3413
10240


Group 3
3001
20
<10
40
80
1280
5120
10240
20480


(400 μg)
3002
<10
40
40
160
640
5120
5120
20480



3003
<10
20
80
160
1280
10240
20480
40960



Mean
<13
<23
53
133
1067
6827
11947
27307


Group 4
4001
<10
40
<10
20
40
80
80
160


(vaccine
4002
<10
40
<10
<10
40
160
160
160


device)
4003
20
40
<10
10
40
80
80
160



Mean
<13
40
<10
<13
40
107
107
160


Group 5
5001
<10
20
80
320
1280
5120
5120
10240


(PBS)
5002
<10
20
40
160
1280
5120
5120
10240



5003
<10
40
40
80
1280
5120
5120
20480



Mean
<10
27
53
187
1280
5120
5120
13653












Assay Positive Control: Anti-H10
Assay Positive Control: Anti H-10




Pool of 9 mouse sera
Pool of 9 mouse sera




M1, M2, M3, of Group 1, N1-methyl
M1, M2, M3 of Group 1, N1-




pseudouridine (m1 Ψ) and 5-methyl
methyl pseudouridine (m1 Ψ) and




cytidine, Group 3 of
5-methyl cytidine, Group 3 of




study day 14
study day 14




HAI titer = 160
HAI titer = 80









Example 28: Determination of Time to Onset of Immunity Using an H7N9 Vaccine in a Ferret Model

The time to onset of immunity (as measured by antibody titers and reduction in viral titers following challenge) of an influenza A/Anhui/l/2013 (H7N9) vaccine was evaluated in a ferrets model of influenza infection. Briefly, twenty groups of 8 ferrets each were vaccinated on day 0 with the H7N9 mRNA NAV vaccine at a dose of 10H/g, 50 μg, or 200 μg, a vH7N9 vaccine lacking the 14 kDa cap at a dose of 200 μg or PBS control via the intradermal route. Five of the 20 groups received a second vaccination (a booster) to determine if a second dose increased protection. The animals were then exposed to influenza A/Anhui/1/2013 (H7N9) virus via the intranasal route. The study design is shown in Table 45:









TABLE 45







Study Design












Group

Day of
No. of
Day of
Day of Blood


No.
Vaccine Dose
Vaccination
Animals
Challenge
Draws















1
H7N9/N1-methyl pseudouridine/
0
8
7
0, 7



C1/MC3, 200 μg






2
H7N9/N1-methyl pseudouridine/
0
8
7
0, 7



C1/MC3, 50 μg






3
H7N9/N1-methyl pseudouridine/
0
8
7
0, 7



C1/MC3, 10 μg






4
PBS
0
8
7
0, 7


5
H7N9/MC3 (−14 kDa Cap) 200 μg
0
8
7
0, 7


6
H7N9/N1-methyl pseudouridine/
0
8
21
0, 21



C1/MC3, 200 μg






7
H7N9/N1-methyl pseudouridine/
0
8
21
0, 21



C1/MC3, 50 μg






8
H7N9/N1-methyl pseudouridine/
0
8
21
0, 21



C1/MC3, 10 μg






9
PBS
0
8
21
0, 21


10
H7N9/MC3 (−14 kDa Cap) 200 μg
0
8
21
0, 21


11
H7N9/N1-methyl pseudouridine/
0
8
49
0, 49



C1/MC3, 200 μg






12
H7N9/N1-methyl pseudouridine/
0
8
49
0, 49



C1/MC3, 50 μg






13
H7N9/N1-methyl pseudouridine/
0
8
49
0, 49



C1/MC3, 10 μg






14
PBS
0
8
49
0, 49


15
H7N9/MC3 (−14 kDa Cap) 200 μg
0
8
49
0, 49


16
H7N9/N1-methyl pseudouridine/
4, 25
8
53
4, 25, 53



C1/MC3, 200 μg






17
H7N9/N1-methyl pseudouridine/
4, 25
8
53
4, 25, 53



C1/MC3, 50 μg






18
H7N9/N1-methyl pseudouridine/
4, 25
8
53
4, 25, 53



C1/MC3, 10 μg






19
PBS
4, 25
8
53
4, 25, 53


20
H7N9/MC3 (−14 kDa Cap) 200 μg
4, 25
8
53
4, 25, 53









Because H7N9 does not induce a lethal disease in ferrets, the primary endpoint was viral burden in tissues (primarily lung) 3 days post-challenge, as determined by TCID50 (50% tissue culture infective dose). In addition to viral titers, blood was collected prior to vaccination and immediately prior to challenge to determine influenza-specific antibody titers, as determined by hemagglutination inhibition (HAI) and microneutralization (MN) assays.


The lung homogenate data show that a single vaccination at any concentration resulted in a reduction in viral titers, with a time to onset of immunity before 7 days post vaccination (Table 46). There was a 1 log reduction in all vaccine groups challenged 7 days post vaccination. This improved for groups challenged 21 days post vaccination in a dose-dependent fashion to 3, 2, and 1 log reduction for the 200-, 50-, and 10-μg groups, respectively (FIG. 20). This further improved for groups challenged 49 days post vaccination to 4, 2, and 3 log reduction for the 200, 50-, and 10-μg groups, respectively. A statistically significant difference was observed relative to PBS control group at 7 days post vaccination in the 10- and 200-μg groups (p<0.05). The 50-μg dose group also tended towards reduced lung viral titers, but only had statistically significant differences from the PBS group when a boost was administered. This was likely due to the occasional outlying high viral titer sample, which increased the variability in this group.









TABLE 46







Virus Burden (TCID50 Group Geographic Means)










Nasal Wash
Lung Homogenate














Day 7
Day 21
Day 49
Day 7
Day 21
Day 49
















H7N9/N1-methyl pseudouridine/
3.7 × 103
3.1 × 103
3.3 × 104
3.0 × 103
4.6 × 101
8.0 × 100


C1/MC3 200 μg








H7N9/N1-methyl pseudouridine/
2.4 × 103
1.6 × 104
6.7 × 104
2.0 × 103
5.9 × 102
9.7 × 102


C1/MC3 50 μg








H7N9/N1-methyl pseudouridine/
3.7 × 103
8.1 × 102
1.0 × 105
2.3 × 103
2.9 × 103
6.2 × 101


C1/MC3 10 μg








PBS
6.0 × 103
2.9 × 103
1.7 × 105
3.8 × 104
3.2 × 104
2.1 × 104


H7N9/MC3 (−14 kDa Cap) 200 μg
1.4 × 104
1.5 × 103
3.6 × 105
7.9 × 103
1.6 × 103
4.8 × 102






158 is the lower limit of detection o the nasal wash TCID50 assay. All below LLOQ values were assigned a value of 79 for producing the geomean values for nasal wash. 15.8 is the lower limit of detection of the lung homogenate TCID50 assay. All below LLOQ values were assigned a value of 8 for producing the geomean values for nasal wash.







There was no statistical benefit observed from the boosting vaccination compared to a single vaccination, but this is likely due to the 2-4 log reduction in viral lung titers by 49 days seen in both the single vaccination and 2 (boost) vaccination groups (Table 47).









TABLE 47







Lung Virus Burden (TCID50 Group Geographic Means)-


Boosted vs. Unboosted













Day 49 with the




Day 49 Unboosted
Day 21 Boost















200 μg Vaccine 
8.0 × 100
8.0 × 100



50 μg Vaccine
9.7 × 102
8.0 × 100



10 μg Vaccine
6.2 × 101
1.1 × 102



PBS
2.1 × 104
2.2 × 104



Empty Vaccine Vector
4.8 × 102
8.0 × 100








15.8 is the lower limit of detection of the lung homogenate TCID50 assay. All below LLOQ values were assigned a value of 8 for producing the geomean values for nasal wash.







Serum was collected from each animal immediately before vaccination and challenge and analyzed by HAI assay. As seen from Table 48, a dose dependent increase was visible 7 days post vaccination, and titers increased over time. The 200-μg to 14-kDa cap vaccine did provide some titer above background, between the 10-μg vaccine and PBS response. The groups receiving a second vaccination showed a dose-dependent, 3 8 fold increase in antibody titers following the second vaccination. The 200-μg to 14-kDa cap vaccine also showed an approximately 2-fold increase in antibody titers following the second vaccination. In all cases, a statistically significant increase relative to the pre-vaccination blood sample was first observed 21 days post-vaccination (p<0.05).









TABLE 48







HAI Antibody Titer Results











Geomean












Cohort
Treatment
Day 0
Day 7
Day 21
Day 49





1
200 μg Vaccine 
5.00
5.45
N/A
N/A


1
50 μg Vaccine
5.00
6.48
N/A
N/A


1
10 μg Vaccine
5.00
5.94
N/A
N/A


1
PBS
5.00
5.00
N/A
N/A


1
Empty Vaccine Vector
5.00
5.45
N/A
N/A


2
200 μg Vaccine 
5.00
N/A
43.62
N/A


2
50 μg Vaccine
5.00
N/A
25.94
N/A


2
10 μg Vaccine
5.00
N/A
25.94
N/A


2
PBS
5.00
N/A
5.00
N/A


2
Empty Vaccine Vector
5.00
N/A
9.35
N/A


3
200 μg Vaccine 
5.00
N/A
N/A
61.69


3
50 μg Vaccine
5.00
N/A
N/A
33.64


3
10 μg Vaccine
5.00
N/A
N/A
25.94


3
PBS
5.00
N/A
N/A
5.00


3
Empty Vaccine Vector
5.00
N/A
N/A
18.34


4
200 μg Vaccine 
5.00
N/A
59.93
480.67


4
50 μg Vaccine
5.00
N/A
29.97
195.85


4
10 μg Vaccine
5.00
N/A
40.00
97.92


4
PBS
5.00
N/A
5.00
5.45


4
Empty Vaccine Vector
5.94
N/A
5.96
36.68






Ten is the lower limit of detection of the HAI assay. All <10 were assigned a value of 5 for producing the geomean values.




NA = Not applicable.







Serum samples were also analyzed by MN assay. As shown in Table 49, increases in MN titer was observed as early as 7 days post vaccination and continued to increase through 49 days post vaccination. The titers were highest in the 200-μg vaccine group, and were similar in the 50- and 10-μg groups. For the 50- and 200-μg vaccine dose groups, a statistically significant increase was observed by 7 days post-vaccination (p<0.05). For the 10-μg vaccine dose groups, the significant increase was not observed until 21 days post-vaccination (p<0.05). The 200-μg to 14-kDa cap vaccine did provide some titer above background, which was statistically significant by 49 days post vaccination (p<0.05) and were lower than the titers for the 50- and 10-μg groups. The groups receiving a second vaccination experienced a 3.0-4.5 fold increase in titers following the second vaccination. The 200-μg to 14-kDa cap vaccine also showed an approximately 1.5-fold increase in titers following the second vaccination.









TABLE 49







MN Antibody Titer Results











Geomean












Co-

Day
Day
Day
Day


hort
Treatment
0
7
21
49





1
H7N9/N1-methyl pseudouridine/
15.00
33.67
N/A
N/A



C1/MC3 200 μg Vaccine






1
H7N9/N1-methyl pseudouridine/
17.38
42.29
N/A
N/A



C1/MC3 50 μg Vaccine






1
H7N9/N1-methyl pseudouridine/
21.21
25.94
N/A
N/A



C1/MC3 10 μg Vaccine






1
PBS
19.58
18.47
N/A
N/A


1
H7N9/MC3 (−14 kDa Cap)
17.43
20.03
N/A
N/A



200 μg






2
H7N9/N1-methyl pseudouridine/
14.69
N/A
92.41
N/A



C1/MC3 200 μg Vaccine






2
H7N9/N1-methyl pseudouridine/
17.49
N/A
42.50
N/A



C1/MC3 50 μg Vaccine






2
H7N9/N1-methyl pseudouridine/
15.07
N/A
43.48
N/A



C1/MC3 10 μg Vaccine






2
PBS
17.89
N/A
13.60
N/A


2
H7N9/MC3 (−14 kDa Cap)
18.52
N/A
17.43
N/A



200 μg






3
H7N9/N1-methyl pseudouridine/
15.51
N/A
N/A
160.08



C1/MC3 200 μg Vaccine






3
H7N9/N1-methyl pseudouridine/
13.16
N/A
N/A
89.80



C1/MC3 50 μg Vaccine






3
H7N9/N1-methyl pseudouridine/
13.12
N/A
N/A
77.51



C1/MC3 10 μg Vaccine






3
PBS
12.70
N/A
N/A
10.68


3
H7N9/MC3 (−14 kDa Cap)
10.33
N/A
N/A
46.21



200 μg






4
H7N9/N1-methyl pseudouridine/
10.33
N/A
63.44
697.88



C1/MC3 200 μg Vaccine






4
H7N9/N1-methyl pseudouridine/
10.68
N/A
29.99
273.04



C1/MC3 50 μg Vaccine






4
H7N9/N1-methyl pseudouridine/
10.68
N/A
31.97
232.65



C1/MC3 10 μg Vaccine






4
PBS
12.01
N/A
11.03
10.68


4
H7N9/MC3 (−14 kDa Cap)
11.78
N/A
16.47
69.06



200 μg






20 is the lower limit of detection of the MN assay. All <20 were assigned a value of 10 for producing the geomean values.




N/A = Not applicable.







Quite surprisingly, the vaccine constructs of the invention reduced viral titers in the lungs when exposed to virus just 7 days following vaccination. Statistically significant increases in antibody titer as measured by HAI and MN were detected as early as 7 days following vaccination. A second vaccination (i.e., booster) did increase antibody Liters, but did not statistically reduce the viral titer, as a single vaccination eliminated all virus in most animals. The −14 kDa cap vaccine at 200 μg/animal provided less protection than 10-μg full vaccine, but did reduce viral burden in the lung and increased antibody titers, both relative to PBS control.


While the present invention has been described at some length and with some particularity with respect to the several described embodiments, it is not intended that it should be limited to any such particulars or embodiments or any particular embodiment, but it is to be construed with references to the appended claims so as to provide the broadest possible interpretation of such claims in view of the prior art and, therefore, to effectively encompass the intended scope of the invention.


All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, section headings, the materials, methods, and examples are illustrative only and not intended to be limiting.


It is to be understood that the words which have been used are words of description rather than limitation, and that changes may be made within the purview of the appended claims without departing from the true scope and spirit of the invention in its broader aspects.

Claims
  • 1. A pharmaceutical composition comprising a ribonucleic acid (RNA) formulated in a lipid nanoparticle, wherein the RNA is not self-replicating and comprises an open reading frame encoding an influenza hemagglutinin protein, wherein the open reading frame comprises nucleosides consisting of N1-methylpseudouridine, adenosine, guanosine, and cytidine, and wherein the composition comprises from 25-100 μg of the RNA.
RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No. 17/683,171, filed Feb. 28, 2022, which is a continuation of U.S. application Ser. No. 16/144,394, filed Sep. 27, 2018, which is a continuation of U.S. application Ser. No. 16/036,318, filed Jul. 16, 2018, which is a continuation of U.S. application Ser. No. 15/089,050, filed Apr. 1, 2016 (now U.S. Pat. No. 10,022,435), which is a continuation of International Patent Application Serial No. PCT/US2015/027400, filed Apr. 23, 2015, which claims the benefit of, under 35 USC 119(e), U.S. Application Ser. No. 62/088,994, filed Dec. 8, 2014, and U.S. Application Ser. No. 61/983,250, filed Apr. 23, 2014. The entire contents of these applications are incorporated herein by reference in their entirety.

Provisional Applications (2)
Number Date Country
62088994 Dec 2014 US
61983250 Apr 2014 US
Continuations (5)
Number Date Country
Parent 17683171 Feb 2022 US
Child 18801174 US
Parent 16144394 Sep 2018 US
Child 17683171 US
Parent 16036318 Jul 2018 US
Child 16144394 US
Parent 15089050 Apr 2016 US
Child 16036318 US
Parent PCT/US2015/027400 Apr 2015 WO
Child 15089050 US