The present invention relates in general to tuberculosis (TB) treatment and control, and more particularly, to a composition and a method of developing a TB vaccine by targeting antigens to human dendritic cells and their subtypes.
None.
The present application includes a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Mar. 12, 2012, is named BHCS1119.txt and is 882,499 bytes in size.
Without limiting the scope of the invention, its background is described in connection with design of fusion proteins and targeting antigens to dendritic cells (DCs) for the purpose of vaccination and to evoke potent humoral and cellular immune responses.
U.S. Patent Application No. 20040146948 (Britton et al. 2003) provides single-chain Fv (scFv) fragment-based compositions and methods for targeting antigens (including Mycobacterial antigens) to antigen-presenting cells (APCs) such as, for example, dendritic cells (DC). The Britton invention further discloses compositions and methods useful in the treatment of diseases including infectious diseases and cancer.
U.S. Pat. No. 7,560,534 issued to Deo et al. (2009) describes molecular conjugates comprising an antigen linked to a human monoclonal antibody that specifically binds to dendritic cells. The '534 patent further discloses pharmaceutical compositions comprising the molecular conjugates and therapeutic methods for using the conjugates.
U.S. Pat. No. 7,261,897 issued to Skeiky et al. (2007) relates to compositions and fusion proteins containing at least two Mycobacterium sp. antigens, and nucleic acids encoding such compositions and fusion proteins. The compositions of the Skeiky invention increase serological sensitivity of sera from individuals infected with tuberculosis, and methods for their use in the diagnosis, treatment, and prevention of tuberculosis infection.
The present invention describes a tuberculosis (TB) vaccine comprising selected TB proteins domains fused to heavy and light chain of antibodies that is used to target and activate dendritic cells (DCs). The vaccine composition described herein delivers antigen specifically to DCs for the purpose of vaccination to evoke potent humoral and cellular immune responses. The vaccine composition of the present invention promotes efficient recall memory induced in blood from TB patients. Targeting. DCs with TB-antigen fused to anti-DC antibodies enables recognition of both human and monkey proteins.
A method for increasing the effectiveness of antigen presentation by an antigen presenting cell (APC) is disclosed in one embodiment of the present invention. The method of the present invention comprises the steps of: isolating and purifying a dendritic cell (DC)-specific antibody or fragment thereof to which one or more antigens or recombinant antigens are attached or conjugated to form an antibody-antigen complex, and contacting the APC with the antibody-antigen complex under conditions wherein the antibody-antigen complex is processed and presented for T cell recognition.
In one aspect of the method described hereinabove the APC comprises an isolated dendritic cell (DC), a peripheral blood mononuclear cell (PBMC), a monocyte, a B cell, a myeloid dendritic cell and combinations thereof that have been cultured in vitro with GM-CSF and IL-4, interferon alpha, antigen and combinations thereof. In one aspect, the one or more antigens or recombinant antigens comprise M. tuberculosis antigens comprises at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211. In another aspect, the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In another aspect, the method of claim 1, wherein a nucleotide sequence for the DC-specific antibody or the antigen is selected from SEQ ID NOS: 6 to 70, 136, 138, 140, 142, 144, 146, 148, 150, 152, 154, 156, 158, 160, 162, 164, 166, 168, 170, 172, 174, 176, 178, 180, 182, 184, 186, 188, 190, 192, 194, 196, 198, 200, 202, 204, 206, 208, 210, 212, 214, 216, 218, or 220.
Another embodiment described herein relates to an immunostimulatory composition for generating an immune response, for prophylaxis, for therapy or any combination thereof against tuberculosis in a human or animal subject comprising: (i) an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more M. tuberculosis antigens or antigenic peptides and (ii) a pharmaceutically acceptable carrier, wherein the conjugate is comprised in an amount effective to generate the immune response against tuberculosis. In one aspect of the composition the one or more M. tuberculosis antigens are selected from the group consisting of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof. In another aspect the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In yet another aspect the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40. In a related aspect the DC-specific antibody is humanized. In another aspect the composition is administered to the human or animal subject by an oral route, a nasal route, topically or as an injection, wherein the injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal:
In yet another embodiment the instant invention discloses a vaccine composition comprising: an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more recombinant or natural M. tuberculosis antigens or antigenic peptides, wherein the antigenic peptides are representative of one or more epitopes of the one or more antigens implicated in tuberculosis and an optional pharmaceutically acceptable carrier or an adjuvant. The vaccine composition of the present invention further comprises a flexible linker between the DC-specific antibody or fragment thereof and the one or more antigens, wherein the one or more antigens or antigenic peptides are conjugated to a heavy-chain, a light-chain or both of the anti-dendritic cell (DC)-specific antibody.
In one aspect of the vaccine composition the one or more M. tuberculosis antigens are selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and any combinations thereof. In another aspect the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In a specific aspect the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40. In a related aspect the DC-specific antibody is humanized and the composition is administered to the human or animal subject by an oral route, a nasal route, topically or as an injection. In one aspect the injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal, intramuscular, and intravenous.
A tuberculosis vaccine composition is disclosed in one embodiment of the instant invention. The composition comprises a dendritic cell (DC)-specific antibody or fragment thereof comprising αDCIR, αLangerin, αLOX-1 or αCD40 fused to one or more antigens or antigenic peptides selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, wherein the antigens or the antigenic peptides are conjugated to a heavy chain of the DC-specific antibody via one or more flexible linkers and an optional pharmaceutically acceptable carrier or an adjuvant.
Another embodiment of the instant invention describes a tuberculosis vaccine comprising: a dendritic cell (DC)-specific antibody or fragment thereof comprising αDCIR, αLangerin, αLOX-1 or αCD40 fused to one or more antigens selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, wherein the antigens or the antigenic peptides are conjugated to a heavy chain of the DC-specific antibody via one or more flexible linkers and an optional pharmaceutically acceptable carrier or an adjuvant. A tuberculosis vaccine comprising a dendritic cell (DC)-specific antibody or fragment thereof comprising αDCIR, αLangerin, αLOX-1 or αCD40 fused to one or more antigens or antigenic peptide comprising SEQ ID NO: 3, wherein the antigen or the antigenic peptide is conjugated to a light chain of the DC-specific antibody via one or more flexible linkers and an optional pharmaceutically acceptable carrier or an adjuvant is also disclosed herein.
In yet another embodiment the instant invention provides a method for increasing effectiveness of one or more dendritic cells (DCs) comprising the steps of: a) isolating the DCs from a patient, b) exposing the DCs to activating amounts of a vaccine comprising a dendritic cell (DC)-specific antibody or fragment thereof loaded, fused or conjugated to one or more antigens selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof wherein the antigens or the antigenic peptides are conjugated to a heavy chain, a light chain or both of the DC-specific antibody via one or more flexible linkers; and an optional pharmaceutically acceptable carrier or an adjuvant, and c) reintroducing the antigen-loaded and activated DCs into the patient. In one aspect of the method the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40.
A method of providing immunostimulation by activation of one or more dendritic cells (DCs) to a human subject for a prophylaxis, a therapy or a combination thereof against one or more viral, bacterial, fungal, parasitic, protozoal, and parasitic diseases, and allergic disorders is disclosed in one embodiment of the present invention. The immunostimulation method comprises the steps of: (i) identifying the human subject in need of immunostimulation for the prophylaxis, the therapy or a combination thereof against the one or more diseases or disorders; (ii) isolating one or more DCs from the human subject; (iii) activating the isolated DCs with an amount of a composition effective to form activated DCs comprising a dendritic cell (DC)-specific antibody or fragment thereof loaded, fused or conjugated to one or more antigens or antigenic peptides, wherein the antigens or the antigenic peptides are conjugated to a heavy chain, a light chain or both of the DC-specific antibody via one or more flexible linkers; and an optional pharmaceutically acceptable carrier or an adjuvant; and (iv) reintroducing the activated DCs into the human subject. In a specific aspect the bacterial disease is tuberculosis. In one aspect of the method the antigens selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof. In another aspect of the method the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In yet another aspect the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40.
In another embodiment the instant invention describes a method for a treatment, a prophylaxis or a combination thereof against tuberculosis in a human subject comprising the steps of: identifying the human subject in need of the treatment, the prophylaxis or a combination thereof against tuberculosis; and administering a vaccine composition comprising an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more recombinant or natural M. tuberculosis antigens or antigenic peptides, wherein the antigenic peptides are representative of one or more epitopes of the one or more antigens implicated in tuberculosis and an optional pharmaceutically acceptable carrier or an adjuvant.
The method as described hereinabove further comprises a flexible linker between the DC-specific antibody or fragment thereof and the one or more antigens. In one aspect the one or more antigens or antigenic peptides are conjugated to a heavy-chain, a light-chain or both of the anti-dendritic cell (DC)-specific antibody. In another aspect the one or more M. tuberculosis antigens are selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof. In yet another aspect the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class 1, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In a related aspect the humanized DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40. In another aspect the composition is administered to the human or animal subject by an oral route, a nasal route, topically or as an injection. In another aspect the injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal, intramuscular, and intravenous.
An immunostimulatory composition for generating an immune response is disclosed in one embodiment of the present invention. The composition provides a prophylaxis, a therapy or any combination thereof against tuberculosis in a human or animal subject and comprises: a) an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more M. tuberculosis antigens or antigenic peptides, b) at least one Toll-Like Receptor (TLR) agonist which is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists and c) a pharmaceutically acceptable carrier, wherein the conjugate is comprised in an amount effective to generate the immune response against tuberculosis. In one aspect the one or more M. tuberculosis antigens are selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, and any combinations thereof. In another aspect the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40.
The present invention also discloses A tuberculosis vaccine comprising: an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more recombinant or natural M. tuberculosis antigens or antigenic peptides, wherein the antigenic peptides are representative of one or more epitopes of the one or more antigens implicated in tuberculosis, at least one Toll-Like Receptor (TLR) agonist which is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists, and one or more optional pharmaceutically acceptable carriers and adjuvants. In one aspect the one or more M. tuberculosis antigens are selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof. In another aspect the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44; CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In yet another aspect the DC-specific antibody is humanized. In another aspect the composition is administered to the human or animal subject by an oral route, a nasal route, topically or as an injection, wherein the injection is selected from the group consisting of subcutaneous, intravenous, intraperitoneal, intramuscular, and intravenous.
In one embodiment the present invention discloses a method for a treatment, a prophylaxis or a combination thereof against tuberculosis in a human subject comprising the steps of: (i) identifying the human subject in need of the treatment, the prophylaxis or a combination thereof against tuberculosis, and (ii) administering a vaccine composition comprising: a) an anti-dendritic cell (DC)-specific antibody or fragment thereof fused or conjugated to at least a portion of one or more recombinant or natural M. tuberculosis antigens or antigenic peptides, wherein the antigenic peptides are representative of one or more epitopes of the one or more antigens implicated in tuberculosis; b) at least one Toll-Like Receptor (TLR) agonist which is selected from the group consisting of TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, and TLR8 agonists; and c) one or more optional pharmaceutically acceptable carriers and adjuvants.
In one aspect the vaccine described hereinabove further comprises a flexible linker between the DC-specific antibody or fragment thereof and the one or more antigens. In another aspect the one or more antigens or antigenic peptides are conjugated to a heavy-chain, a light-chain or both of the anti-dendritic cell (DC)-specific antibody. In yet another aspect the one or more M. tuberculosis antigens are selected from at least one of SEQ ID NOS: 1, 2, 3, 4, 5, 71 to 135, 137, 139, 141, 143, 145, 147, 149, 151, 153, 155, 157, 159, 161, 163, 165, 167, 169, 171, 173, 175, 177, 179, 181, 183, 185, 187, 189, 191, 193, 195, 197, 199, 201, 203, 205, 207, 209, 211, 213, 215, 217, 219, or 211, and any combinations thereof. In another aspect the DC-specific antibody or fragment is selected from an anti-DCIR, αDCIR, MHC class I, MHC class II, CD1, CD2, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD19, CD20, CD29, CD31, αCD40, CD43, CD44, CD45, CD54, CD56, CD57, CD58, CD83, CD86, CMRF-44, CMRF-56, DCIR, DC-ASPGR, CLEC-6, CD40, BDCA-2, MARCO, DEC-205, mannose receptor, αLangerin, DECTIN-1, B7-1, B7-2, IFN-γ receptor and IL-2 receptor, ICAM-1, Fcγ receptor, αLOX-1 or ASPGR. In related aspects the DC-specific antibody or fragment comprises αDCIR, αLangerin, αLOX-1 or αCD40 and further the DC-specific antibody is humanized.
For a more complete understanding of the features and advantages of the present invention, reference is now made to the detailed description of the invention along with the accompanying figures and in which:
While the making and using of various embodiments of the present invention are discussed in detail below, it should be appreciated that the present invention provides many applicable inventive concepts that can be embodied in a wide variety of specific contexts. The specific embodiments discussed herein are merely illustrative of specific ways to make and use the invention and do not delimit the scope of the invention.
To facilitate the understanding of this invention, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the present invention. Terms such as “a”, “an,” and “the” are not intended to refer to only a singular entity, but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the invention, but their usage does not delimit the invention, except as outlined in the claims.
As used herein, the term “Antigen Presenting Cells” (APC) refers to cells that are capable of activating T cells, and include, but are not limited to, certain macrophages, B cells and dendritic cells. “Dendritic cells” (DCs) refers to any member of a diverse population of morphologically similar cell types found in lymphoid or non-lymphoid tissues. These cells are characterized by their distinctive morphology, high levels of surface MHC-class II expression (Steinman, et al., Ann. Rev. Immunol. 9:271 (1991); incorporated herein by reference for its description of such cells). These cells can be isolated from a number of tissue sources, and conveniently, from peripheral blood, as described herein. Dendritic cell binding proteins refers to any protein for which receptors are expressed on a dendritic cell. Examples include GM-CSF, IL-1, TNF, IL-4, CD40L, CTLA4, CD28, and FLT-3 ligand.
For the purpose of the present invention, the term “vaccine composition” is intended to mean a composition which can be administered to humans or to animals in order to induce an immune system response; this immune system response can result in a production of antibodies or simply in the activation of certain cells, in particular antigen-presenting cells, T lymphocytes and B lymphocytes. The vaccine composition can be a composition for prophylactic purposes or for therapeutic purposes, or both. As used herein, the term “antigen” refers to any antigen which can be used in a vaccine, whether it involves a whole microorganism or a subunit, and whatever its nature: peptide, protein, glycoprotein, polysaccharide, glycolipid, lipopeptide, etc. They may be viral antigens, bacterial antigens, or the like; the term “antigen” also comprises the polynucleotides, the sequences of which are chosen so as to encode the antigens whose expression by the individuals to which the polynucleotides are administered is desired, in the case of the immunization technique referred to as DNA immunization. They may also be a set of antigens, in particular in the case of a multivalent vaccine composition which comprises antigens capable of protecting against several diseases, and which is then generally referred to as a vaccine combination, or in the case of a composition which comprises several different antigens in order to protect against a single disease, as is the case for certain vaccines against whooping cough or the flu, for example. The term “antibodies” refers to immunoglobulins, whether natural or partially or wholly produced artificially, e.g. recombinant. An antibody may be monoclonal or polyclonal. The antibody may, in some cases, be a member of one, or a combination immunoglobulin classes, including: IgG, IgM, IgA, IgD, and IgE.
The term “adjuvant” refers to a substance that enhances, augments or potentiates the host's immune response to a vaccine antigen.
The term “gene” is used to refer to a functional protein, polypeptide or peptide-encoding unit. As will be understood by those in the art, this functional term includes both genomic sequences, cDNA sequences, or fragments or combinations thereof, as well as gene products, including those that may have been altered by the hand of man. Purified genes, nucleic acids, protein and the like are used to refer to these entities when identified and separated from at least one contaminating nucleic acid or protein with which it is ordinarily associated.
As used herein, the term “nucleic acid” or “nucleic acid molecule” refers to polynucleotides, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), oligonucleotides, fragments generated by the polymerase chain reaction (PCR), and fragments generated by any of ligation, scission, endonuclease action, and exonuclease action. Nucleic acid molecules can be composed of monomers that are naturally-occurring nucleotides (such as DNA and RNA), or analogs of naturally-occurring nucleotides (e.g., α-enantiomeric forms of naturally-occurring nucleotides), or a combination of both. Modified nucleotides can have alterations in sugar moieties and/or in pyrimidine or purine base moieties. Sugar modifications include, for example, replacement of one or more hydroxyl groups with halogens, alkyl groups, amines, and azido groups, or sugars can be functionalized as ethers or esters. Moreover, the entire sugar moiety can be replaced with sterically and electronically similar structures, such as aza-sugars and carbocyclic sugar analogs. Examples of modifications in a base moiety include alkylated purines and pyrimidines, acylated purines or pyrimidines, or other well-known heterocyclic substitutes. Nucleic acid monomers can be linked by phosphodiester bonds or analogs of such linkages. Analogs of phosphodiester linkages include phosphorothioate, phosphorodithioate, phosphoroselenoate, phosphorodiselenoate, phosphoroanilothioate, phosphoranilidate, phosphoramidate, and the like. The term “nucleic acid molecule” also includes so-called “peptide nucleic acids,” which comprise naturally-occurring or modified nucleic acid bases attached to a polyamide backbone. Nucleic acids can be either single stranded or double stranded.
As used in this application, the term “amino acid” means one of the naturally occurring amino carboxylic acids of which proteins are comprised. The term “polypeptide” as described herein refers to a polymer of amino acid residues joined by peptide bonds, whether produced naturally or synthetically. Polypeptides of less than about 10 amino acid residues are commonly referred to as “peptides.” A “protein” is a macromolecule comprising one or more polypeptide chains. A protein may also comprise non-peptidic components, such as carbohydrate groups. Carbohydrates and other non-peptidic substituents may be added to a protein by the cell in which the protein is produced, and will vary with the type of cell. Proteins are defined herein in terms of their amino acid backbone structures; substituents such as carbohydrate groups are generally not specified, but may be present nonetheless.
As used herein, the term “in vivo” refers to being inside the body. The term “in vitro” used as used in the present application is to be understood as indicating an operation carried out in a non-living system.
As used herein, the term “treatment” or “treating” means any administration of a compound of the present invention and includes (1) inhibiting the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., arresting further development of the pathology and/or symptomatology), or (2) ameliorating the disease in an animal that is experiencing or displaying the pathology or symptomatology of the diseased (i.e., reversing the pathology and/or symptomatology).
The present invention describes a novel tuberculosis (TB) human vaccine based on in vivo dendritic cell (DC)-targeting. The vaccine comprises a conjugate of one or more high affinity monoclonal antibodies against several DC receptors with several M. tuberculosis protein antigens. The vaccine composition described herein delivers antigen specifically to DCs for the purpose of vaccination to evoke potent humoral and cellular immune responses. The vaccine composition of the present invention promotes efficient recall memory induced in blood from TB patients.
TB is a leading cause of death: in 2006, there were 9.2 million new cases of active TB and an estimated 1.5 million deaths in the world, according to the World Health Organization. It is estimated that one-third of the world's population harbors Mycobacterium tuberculosis (M. tuberculosis) in the form of non-replicating bacilli (latent tuberculosis) (1). In addition, an increasing proportion of TB cases results from infection with M. tuberculosis resistant to first line chemotherapy (multi-drug resistant TB or MDR-TB) (2). M. bovis BCG, the only vaccine against TB currently available, prevents 80% of childhood military disease and meningitis, but its efficacy in preventing pulmonary disease in adulthood is rather low (3). Therefore, efficient therapeutic vaccines are urgently needed to cure active and latent TB patients. Furthermore, according to the World Health Organization, M. tuberculosis is also the major opportunistic pathogen associated with HIV disease, contributing significantly to HIV-associated mortality (almost 25% of HIV-related deaths are from TB).
Dendritic cells (DCs) are leukocytes specialized in the uptake, processing and presentation of antigens and play fundamental roles in regulating both innate and adaptive immunity functions and in maintaining immunological tolerance. They are mainly localized at the interface between body surfaces and the environment, continuously scrutinizing incoming antigen for the potential threat it may represent for the body. To control immune responses against a large variety of microorganisms including viruses and bacteria they exhibit at their surface a large number of receptors, which have been shown to be crucial in DC biological functions in vivo by sensing pathogen-associated molecular patterns (PAMPs). These specialized pathogen recognition receptors (PRRs) whose engagement modulates the functional activity of DCs, include C-type lectin receptors (CLRs) and Toll-like receptors (TLRs) (4). Following pathogen contact, PRRs are endocytosed by immature DCs, which induce the DC to enter a developmental program called maturation, which transforms DCs from sentinels into efficient APCs and T cell stimulators (5). With the induction of maturation, DCs undergo massive morphological and functional changes. Antigen internalization is down modulated due to repression of most antigen-receptors and to an overall reduction in phagocytosis and macropinocytosis. In addition, MHC molecules are redistributed from intracellular endocytic compartments to the cell surface (6,7). Peptide loading as well as the half-life of MHC molecules is increased (6,7). Finally, the surface expression of T cell costimulatory molecules also rises. Concomitant with the modifications of their antigen presentation abilities, maturation induces migration of DCs out of peripheral tissues (8). Modifications in the expression of chemokine receptors and adhesion molecules, as well as profound changes of the cytoskeleton organization, contribute to the migration of DCs, through the lymph, towards secondary lymphoid organs (9). By linking antigen uptake, peptide loading, and cell migration to the encounter of a pathogen, DCs restrict antigen presentation to those antigens internalized during maturation, thus favoring the stimulation of T cells specific for potentially pathogenic antigens.
All these biological events result in the activation of specific signaling pathways that lead to the induction of specific immune responses against these pathogens, in part through expression of effector cytokines. The resulting T cell responses following these interactions between PRRs and PAMPs have been extensively studied. However, little is known about the way the PPRs are internalized and how from inside the cell, they are able to dictate and orientate immune responses. The present inventors have previously produced high affinity monoclonal antibodies against several DC receptors, and prepared fusion proteins with antigens for DC-targeting vaccine generation. Targeting antigens to DCs using these fusion proteins recognizing different CLRs resulted in different biological responses. The inventors hypothesize is that subsets of human DCs express distinct receptors that need to be mobilized in order to mount a durable immune response adapted to each microbial invasion, depending on the pathogen to be eliminated. To test this hypothesis, the inventors have prepared high affinity monoclonal antibodies against several DC receptors to which antibodies have been conjugated to several M. tuberculosis protein antigens to develop novel human vaccines based on in vivo DC-targeting.
Construction of TB vaccine, Antigen selection: M. tuberculosis genome encodes for more than 4000 genes. Antigens selected were tested with PBMCs from active or latent TB patients. IFNγ secretion was measured to identify antigens recognized (
Vaccine description: Vaccines are recombinant monoclonal antibodies recognizing specific receptors expressed at the surface of DCs. These recombinant mAb are then conjugated to selected antigens (fusion to the C terminus of the heavy chain or the light chain). The inventors selected four recombinant antibodies: αCD40, αDCIR, αLox-1 and αLangerin. These antibodies have been conjugated to the selected antigens Ag85BΔ41, ESAT6, Rv0288 and Rv1980Δ24 from M. tuberculosis (
Vaccine evaluation: Vaccine candidates were tested in targeting studies by incubating vaccines with peripheral blood mononuclear cells (PBMCs) from TB patients (latent or active) or by loading monocyte-derived DCs with the recombinant mAb follow by addition of T-lymphocytes. After 11 days of culture, the efficiency of each vaccine in eliciting an immune recall response was assessed by cytokines secretion (in the culture supernatant or following intracellular staining) as seen in
ESAT6 and CFP-10 were fused to IgG4, αCD40 and αDCIR and incubated with PBMCs from TB patients at different concentration (from 10 nM to 1 pM). Cells were cultivated for 8 days with addition of 100 U of IL-2 at day 2 and day 5. At day 8, cells were washed in DPBS and rested for 36 h. At day 9.5, cluster of peptides (10 μM each peptide) were used to stimulate cells for another 36 h. Supernatants were recovered and IFNγ secretion measured. IFNγ secretion is indicated in pg/ml.
The data presented hereinabove shows that both αCD40 and αDCIR vaccines bearing TB antigens can recall a potent memory antigen-specific T cell response in vitro resulting in IFNγ secretion. Specific immune responses were observed with low doses of vaccines, i.e., between 1 and 100 pM. Both constructs induced similar levels of IFNγ secretion in different patients.
Non-limiting examples different DC-specific antibodies or fragments (both nucleotide and protein sequences) that may be used in the preparation of the TB vaccine of the present invention are shown herein below:
CTGCAGAGTTCGTTAGGCGCCGGCGAATTCCCCACCAGCACCCCCGCCGACAGCAGCACCATC
TGGAATTTCGCGGGTATCGAGGCCGCGGCAAGCGCAATCCAGGGAAATGTCACGTCCATTCAT
ACGTCACTGGGATGTTCGCAAAGCTTGGCGGCGCGCCTACCAACGGCAGCATCACCGTGGCCG
QDDYNGWDINTPAFEWYYQSGLSIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSEL
PQWLSANRAVKPTGSAAIGLSMAGSSAMILAAYHPQQFIYAGSLSALLDPSQGMGPSLIGLAM
GDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVANNTRLWVYCGNGTPNELGGANIPAEFL
ENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQLNAMKGDLQSSLGAGEFPTS
WGGSGSEAYQGVQQKWDATATEL
NNALQNLARTISEAGQAMASTEGNVTGMFA
KLGGAPT
EF
QKSLENYIAQTRDKFLSAATSSTPREAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPT
TTYKAFDWDQAYRKPITYDTLWQADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQ
NFAVTNDGVIFFFNPGELLPEAAGPTQVLVPRSAIDSMLAKLGGAPTNGSITVAATAPTVTPTVN
AQWNQAMEDLVRAYHAMSSTHEANTMAMMARDTAEAAKWGGEFPTSTPADSSTITPTATPTATP
GLSIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSELPQWLSANRAVKPTGSAAIGLSMAGSSAMI
LAAYHPQQFIYAGSLSALLDPSQGMGPSLIGLAMGDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVA
NNTRLWVYCGNGTPNELGGANIPAEFLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQ
LNAMKGDLQSSLGAG
CAGAGCAGCAGTGGAATTTCGCGGGTATCGAGGCCGCGGCAAGCGCAATCCAGGGAAATGTC
CGACCGAAGGCAACGTCACTGGGATGTTCGCAAAGCTTGGCGGCGCGCCTACCAACGGCAGC
AQDDYNGWDINTPAFEWYYQSGLSIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSE
LPQWLSANRAVKPTGSAAIGLSMAGSSAMILAAYHPQQFIYAGSLSALLDPSQGMGPSLIGLA
MGDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVANNTRLWVYCGNGTPNELGGANIPAE
FLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQLNAMKGDLQSSLGAGEFP
WGGSGSEAYQGVQQKWDATATELNNALQNLARTISEAGQAMASTEGNVTGMFAKLGGAPTNGSI
AQTRDKFLSAATSSTPREAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPTTTYKAFDWDQAYRKP
ITYDTLWQADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQNFAVTNDGVIFFFNPGELLPEAA
GPTQVLVPRSAIDSMLAEF
GCGAATTCCCCACCAGCACCCCCGCCGACAGCAGCACCATCACCCCCACCGCCACCCCCACCG
CGGCCG
LENYIAQTRDKFLSAATSSTPREAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPTTTY
KAFDWDQAYRKPITYDTLWQADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQNFA
VTNDGVIFFFNPGELLPEAAGPTQVLVPRSAIDSMLAKLGGAPTNGSITVAATAPTVTPTVNATP
WNQAMEDLVRAYHAMSSTHEANTMAMMARDTAEAAKWGGEFPTSTPADSSTITPTATPTATPTI
SIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSELPQWLSANRAVKPTGSAAIGLSMAGSSAMILA
AYHPQQFIYAGSLSALLDPSQGMGPSLIGLAMGDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVANN
TRLWVYCGNGTPNELGGANIPAEFLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQLN
AMKGDLQSSLGAG
TGACCTGCAGAGTTCGTTAGGCGCCGGCGAATTCCCCACCAGCACCCCCGCCGACAGCAGCAC
GCAGTGGAATTTCGCGGGTATCGAGGCCGCGGCAAGCGCAATCCAGGGAAATGTCACGTCCAT
GGCAACGTCACTGGGATGTTCGCAAAGCTTGGCGGCGCGCCTACCAACGGCAGCATCACCGTG
AQDDYNGWDINTPAFEWYYQSGLSIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSE
LPQWLSANRAVKPTGSAAIGLSMAGSSAMILAAYHPQQFIYAGSLSALLDPSQGMGPSLIGLA
MGDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVANNTRLWVYCGNGTPNELGGANIPAE
FLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQLNAMKGDLQSSLGAGEFP
WGGSGSEAYQGVQQKWDATATELNNALQNLARTISEAGQAMASTEGNVTGMFAKLGGAPTNGSI
AQTRDKFLSAATSSTPREAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPTTTYKAFDWDQAYRKP
ITYDTLWQADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQNFAVTNVDGVIFFFNPGELLPEAA
GPTQVLVPRSAIDSMLAEF
LENYIAQTRDKFLSAATSSTPREAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPTTTY
KAFDWDQAYRKPITYDTLWQADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQNFA
VTNDGVIFFFNPGELLPEAAGPTQVLVPRSAIDSMLAKLGGAPTNGSITVAATAPTVTPTVNATP
WNQAMEDLVRAYHAMSSTHEANTMAMMARDTAEAAKWGGEFPTSTPADSSTITPTATPTATPTI
SIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSELPQWLSANRAVKPTGSAAIGLSMAGSSAMILA
AYHPQQFIYAGSLSALLDPSQGMGPSLIGLAMGDAGGYKAADMWGPSSDPAWERNDPTQQIPKLVANN
TRLWVYCGNGTPNELGGANIPAEFLENFVRSSNLKFQDAYNAAGGHNAVFNFPPNGTHSWEYWGAQLN
AMKGDLQSSLGAG
CTCGCGCAGGAGGCAGGTAATTTCGAGCGGATCTCCGGCGACCTGAAAACCCAGATCGACCAG
GTGGAGTCGACGGCAGGTTCGTTGCAGGGCCAGTGGCGCGGCGCGGCGGGGACGGCCGCCCA
GGCCGCGGTGGTGCGCTTCCAAGAAGCAGCCAATAAGCAGAAGCAGGAACTCGACGAGATCT
CGACGAATATTCGTCAGGCCGGCGTCCAATACTCGAGGGCCGACGAGGAGCAGCAGCAGGCG
CTGTCCTCGCAAATGGGCTTCGAATTCCCCACCAGCACCCCCGCCGACAGCAGCACCATCACC
CCCACCGCCACCCCCACCGCCACCCCCACCATCAAGGGCACTAGCATGACAGAGCAGCAGTGG
AATTTCGCGGGTATCGAGGCCGCGGCAAGCGCAATCCAGGGAAATGTCACGTCCATTCATTCC
CTCCTTGACGAGGGGAAGCAGTCCCTGACCAAGCTCGCAGCGGCCTGGGGCGGTAGCGGTTCG
GAGGCGTACCAGGGTGTCCAGCAAAAATGGGACGCCACGGCTACCGAGCTGAACAACGCGCT
GCAGAACCTGGCGCGGACGATCAGCGAAGCCGGTCAGGCAATGGCTTCGACCGAAGGCAACG
TCACTGGGATGTTCGCATAGGCGGCC
MKTDAATLAQEAGNFERISGDLKTQIDQVESTAGSLQGQWRGAAGTAAQAAVVRFQEAANK
QKQELDEISTNIRQAGVQYSRADEEQQQALSSQMGFEFPTSTPADSSTITPTATPTATPTIKGTSM
TEQQWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATEL
NNALQNLARTISEAGQAMASTEGNVTGMFA
CCGCTACCCTCGCGCAGGAGGCAGGTAATTTCGAGCGGATCTCCGGCGACCTGAAAACCCAGA
TCGACCAGGTGGAGTCGACGGCAGGTTCGTTGCAGGGCCAGTGGCGCGGCGCGGCGGGGACG
GCCGCCCAGGCCGCGGTGGTGCGCTTCCAAGAAGCAGCCAATAAGCAGAAGCAGGAACTCGA
CGAGATCTCGACGAATATTCGTCAGGCCGGCGTCCAATACTCGAGGGCCGACGAGGAGCAGC
AGCAGGCGCTGTCCTCGCAAATGGGCTTCGAATTCCCCACCAGCACCCCCGCCGACAGCAGCA
CCATCACCCCCACCGCCACCCCCACCGCCACCCCCACCATCAAGGGCACTAGCATGACAGAGC
AGCAGTGGAATTTCGCGGGTATCGAGGCCGCGGCAAGCGCAATCCAGGGAAATGTCACGTCC
ATTCATTCCCTCCTTGACGAGGGGAAGCAGTCCCTGACCAAGCTCGCAGCGGCCTGGGGCGGT
AGCGGTTCGGAGGCGTACCAGGGTGTCCAGCAAAAATGGGACGCCACGGCTACCGAGCTGAA
CAACGCGCTGCAGAACCTGGCGCGGACGATCAGCGAAGCCGGTCAGGCAATGGCTTCGACCG
AAGGCAACGTCACTGGGATGTTCGCATAGGCGGCC
TDAATLAQEAGNFERISGDLKTQIDQVESTAGSLQGQWRGAAGTAAQAAVVRFQEAANKQK
QELDEISTNIRQAGVQYSRADEEQQQALSSQMGFEFPTSTPADSSTITPTATPTATPTIKGTSMTE
QQWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATELNN
ALQNLARTISEAGQAMASTEGNVTGMFA
TDAATLAQEAGNFERISGDLKTQIDQVESTAGSLQGQWRGAAGTAAQAAVVRFQEAANKQK
QELDEISTNIRQAGVQYSRADEEQQQALSSQMGFEFPTSTPADSSTITPTATPTATPTIKGTSMTE
QQWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATELNN
ALQNLARTISEAGQAMASTEGNVTGMFA
RLEDEMKEGRYEVRAELPGVDPDKDVDIMVRDGQLTIKAERTEQKDFDGRSEFAYGSFVR
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCATGACCGGCCCCACCACCGACGCCGATGCCGCTGTCCCACG
MTGPTTDADAAVPRRVLIAEDEALIRMDLAEMLREEGYEIVGEAGDGQEAVELAELHKPDLV
IMDVKMPRRDGIDAASEIASKRIAPIVVLTAFSQRDLVERARDAGAMAYLVKPFSISDLIPAIEL
AVSRFREITALEGEVATLSERLETRKLVERAKGLLQTKHGMTEPDAFKWIQRAAMDRRTTM
KRVAEVVLETLGTPKDT
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGCGATCCACTGTTGCTGTCGCCGTAGCGGCAGCCGT
GATCGCAGCGTCCAGTGGTTGCGGCTCCGATCAACCGGCCCATAAGGCGTCACAATCGA
TGATCACGCCCACCACCCAGATCGCCGGCGCCGGGGTGCTGGGAAACGACAGAAAGCCG
GATGAGTCGTGCGCGCGTGCGGCGGCCGCGGCCGATCCGGGGCCACCGACCCGACCAG
CGCACAATGCGGCGGGAGTCAGCCCGGAGATGGTGCAGGTGCCGGCGGAGGCGCAGCG
CATCGTGGTGCTCTCCGGTGACCAGCTCGACGCGCTGTGCGCGCTGGGCCTGCAATCGC
GGATCGTCGCCGCCGCGTTGCCGAACAGCTCCTCAAGTCAACCTTCCTATCTGGGCACG
ACCGTGCATGATCTGCCCGGTGTCGGTACTCGCAGCGCCCCCGACCTGCGCGCCATTGC
GGCGGCTCACCCGGATCTGATCCTGGGTTCGCAGGGTTTGACGCCGCAGTTGTATCCGC
AGCTGGCGGCGATCGCCCCGACGGTGTTTACCGCGGCACCGGGCGCGGACTGGGAAAAT
AACCTGCGTGGTGTCGGTGCCGCCACGGCCCGTATCGCCGCGGTGGACGCGCTGATCAC
CGGGTTCGCCGAACACGCCACCCAGGTCGGGACCAAGCATGACGCGACCCACTTCCAAG
CGTCGATCGTGCAGCTGACCGCCAACACCATGCGGGTATACGGCGCCAACAACTTCCCG
GCCAGCGTGCTGAGCGCGGTCGGCGTCGACCGACCGCCGTCTCAACGGTTCACCGACAA
GGCCTACATCGAGATCGGCACCACGGCCGCCGACCTGGCGAAATCACCGGACTTCTCGG
CGGCCGACGCCGATATCGTCTACCTGTCGTGCGCGTCGGAAGCAGCCGCGGAACGCGCG
GCCGTCATCCTGGATAGCGACCCATGGCGCAAGCTGTCCGCCAACCGTGACAACCGGGT
CTTCGTCGTCAACGACCAGGTATGGCAGACCGGCGAGGGTATGGTCGCTGCCCGCGGCA
TTGTCGATGATCTGCGCTGGGTCGACGCGCCGATCAACTAGAAGCTTGCGGCCGCACTCG
MRSTVAVAVAAAVIAASSGCGSDQPAHKASQSMITPTTQIAGAGVLGNDRKPDESCARAAAA
ADPGPPTRPAHNAAGVSPEMVQVPAEAQRIVVLSGDQLDALCALGLQSRIVAAALPNSSSSQP
SYLGTTVHDLPGVGTRSAPDLRAIAAAHPDLILGSQGLTPQLYPQLAAIAPTVFTAAPGADWE
NNLRGVGAATARIAAVDALITGFAEHATQVGTKHDATHFQASIVQLTANTMRVYGANNFPAS
VLSAVGVDRPPSQRFTDKAYIEIGTTAADLAKSPDFSAADADIVYLSCASEAAAERAAVILDSD
PWRKLSANRDNRVFVVNDQVWQTGEGMVAARGIVDDLRWVDAPIN
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAG
ATGCAGCTAGCATGCAGCTTGTTGACAGGGTTCGTGGCGCCGTCACGGG
TATGTCGCGTCGACTCGTGGTCGGGGCCGTCGGCGCGGCCCTAGTGTCGGGTCTGGTCG
GCGCCGTCGGTGGCACGGCGACCGCGGGGGCATTTTCCCGGCCGGGCTTGCCGGTGGA
GTACCTGCAGGTGCCGTCGCCGTCGATGGGCCGTGACATCAAGGTCCAATTCCAAAGTG
GTGGTGCCAACTCGCCCGCCCTGTACCTGCTCGACGGCCTGCGCGCGCAGGACGACTTC
AGCGGCTGGGACATCAACACCCCGGCGTTCGAGTGGTACGACCAGTCGGGCCTGTCGGT
GGTCATGCCGGTGGGTGGCCAGTCAAGCTTCTACTCCGACTGGTACCAGCCCGCCTGCG
GCAAGGCCGGTTGCCAGACTTACAAGTGGGAGACCTTCCTGACCAGCGAGCTGCCGGGG
TGGCTGCAGGCCAACAGGCACGTCAAGCCCACCGGAAGCGCCGTCGTCGGTCTTTCGAT
GGCTGCTTCTTCGGCGCTGACGCTGGCGATCTATCACCCCCAGCAGTTCGTCTACGCGG
GAGCGATGTCGGGCCTGTTGGACCCCTCCCAGGCGATGGGTCCCACCCTGATCGGCCTG
GCGATGGGTGACGCTGGCGGCTACAAGGCCTCCGACATGTGGGGCCCGAAGGAGGACC
CGGCGTGGCAGCGCAACGACCCGCTGTTGAACGTCGGGAAGCTGATCGCCAACAACACC
CGCGTCTGGGTGTACTGCGGCAACGGCAAGCCGTCGGATCTGGGTGGCAACAACCTGCC
GGCCAAGTTCCTCGAGGGCTTCGTGCGGACCAGCAACATCAAGTTCCAAGACGCCTACA
ACGCCGGTGGCGGCCACAACGGCGTGTTCGACTTCCCGGACAGCGGTACGCACAGCTGG
GAGTACTGGGGCGCGCAGCTCAACGCTATGAAGCCCGACCTGCAACGGGCACTGGGTGC
CACGCCCAACACCGGGCCCGCGCCCCAGGGCGCCTAGGCGGCCGCACTCGAGCACCACCA
MQLVDRVRGAVTGMSRRLVVGAVGAALVSGLVGAVGGTATAGAFSRPGLPVEYLQVPSPSM
GRDIKVQFQSGGANSPALYLLDGLRAQDDFSGWDINTPAFEWYDQSGLSVVMPVGGQSSFYS
DWYQPACGKAGCQTYKWETFLTSELPGWLQANRHVKPTGSAVVGLSMAASSALTLAIYHPQ
QFVYAGAMSGLLDPSQAMGPTLIGLAMGDAGGYKASDMWGPKEDPAWQRNDPLLNVGKLI
ANNTRVWVYCGNGKPSDLGGNNLPAKFLEGFVRTSNIKFQDAYNAGGGHNGVFDFPDSGTH
SWEYWGAQLNAMKPDLQRALGATPNTGPAPQGA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC CAAGGGACG
ATTGGCGGCACTGGCTATCGCGGCGATGGCCAGCGCCAGCCTGGTGACCGTTGCGGTGC
CCGCGACCGCCAACGCCGATCCGGAGCCAGCGCCCCCGGTACCCACAACGGCCGCCTCG
CCGCCGTCGACCGCTGCAGCGCCACCCGCACCGGCGACACCTGTTGCCCCCCCACCACC
GGCCGCCGCCAACACGCCGAATGCCCAGCCGGGCGATCCCAACGCAGCACCTCCGCCGG
CCGACCCGAACGCACCGCCGCCACCTGTCATTGCCCCAAACGCACCCCAACCTGTCCGG
ATCGACAACCCGGTTGGAGGATTCAGCTTCGCGCTGCCTGCTGGCTGGGTGGAGTCTGA
CGCCGCCCACTTCGACTACGGTTCAGCACTCCTCAGCAAAACCACCGGGGACCCGCCAT
TTCCCGGACAGCCGCCGCCGGTGGCCAATGACACCCGTATCGTGCTCGGCCGGCTAGAC
CAAAAGCTTTACGCCAGCGCCGAAGCCACCGACTCCAAGGCCGCGGCCCGGTTGGGCTC
GGACATGGGTGAGTTCTATATGCCCTACCCGGGCACCCGGATCAACCAGGAAACCGTCT
CGCTCGACGCCAACGGGGTGTCTGGAAGCGCGTCGTATTACGAAGTCAAGTTCAGCGAT
CCGAGTAAGCCGAACGGCCAGATCTGGACGGGCGTAATCGGCTCGCCCGCGGCGAACGC
ACCGGACGCCGGGCCCCCTCAGCGCTGGTTTGTGGTATGGCTCGGGACCGCCAACAACC
CGGTGGACAAGGGCGCGGCCAAGGCGCTGGCCGAATCGATCCGGCCTTTGGTCGCCCCG
CCGCCGGCGCCGGCACCGGCTCCTGCAGAGCCCGCTCCGGCGCCGGCGCCGGCCGGGG
AAGTCGCTCCTACCCCGACGAC
ACCGACACCGCAGCGGACCTTACCGGCCGAATTCTGAG
CGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAG
MHQVDPNLTRRKGRLAALAIAAMASASLVTVAVPATANADPEPAPPVPTTAASPPSTAAAPPA
PATPVAPPPPAAANTPNAQPGDPNAAPPPADPNAPPPPVIAPNAPQPVRIDNPVGGFSFALPAG
WVESDAAHFDYGSALLSKTTGDPPFPGQPPPVANDTRIVLGRLDQKLYASAEATDSKAAARL
GSDMGEFYMPYPGTRINQETVSLDANGVSGSASYYEVKFSDPSKPNGQIWTGVIGSPAANAPD
AGPPQRWFVVWLGTANNPVDKGAAKALAESIRPLVAPPPAPAPAPAEPAPAPAPAGEVAPTP
TTPTPQRTLPA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGTGTGTCGTTCGTGGTCACAGTGCCGGAGGCCGTGGCGGCTGC
GGCGGGGGATTTGGCGGCCATCGGCTCGACGCTTCGGGAAGCGACCGCTGCGGCGGCGGGCC
CCACGACCGGGCTGGCGGCCGCGGCCGCCGACGACGTGTCGATCGCTGTCTCGCAGCTGTTCG
GCAGGTACGGCCAGGAATTTCAAACCGTGAGCAACCAACTGGCCGCGTTTCATACCGAGTTCG
TACGCACGTTGAACCGCGGCGCGGCGGCGTATCTCAACACCGAAAGCGCTAACGGCGGGCAG
CTGTTCGGTCAGATCGAGGCGGGACAGCGCGCCGTTTCCGCGGCCGCGGCCGCCGCTCCGGGC
GGCGCATACGGCCAACTCGTTGCCAACACGGCCACCAACCTGGAATCCCTCTACGGCGCATGG
TCGGCCAACCCGTTCCCATTCCTCCGCCAGATCATCGCCAACCAGCAGGTTTACTGGCAGCAG
ATCGCCGCGGCGCTCGCCAACGCCGTCCAGAACTTCCCCGCCCTGGTGGCGAATTTGCCAGCG
GCCATCGACGCGGCCGTCCAGCAATTCCTGGCCTTCAACGCGGCGTACTACATCCAACAGATT
ATTAGCTCGCAGATCGGCTTCGCCCAGCTATTCGCCACGACGGTCGGTCAGGGGGTCACCAGC
GTCATTGCCGGGTGGCCCAACCTTGCGGCGGAGCTTCAGCTAGCGTTTCAACAGCTTCTGGTGG
GTGACTACAACGCCGCGGTGGCGAACCTGGGTAAGGCCATGACAAACCTTCTGGTCACCGGGT
TCGACACCAGCGACGTGACGATCGGCACAATGGGCACCACCATTAGTGTCACCGCGAAACCCA
AGCTGCTGGGCCCGCTGGGAGATCTGTTCACCATCATGACCATCCCGGCACAAGAGGCGCAGT
ACTTCACCAACCTGATGCCCCCCTCCATCCTGCGAGAC
ATGTCGCAGAACTTCACCAACGTG
CTCACGACGCTCTCCAACCCGAACATCCAGGCGGTCGCTTCGTTCGATATCGCAACCACC
GCCGGGACTTTGAGCACCTTCTTCGGGGTGCCATTGGTGCTCACTTACGCCACATTGGGT
GCGCCGTTCGCGTCACTGAACGCGATTGCGACGAGCGCGGAAACCATCGAGCAGGCCCT
GTTGGCCGGCAACTACCTAGGGGCGGTGGGTGCGCTTATCGACGCCCCGGCCCACGCGT
TAGACGGCTTCCTCAACAGCGCAACCGTGTTGGATACGCCGATCCTGGTGCCCACGGGG
CTCCCGTCCCCTCTGCCCCCGACGGTCGGGATCACGCTGCACTTGCCTTTCGACGGGATT
CTCGTGCCGCCGCATCCCGTCACCGCGACGATCAGCTTCCCGGGTGCTCCGGTTCCTATT
CCCGGTTTCCCAACCACCGTAACCGTTTTCGGCACACCCTTCATGGGAATGGCTCCGCTG
CTGATCAACTACATTCCCCAACAGCTCGCCCTGGCAATCAAACCGGCGGCTTAGCTCGAG
VSFVVTVPEAVAAAAGDLAAIGSTLREATAAAAGPTTGLAAAAADDVSIAVSQLFGRYGQEFQ
TVSNQLAAFHTEFVRTLNRGAAAYLNTESANGGQLFGQIEAGQRAVSAAAAAAPGGAYGQL
VANTATNLESLYGAWSANPFPFLRQIIANQQVYWQQIAAALANAVQNFPALVANLPAAIDAA
VQQFLAFNAAYYIQQIISSQIGFAQLFATTVGQGVTSVIAGWPNLAAELQLAFQQLLVGDYNA
AVANLGKAMTNLLVTGFDTSDVTIGTMGTTISVTAKPKLLGPLGDLFTIMTIPAQEAQYFTNL
MPPSILRDMSQNFTNVLTTLSNPNIQAVASFDIATTAGTLSTFFGVPLVLTYATLGAPFASLNAI
ATSAETIEQALLAGNYLGAVGALIDAPAHALDGFLNSATVLDTPILVPTGLPSPLPPTVGITLH
LPFDGILVPPHPVTATISFPGAPVPIPGFPTTVTVFGTPFMGMAPLLINYIPQQLALAIKPAA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGGCTGAACCGTTGGCCGTCGATCCCACCGGCTTGAG
CGCAGCGGCCGCGAAATTGGCCGGCCTCGTTTTTCCGCAGCCTCCGGCGCCGATCGCGG
TCAGCGGAACGGATTCGGTGGTAGCAGCAATCAACGAGACCATGCCAAGCATCGAATCG
CTGGTCAGTGACGGGCTGCCCGGCGTGAAAGCCGCCCTGACTCGAACAGCATCCAACAT
GAACGCGGCGGCGGACGTCTATGCGAAGACCGATCAGTCACTGGGAACCAGTTTGAGCC
AGTATGCATTCGGCTCGTCGGGCGAAGGCCTGGCTGGCGTCGCCTCGGTCGGTGGTCAG
CCAAGTCAGGCTACCCAGCTGCTGAGCACACCCGTGTCACAGGTCACGACCCAGCTCGG
CGAGACGGCCGCTGAGCTGGCACCCCGTGTTGTTGCGACGGTGCCGCAACTCGTTCAGC
TGGCTCCGCACGCCGTTCAGATGTCGCAAAACGCATCCCCCATCGCTCAGACGATCAGTC
AAACCGCCCAACAGGCCGCCCAGAGCGCGCAGGGCGGCAGCGGCCCAATGCCCGCACA
GCTTGCCAGCGCTGAAAAACCGGCCACCGAGCAAGCGGAGCCGGTCCACGAAGTGACAA
ACGACGATCAGGGCGACCAGGGCGACGTGCAGCCGGCCGAGGTCGTTGCCGCGGCACG
TGACGAAGGCGCCGGCGCATCACCGGGCCAGCAGCCCGGCGGGGGCGTTCCCGCGCAA
GCCATGGATACCGGAGCCGGTGCCCGCCCAGCGGCGAGTCCGCTGGCGGCCCCCGTCG
ATCCGTCGACTCCGGCACCCTCAACAACCACAACGTTGGAATTCTAAAAGCTTGCGGCCGC
MAEPLAVDPTGLSAAAAKLAGLVFPQPPAPIAVSGTDSVVAAINETMPSIESLVSDGLPGVKAA
LTRTASNMNAAADVYAKTDQSLGTSLSQYAFGSSGEGLAGVASVGGQPSQATQLLSTPVSQV
TTQLGETAAELAPRVVATVPQLVQLAPHAVQMSQNASPIAQTISQTAQQAAQSAQGGSGPMP
AQLASAEKPATEQAEPVHEVTNDDQGDQGDVQPAEVVAAARDEGAGASPGQQPGGGVPAQ
AMDTGAGARPAASPLAAPVDPSTPAPSTTTTLEF
TCGGGTGCTCTACGACTTCGTGAACAATGAAGCCCTGCCTGGCACCGATATCGACCCGG
ACAGCTTCTGGGCGGGCGTCGACAAGGTCGTCGCCGACCTGACCCCGCAGAACCAAGCT
CTGTTGAACGCCCGCGACGAGCTGCAGGCGCAGATCGACAAGTGGCACCGGCGTCGGGT
GATCGAGCCCATCGACATGGATGCCTACCGCCAGTTCCTCACCGAGATCGGCTACCTGCT
TCCCGAACCTGATGACTTCACCATCACCACGTCCGGTGTCGACGCTGAGATCACCACGAC
CGCCGGCCCCCAGCTGGTGGTGCCGGTGCTCAACGCGCGGTTTGCTCTGAACGCGGCCA
ACGCTCGCTGGGGCTCCCTCTACGACGCCTTGTATGGCACCGATGTCATCCCCGAGACC
GACGGCGCCGAAAAAGGCCCCACGTACAACAAGGTTCGTGGCGACAAGGTGATCGCGTA
TGCCCGCAAGTTCCTCGACGACAGTGTTCCGCTGTCGTCGGGTTCCTTTGGCGACGCCAC
CGGTTTCACAGTGCAGGATGGCCAGCTCGTGGTTGCCTTGCCGGATAAGTCCACCGGCC
TGGCCAACCCCGGCCAGTTCGCCGGCTACACCGGCGCAGCCGAGTCGCCGACATCGGTG
CTGCTAATCAATCACGGTTTGCACATCGAGATCCTGATCGATCCGGAGTCGCAGGTCGGC
ACCACCGACCGGGCCGGCGTCAAGGACGTGATCCTGGAATCCGCGATCACCACGATCAT
GGACTTCGAGGACTCGGTGGCCGCCGTGGACGCCGCCGACAAGGTGCTGGGTTATCGGA
ACTGGCTCGGCCTGAACAAGGGCGACCTGGCAGCAGCGGTAGACAAGGACGGCACCGCT
TTCCTGCGGGTGCTCAATAGGGACCGGAACTACACCGCACCCGGCGGTGGCCAGTTCAC
GCTGCCTGGACGCAGCCTCATGTTCGTCCGCAACGTCGGTCACTTGATGACGAATGACG
CCATCGTCGACACTGACGGCAGCGAGGTGTTCGAAGGCATCATGGATGCCCTATTCACC
GGCCTGATCGCCATCCACGGGCTAAAGGCCAGCGACGTCAACGGGCCGCTGATCAACAG
CCGCACCGGCTCCATCTACATCGTCAAGCCGAAGATGCACGGTCCGGCCGAGGTGGCGT
TTACCTGCGAACTGTTCAGCCGGGTTGAAGATGTGCTGGGGTTGCCGCAAAACACCATG
AAGATCGGCATCATGGACGAGGAACGCCGGACCACGGTCAACCTCAAGGCGTGCATCAA
AGCTGCCGCGGACCGCGTGGTGTTCATCAACACCGGGTTCCTGGACCGCACCGGCGATG
AAATCCACACCTCGATGGAGGCCGGCCCGATGGTGCGCAAGGGCACCATGAAGAGCCAG
CCGTGGATCTTGGCCTACGAGGACCACAACGTCGATGCCGGCCTGGCCGCCGGGTTCAG
CGGCCGAGCCCAGGTCGGCAAGGGCATGTGGACAATGACCGAGCTGATGGCCGACATG
GTCGAGACAAAAATCGCCCAGCCGCGCGCCGGGGCCAGCACCGCCTGGGTTCCCTCTCC
CACTGCGGCCACCCTGCATGCGCTGCACTACCACCAGGTCGACGTCGCCGCGGTGCAAC
AAGGACTGGCGGGGAAGCGTCGCGCCACCATCGAACAATTGCTGACCATTCCGCTGGCC
AAGGAATTGGCCTGGGCTCCCGACGAGATCCGCGAAGAGGTCGACAACAACTGTCAATC
CATCCTCGGCTACGTGGTTCGCTGGGTTGATCAAGGTGTCGGCTGCTCGAAGGTGCCCG
ACATCCACGACGTCGCGCTCATGGAGGACCGGGCCACGCTGCGAATCTCCAGCCAATTG
TTGGCCAACTGGCTGCGCCACGGTGTGATCACCAGCGCGGATGTGCGGGCCAGCTTGGA
GCGGATGGCGCCGTTGGTCGATCGACAAAACGCGGGCGACGTGGCATACCGACCGATGG
CACCCAACTTCGACGACAGTATCGCCTTCCTGGCCGCGCAGGAGCTGATCTTGTCCGGG
GCCCAGCAGCCCAACGGCTACACCGAGCCGATCCTGCACCGACGTCGTCGGGAGTTTAA
GGCCCGGGCCGCTGAGAAGCCGGCCCCATCG
GACAGGGCCGGTGACGATGCGGCCCGC
MTDRVSVGNLRIARVLYDFVNNEALPGTDIDPDSFWAGVDKVVADLTPQNQALLNARDELQA
QIDKWHRRRVIEPIDMDAYRQFLTEIGYLLPEPDDFTITTSGVDAEITTTAGPQLVVPVLNARF
ALNAANARWGSLYDALYGTDVIPETDGAEKGPTYNKVRGDKVIAYARKFLDDSVPLSSGSFG
DATGFTVQDGQLVVALPDKSTGLANPGQFAGYTGAAESPTSVLLINHGLHIEILIDPESQVGTT
DRAGVKDVILESAITTIMDFEDSVAAVDAADKVLGYRNWLGLNKGDLAAAVDKDGTAFLRV
LNRDRNYTAPGGGQFTLPGRSLMFVRNVGHLMTNDAIVDTDGSEVFEGIMDALFTGLIAIHG
LKASDVNGPLINSRTGSIYIVKPKMHGPAEVAFTCELFSRVEDVLGLPQNTMKIGIMDEERRT
TVNLKACIKAAADRVVFINTGFLDRTGDEIHTSMEAGPMVRKGTMKSQPWILAYEDHNVDA
GLAAGFSGRAQVGKGMWTMTELMADMVETKIAQPRAGASTAWVPSPTAATLHALHYHQV
DVAAVQQGLAGKRRATIEQLLTIPLAKELAWAPDEIREEVDNNCQSILGYVVRWVDQGVGCS
KVPDIHDVALMEDRATLRISSQLLANWLRHGVITSADVRASLERMAPLVDRQNAGDVAYRP
MAPNFDDSIAFLAAQELILSGAQQPNGYTEPILHRRRREFKARAAEKPAPSDRAGDDAAR
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCGCGGAACCCACCGCCAAGGCCGCCCCATACGAGAACCTGAT
AEPTAKAAPYENLMVPSPSMGRDIPVAFLAGGPHAVYLLDAFNAGPDVSNWVTAGNAMNTL
AGKGISVVAPAGGAYSMYTNWEQDGSKQWDTFLSAELPDWLAANAIAAGMQQFGGVDTNG
MWGAPQLGRWKWHDPWVHASLLAQNNTRVWVWSPTNPGASDPAAMIGQAAEAMGNSRM
FYNQYRSVGGHNGHFDFPASGDNGWGSWAPQLGAMSGDIVGAIREF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCATGGCCACCACCCTTCCCGTTCAGCGCCACCCGCGGTCCCTC
MATTLPVQRHPRSLFPEFSELFAAFPSFAGLRPTFDTRLMRLEDEMKEGRYEVRAELPGVDP
DKDVDIMVRDGQLTIKAERTEQKDFDGRSEFAYGSFVRTVSLPVGADEDDIKATYDKGILTVS
VAVSEGKPTEKHIQIRSTN
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCATGAAGGTAAAGAACACAATTGCGGCAACCAGTTTCGCGGC
MKVKNTIAATSFAAAGLAALAVAVSPPAAAGDLVGPGCAEYAAANPTGPASVQGMSQDPVA
VAASNNPELTTLTAALSGQLNPQVNLVDTLNSGQYTVFAPTNAAFSKLPASTIDELKTNSSLLT
SILTYHVVAGQTSPANVVGTRQTLQGASVTVTGQGNSLKVGNADVVCGGVSTANATVYMIDS
VLMPPA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCATGAGCAATTCGCGCCGCCGCTCACTCAGGTGGTCATGGTT
MSNSRRRSLRWSWLLSVLAAVGLGLATAPAQAAPPALSQDRFADFPALPLDPSAMVAQVGPQ
VVNINTKLGYNNAVGAGTGIVIDPNGVVLTNNHVIAGATDINAFSVGSGQTYGVDVVGYDRT
QDVAVLQLRGAGGLPSAAIGGGVAVGEPVVAMGNSGGQGGTPRAVPGRVVALGQTVQASD
SLTGAEETLNGLIQFDAAIQPGDSGGPVVNGLGQVVGMNTAASDNFQLSQGGQGFAIPIGQA
MAIAGQIRSGGGSPTVHIGPTAFLGLGVVDNNGNGARVQRVVGSAPAASLGISTGDVITAVDG
APINSATAMADALNGHHPGDVISVTWQTKSGGTRTGNVTLAEGPPA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCGTGGGTGTCAGCTGGCCGGCGAAAGTCCGGCGCCGGGATG
GCGGGCCGCTCCTGCGAGTTCTGAGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGAT
VGVSWPAKVRRRDGTLVPFDIARIEAAVTRAAREVACDDPDMPGTVAKAVADALGRGIAPVE
DIQDCVEARLGEAGLDDVARVYIIYRQRRAELRTAKALLGVRDELKLSLAAVTVLRERYLLH
DEQGRPAESTGELMDRSARCVAAAEDQYEPGSSRRWAERFATLLRNLEFLPNSPTLMNSGTD
LGLLAGCFVLPIEDSLQSIFATLGQAAELQRAGGGTGYAFSHLRPAGDRVASTGGTASGPVSF
LRLYDSAAGVVSMGGRRRGACMAVLDVSHPDICDFVTAKAESPSELPHFNLSVGVTDAFLRA
VERNGLHRLVNPRTGKIVARMPAAELFDAICKAAHAGGDPGLVFLDTINRANPVPGRGRIEA
TNPCGEVPLLPYESCNLGSINLARMLADGRVDWDRLEEVAGVAVRFLDDVIDVSRYPFPELG
EAARATRKIGLGVMGLAELLAALGIPYDSEEAVRLATRLMRRIQQAAHTASRRLAEERGAFP
AFTDSRFARSGPRRNAQVTSVAPTGTISLIAGTTAGIEPMFAIAFTRAIVGRHLLEVNPCFDRL
ARDRGFYRDELIAEIAQRGGVRGYPRLPAEVRAAFPTAAEIAPQWHLRMQAAVQRHVEAAV
SKTVNLPATATVDDVRAIYVAAWKAKVKGITVYRYGSREGQVLSYAAPKPLLAQADTEFSGG
CAGRSCEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCGCCGCGCCCAAGACCTACTGCGAGGAGTTGAAAGGCACCG
CGATGCTGGCCGAATTCTAGGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGG
AAPKTYCEELKGTDTGQACQIQMSDPAYNINISLPSYYPDQKSLENYIAQTRDKFLSAATSSTP
REAPYELNITSATYQSAIPPRGTQAVVLKVYQNAGGTHPTTTYKAFDWDQAYRKPITYDTLW
QADTDPLPVVFPIVQGELSKQTGQQVSIAPNAGLDPVNYQNFAVTNDGVIFFFNPGELLPEAA
GPTQVLVPRSAIDSMLAEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCTGCAGCTGTATGGCTGAAAACTCGAACATTGATGACATCAA
GGCTCCGTTGCTTGCCGCGCTTGGAGCGGCCGACCTGGCCTTGGCCACTGTCAACGAGTTGATC
AAGTGCAGCTGTTAGGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCT
CSCMAENSNIDDIKAPLLAALGAADLALATVNELITNLRERAEETRTDTRSRVEESRARLTKL
QEDLPEQLTELREKFTAEELRKAAEGYLEAATSRYNELVERGEAALERLRSQQSFEEVSARA
EGYVDQAVELTQEALGTVASQTRAVGERAAKLVGIELPKKAAPAKKAAPAKKAAPAKKAAA
KKAPAKKAAAKKVTQKCSC
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCATGTCGCAAATCATGTACAACTACCCCGCGATGTTGGGTCA
GCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAA
MSQIMYNYPAMLGHAGDMAGYAGTLQSLGAEIAVEQAALQSAWQGDTGITYQAWQAQWN
QAMEDLVRAYHAMSSTHEANTMAMMARDTAEAAKWGG
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCTCCCGGCCGGGGCTGCCGGTCGAGTACCTGCAGGTGCCGTC
GCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGC
SRPGLPVEYLQVPSPSMGRDIKVQFQSGGNNSPAVYLLDGLRAQDDYNGWDINTPAFEWYYQ
SGLSIVMPVGGQSSFYSDWYSPACGKAGCQTYKWETFLTSELPQWLSANRAVKPTGSAAIGL
SMAGSSAMILAAYHPQQFIYAGSLSALLDPSQGMGPSLIGLAMGDAGGYKAADMWGPSSDPA
WERNDPTQQIPKLVANNTRLWVYCGNGTPNELGGANIPAEFLENFVRSSNLKCFQDAYNAAG
GHNAVFNFPPNGTHSWEYWGAQLNAMKGDLQSSLGAG
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGGCAGAGATGAAGACCGATGCCGCTACCCTCGCGCA
GGAGGCAGGTAATTTCGAGCGGATCTCCGGCGACCTGAAAACCCAGATCGACCAGGTGG
AGTCGACGGCAGGTTCGTTGCAGGGCCAGTGGCGCGGCGCGGCGGGGACGGCCGCCCA
GGCCGCGGTGGTGCGCTTCCAAGAAGCAGCCAATAAGCAGAAGCAGGAACTCGACGAGA
TCTCGACGAATATTCGTCAGGCCGGCGTCCAATACTCGAGGGCCGACGAGGAGCAGCAG
CAGGCGCTGTCCTCGCAAATGGGCTTCTGAGCGGCCGCACTCGAGCACCACCACCACCA
CCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTG
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANC
DFVYSYDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVA
KVKEGAPNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MAEMKTDAATLAQEAGNFERISGDLKTQIDQVESTAGSLQGQWRGAAGTAAQAAVVRFQE
AANKQKQELDEISTNIRQAGVQYSRADEEQQQALSSQMGF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGACAGAGCAGCAGTGGAATTTCGCGGGTATCGAGGC
CGCGGCAAGCGCAATCCAGGGAAATGTCACGTCCATTCATTCCCTCCTTGACGAGGGGA
AGCAGTCCCTGACCAAGCTCGCAGCGGCCTGGGGCGGTAGCGGTTCGGAGGCGTACCAG
GGTGTCCAGCAAAAATGGGACGCCACGGCTACCGAGCTGAACAACGCGCTGCAGAACCT
GGCGCGGACGATCAGCGAAGCCGGTCAGGCAATGGCTTCGACCGAAGGCAACGTCACTG
GGATGTTCGCATAGGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCT
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MTEQ
QWNFAGIEAAASAIQGNVTSIHSLLDEGKQSLTKLAAAWGGSGSEAYQGVQQKWDATATEL
NNALQNLARTISEAGQAMASTEGNVTGMFA
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
GTGGTGGATTTCGGGGCGTTACCACCGGAGATCAACTC
CGCGAGGATGTACGCCGGCCCGGGTTCGGCCTCGCTGGTGGCCGCCGCGAAGATGTGG
GACAGCGTGGCGAGTGACCTGTTTTCGGCCGCGTCGGCGTTTCAGTCGGTGGTCTGGGG
TCTGACGGTGGGGTCGTGGATAGGTTCGTCGGCGGGTCTGATGGCGGCGGCGGCCTCGC
CGTATGTGGCGTGGATGAGCGTCACCGCGGGGCAGGCCCAGCTGACCGCCGCCCAGGTC
CGGGTTGCTGCGGCGGCCTACGAGACAGCGTATAGGCTGACGGTGCCCCCGCCGGTGAT
CGCCGAGAACCGTACCGAACTGATGACGCTGACCGCGACCAACCTCTTGGGGCAAAACA
CGCCGGCGATCGAGGCCAATCAGGCCGCATACAGCCAGATGTGGGGCCAAGACGCGGA
GGCGATGTATGGCTACGCCGCCACGGCGGCGACGGCGACCGAGGCGTTGCTGCCGTTCG
AGGACGCCCCACTGATCACCAACCCCGGCGGGCTCCTTGAGCAGGCCGTCGCGGTCGAG
GAGGCCATCGACACCGCCGCGGCGAACCAGTTGATGAACAATGTGCCCCAAGCGCTGCA
ACAGCTGGCCCAGCCAGCGCAGGGCGTCGTACCTTCTTCCAAGCTGGGTGGGCTGTGGA
CGGCGGTCTCGCCGCATCTGTCGCCGCTCAGCAACGTCAGTTCGATAGCCAACAACCAC
ATGTCGATGATGGGCACGGGTGTGTCGATGACCAACACCTTGCACTCGATGTTGAAGGG
CTTAGCTCCGGCGGCGGCTCAGGCCGTGGAAACCGCGGCGGAAAACGGGGTCTGGGCG
ATGAGCTCGCTGGGCAGCCAGCTGGGTTCGTCGCTGGGTTCTTCGGGTCTGGGCGCTGG
GGTGGCCGCCAACTTGGGTCGGGCGGCCTCGGTCGGTTCGTTGTCGGTGCCGCCAGCAT
GGGCCGCGGCCAACCAGGCGGTCACCCCGGCGGCGCGGGCGCTGCCGCTGACCAGCCT
GACCAGCGCCGCCCAAACCGCCCCCGGACACATGCTGGGCGGGCTACCGCTGGGGCACT
CGGTCAACGCCGGCAGCGGTATCAACAATGCGCTGCGGGTGCCGGCACGGGCCTACGCG
ATACCCCGCACACCGGCCGCCGGATAGGCGGCCGCACTCGAGCACCACCACCACCACCACT
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
VVDF
GALPPEINSARMYAGPGSASLVAAAKMWDSVASDLFSAASAFQSVVWGLTVGSWIGSSAGLM
AAAASPYVAWMSVTAGQAQLTAAQVRVAAAAYETAYRLTVPPPVIAENRTELMTLTATNLL
GQNTPAIEANQAAYSQMWGQDAEAMYGYAATAATATEALLPFEDAPLITNPGGLLEQAVAV
EEAIDTAAANQLMNNVPQALQQLAQPAQGVVPSSKLGGLWTAVSPHLSPLSNVSSIANNHMS
MMGTGVSMTNTLHSMLKGLAPAAAQAVETAAENGVWAMSSLGSQLGSSLGSSGLGAGVAA
NLGRAASVGSLSVPPAWAAANQAVTPAARALPLTSLTSAAQTAPGHMLGGLPLGHSVNAGSG
INNALRVPARAYAIPRTPAAG
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
GTGAAAATTCGTTTGCATACGCTGTTGGCCGTGTTGACC
GCTGCGCCGCTGCTGCTAGCAGCGGCGGGCTGTGGCTCGAAACCACCGAGCGGTTCGCC
TGAAACGGGCGCCGGCGCCGGTACTGTCGCGACTACCCCCGCGTCGTCGCCGGTGACGT
TGGCGGAGACCGGTAGCACGCTGCTCTACCCGCTGTTCAACCTGTGGGGTCCGGCCTTT
CACGAGAGGTATCCGAACGTCACGATCACCGCTCAGGGCACCGGTTCTGGTGCCGGGAT
CGCGCAGGCCGCCGCCGGGACGGTCAACATTGGGGCCTCCGACGCCTATCTGTCGGAAG
GTGATATGGCCGCGCACAAGGGGCTGATGAACATCGCGCTAGCCATCTCCGCTCAGCAG
GTCAACTACAACCTGCCCGGAGTGAGCGAGCACCTCAAGCTGAACGGAAAAGTCCTGGC
GGCCATGTACCAGGGCACCATCAAAACCTGGGACGACCCGCAGATCGCTGCGCTCAACC
CCGGCGTGAACCTGCCCGGCACCGCGGTAGTTCCGCTGCACCGCTCCGACGGGTCCGGT
GACACCTTCTTGTTCACCCAGTACCTGTCCAAGCAAGATCCCGAGGGCTGGGGCAAGTC
GCCCGGCTTCGGCACCACCGTCGACTTCCCGGCGGTGCCGGGTGCGCTGGGTGAGAACG
GCAACGGCGGCATGGTGACGGTTGCGCCGAGACACCGGGCTGCGTGGCCTATATCGGCA
TCAGCTTCCTCGACCAGGCCAGTCAACGGGGACTCGGCGAGGCCCAACTAGGCAATAGC
TCTGGCAATTTCTTGTTGCCCGACGCGCAAAGCATTCAGGCCGCGGCGGCTGGCTTCGC
ATCGAAAACCCCGGCGAACCAGGCGATTTCGATGATCGACGGGCCCGCCCCGGACGGCT
ACCCGATCATCAACTACGAGTACGCCATCGTCAACAACCGGCAAAAGGACGCCGCCACC
GCGCAGACCTTGCAGGCATTTCTGCACTGGGCGATCACCGACGGCAACAAGGCCTCGTT
CCTCGACCAGGTTCATTTCCAGCCGCTGCCGCCCGCGGTGGTGAAGTTGTCTGACGCGT
TGATCGCGACGATTTCCAGCTAG
CGGCCGCACTCGAGCACCACCACCACCACCACTGAGAT
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
GCGS
KPPSGSPETGAGAGTVATTPASSPVTLAETGSTLLYPLFNLWGPAFHERYPNVTITAQGTGSG
AGIAQAAAGTVNIGASDAYLSEGDMAAHKGLMNIALAISAQQVNYNLPGVSEHLKLNGKVLA
AMYQGTIKTWDDPQIAALNPGVNLPGTAVVPLHRSDGSGDTFLFTQYLSKQDPEGWGKSPG
FGTTVDFPAVPGALGENGNGGMVTGCAETPGCVAYIGISFLDQASQRGLGEAQLGNSSGNFL
LPDAQSIQAAAAGFASKTPANQAISMIDGPAPDGYPIINYEYAIVNNRQKDAATAQTLQAFLH
WAITDGNKASFLDQVHFQPLPPAVVKLSDALIATISSEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGTATGAATTTCGCCGTTTTGCCGCCGGAGGTGAATTCGGCGCG
CATATTCGCCGGTGCGGGCCTGGGCCCAATGCTGGCGGCGGCGTCGGCCTGGGACGGGTTGGC
CGAGGAGTTGCATGCCGCGGCGGGCTCGTTCGCGTCGGTGACCACCGGGTTGGCGGGCGACGC
GTGGC
ATGGTCCGGCGTCGCTGGCGATGACCCGCGCGGCCAGCCCGTATGTGGGGTGGT
TGAACACGGCGGCGGGTCAGGCCGCGCAGGCGGCCGGCCAGGCGCGGCTAGCGGCGAG
CGCGTTCGAGGCGACGCTGGCGGCCACCGTGTCTCCAGCGATGGTCGCGGCCAACCGGA
CACGGCTGGCGTCGCTGGTGGCAGCCAACTTGCTGGGCCAGAACGCCCCGGCGATCGCG
GCCGCGGAGGCTGAATACGAGCAGATATGGGCCCAGGACGTGGCCGCGATGTTCGGCTA
TCACTCCGCCGCGTCGGCGGTGGCCACGCAGCTGGCGCCTATTCAAGAGGGTTTGCAGC
AGCAGCTGCAAAACGTGCTGGCCCAGTTGGCTAGCGGGAACCTGGGCAGCGGAAATGTG
GGCGTCGGCAACATCGGCAACGACAACATTGGCAACGCAAACATCGGCTTCGGAAATCG
AGGCGACGCCAACATCGGCATCGGGAATATCGGCGACAGAAACCTCGGCATTGGGAACA
CCGGCAATTGGAATATCGGCATCGGCATCACCGGCAACGGACAAATCGGCTTCGGCAAG
CCTGCCAACCCCGACGTCTTGGTGGTGGGCAACGGCGGCCCGGGAGTAACCGCGTTGGT
CATGGGCGGCACCGACAGCCTACTGCCGCTGCCCAACATCCCCTTACTCGAGTACGCTG
CGCGGTTCATCACCCCCGTGCATCCCGGATACACCGCTACGTTCCTGGAAACGCCATCGC
AGTTTTTCCCATTCACCGGGCTGAATAGCCTGACCTATGACGTCTCCGTGGCCCAGGGCG
TAACGAATCTGCACACCGCGATCATGGCGCAACTCGCGGCGGGAAACGAAGTCGTCGTC
TTCGGCACCTCCCAAAGCGCCACGATAGCCACCTTCGAAATGCGCTATCTGCAATCCCTG
CCAGCACACCTGCGTCCGGGTCTCGACGAATTGTCCTTTACGTTGACCGGCAATCCCAAC
CGGCCCGACGGTGGCATTCTTACGCGTTTTGGCTTCTCCATACCGCAGTTGGGTTTCACA
TTGTCCGGCGCGACGCCCGCCGACGCCTACCCCACCGTCGATTACGCGTTCCAGTACGA
CGGCGTCAACGACTTCCCCAAATACCCGCTGAATGTCTTCGCGACCGCCAACGCGATCG
CGGGCATCCTTTTCCTGCACTCCGGGTTGATTGCGTTGCCGCCCGATCTTGCCTCGGGCG
TGGTTCAACCGGTGTCCTCACCGGACGTCCTGACCACCTACATCCTGCTGCCCAGCCAAG
ATCTGCCGCTGCTGGTCCCGCTGCGTGCTATCCCCCTGCTGGGAAACCCGCTTGCCGAC
CTCATCCAGCCGGACTTGCGGGTGCTCGTCGAGTTGGGTTATGACCGCACCGCCCACCA
GGACGTGCCCAGCCCGTTCGGACTGTTTCCGGACGTCGATTGGGCCGAGGTGGCCGCGG
ACCTGCAGCAAGGCGCCGTGCAAGGCGTCAACGACGCCCTGTCCGGACTGGGGCTGCCG
CCGCCGTGGCAGCCGGCGCTACCCCGACTTTTCTAAAAGCTTGCGGCCGCACTCGAGCA
CCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTG
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MNFA
VLPPEVNSARIFAGAGLGPMLAAASAWDGLAEELHAAAGSFASVTTGLAGDAWHGPASLAM
TRAASPYVGWLNTAAGQAAQAAGQARLAASAFEATLAATVSPAMVAANRTRLASLVAANLL
GQNAPAIAAAEAEYEQIWAQDVAAMFGYHSAASAVATQLAPIQEGLQQQLQNVLAQLASGN
LGSGNVGVGNIGNDNIGNANIGFGNRGDANIGIGNIGDRNLGIGNTGNWNIGIGITGNGQIGFG
KPANPDVLVVGNGGPGVTALVMGGTDSLLPLPNIPLLEYAARFITPVHPGYTATFLETPSQFF
PFTGLNSLTYDVSVAQGVTNLHTAIMAQLAAGNEVVVFGTSQSATIATFEMRYLQSLPAHLRP
GLDELSFTLTGNPNRPDGGILTRFGFSIPQLGFTLSGATPADAYPTVDYAFQYDGVNDFPKYPL
NVFATANAIAGILFLHSGLIALPPDLASGVVQPVSSPDVLTTYILLPSQDLPLLVPLRAIPLLGNP
LADLIQPDLRVLVELGYDRTAHQDVPSPFGLFPDVDWAEVAADLQQGAVQGVNDALSGLGL
PPPWQPALPRLF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGGCATCGGGTAGCGGTCTTTGCAAGACGACGAGTAA
CTTTATTTGGGGCCAGTTACTCTTGCTTGGAGAGGGAATCCCCGACCCAGGCGACATTTT
CAACACCGGTTCGTCGCTGTTCAAACAAATCAGCGACAAAATGGGACTCGCCATTCCGG
GCACCAACTGGATCGGCCAAGCGGCGGAAGCTTACCTAAACCAGAACATCGCGCAACAA
CTTCGCGCACAGGTGATGGGCGATCTCGACAAATTAACCGGCAACATGATCTCGAATCA
GGCCAAATACGTCTCCGATACGCGCGACGTCCTGCGGGCCATGAAGAAGATGATTGACG
GTGTCTACAAGGTTTGTAAGGGCCTCGAAAAGATTCCGCTGCTCGGCCACTTGTGGTCGT
GGGAGCTCGCAATCCCTATGTCCGGCATCGCGATGGCCGTTGTCGGCGGCGCATTGCTC
TATCTAACGATTATGACGCTGATGAATGCGACCAACCTGAGGGGAATTCTCGGCAGGCT
GATCGAGATGTTGACGACCTTGCCAAAGTTCCCCGGCCTGCCCGGGTTGCCCAGCCTGC
CCGACATCATCGACGGCCTCTGGCCGCCGAAGTTGCCCGACATTCCGATCCCCGGCCTG
CCCGACATCCCGGGCCTACCCGACTTCAAATGGCCGCCCACCCCCGGCAGCCCGTTGTT
CCCCGACCTCCCGTCGTTCCCAGGGTTCCCCGGGTTCCCGGAGTTCCCCGCCATCCCCG
GGTTCCCCGCACTGCCCGGGTTGCCCAGCATTCCCAACTTGTTCCCCGGCTTGCCGGGTC
TGGGCGACCTGCTGCCCGGCGTAGGCGATTTGGGCAAGTTACCCACCTGGACTGAGCTG
GCCGCTTTGCCTGACTTCTTGGGCGGCTTCGCCGGCCTGCCCAGCTTGGGTTTTGGCAAT
CTGCTCAGCTTTGCCAGTTTGCCCACCGTGGGTCAGGTGACCGCCACCATGGGTCAGCT
GCAACAGCTCGTGGCGGCCGGCGGTGGCCCCAGCCAACTGGCCAGCATGGGCAGCCAA
CAAGCGCAACTGATCTCGTCGCAGGCCCAGCAAGGAGGCCAGCAGCACGCCACCCTCGT
GAGCGACAAGAAGGAAGACGAGGAAGGCGTGGCCGAGGCGGAGCGTGCACCCATCGAC
GCTGGCACCGCGGCCAGCCAACGGGGGCAGGAGGGGACCGTCCTTTGACTCGAGTAAGC
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MASG
SGLCKTTSNFIWGQLLLLGEGIPDPGDIFNTGSSLFKQISDKMGLAIPGTNWIGQAAEAYLNQ
NIAQQLRAQVMGDLDKLTGNMISNQAKYVSDTRDVLRAMKKMIDGVYKVCKGLEKIPLLG
HLWSWELAIPMSGIAMAVVGGALLYLTIMTLMNATNLRGILGRLIEMLTTLPKFPGLPGLPS
LPDIIDGLWPPKLPDIPIPGLPDIPGLPDFKWPPTPGSPLFPDLPSFPGFPGFPEFPAIPGFPALPG
LPSIPNLFPGLPGLGDLLPGVGDLGKLPTWTELAALPDFLGGFAGLPSLGFGNLLSFASLPTV
GQVTATMGQLQQLVAAGGGPSQLASMGSQQAQLISSQAQQGGQQHATLVSDKKEDEEGVA
EAERAPIDAGTAASQRGQEGTVLLE
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC AGCAAGAGAT
TTTGAACAGGGCCAACGAGGTGGAGGCCCCGATGGCGGACCCACCGACTGATGTCCCCA
TCACACCGTGCGAACTCACGGCGGCTAAAAACGCCGCCCAACAGCTGGTATTGTCCGCC
GACAACATGCGGGAATACCTGGCGGCCGGTGCCAAAGAGCGGCAGCGTCTGGCGACCTC
GCTGCGCAACGCGGCCAAGGCGTATGGCGAGGTTGATGAGGAGGCTGCGACCGCGCTG
GACAACGACGGCGAAGGAACTGTGCAGGCAGAATCGGCCGGGGCCGTCGGAGGGGACA
GTTCGGCCGAACTAACCGATACGCCGAGGGTGGCCACGGCCGGTGAACCCAACTTCATG
GATCTCAAAGAAGCGGCAAGGAAGCTCGAAACGGGCGACCAAGGCGCATCGCTCGCGCA
CTTTGCGGATGGGTGGAACACTTTCAACCTGACGCTGCAAGGCGACGTCAAGCGGTTCC
GGGGGTTTGACAACTGGGAAGGCGATGCGGCTACCGCTTGCGAGGCTTCGCTCGATCAA
CAACGGCAATGGATACTCCACATGGCCAAATTGAGCGCTGCGATGGCCAAGCAGGCTCA
ATATGTCGCGCAGCTGCACGTGTGGGCTAGGCGGGAACATCCGACTTATGAAGACATAG
TCGGGCTCGAACGGCTTTACGCGGAAAACCCTTCGGCCCGCGACCAAATTCTCCCGGTG
TACGCGGAGTATCAGCAGAGGTCGGAGAAGGTGCTGACCGAATACAACAACAAGGCAGC
CCTGGAACCGGTAAACCCGCCGAAGCCTCCCCCCGCCATCAAGATCGACCCGCCCCCGC
CTCCGCAAGAGCAGGGATTGATCCCTGGCTTCCTGATGCCGCCGTCTGACGGCTCCGGT
GTGACTCCCGGTACCGGGATGCCAGCCGCACCGATGGTTCCGCCTACCGGATCGCCGGG
TGGTGGCCTCCCGGCTGACACGGCGGCGCAGCTGACGTCGGCTGGGCGGGAAGCCGCA
GCGCTGTCGGGCGACGTGGCGGTCAAAGCGGCATCGCTCGGTGGCGGTGGAGGCGGCG
GGGTGCCGTCGGCGCCGTTGGGATCCGCGATCGGGGGCGCCGAATCGGTGCGGCCCGC
TGGCGCTGGTGACATTGCCGGCTTAGGCCAGGGAAGGGCCGGCGGCGGCGCCGCGCTG
GGCGGCGGTGGCATGGGAATGCCGATGGGTGCCGCGCATCAGGGACAAGGGGGCGCCA
AGTCCAAGGGTTCTCAGCAGGAAGACGAGGCGCTCTACACCGAGGATCGGGCATGGACC
GAGGCCGTCATTGGTAAC GAATTCTGAGCGGCC
GCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCT
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MTQS
QTVTVDQQEILNRANEVEAPMADPPTDVPITPCELTAAKNAAQQLVLSADNMREYLAAGAKE
RQRLATSLRNAAKAYGEVDEEAATALDNDGEGTVQAESAGAVGGDSSAELTDTPRVATAGE
PNFMDLKEAARKLETGDQGASLAHFADGWNTFNLTLQGDVKRFRGFDNWEGDAATACEAS
LDQQRQWILHMAKLSAAMAKQAQYVAQLHVWARREHPTYEDIVGLERLYAENPSARDQILP
VYAEYQQRSEKVLTEYNNKAALEPVNPPKPPPAIKIDPPPPPQEQGLIPGFLMPPSDGSGVTPG
TGMPAAPMVPPTGSPGGGLPADTAAQLTSAGREAAALSGDVAVKAASLGGGGGGGVPSAPL
GSAIGGAESVRPAGAGDIAGLGQGRAGGGAALGGGGMGMPMGAAHQGQGGAKSKGSQQE
DEALYTEDRAWTEAVIGNRRRQDSKESK
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGT
GTGATAGCGGGCGTCGACCAGGCGCTTGCAGCAACAGG
CCAGGCTAGCCAGCGGGCGGCAGGCGCATCTGGTGGGGTCACCGTCGGTGTCGGCGTG
GGCACGGAACAGAGGAACCTTTCGGTGGTTGCACCGAGTCAGTTCACATTTAGTTCACG
CAGCCCAGATTTTGTGGATGAAACCGCAGGTCAATCGTGGTGCGCGATACTGGGATTGA
ACCAGTTTCACGAATTCTAGGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCG
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
VIAGV
DQALAATGQASQRAAGASGGVTVGVGVGTEQRNLSVVAPSQFTFSSRSPDFVDETAGQSWCA
ILGLNQFHEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
AAACCCGTGTCGCAAGACACCAGCCCGAAACCGGCGAC
CAGCCCGGCGGCGCCCGTTACCACGGCGGCAATGGCTGACCCCGCAGCGGACCTGATTG
GTCGTGGGTGCGCGCAATACGCGGCGCAAAATCCCACCGGTCCCGGATCGGTGGCCGGA
ATGGCGCAAGACCCGGTCGCTACCGCGGCTTCCAACAACCCGATGCTCAGTACCCTGAC
CTCGGCTCTGTCGGGCAAGCTGAACCCGGATGTGAATCTGGTCGACACCCTCAACGGCG
GCGAGTACACCGTTTTCGCCCCCACCAACGCCGCATTCGACAAGCTGCCGGCGGCCACT
ATCGATCAACTCAAGACTGACGCCAAGCTGCTCAGCAGCATCCTGACCTACCACGTGATA
GCCGGCCAGGCGAGTCCGAGCAGGATCGACGGCACCCATCAGACCCTGCAAGGTGCCGA
CCTGACGGTGATAGGCGCCCGCGACGACCTCATGGTCAACAACGCCGGTTTGGTATGTG
GCGGAGTTCACACCGCCAACGCGACGGTGTACATGATCGATACGGTGCTGATGCCCCCG
GCACAGGAATTCTAAGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCT
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
KPVSQ
DTSPKPATSPAAPVTTAAMADPAADLIGRGCAQYAAQNPTGPGSVAGMAQDPVATAASNNP
MLSTLTSALSGKLNPDVNLVDTLNGGEYTVFAPTNAAFDKLPAATIDQLKTDAKLLSSILTYH
VIAGQASPSRIDGTHQTLQGADLTVIGARDDLMVNNAGLVCGGVHTANATVYMIDTVLMPP
AQEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC AGCCCAACGC
ACCCGTTGCCCTGGTGACGGTGGAAATCCGTCACCCGACAACGGATTCGCTCACCGAAT
CAGCGAACCGGGAGCTCAAACACCTGCTTATCAATGATCTACCGATCGAACGCCAGGCG
CAGGACGTCAGCTGGGGGATGACGGCGCCCGGTGGAGCCCCCACCCCGGTCGCGGATC
GTTTCGTTCGTTATGTCAATCGCGATAACACCACCGCCGCTTCACTGAAGAACCAGGCGA
TAGTCGTGGAGACCACCGCCTACCGCAGCTTTGAGGCCTTTACCGACGTTGTGATGCGG
GTCGTGGATGCTCGCGCGCAGGTCTCGTCAATCGTTGGGTTGGAGCGTATCGGTCTTCG
CTTTGTTCTGGAGATCCGCGTCCCCGCGGGTGTCGACGGCCGGATCACGTGGAGCAACT
GGATCGACGAGCAGCTGCTCGGGCCGCAGCGTTTCACTCCCGGCGGCCTGGTCCTGACC
GAGTGGCAGGGTGCCGCAGTCTACCGTGAGCTACAACCAGGCAAATCGCTCATCGTGCG
CTACGGCCCGGGTATGGGCCAAGCGCTTGATCCCAATTACCATCTGCGCCGAATAACAC
CCGCCCAAACCGGACCATTCTTCCTGCTGGACATCGATAGCTTTTGGACTCCCAGTGGCG
GCTCCATTCCCGAGTACAACAGGGACGCCTTAGTGTCGACATTCCAGGACCTGTACGGTC
CGGCCCAGGTCGTGTTTCAGGAGATGAT
GAATTCTAAGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAG
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MLPE
TNQDEVQPNAPVALVTVEIRHPTTDSLTESANRELKHLLINDLPIERQAQDVSWGMTAPGGAP
TPVADRFVRYVNRDNTTAASLKNQAIVVETTAYRSFEAFTDVVMRVVDARAQVSSIVGLERIG
LRFVLEIRVPAGVDGRITWSNWIDEQLLGPQRFTPGGLVLTEWQGAAVYRELQPGKSLIVRY
GPGMGQALDPNYHLRRITPAQTGPFFLLDIDSFWTPSGGSIPEYNRDALVSTFQDLYGPAQVV
FQEMITSRLKDELLRQ
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC
ATGAGCGACCCGGTCAGCTATACCCGCAAGGATTCCATC
GCCGTCATCAGTATGGACGACGGCAAGGTCAACGCACTGGGCCCGGCGATGCAACAAGC
CCTCAATGCAGCGATCGACAACGCGGACCGTGATGATGTTGGGGCGCTGGTGATCACCG
GTAATGGCCGGGTATTCAGCGGAGGCTTCGACCTGAAGATCCTCACCTCCGGTGAAGTG
CAGCCCGCGATCGACATGCTCAGGGGCGGCTTCGAGCTGGCGTATCGCCTCTTGTCCTA
CCCCAAACCGGTGGTGATGGCGTGCACCGGTCACGCCATCGCCATGGGCGCGTTTCTGT
TGTCCTGCGGCGATCATCGGGTGGCGGCCCACGCATACAACATCCAGGCCAATGAGGTC
GCGATCGGCATGACCATTCCGTACGCGGCGTTAGAGATCATGAAGCTGCGACTGACCCG
GTCGGCATACCAGCAGGCAACCGGGCTGGCCAAGACGTTCTTCGGGGAAACCGCGCTGG
CCGCCGGGTTTATCGACGAGATCGCCCTGCCGGAGGTGGTGGTCAGCCGCGCCGAGGAA
GCCGCACGAGAGTTCGCCGGTCTCAACCAACACGCCCATGCCGCGACCAAGTTGCGCTC
CCGCGCCGACGCGCTCACTGCGATTCGGGCCGGGATCGACGGGATAGCAGCCGAGTTCG
GGCTG
GAATTCTAAGCGGCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTA
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MSDP
VSYTRKDSIAVISMDDGKVNALGPAMQQALNAAIDNADRDDVGALVITGNGRVFSGGFDLKI
LTSGEVQPAIDMLRGGFELAYRLLSYPKPVVMACTGHAIAMGAFLLSCGDHRVAAHAYNIQA
NEVAIGMTIPYAALEIMKLRLTRSAYQQATGLAKTFFGETALAAGFIDEIALPEVVVSRAEEA
AREFAGLNQHAHAATKLRSRADALTAIRAGIDGIAAEFGLEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGCTGCAGCTGT
CGCAGCGACAACCCTGCCGCGCCGGCTGGCTATCGCGGCTATGGGGGCTGTCCTGGT
TTACGGTCTGGTCGGTACCTTCGGCGGGCCGGCCACCGCGGGCGCATTCTCTAGGCCCG
GTCTTCCAGTGGAATATCTGCAGGTGCCATCCGCGTCGATGGGCCGCGACATCAAGGTC
CAGTTCCAGGGCGGCGGACCGCACGCGGTCTACCTGCTCGACGGTCTGCGGGCCCAGGA
TGACTACAACGGCTGGGACATCAACACCCCGGCCTTCGAGGAGTACTACCAGTCAGGGT
TGTCGGTGATCATGCCCGTGGGCGGCCAATCCAGTTTCTACACCGACTGGTATCAGCCCT
CGCAGAGCAACGGCCAGAACTACACCTACAAGTGGGAGACCTTCCTTACCAGAGAGATG
CCCGCCTGGCTACAGGCCAACAAGGGCGTGTCCCCGACAGGCAACGCGGCGGTGGGTCT
TTCGATGTCGGGCGGTTCCGCGCTGATCCTGGCCGCGTACTACCCGCAGCAGTTCCCGT
ACGCCGCGTCGTTGTCGGGCTTCCTCAACCCGTCCGAGGGCTGGTGGCCGACGCTGATC
GGCCTGGCGATGAACGACTCGGGCGGTTACAACGCCAACAGCATGTGGGGTCCGTCCAG
CGACCCGGCCTGGAAGCGCAACGACCCAATGGTTCAGATTCCCCGCCTGGTCGCCAACA
ACACCCGGATCTGGGTGTACTGCGGTAACGGCACACCCAGCGACCTCGGCGGCGACAAC
ATACCGGCGAAGTTCCTGGAAGGCCTCACCCTGCGCACCAACCAGACCTTCCGGGACAC
CTACGCGGCCGACGGTGGACGCAACGGGGTGTTTAACTTCCCGCCCAACGGAACACACT
CGTGGCCCTACTGGAACGAGCAGCTGGTCGCCATGAAGGCCGATATCCAGCATGTGCTC
AACGGCGCG GCAGCTGTTGAGCGGCCGCA
CTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAG
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAASCSC
MT
FFEQVRRLRSAATTLPRRLAIAAMGAVLVYGLVGTFGGPATAGAFSRPGLPVEYLQVPSASM
GRDIKVQFQGGGPHAVYLLDGLRAQDDYNGWDINTPAFEEYYQSGLSVIMPVGGQSSFYTD
WYQPSQSNGQNYTYKWETFLTREMPAWLQANKGVSPTGNAAVGLSMSGGSALILAAYYPQ
QFPYAASLSGFLNPSEGWWPTLIGLAMNDSGGYNANSMWGPSSDPAWKRNDPMVQIPRLVA
NNTRIWVYCGNGTPSDLGGDNIPAKFLEGLTLRTNQTFRDTYAADGGRNGVFNFPPNGTHSW
PYWNEQLVAMKADIQHVLNGATPPAAPAAPAACSC
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC TGCAACTGCGA
CGACGAACCGGGAGCGCTCATCATCGCCTGGATCGACGACGAACGACCCGCCGGCGGGC
ACATACAGATGCGGTCGAACACCCGCTTCACCGAAACACAGTGGGGCCGCCATATCGAG
TGGAAACTCGAATGCCGGGCATGCCGAAAGTATGCGCCGATATCCGAGATGACCGCCGC
GGCGATCCTCGACGGTTTCGGGGCGAAGCTTCACGAGCTGAGAACGTCGACCATCCCCG
ACGCTGACGATCCATCAATAGCAGAGGCGCGACACGTAATTCCGTTCAGC
GAATTCTAAGCGGCCGCACTCGAGCACCACCACCACCACCAC
TGAGATCCGGCTGCTAACAAAGCCCGAAAGGAAGCTGAGTTGGCTGCTGCCACCGCTGAGCAA
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MADA
VKYVVMCNCDDEPGALIIAWIDDERPAGGHIQMRSNTRFTETQWGRHIEWKLECRACRKYA
PISEMTAAAILDGFGAKLHELRTSTIPDADDPSIAEARHVIPFSALCLRLSQLGGEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC AATTCGGTCG
CATCCGACAGTTCAACTCCGGCCGCTGGCAAGCCAGCTACACCGGCCCCGACGGCCGCG
TGTACATCGCCCCCAAAACCTTCAACGCCAAGATCGACGCCGAAGCATGGCTCACCGAC
CGCCGCCGCGAAATCGACCGACAACTATGGTCCCCGGCATCGGGTCAGGAAGACCGCCC
CGGAGCCCCATTCGGTGAGTACGCCGAAGGATGGCTGAAGCAGCGTGGAATCAAGGACC
GCACCCGCGCCCACTATCGCAAACTGCTGGACAACCACATCCTGGCCACCTTCGCTGACA
CCGACCTACGCGACATCACCCCGGCCGCCGTGCGCCGCTGGTACGCCACCACCGCCGTG
GGCACACCGACCATGCGGGCACACTCCTACAGCTTGCTGCGCGCAATCATGCAGACCGC
CTTGGCCGACGACCTGATCGACTCCAACCCCTGCCGCATCTCAGGCGCGTCCACCGCCC
GCCGCGTCCACAAGATCAGGCCCGCCACCCTCGACGAGCTGGAAACCATCACCAAAGCC
ATGCCCGACCCCTACCAGGCGTTCGTGCTGATGGCGGCATGGCTGGCCATGCGCTACGG
CGAGCTGACCGAATTACGCCGCAAAGACATCGACCTGCACGGCGAGGTTGCGCGGGTGC
GGCGGGCTGTCGTTCGGGTGGGCGAAGGCTTCAAGGTGACGACACCGAAAAGCGATGC
GGGAGTGCGCGACATAAGTATCCCGCCACATCTGATACCCGCCATCGAAGACCACCTTC
ACAAACACGTCAACCCCGGCCGGGAGTCCCTGCTGTTCCCATCGGTCAACGACCCCAAC
CGTCACCTAGCACCCTCGGCGCTGTACCGCATGTTCTACAAGGCCCGAAAAGCCGCCGG
CCGACCAGACTTACGGGTGCACGACCTTCGACACTCCGGCGCCGTGTTGGCTGCATCCA
CCGGCGCCACACTGGCCGAACTGATGCAGCGGCTAGGACACAGCACAGCCGGCGCCGCA
CTCCGCTACCAGCACGCCGCCAAGGGCCGGGACCGCGAAATCGCCGCACTGTTAAGCAA
ACTGGCCGAGAACCAGGAGATGGAATTCTAAGCGGCCGCACTCGAGCACCACCACCACCAC
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
VTQT
GKRQRRKFGRIRQFNSGRWQASYTGPDGRVYIAPKTFNAKIDAEAWLTDRRREIDRQLWSPA
SGQEDRPGAPFGEYAEGWLKQRGIKDRTRAHYRKLLDNHILATFADTDLRDITPAAVRRWY
ATTAVGTPTMRAHSYSLLRAIMQTALADDLIDSNPCRISGASTARRVHKIRPATLDELETITKA
MPDPYQAFVLMAAWLAMRYGELTELRRKDIDLHGEVARVRRAVVRVGEGFKVTTPKSDAG
VRDISIPPHLIPAIEDHLHKHVNPGRESLLFPSVNDPNRHLAPSALYRMFYKARKAAGRPDLRV
HDLRHSGAVLAASTGATLAELMQRLGHSTAGAALRYQHAAKGRDREIAALLSKLAENQEMEF
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGT CCGAACTG
GGTCGACCTTCAGACCACCGATCAGTCCGCCGCCAAAAAGTTCTACACATCGTTGTTCGG
CTGGGGTTACGACGACAACCCGGTCCCCGGAGGCGGTGGGGTCTATTCCATGGCCACGC
TGAACGGCGAAGCCGTGGCCGCCATCGCACCGATGCCCCCGGGTGCACCGGAGGGGAT
GCCGCCGATCTGGAACACCTATATCGCGGTGGACGACGTCGATGCGGTGGTGGACAAGG
TGGTGCCCGGGGGCGGGCAGGTGATGATGCCGGCCTTCGACATCGGCGATGCCGGCCG
GATGTCGTTCATCACCGATCCGACCGGCGCTGCCGTGGGCCTATGGCAGGCCAATCGGC
ACATCGGAGCGACGTTGGTCAACGAGACGGGCACGCTCATCTGGAACGAACTGCTCACG
GACAAGCCGGATTTGGCGCTAGCGTTCTACGAGGCTGTGGTTGGCCTCACCCACTCGAG
CATGGAGATAGCTGCGGGCCAGAACTATCGGGTGCTCAAGGCCGGCGACGCGGAAGTCG
GCGGCTGTATGGAACCGCCGATGCCCGGCGTGCCGAATCATTGGCACGTCTACTTTGCG
GTGGATGACGCCGACGCCACGGCGGCCAAAGCCGCCGCAGCGGGCGGCCAGGTCATTG
CGGAACCGGCTGACATTCCGTCGGTGGGCCGGTTCGCCGTGTTGTCCGATCCGCAGGGC
GCG GCGGCCGCACTCGAGCACCACCACC
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MPKR
SEYRQGTPNWVDLQTTDQSAAKKFYTSLFGWGYDDNPVPGGGGVYSMATLNGEAVAAIAP
MPPGAPEGMPPIWNTYIAVDDVDAVVDKVVPGGGQVMMPAFDIGDAGRMSFITDPTGAAVG
LWQANRHIGATLVNETGTLIWNELLTDKPDLALAFYEAVVGLTHSSMEIAAGQNYRVLKAG
DAEVGGCMEPPMPGVPNHWHVYFAVDDADATAAKAAAAGGQVIAEPADIPSVGRFAVLSDP
QGAIFSVLKPAPQQ
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC GGGTGGGCA
GGGATTCGCCATTCCGATCGGGCAGGCGATGGCGATCGCGGGCCAGATCCGATCGGGTG
GGGGGTCACCCACCGTTCATATCGGGCCTACCGCCTTCCTCGGCTTGGGTGTTGTCGAC
AACAACGGCAACGGCGCACGAGTCCAACGCGTGGTCGGGAGCGCTCCGGCGGCAAGTCT
CGGCATCTCCACCGGCGACGTGATCACCGCGGTCGACGGCGCTCCGATCAACTCGGCCA
CCGCGATGGCGGACGCGCTTAACGGGCATCATCCCGGTGACGTCATCTCGGTGACCTGG
CAAACCAAGTCGGGCGGCACGCGTACAGG G
AATTC AACTCCGCGAGGATGTACGCCGGC
CCGGGTTCGGCCTCGCTGGTGGCCGCGGCTCAGATGTGGGACAGCGTGGCGAGTGACCT
GTTTTCGGCCGCGTCGGCGTTTCAGTCGGTGGTCTGGGGTCTGACGGTGGGGTCGTGGA
TAGGTTCGTCGGCGGGTCTGATGGTGGCGGCGGCCTCGCCGTATGTGGCGTGGATGAGC
GTCACCGCGGGGCAGGCCGAGCTGACCGCCGCCCAGGTCCGGGTTGCTGCGGCGGCCT
ACGAGACGGCGTATGGGCTGACGGTGCCCCCGCCGGTGATCGCCGAGAACCGTGCTGAA
CTGATGATTCTGATAGCGACCAACCTCTTGGGGCAAAACACCCCGGCGATCGCGGTCAA
CGAGGCCGAATACGGCGAGATGTGGGCCCAAGACGCCGCCGCGATGTTTGGCTACGCCG
CGGCGACGGCGACGGCGACGGCGACGTTGCTGCCGTTCGAGGAGGCGCCGGAGATGAC
CAGCGCGGGTGGGCTCCTCGAGCAGGCCGCCGCGGTCGAGGAGGCCTCCGACACCGCC
GCGGCGAACCAGTTGATGAACAATGTGCCCCAGGCGCTGCAACAGCTGGCCCAGCCCAC
GCAGGGCACCACGCCTTCTTCCAAGCTGGGTGGCCTGTGGAAGACGGTCTCGCCGCATC
GGTCGCCGATCAGCAACATGGTGTCGATGGCCAACAACCACATGTCGATGACCAACTCG
GGTGTGTCGATGACCAACACCTTGAGCTCGATGTTGAAGGGCTTTGCTCCGGCGGCGGC
CGCCCAGGCCGTGCAAACCGCGGCGCAAAACGGGGTCCGGGCGATGAGCTCGCTGGGC
AGCTCGCTGGGTTCTTCGGGTCTGGGCGGTGGGGTGGCCGCCAACTTGGGTCGGGCGGC
CTCGGTCGGTTCGTTGTCGGTGCCGCAGGCCTGGGCCGCGGCCAACCAGGCAGTCACCC
CGGCGGCGCGGGCGCTGCCGCTGACCAGCCTGACCAGCGCCGCGGAAAGAGGGCCCGG
GCAGATGCTGGGCGGGCTGCCGGTGGGGCAGATGGGCGCCAGGGCCGGTGGTGGGCTC
AGTGGTGTGCTGCGTGTTCCGCCGCG
CCGACTTCCCCGCGCTGCCCCTCGACC
CGTCCGCGATGGTCGCCCAAGTGGGGCCACAGGTGGTCAACATCAACACCAAACTGGGC
TACAACAACGCCGTGGGCGCCGGGACCGGCATCGTCATCGATCCCAACGGTGTCGTGCT
GACCAACAACCACGTGATCGCGGGCGCCACCGACATCAATGCGTTCAGCGTCGGCTCCG
GCCAAACCTACGGCGTCGATGTGGTCGGGTATGACCGCACCCAGGATGTCGCGGTGCTG
CAGCTGCGCGGTGCCGGTGGCCTGCCGTCGGCGGCGATCGGTGGCGGCGTCGCGGTTG
GTGAGCCCGTCGTCGCGATGGGCAACAGCGGTGGGCAGGGCGGAACGCCCCGTGCGGT
GCCTGGCAGGGTGGTCGCGCTCGGCCAAACCGTGCAGGCGTCGGATTCGCTGACCGGTG
CCGAAGAGACATTGAACGGGTTGATCCAGTTCGATGCCGCGATCCAGCCCGGTGATTCG
GGCGGGCCCGTCGTCAACGGCCT
GCACTCGAGCACCACCACCACCACCAC GATCCGGCTGCTAACAAAGCC
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
TAASD
NFQLSQGGQGFAIPIGQAMAIAGQIRSGGGSPTVHIGPTAFLGLGVVDNNGNGARVQRVVGS
APAASLGISTGDVITAVDGAPINSATAMADALNGHHPGDVISVTWQTKSGGTRTGNVTLAEGP
PAEFMVDFGALPPEINSARMYAGPGSASLVAAAQMWDSVASDLFSAASAFQSVVWGLTVGS
WIGSSAGLMVAAASPYVAWMSVTAGQAELTAAQVRVAAAAYETAYGLTVPPPVIAENRAEL
MILIATNLLGQNTPAIAVNEAEYGEMWAQDAAAMFGYAAATATATATLLPFEEAPEMTSAG
GLLEQAAAVEEASDTAAANQLMNNVPQALQQLAQPTQGTTPSSKLGGLWKTVSPHRSPISN
MVSMANNHMSMTNSGVSMTNTLSSMLKGFAPAAAAQAVQTAAQNGVRAMSSLGSSLGSSG
LGGGVAANLGRAASVGSLSVPQAWAAANQAVTPAARALPLTSLTSAAERGPGQMLGGLPVG
QMGARAGGGLSGVLRVPPRPYVMPHSPAAGDIAPPALSQDRFADFPALPLDPSAMVAQVGPQ
VVNINTKLGYNNAVGAGTGIVIDPNGVVLTNNHVIAGATDINAFSVGSGQTYGVDVVGYDRT
QDVAVLQLRGAGGLPSAAIGGGVAVGEPVVAMGNSGGQGGTPRAVPGRVVALGQTVQASD
SLTGAEETLNGLIQFDAAIQPGDSGGPVVNGLGQVVGMNTAAS
GGCTAGTATGGATCTGGATGCAGTAAGGATTAAAGTGGACACAGTAAATGCAAAACCGGGAG
ACACAGTAAATATACCTGTAAGATTCAGTGGTATACCATCCAAGGGAATAGCAAACTGTGACT
TTGTATACAGCTATGACCCGAATGTACTTGAGATAATAGAGATAAAACCGGGAGAATTGATAG
TTGACCCGAATCCTACCAAGAGCTTTGATACTGCAGTATATCCTGACAGAAAGATGATAGTAT
TCCTGTTTGCGGAAGACAGCGGAACAGGAGCGTATGCAATAACTAAAGACGGAGTATTTGCTA
CGATAGTAGCGAAAGTAAAAGAAGGAGCACCTAACGGGCTCAGTGTAATCAAATTTGTAGAA
GTAGGCGGATTTGCGAACAATGACCTTGTAGAACAGAAGACACAGTTCTTTGACGGTGGAGTA
AATGTTGGAGATACAACAGAACCTGCAACACCTACAACACCTGTAACAACACCGACAACAAC
AGATGATCTAGATGCAGCTAGC TCGCCGTCCT
CGCCGCCGTTAGCATCGCCGCCACTGTCGTTGCCGGCTGCTCGTCGGGCTCGAAGCCAA
GCGGCGGACCACTTCCGGACGCGAAGCCGCTGGTCGAGGAGGCCACCGCGCAGACCAA
GGCTCTCAAGAGCGCGCACATGGTGCTGACGGTCAACGGCAAGATCCCGGGACTGTCTC
TGAAGACGCTGAGCGGCGATCTCACCACCAACCCCACCGCCGCGACGGGAAACGTCAAG
CTCACGCTGGGTGGGTCTGATATCGATGCCGACTTCGTGGTGTTCGACGGGATCCTGTA
CGCCACCCTGACGCCCAACCAGTGGAGCGATTTCGGTCCCGCCGCCGACATCTACGACC
CCGCCCAGGTGCTGAATCCGGATACCGGCCTGGCCAACGTGCTGGCGAATTTCGCCGAC
GCAAAAGCCGAAGGGCGGGATACCATCAACGGCCAGAACACCATCCGCATCAGCGGGAA
GGTATCGGCACAGGCGGTGAACCAGATAGCGCCGCCGTTCAACGCGACGCAGCCGGTGC
CGGCGACCGTCTGGATTCAGGAGACCGGCGATCATCAACTGGCACAGGCCCAGTTGGAC
CGCGGCTCGGGCAATTCCGTCCAGATGACCTTGTCGAAATGGGGCGAGA
CTGCCTGAGACTGGTGAAGCACATCACCATCACCATCACTGAGCG
GCCGCACTCGAGCACCACCACCACCACCACTGAGATCCGGCTGCTAACAAAGCCCGAAAGGAA
MGSSHHHHHHSSGLVPRGSHMASMDLDAVRIKVDTVNAKPGDTVNIPVRFSGIPSKGIANCDFVYS
YDPNVLEIIEIKPGELIVDPNPTKSFDTAVYPDRKMIVFLFAEDSGTGAYAITKDGVFATIVAKVKEG
APNGLSVIKFVEVGGFANNDLVEQKTQFFDGGVNVGDTTEPATPTTPVTTPTTTDDLDAAS
MRTP
RRHCRRIAVLAAVSIAATVVAGCSSGSKPSGGPLPDAKPLVEEATAQTKALKSAHMVLTVNG
KIPGLSLKTLSGDLTTNPTAATGNVKLTLGGSDIDADFVVFDGILYATLTPNQWSDFGPAADIY
DPAQVLNPDTGLANVLANFADAKAEGRDTINGQNTIRISGKVSAQAVNQIAPPFNATQPVPAT
VWIQETGDHQLAQAQLDRGSGNSVQMTLSKWGEKVQVTKPPVSLPETGEAHHHHHH
It is contemplated that any embodiment discussed in this specification can be implemented with respect to any method, kit, reagent, or composition of the invention, and vice versa. Furthermore, compositions of the invention can be used to achieve methods of the invention.
It may be understood that particular embodiments described herein are shown by way of illustration and not as limitations of the invention. The principal features of this invention can be employed in various embodiments without departing from the scope of the invention. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the claims.
All publications and patent applications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this invention pertains. All publications and patent applications are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.
The use of the word “a” or “an” when used in conjunction with the term “comprising” in the claims and/or the specification may mean “one,” but it is also consistent with the meaning of “one or more,” “at least one,” and “one or more than one.” The use of the term “or” in the claims is used to mean “and/or” unless explicitly indicated to refer to alternatives only or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and/or.” Throughout this application, the term “about” is used to indicate that a value includes the inherent variation of error for the device, the method being employed to determine the value, or the variation that exists among the study subjects.
As used in this specification and claim(s), the words “comprising” (and any form of comprising, such as “comprise” and “comprises”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”) or “containing” (and any form of containing, such as “contains” and “contain”) are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.
The term “or combinations thereof” as used herein refers to all permutations and combinations of the listed items preceding the term. For example, “A, B, C, or combinations thereof” is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, MB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.
All of the compositions and/or methods disclosed and claimed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of this invention have been described in terms of preferred embodiments, it may be apparent to those of skill in the art that variations may be applied to the compositions and/or methods and in the steps or in the sequence of steps of the method described herein without departing from the concept, spirit and scope of the invention. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.
This application claims priority to U.S. Provisional Application Ser. No. 61/466,292, filed Mar. 22, 2011, the entire contents of which are incorporated herein by reference.
Number | Date | Country | |
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61466292 | Mar 2011 | US |