Method for the prophylaxis and/or treatment of medical disorders

Abstract

The present invention relates generally to a method for the prophylaxis and/or treatment of skin disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a most preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis.

Description

FIELD OF THE INVENTION

The present invention relates generally to a method for the prophylaxis and/or treatment of medical disorders, and in particular proliferative and/or inflammatory skin disorders, and to genetic molecules useful for same. The present invention is particularly directed to genetic molecules capable of modulating growth factor interaction with its receptor on cells such as epidermal keratinocytes to inhibit, reduce or otherwise decrease stimulation of this layer of cells. The present invention contemplates, in a particularly preferred embodiment, a method for the prophylaxis and/or treatment of psoriasis or neovascularization conditions such as neovascularization of the retina. The present invention is further directed to the subject genetic molecules in adjunctive therapy for epidermal hyperplasia, such as in combination with UV treatment, and to facilitate apoptosis of cancer cells and in particular cancer cells comprising keratinocytes.

BACKGROUND OF THE INVENTION

Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description.

The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia or any other country.

Psoriasis and other similar conditions are common and often distressing proliferative and/or inflammatory skin disorders affecting or having the potential to affect a significant proportion of the population. The condition arises from over proliferation of basal keratinocytes in the epidermal layer of the skin associated with inflammation in the underlying dermis. Whilst a range of treatments have been developed, none is completely effective and free of adverse side effects. Although the underlying cause of psoriasis remains elusive, there is some consensus of opinion that the condition arises at least in part from over expression of local growth factors and their interaction with their receptors supporting keratinocyte proliferation via keratinocyte receptors which appear to be more abundant during psoriasis.

One important group of growth factors are the dermally-derived insulin-like growth factors (IGFs) which support keratinocyte proliferation. In particular, IGF-I and IGF-II are ubiquitous peptides each with potent mitogenic effects on a broad range of cells. Molecules of the IGF type are also known as “progression factors” promoting “competent” cells through DNA synthesis. The IGFs act through a common receptor known as the Type I or IGF-I receptor, which is tyrosine kinase linked. They are synthesised in mesenchymal tissues, including the dermis, and act on adjacent cells of mesodermal, endodermal or ectodermal origin. The regulation of their synthesis involves growth hormone (GH) in the liver, but is poorly defined in most tissues [1].

Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability [2]. Six IGFBPs have so far been identified. The exact effects of the IGFBPs is not clear and observed effects in vitro have been inhibitory or stimulatory depending on the experimental method employed [3]. There is some evidence, however, that certain IGFBPs are involved in targeting IGF-I to its cell surface receptor.

Skin, comprising epidermis and underlying dermis, has GH receptors on dermal fibroblasts [4]. Fibroblasts synthesize IGF-I as well as IGFBPs-3, -4, -5 and -6 [5] which may be involved in targeting IGF-I to adjacent cells as well as to the overlaying epidermis. The major epidermal cell type, the keratinocyte, does not synthesize IGF-I, but possesses IGF-I receptors and is responsive to IGF-I [6].

It is apparent, therefore, that IGF-I and other growth promoting molecules, are responsible for or at least participate in a range of skin cell activities. In accordance with the present invention, the inventors have established that aberrations in the normal functioning of these molecules or aberrations in their interaction with their receptors is an important factor in a variety of medical disorders such as proliferative and/or inflammatory skin disorders. It is proposed, therefore, to target these molecules or other molecules which facilitate their functioning or interaction with their receptors to thereby ameliorate the effects of aberrant activity during or leading to skin disease conditions and other medical conditions such as those involving neovascularization. Furthermore, these molecules may also be used to facilitate apoptosis of target cells and may be useful as adjunctive therapy for epidermal hyperplasia.

SUMMARY OF THE INVENTION

Nucleotide and amino acid sequences are referred to by a sequence identifier, i.e. (<400>1), (<400>2), etc. A sequence listing is provided after the claims.

Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.

According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.

According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to <400>1 or <400>2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.

Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3. In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.

Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents.

Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor.

Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder.

The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a representation of the nucleotide sequence of IGFBP-2. LOCUS HSIGFBP2 1433 bp RNA PRI 31-JAN-1990 5 DEFINITION Human mRNA for insulin-like growth factor binding protein (IGFBP-2) ACCESSION X16302 KEYWORDS insulin-like growth factor binding protein. SOURCE human ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia;

Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae. REFERENCE 1 (bases 1 to 1433) AUTHORS Binkert,C., Landwehr,J., Mary,J.L., Schwander,J. and Heinrich,G. TITLE Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2) JOURNAL EMBO J. 8, 2497-2502 (1989) STANDARD full automatic COMMENT NCBI gi: 33009

FEATURES     Location/Qualifiers
source       1. .1433
             /organism=“Homo sapiens”
             /dev_stage=“fetal”
             /tissue_type=“liver”
misc_feature 1416. .1420
             /note=“pot. polyadenylation signal”
polyA site   1433
             /note=“polyadenylation site”
CDS          118. .1104
             /note=“precursor polypeptide;
             (AA −39 to 289);
             NCBI gi:33010.”
             /codon start=1
             /translation=“MLPRVGCPALPLPPPPLLPLLPL
             LLLLLGASGGGGGARAEVLFRCPPCTPERLAACGPPP
             VAPPAAVAAVAGGARNPCAELVREPGCGCCSVCARLE
             GEACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTC
             EKRRDAEYGASPEQVADNGDDHSEGGLVENHVDSTMN
             TMNMLGGGGSAGRKPLKSGMKELAVFREKVTEQHRQM
             GKGGKNHLGLEEPKKLRPPPARTPCQQELDQVLERIS
             TMRLPDERGPLEHLYSLHIPNCDKHGLYNLKQCKMSL
             NGORGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQ
             QEACGVHTQRMQ”
             (<400>21)
CDS          118. .234
             /note=“signal peptide;
             (AA −39 to −1); NCBI gi: 33011.”
             /codon_start=1
             /translation=“MLPRVGCPALPLPPPPLLPLLPL
             LLLLLGASGGGGGARA”
             (<400>22)
CDS          235. .1101
             /note=“mature IGFBP-2;
             (AA 1 to 289); NCBI gi: 33012.”
             /codon_start=1
             /translation=“EVLFRCPPCTPERLAACGPPPVA
             PPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGE
             ACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEK
             RRDAEYGASPEQVADNGDDHSEGGLVENHVDSTMNML
             GGGGSAGRKPLKSGMKELAVFREKVTEQHRQMGKGGI
             GKHHLGLEEPKKLRPPPARTPCQQELDQVLERISTMR
             LPDERGPLEHLYSLHIPNCDKHGLYNLKQCKNSLNGQ
             RGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEA
             CGVHTQRMQ” (<400>23)
BASE COUNT   239 a  466 c  501 g  227 t
ORIGIN
HSIGFBP2 Length: 1433 May 11, 1994 10:06 Type:
N Check: 6232 . .

FIG. 2 is a representation of the nucleotide sequence of IGFBP-3. LOCUS HUMGFIBPA 2474 bp ss-mRNA PRI 15-JUN-1990 DEFINITION Human growth hormone-dependent insulin-like growth factor-binding protein mRNA, complete cds. ACCESSION M31159 KEYWORDS insulin-like growth factor binding protein. SOURCE Human plasma, cDNA to mRNA, clone BP-53. ORGANISM Homo sapiens Eukaryota; Animalia; Chordata; Vertebrata; Mammalia; Theria;

Eutheria; Primates; Haplorhini; Catarrhini; Hominidae. REFERENCE 1 (bases 1 to 2474) AUTHORS Wood,W.I., Cachianes,G., Henzel,W.J., Winslow,G.A., Spencer,S.A., Hellmiss,R., Martin,J.L. and Baxter,R.C.

TITLE Cloning and expression of the growth hormone-dependent insulin-like growth factor-binding protein JOURNAL Mol. Endocrinol. 2, 1176-1185 (1988) STANDARD full automatic 30 COMMENT NCBI gi: 183115

FEATURES     Location/Qualifiers
mRNA         <1. .2474
             /note=“GFIBP mRNA”
CDS          110. .985
             /gene=“IGFBP1”
             /note=“insulin-like growth factor-
             binding protein; NCBI
             gi: 183116.”
             /codon_start=1
             /translation=“MQRARPTLWAAALTLLVLLRGPP
             VARAGASSGGLGPVVRCEPCDARALAQCAPPPAVCAE
             LVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPS
             PDEARPLQALLDGRGLCVNASAVSRLRAYLLPAPPAP
             GNASESEEDRSAGSVESPSVSSTHRVSDPKFHPLHSK
             IIIIKKGHAXDSQRYKVDYESQSTDTQNFSSESKRET
             EYGPCRREMEDTLNHLKFLNVLSPRGVHIPNCDKKGF
             YKKKQCRPSKGRKRGFCWCVDKYGQPLPGYTTKGKED
             VHCYSMQSK” (<400>24>)
source       1. .2474
             /organism=“Homo sapiens”
BASECOUNT    597 a  646 c  651 g  580 t
ORIGIN
misc_feature 1343. .1351
             /note=“pot.N-linked glycosylation
             site (AA 408-410)”
misc_feature 1631. .1639
             /note=“pot.N-linked glycostlation
             site (AA 504-506)”
misc_feature 1850. .1858
             /note=“pot.N-linked glycosylation
             site (AA 577-579)”
misc_feature 1895. .1903
             /note=“pot.N-linked glycosylation
             site (AA 592-594)”
misc_feature 1949. .1957
             /note=“pot.N-linked glycosylation
             site (AA 610-612)”
misc_feature 2240. .2251
             /note=“putative proreceptor
             processing site (AA 707-710)
misc_feature 2252. .4132
             /note=“beta-subunit (AA 711-1337)”
misc_feature 2270. .2278
             /note=“pot.N-linked glycosylation
             site (AA 717-719]”
misc_feature 2297. .2305
             /note=“pot.N-linked glycosylation
             site (AA 726-728)”
misc_feature 2321. .2329
             /note=“pot.N-linked glycosylation
             site (AA 734-736)”
misc_feature 2729. .2737
             /note=“pot.N-linked glycosylation
             site (AA 870-872)”
misc_feature 2768. .2776
             /note=“pot.N-linked glycosylation
             site (AA 883-885)”
misc_feature 2837. .2908
             /note=“transmembrane region
             (AA 906-929)”
misc_feature 2918. .2926
             /note=“pot.N-linked glycosylation
             site (AA 933-935)”
misc_feature 3047. .3049
             /note=“pot.ATP binding site (AA 976)”
misc_feature 3053. .3055
             /note=“pot.ATP binding site (AA 978)”
misc_feature 3062. .3064
             /note=“pot.ATP binding site (AA 981)”
misc_feature 3128. .3130
             /note=“pot.ATP binding site
             (AA 1003)”
CDS          32. .4132
             /product=“IGF-I receptor”
             /note=“50 stops when translation
             attempted, frame 1, code 0”
BASE COUNT   1216 a  1371 c  1320 g  1082 t
ORIGIN
HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N
Check: 133 . .

FIG. 4A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosphorothioate oligonucleotides (BP3AS2, BP3AS3 and BP3S) at 0.5 μM and 5 μM; * no oligonucleotide added.

FIG. 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (FIG. 4A), showing relative band intensities of IGFBP-3 and the 24 kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides; * no oligonucleotide added.

FIG. 5A is a photographic representation of a Western ligand blot of HaCaT conditioned medium showing IGFBP-3 secreted in 24 hours after 7 day treatment with phosophorothioate oligonucleotide BP3AS2 at 0.5 μM compared with several control oligonucleotides at 0.5 μM. (a) oligonucleotide BP3AS2NS; (b) oligonucleotide BP3AS4; (c) oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.

FIG. 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (FIG. 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in FIG. 5A, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide.

FIG. 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense; IGFR.S: sense.

FIG. 7 is a graphical representation showing inhibition of IGFBP-3 production in culture medium following initial treatment with antisense oligonucleotides once daily over a 2 day period.

FIG. 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.

FIG. 9 is a diagramatic representation of a map of IGF-1 Receptor mRNA and position of target ODNs.

FIG. 10 is a photographical representation showing Lipid-mediated uptake of oligonucleotide in keratinocytes. HaCaT keratinocytes were incubated for 24 hours in medium 10 (DMEM plus 10% v/v FCS) containing fluorescently labelled ODN (R451, 30 nM) and cytofectin GSV (2 μg/ml). The cells were then transferred to ODN-free medium and fluorescence microscopy (a) and phase contrast (b) images of the cells were obtained.

FIG. 11 is a graphical representation of uptake (A) and toxicity (B) of ODN/lipid complexes in keratinocytes. Confluence HaCaT keratinocytes were incubated in DMEM containing fluoresently labelled ODN (R451) plus liposome over 120 hours, viewed using fluorescene microscopy and trypan blue stained and counted.

FIG. 12 is a graphical representation of an IGF-1 Receptor mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml GSV). HaCaT keratinocytes were treated for 96 hours with C-5 propynyl, dU, dC ODNs complexed with cytofectin GSV. Cells were treated with ODNs complementary to the human IGF-I receptor mRNA (27, 32, 74 and 78), 2 randomised sequence ODNs (R451) and R766), liposome alone (GSV) or were left untreated (UT). Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase Protection and Phosphorlmager quantitiation.

(A) Electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase Protection. Molecular weight markers are shown on the right hand side. Full length probe is shown on the left hand side (G-probe and I-probe). GAPDH protected fragments (G) are seen at 316 bases and IGF-I receptor protected fragments (1) are seen at 276 bases.

(B) Relative level of IGF-I receptor mRNA following each treatment is shown.

FIG. 13 is a graphical representation of an IGF-1 receptor mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml GSV). Summary of IGF-I receptor ODN screening data. HaCaT keratinocytes were treated for 96 hours with C-5 propynyl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGF-I receptor mRNA and GAPDH mRNA levels by RNase protection and phosphorImager quantitiation. Relative level of IGF-I receptor mRNA is shown after treatment with ODNs complementary to the human IGF-I receptor mRNA, 4 randomised sequence ODNs and liposome alone. (26-86=IGF-I receptor ODNs; R1, R4, R7 and R9=randomised ODNs (R1=R121, R4=R451, R7=R766, R9=R961); GSV=liposome alone; UT=untreated). *indicates a significant difference in relative IGF-I receptor mRNA from GSV treated cells (n=4-10, p<0.05).

FIG. 14 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes. HaCaT cells were grown to confluence in 24-well plates in DMEM containing 10% v/v FCS. Oligodeoxynucleotide (ODN) and Cytofectin GSV (GSV, Glen Research) were mixed together in serum-free DMEM, incubated at room temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells. Cells were incubated for 72 hours with 30 nM random sequence or antisense ODN and 2 μg/ml GSV or with GSV alone in DMEM containing 10% v/v FCS with solutions replaced every 24 hours. This was followed by incubation with ODN/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37° C. Wells were washed twice with 1 ml cold PBS. Serum-free DMEM containing 10⁻¹⁰M ¹²⁵I-IGF-I was added with or without the IGF-I analogue, des (1-3) IGF-I, at 10⁻¹⁰M to 10⁻⁷M. Cells were incubated at 4° C. for 17 hours with gentle shaking then washed three times with 1 ml cold PBS and lysed in 250 μl 0.5M NaOH/0.1% v/v Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a γ counter.

FIG. 15 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes.

FIG. 16 is a photographical representation of H & E stained sections of (A) psoriatic skin biopsy prior to grafting and (B) 49 day old psoriatic skin graft using skin from the same donor.

FIG. 17 is a photographical representation of uptake of oligonucleotide after intradermal injection into psoriatic skin graft on a nude mouse. Psoriatic skin graft was intradermally injected with ODN (R451, 50 μl, 10 μM). The graft was removed and sectioned after 24 hours, then viewed using confocal microscopy.

FIG. 18(a) is a photographical representation of Pregraft, Donor JH, Donor JH, PBS treated, 50 μl, Donor JH, #50 treated, 50 μl, 10 μM.

FIG. 18(b) is a photographical representation of Donor LB, pregraft, Donor LB, PBS treated (50 μl), Donor LB, #74 treated (50 μl, 10 μM).

FIG. 18(c) is a photographical representation of Donor PW, pregraft, Donor PW, R451 treated (50 μl, 10 μM), Donor LB, #74 treated (50 μl, 10 μM).

FIG. 18(d) is a photographical representation of Donor GM, pregraft, Donor GB, R451 treated (50 μl, 10 μM), Donor GM, #27 treated (50 μl, 10 μM).

FIG. 19(a) is a photographical representation showing Donor JH pregraft, Donor JH PBS treated 50, μl, Donor JH #50 treated 50 μl, 10 μM.

FIG. 19(b) is a photographical representation Donor LB pregraft, Donor LB PBS treated 50 μl, Donor LB #74 treated 50 μl, 10 μM.

FIG. 19(c) is a photographical representational showing Donor PW pregraft, Donor PW R451 treated 50 μl, 10 μM, Donor PW #74 treated 50 μl, 10 μM.

FIG. 19(d) is a photographical representation showing Donor GM pregraft, Donor GM R451 treated 50, μl, 10 μM, Donor #27 treated 50, μl, 10 μM.

FIG. 20 is a graphical representation showing suppression of psoriasis after treatment with oligonucleotide (quantification). Oligonucleotide (50 μl, 10 μM) was injected every two days for 20 days, as were control treatments. Skin thickness was measured by removing the skin and using computer software (MCID analysis) to measure the exact thickness of each graft. N=3-4 for each treatment. *indicates a significant difference from the pregraft value (ANOVA, P<0.05)

FIG. 21 is a photographic representation of αhKi-67 imunobiological binding.

FIG. 22 is a photographical representation showing penetration of oligonucleotide into human skin after topical treatment. Fluorescently labelled oligonucleotide (10 μM R451) was applied topically after formulation with cytofectin GSV (10 μg/ml) and viewed using confocal microscopy.

FIG. 23 is a photographical representation showing penetration of oligonucleotide into human skin after application of topical gel formation. Fluorescently labelled oligonucleotide (10 μM R451) was applied topically after complexing with cytofectin GSV (10 μg/ml) and formulation into 3% methylcellulose gel. Image was obtained using confocal microscopy.

FIG. 24 is a graphical representation showing IGFBP-3 mRNA.

FIG. 25(a) is a graphical representation showing IGFBP-3 mRNA in AON treated (10 nM) HaCaT cells (2 μg/ml GSV).

FIG. 25(b) is a graphical representation showing IGFBP-3 mRNA levels of AON treated (100 nm) HaCaT cells (2 μg/ml GSV).

FIG. 25(c) is a graphical representation showing IGFBP-3 mRNA in AON treated (30 nM) HaCaT cells (2 μg/ml GSV).

FIG. 25(d) is a graphical representation showing IGFBP-3 mRNA in AON treated (30 nM) HaCaT cells (2 μg/ml GSV).

FIG. 26(a) is a graphical representation showing IGFBP-3 mRNA in ODN treated (30 nM) HaCaT cells (2 μg/ml). HaCaT keratinocytes were treated for 51 hours with C-5 propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP-3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation. Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and lipsome alone. (1-24=IGFBP-3 ODNs; R1, R4, R7 and R9=randomised ODNs (R1=R121, R4=R451, R7=R766, R9 R961); GS=liposome alone; UT=untreated). *indicates a significant different in relative IGFBP-3 mRNA from GSV treated cells (n-5-8, p<0.01), **indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells (n=5-8, p<0.05).

FIG. 26(b) is a graphical representation showing IGFBP-3 mRNA in ODN treated (100 nM) HaCaT cells (2 μg/ml GSV). HaCaT keratinocytes were treated for 51 hours with C-5 propynl, dU, dC ODNs complexed with cytofectin GSV. Total RNA was isolated then analysed for IGFBP-3 mRNA and GAPDH mRNA levels by Northern analysis and phosphorimager quantitation. Relative level of IGFBP-3 mRNA is shown after treatment with ODNs complementary to the human IGFBP-3 mRNA, 4 randomised sequence ODNs and liposome alone. (1-24=IGFBP-3 ODNs; R1, R4, R7 and R9=randomised ODNs (R1-R121, R4=R451, R7=R766, R9-R961), GS=lipsome alone; UT=untreated). *indicates a significant difference in relative IGFBP-3 mRNA from GSV treated cells (n-6-8, p<0.01).

FIG. 27 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT cells following treatment with antisense oligonucleotides. Confluent HaCaT cells were treated every 24 h for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA by RNase protection assay. (a). Representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. In this example, a reduction in IGFR band intensity relative to GAPDH can be seen with AON #27 and #78, but not with #32, #74 or the controls (R4, R7, random oligonucleotides R451 and R766, respectively; G, GSV lipid; UT, untreated).

(b) Densitometric quantitation of IGF-I receptor mRNA (normalised to GAPDH mRNA) in HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black), random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar). Each oligonucleotide was assayed in duplicate in at least two separate experiments.

Results are presented as mean±SEM. A one-way ANOVA followed by Tukey's (▴) test was performed; ▴ indicates a significant difference between cells treated with IGF-I receptor specific AONs and all of the control treatments (p<0.05). n=4 except for #27 and #32 (n=6), #28 and #68 (n=3), R766 (n=9), and R451, GSV and untreated (n=10).

FIG. 28 is a representation showing a reduction in total cellular IGF-I receptor protein following antisense oligonucleotide treatment. Confluent HaCaT cells were treated every 24 h for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONs (#27, #50 and #64) or the random sequence oligonucleotide, R451. Total cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with an antibody specific for the human IGF-I receptor. (a) Duplicate treated cellular extracts showing the IGF-I receptor at the predicted size of 110 kD

(b) Densitometric quantitation of IGF-I receptor protein. Results are presented as mean±SEM of four different experiments each performed in duplicate. A one-way ANOVA followed by a Dunnett's test was performed; * indicates a significant difference from GSV treated cells (p<0.01). GSV, GSV lipid alone; UT, untreated; R451, random sequence oligonucleotide; 64, 50, 27, IGF-I receptor-specific AONs.

FIG. 29 is a representation showing a reduction in IGF-I receptor numbers on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were transfected with IGF-I receptor specific AONs #27 (-▴-), #50 (-x-), #64 (---▪---), a random sequence oligonucleotide R451 (-o-), or treated with GSV lipid alone (--□--) every 24 h for four days (untreated cells, --*--). Competition binding assays using ¹²⁵I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I, were performed (inset); plotted values are means ±standard error. The mean values were then subjected to Scatchard analysis.

FIG. 30 is a representation showing a reduction in keratinocyte cell number following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6416, or treated with GSV lipid alone every 24 h for 2 days (UT, untreated cells). Cell number was measured in the culture wells using a dye binding assay (Experimental protocol). Results are presented as mean±SD. A one-way ANOVA was performed, followed by a Tukey's multiple comparison test. ▴ indicates a significant difference between cells treated with AON #64 and all of the control treatments (p<0.001).

FIG. 31 is a representation showing a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides

Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed histologically. (a) Donor A graft treated with AON #50 showing epidermal thinning compared

with pregraft and control (PBS) treated graft, and Donor B graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. E, epidermis; Scale bar, 400 mm; all pictures are at the same magnification. (b) Mean epidermal cross-sectional area over the full width of grafts was determined by digital image analysis. Results are presented as mean±SEM. Shaded bars, control treatments: R451, random oligonucleotide sequence; solid bars, treatments with oligonucleotides that inhibited IGF-I receptor expression in vitro. * indicates a significant difference from the vehicle treated graft (p<0.01, n=5-7), ++ indicates a significant difference from the random sequence (R451) treated graft (p<0.01, n=5-7). (c) Parakeratosis (arrow) was absent in grafts treated with IGF-I receptor AONs (AON #50) but persisted in pregraft and control (PBS) treated graft. Scale bar, 100 mm.

FIG. 32 is a representation showing a reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides (a) A psoriasis lesion prior to grafting, and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) was immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). Scale bar, 250 mm; all pictures are at the same magnification. (b) The same lesion prior to grafting and after oligonucleotide treatment as in (a) was subjected to in situ hybridisation with a ³⁵S-labeled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains (tiny black speckles), which are almost eliminated in the epidermis of the lesion treated with the IGF-I receptor-specific oligonucleotide #27 (AON #27). Arrows indicate the basal layer of the epidermis with dermis underneath. Scale bar, 50 μm.

FIG. 33 is a representation showing a reduction in IGF-I receptor mRNA in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to 90% confluence in DMEM contianing 10% v/v fetal calf serum were treated with 24 h for two days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially availble ribonuclease protection assay kit (RPAII, Ambicon Inc, Austin, Tex.). Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, Calif.).

FIG. 34 is a representation showing a reduction in IGF-I receptor protein in HaCaT keratinocytes following treatment with oligonucleotides. HaCaT cell monolayers grown to 90% confluence in DMEM containing 10% v/v fetal calf serum were treated every 24 h for four days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Cells were lyased in a buffer containing 50 mM HEPES, 150 mM NaCl, 10% v/v gycerol, 1% v/v Triton X-100 and 100 μg/ml aprotinin on ice for 30 mins, then 30 μg of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane (Millipore, Bedford, Mass.). Membranes were incubated with the anti-IGF-I receptor antibody C20 (Sanra Cruz Biotechnology Inc., Santa Cruz, Calif., 25 ng/ml in 150 mM NaCl, 10 mM Tris-HCl, pH 7.4, 0.1% v/v Tween 20) for 1 h at room temperature and developed using the Vistra ECF western blotting kit (Amersham, Buckinghamshire, England). Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, Calif.).

FIG. 35 is a representation showing a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. HaCaT cell monolayers grown to 40% confluence in DMEM containing 10% fetal calf serum were treated every 24 h for three days with 2 μg/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell number was measured every 24 h using the amido black dye binding assay [32].

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention is predicated in part on the use of molecules and in particular genetic molecules and more particularly antisense molecules to down-regulate a growth factor, its receptor and/or growth factor expression facilitating sequences.

Accordingly, one aspect of the present invention contemplates a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved in the said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation and/or other medical disorder.

Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and these and other medical disorders may be mediated by any number of molecules such as but not limited to IGF-I, keratinocyte growth factor (KGF), transforming growth factor-α (TGFα), tumour necrosis factor-α (TNFα), interleukin-1, -4, -6 and 8 (IL-1, IL-4, IL-6 and IL-8, respectively), basic fibroblast growth factor (bFGF) or a combination of one or more of the above. The present invention is particularly described and exemplified with reference to IGF-I and its receptor (IGF-I receptor) and to IGF-I facilitating molecules, IGFBPs, since targeting these molecules according to the methods contemplated herein provides the best results to date. This is done, however, with the understanding that the present invention extends to any growth factor or cytokine-like molecule, a receptor thereof or a facilitating molecule like the IGFBPs involved in skin cell proliferation such as those molecules contemplated above and/or their receptors and/or facilitating molecules therefor.

According to this preferred embodiment, there is provided a method for ameliorating the effects of a medical disorder such as a proliferative and/or inflammatory skin disorder in a mammal, said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation or a cell otherwise involved with said medical disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation and/or other medical disorder.

The present invention is particularly described by psoriasis as the proliferative skin disorder. However, the subject invention extends to a range of proliferative and/or inflammatory skin disorders or epidermal hyperplasias such as but not limited to psoriasis, ichthyosis, pityriasis rubra pilaris (“PRP”), seborrhoea, keloids, keratoses, neoplasias and scleroderma, warts, benign growths and cancers of the skin. The present invention extends to a range of other disorders such as neovascularization conditions such as but not limited to hyperneovasularization such as neovascularization of the retina, lining of the brain, skin, hyperproliferation of the inside of blood vessels, kidney disease, atherosclerotic disease, hyperplasias of the gut epithelium or growth factor mediated malignancies such as IGF1-mediated malignancies.

Furthermore, down-regulation of IGF-I receptor is useful as adjunctive therapy for epidermal hyperplasia. In accordance with this aspect of the present invention it is known that IGF-I receptor elicits separate intracellular signals which prevent apoptosis [19]. In keratinocytes, IGF-I receptor activation has been shown to protect UV-irradiated cells from apoptosis [20]. In another cell type, a number of IGF-I receptors expressed by the cells correlated with tumorigenicity and apoptotic resistance [21]. Consequently, in accordance with the present invention, by inactivating IGF-I receptor on cells such as epidermal keratinocytes will achieve three important outcomes:

• • (i) Acute epidermal hyperplasia following UV has been suggested to increase the risk of keratinocyte carcinogenic transformation [22]. By reducing IGF-I receptor expression in the epidermis, the incidence of epidermal hyperplasia following UV exposure is likely to be reduced leading to an overall acceleration in normalization of the lesion and reduced carcinogenic risk.
  • (ii) Inhibition of anti-apoptotic action of IGF-I receptor will enhance the reversal of epidermal thickening and accelerate normalization of differentiation. Topical or injected IGF-I receptor antisense as adjunctive treatment will increase apoptosis in the epidermal layer thereby enhancing the reduction in acanthosis observed in UV treatments.
  • (iii) Survival of keratinocytes, ie. those which evade apoptosis is likely to occur when cells have damaged DNA. Such mutations may be in the tumor suppressor region. Consequently, the use of antisense therapy will result in less frequent selection of mutated keratinocytes and therefore reduced incidence of basal cell carcinomas and squamous.

According to this embodiment, there is provided a method for ameliorating the effects of a proliferative and/or inflammatory skin disorder such as psoriasis said method comprising contacting the proliferating and/or inflamed skin or skin capable of proliferation and/or inflammation with effective amounts of UV treatment and a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

The UV treatment and nucleic acid molecule or its chemical analogue may be administered in any order or may be done simultaneously. This method is particularly useful in treating psoriasis by combination of UV and antisense therapy. Preferably the antisense therapy is directed to the IGF-I receptor.

In a preferred embodiment, the present invention is directed to a method for ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said disorder with an effective amount of a nucleic acid molecule or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder.

The present invention extends to any mammal such as but not limited to humans, livestock animals (e.g. horses, sheep, cows, goats, pigs, donkeys), laboratory test animals (e.g. rabbits, mice, guinea pigs), companion animals (e.g. cats, dogs) and captive wild animals. However, the instant invention is particularly directed to proliferative and/or inflammatory skin disorders such as psoriasis in humans as well as medical disorders contemplated above.

The aspects of the subject invention instantly contemplated are particularly directed to the topical application of one or more suitable nucleic molecules capable of inhibiting, reducing or otherwise interfering with IGF-mediated cell proliferation and/or inflammation. More particularly, the nucleic acid molecule targets IGF-I interaction with its receptor. Conveniently, therefore, the nucleic acid molecule is an antagonist of IGF-I interaction with its receptor. Most conveniently, the nucleic acid molecule antagonist is an antisense molecule to the IGF-I receptor, to IGF-I itself or to a molecule capable of facilitating IGF-I interaction with its receptor such as but not limited to an IGFBP.

Insofar as the invention relates to IGFBPs, the preferred molecules are IGFBP-2, -3, -4, -5 and -6. The most preferred molecules are IGFBP-2 and IGFBP-3.

The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth in FIGS. 1 (<400>1) and 2 (<400 >2), respectively. According to a particularly preferred aspect of the present invention, there is provided a nucleic acid molecule comprising at least about ten nucleotides capable of hybridising to, forming a heteroduplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to a genomic form of <400>1 and/or <400>2 and which thereby reduces or inhibits translation of said mRNA molecule. Preferably, the nucleic acid molecule is at least about 15 nucleotides in length and more preferably at least about 20-25 nucleotides in length. However, the instant invention extends to any length nucleic acid molecule including a molecule of 100-200 nucleotides in length to correspond to the full length of or near full length of the subject genes.

The nucleotide sequence of the antisense molecules may correspond exactly to a region or portion of <400>1 or <400>2 or may differ by one or more nucleotide substitutions, deletions and/or additions. It is a requirement, however, that the nucleic acid molecule interact with an mRNA molecule to thereby reduce its translation into active protein.

Examples of potential antisense molecules for IGFBP-2 and IGFBP-3 are those capable of interacting with sequences selected from the lists in Examples 6 and 7, respectively.

The nucleic acid molecules in the form of an antisense molecule may be linear or covalently closed circular and single stranded or partially double stranded. A double stranded molecule may form a triplex with target mRNA or a target gene. The molecule may also be protected from, for example, nucleases, by any number of means such as using a nonionic backbone or a phosphorothioate linkage. A convenient nonionic backbone contemplated herein is ethylphosphotriester linkage or a 2′-O-methylribosyl derivative. A particularly useful modification modifies the DNA backbone by introducing phosphorothioate internucleotide linkages. Alternatively or in addition to the pyrimidine bases are modified by inclusion of a C-5 propyne substitution which modification is proposed to enhance duplex stability [23]. The present invention extends to any chemical modification to the bases and/or RNA or DNA backbone. Reference to a “chemical analogue” of a nucleic acid molecule includes reference to a modified base, nucleotide, nucleoside or phosphate backbone.

Examples of suitable oligonucleotide analogues are conveniently described in Ts'O et al [7]. Further suitable examples of oligonucleotide analogues and chemical modifications are described in references 25 to 31.

Alternatively, the antisense molecules of the present invention may target the IGF-I gene itself or its receptor or a multivalent antisense molecule may be constructed or separate molecules administered which target at least two or an IGFBP, IGF-I and/or IGF-I-receptor. Examples of suitable antisense molecules capable of targetting the IGF-I receptor are those capable of interacting with sequences selected from the list in Example 8. One particularly useful antisense molecule is 5′-ATCTCTCCGCTTCCTTTC-3′ (<400>10).

Other particularly useful antisense molecules are:

#27 UCCGGAGCCAGACUU
#64 CACAGUUGCUGCAAG
#78 UCUCCGCUUCCUUUC
#28 AGCCCCCACAGCGAG
#32 GCCUUGGAGAUGAGC
#40 UAACAGAGGUCAGCA
#42 GGAUCAGGGACCAGU
#46 CGGCAAGCUACACAG
#50 GGCAGGCAGGCACAC

Particularly useful molecules are selected from #27, #64 and #78. In a preferred embodiment these molecules comprise a C-5 propynyl dU, dC phosphorothioate modification.

A particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis or other medical disorder, said method comprising contacting proliferating skin or skin capable of proliferation or cells associated with said medical disorder with an effective amount of one or more nucleic acid molecules or chemical analogues thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or ameliorating the medical disorder wherein said one or more molecules comprises a polynucleotide capable of interacting with mRNA directed from an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3.

Preferably, the nucleic acid molecule are antisense molecules. Particularly useful antisense molecules are:

#27 UCCGGAGCCAGACUU
#64 CACAGUUGCUGCAAG
#78 UCUCCGCUUCCUUUC
#28 AGCCCCCACAGCGAG
#32 GCCUUGGAGAUGAGC
#40 UAACAGAGGUCAGCA
#42 GGAUCAGGGACCAGU
#46 CGGCAAGCUACACAG
#50 GGCAGGCAGGCACAC

Even more particularly useful molecules are selected from #27, #64 and #78.

In accordance with one aspect of the present invention the nucleic acid molecule is topically applied in aqueous solution or in conjunction with a cream, ointment, oil or other suitable carrier and/or diluent. A single application may be sufficient depending on the severity or exigencies of the condition although more commonly, multiple applications are required ranging from hourly, multi-hourly, daily, multi-daily, weekly or monthly, or in some other suitable time interval. The treatment might comprise solely the application of the nucleic acid molecule or this may be applied in conjunction with other treatments for the skin proliferation and/or inflammatory disorder being treated or for other associated conditions including microbial infection, bleeding and the formation of a variety of rashes.

As an alternative to or in conjunction with antisense therapy, the subject invention extends to the nucleic acid molecule as, or incorporating, a ribozyme including a minizyme to, for example, IGF-I, its receptor or to molecules such as IGFBPs and in particular IGFBP-2 and -3. Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach [8] and in International Patent Application No. WO 89/05852. The present invention extends to ribozymes which target mRNA specified by genes encoding IGF-I, its receptor or one or more IGFBPs such as IGFBP-2 and/or IGFBP-3.

According to this embodiment, there is provided in a particularly preferred aspect a ribozyme comprising a hybridising region and a catalytic region wherein the hybridising region is capable of hybridising to at least part of a target mRNA sequence transcribed from a genomic gene corresponding to (<400>1) or (<400>2) wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation and/or inflammation and/or other medical disorders.

Yet another aspect of the present invention contemplates co-suppression to reduce expression or to inhibit translation of an endogenous gene encoding, for example, IGF-I, its receptor, or IGFBPs such as IGFBP-2 and/or -3. In co-suppression, a second copy of an endogenous gene or a substantially similar copy or analogue of an endogenous gene is introduced into a cell following topical administration. As with antisense molecules, nucleic acid molecules defining a ribozyme or nucleic acid molecules useful in co-suppression may first be protected such as by using a nonionic backbone.

The efficacy of the nucleic acid molecules of the present invention can be conveniently tested and screened using an in vitro system comprising a basal keratinocyte cell line. A particularly useful system comprises the HaCaT cell line described by Boukamp et al [9]. In one assay, IGF-I is added to an oligonucleotide treated HaCaT cell line. Alternatively, growth of oligonucleotide treated HaCaT cells is observed on a feeder layer of irradiated 3T3 fibroblasts. Using such in vitro assays, it is observed that antisense oligonucleotides to IGFBP-3, for example, inhibit production of IGFBP-3 by HaCaT cells. Other suitable animal models include the nude mouse/human skin graft model (15; 16) and the “flaky skin” mouse model (17; 18). In the nude mouse model, microdermatome biopsies of psoriasis lesions are taken under local anaesthetic from volunteers then transplanted to congenital athymic (nude) mice. These transplanted human skin grafts maintain the characteristic hyperproliferating epidermis for 6-8 weeks. They are an established model for testing the efficacy of topically applied therapies for psoriasis. In the “flaky skin” mouse model, the fsn/fsn mutation produces mice with skin resembling human psoriasis. This mouse, or another mutant mouse with a similar phenotype is a further in vivo model to test the efficacy of topically applied therapies for psoriasis.

Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents. Preferably, the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for co-suppression of one or more of these targets. The composition may comprise a single species of a nucleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.

The nucleic acid molecules may be administered in dispersions prepared in creams, ointments, oil or other suitable carrier and/or diluent such as glycerol, liquid polyethylene glycols and/or mixtures thereof. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.

The pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersions. In all cases, the form is preferably sterile although this is not an absolute requirement and is stable under the conditions of manufacture and storage. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of superfactants. The prevention of the action of microorganism can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride.

Topical solutions are prepared by incorporating the nucleic acid molecule compound in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by where necessary filter sterilization.

The active agent may alternatively be administered by intravenous, subcutaneous, nasal drip, suppository, implant means amongst other suitable routes of administration including intraperitoneal, intramuscular, absorption through epithelial or mucocutaneous linings for example via nasal, oral, vaginal, rectal or gastrointestinal administration. Reference may conveniently be made to reference 24.

As used herein “pharmaceutically acceptable carriers and/or diluents” include any and all solvents, dispersion media, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions. Conveniently, the nucleic acid molecules of the present invention are stored in freeze-dried form and are reconstituted prior to use.

Yet another aspect of the present invention contemplates the use of a nucleic acid molecule in the manufacture of a medicament for the treatment of proliferative and/or inflammatory skin disorders or other medical disorders mediated by a growth factor. The proliferative and/or inflammatory skin disorder is generally psoriasis or other medical disorders as described above and the nucleic acid molecule targets IGF-I, the IGF-I receptor and/or an IGFBP such as IGFBP-2 and/or IGFBP-3.

Still a further aspect of the present invention contemplates an agent comprising a nucleic acid molecule as hereinbefore defined useful in the treatment of proliferative and/or inflammatory skin disorders, such as psoriasis or other medical disorder.

The present invention further contemplates the use of the genetic molecules and in particular the antisense molecules to inhibit the anti-apoptotic activity of IGF-I receptor. Such a use is appropriate for the treatment of certain cancers and as adjunct therapy for epidermal hyperplasia such as in combination with UV treatment.

The present invention is further described by the following non-limiting Examples.

EXAMPLE 1

The differentiated human keratinocyte cell line, HaCaT [9] was used in the in vitro assay. Cells at passage numbers 33 to 36 were maintained as monolayer cultures in 5% V/V CO₂ at 37° C. in Keratinocyte-SFM (Gibco) containing EGF and bovine pituitary extract as supplied. Media containing foetal calf serum were avoided because of the high content of IGF-I binding proteins in serum.

Feeder layer plates of lethally irradiated 3T3 fibroblasts were prepared exactly as described by Rheinwald and Green [10].

EXAMPLE 2

Cells were grown to 4 days post confluence in 2 cm² wells with daily medium changes of Keratinocyte-SFM, then the medium was changed to DMEM (Cytosystems, Australia), with the following additions: 25 mM Hepes, 0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co, USA), 50IU/ml penicillin and 50 μg/ml streptomycin (Flow Laboratories). After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in 0.5 ml fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours. [³H]-Thymidine (0.1 μCi/well) was then added and the cells incubated for a further 3 hours. The medium was then aspirated and the cells washed once with ice-cold PBS and twice with ice-cold 10% v/v TCA. The TCA-precipitated monolayers were then solubilized with 0.25M NaOH (200 μl/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).

EXAMPLE 3

HaCaT conditioned medium (250 μl) was concentrated by adding 750 μl cold ethanol, incubating at −20° C. for 2 hours and centrifuging at 16,000 g for 20 min at 4° C. The resulting pellet was air dried, resuspended thoroughly in non-reducing Laemmli sample buffer, heated to 90° C. for 5 minutes and separated on 12% w/v SDS-PAGE according to the method of Laemmli (1970).

Separated proteins were electrophoretically transferred to nitrocellulose membrane (0.45 mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25 mM Tris, 192 mM glycine and 20% v/v methanol. IGFBPs were then visualised by the procedure of Hossenlopp et al [11], using [¹²⁵I]-IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.

EXAMPLE 4

Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Adelaide, South Australia, Australia. The following antisense sequences were used: BP3AS2, 5′-GCG CCC GCT GCA TGA CGC CTG CAA C-3′ (<400>4), a 25 mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, 5′-CGG GCG GCT CAC CTG GAG CTG GCG-3′ (<400>5), a 24 mer complementary to the exon 1/intron 1 splice site; BP3AS4, 5′-AGG CGG CTG ACG GCA CTA-3′(<400>6), an 18 mer complementary to a region of the coding sequence lacking RNA secondary structure and oligonucleotide-dimer formation (using the computer software “OLIGO for PC”). Since BP3AS4 was found to be ineffective at inhibiting IGFBP-3 synthesis, it was used as a control. The following additional control oligonucleotide sequences were used: BP3S, 5′-CAG GCG TCA TGC AGC GGG C-3′ (<400>7), an 18 mer sense control sequence equivalent to the start codon region; BP3AS2NS, 5′-CGG AGA TGC CGC ATG CCA GCG CAG G-3′ (<400>8), a 25 mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, 5′-GAC AGC GTC GGA GCG ATC-3′ (<400>9), an 18 mer randomised sequence with the same GC content as BP3AS4NS. Design of the oligonucleotides was based on the human IGFBP-3 cDNA sequence of Spratt et al [12].

Cells were grown to one day post confluence in 2 cm² wells with daily medium changes of 0.5 ml Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte-SFM for a further 4 days. Daily additions of 0.5 ml fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 5 μl oligonucleotide in PBS was added to give the final concentrations indicated, then the wells were shaken to mix the oligonucleotide. After the final addition, cells were incubated for 24 hours and the medium collected for assay of IGFBPs. Cells were then counted after trypsinisation in a Coulter Industrial D Counter, Coulter Bedfordshire, UK. Cell numbers after oligonucleotide treatment differed by less than 10%.

EXAMPLE 5

HaCaT cells secrete mainly IGFBP-3 (>95%), with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 (<5%). The effect on IGFBP-3 and IGFBP-4 synthesis of antisense oligonucleotides at two concentrations, 5 μM and 0.5 μM, was tested. Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in FIGS. 4A and 4B, all oligonucleotides at 5 μM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately 50% compared to the sense control (FIG. 4B). The antisense oligonucleotide directed to the start codon appeared to be more effective of the two, the difference being more apparent at the lower concentration of 0.5 μM. The cells of IGFBP-4 secreted by the HaCaT cells make photographic reproduction of the bands on Western ligand blots difficult, however densitometry measurements provide adequate relative quantitation. This resulted in the significant observation that IGFBP-4 levels were unaffected by oligonucleotide addition to the cells, suggesting that the observed inhibitory effects on IGFBP-3 are specific.

To further investigate the inhibitory effects of the more effective of the two antisense oligonucleotides, BP3AS2, inhibition by this oligonucleotide at 0.5 μM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5 μM. As shown in FIGS. 5A and 5B, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of BP3AS2. The other control oligonucleotides caused no reduction in IGFBP-3 levels at 0.5 μM, compared to untreated cells.

Of possible significance is the fact that this control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has the highest potential T_m of the three control oligonucleotides used in this experiment, enhancing the probability of non-specific base pairing with non-target mRNAs. However, the lack of inhibition of IGFBP-4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.

EXAMPLE 6

Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:

ATTCGGGGCGAGGGA	AGGAGGCGGCTCCCG	CACCTGCCCGCCCGC
TTCGGGGCGAGGGAG	GGAGGCGGCTCCCGC	ACCTGCCCGCCCGCC
TCGGGGCGAGGGAGG	GAGGCGGCTCCCGCT	CCTGCCCGCCCGCCC
CGGGGCGAGGGAGGA	AGGCGGCTCCCGCTC	CTGCCCGCCCGCCCG
GGGGCGAGGGAGGAG	GGCGGCTCCCGCTCG	TGCCCGCCCGCCCGC
GGGCGAGGGAGGAGG	GCGGCTCCCGCTCGC	GCCCGCCCGCCCGCT
GGCGAGGGAGGAGGA	CGGCTCCCGCTCGCA	CCCGCCCGCCCGCTC
GCGAGGGAGGAGGAA	GGCTCCCGCTCGCAG	CCGCCCGCCCGCTCG
CGAGGGAGGAGGAAG	GCTCCCGCTCGCAGG	CGCCCGCCCGCTCGC
GAGGGAGGAGGAAGA	CTCCCGCTCGCAGGG	GCCCGCCCGCTCGCT
AGGGAGGAGGAAGAA	TCCCGCTCGCAGGGC	CCCGCCCGCTCGCTC
GGGAGGAGGAAGAAG	CCCGCTCGCAGGGCC	CCGCCCGCTCGCTCG
GGAGGAGGAAGAAGC	CCGCTCGCAGGGCCG	CGCCCGCTCGCTCGC
GAGGAGGAAGAAGCG	CGCTCGCAGGGCCGT	GCCCGCTCGCTCGCT
AGGAGGAAGAAGCGG	GCTCGCAGGGCCGTG	CCCGCTCGCTCGCTC
GGAGGAAGAAGCGGA	CTCGCAGGGCCGTGC	CCGCTCGCTCGCTCG
GAGGAAGAAGCGGAG	TCGCAGGGCCGTGCA	CGCTCGCTCGCTCGC
AGGAAGAAGCGGAGG	CGCAGGGCCGTGCAC	GCTCGCTCGCTCGCC
GGAAGAAGCGGAGGA	GCAGGGCCGTGCACC	CTCGCTCGCTCGCCC
GAAGAAGCGGAGGAG	CAGGGCCGTGCACCT	TCGCTCGCTCGCCCG
AAGAAGCGGAGGAGG	AGGGCCGTGCACCTG	CGCTCGCTCGCCCGC
AGAAGCGGAGGAGGC	GGGCCGTGCACCTGC	GCTCGCTCGCCCGCC
GAAGCGGAGGAGGCG	GGCCGTGCACCTGCC	CTCGCTCGCCCGCCG
AAGCGGAGGAGGCGG	GCCGTGCACCTGCCC	TCGCTCGCCCGCCGC
AGCGGAGGAGGCGGC	CCGTGCACCTGCCCG	CGCTCGCCCGCCGCG
GCGGAGGAGGCGGCT	CGTGCACCTGCCCGC	GCTCGCCCGCCGCGC
CGGAGGAGGCGGCTC	GTGCACCTGCCCGCC	CTCGCCCGCCGCGCC
GGAGGAGGCGGCTCC	TGCACCTGCCCGCCC	TCGCCCGCCGCGCCG
GAGGAGGCGGCTCCC	GCACCTGCCCGCCCG	CGCCCGCCGCGCCGC
GCCCGCCGCGCCGCG	GGGCTGCCCCGCGCT	TGCTGCCGCTGCTGC
CCCGCCGCGCCGCGC	GGCTGCCCCGCGCTG	GCTGCCGCTGCTGCT
CCGCCGCGCCGCGCT	GCTGCCCCGCGCTGC	CTGCCGCTGCTGCTG
CGCCGCGCCGCGCTG	CTGCCCCGCGCTGCC	TGCCGCTGCTGCTGC
GCCGCGCCGCGCTGC	TGCCCCGCGCTGCCG	GCCGCTGCTGCTGCT
CCGCGCCGCGCTGCC	GCCCCGCGCTGCCGC	CCGCTGCTGCTGCTG
CGCGCCGCGCTGCCG	CCCCGCGCTGCCGCT	CGCTGCTGCTGCTGC
GCGCCGCGCTGCCGA	CCCGCGCTGCCGCTG	GCTGCTGCTGCTGCT
CGCCGCGCTGCCGAC	CCGCGCTGCCGCTGC	CTGCTGCTGCTGCTA
GCCGCGCTGCCGACC	CGCGCTGCCGCTGCC	TGCTGCTGCTGCTAC
CCGCGCTGCCGACCG	GCGCTGCCGCTGCCG	GCTGCTGCTGCTACT
CGCGCTGCCGACCGC	CGCTGCCGCTGCCGC	CTGCTGCTGCTACTG
GCGCTGCCGACCGCC	GCTGCCGCTGCCGCC	TGCTGCTGCTACTGG
CGCTGCCGACCGCCA	CTGCCGCTGCCGCCG	GCTGCTGCTACTGGG
GCTGCCGACCGCCAG	TGCCGCTGCCGCCGC	CTGCTGCTACTGGGC
CTGCCGACCGCCAGC	GCCGCTGCCGCCGCC	TGCTGCTACTGGGCG
TGCCGACCGCCAGCA	CCGCTGCCGCCGCCG	GCTGCTACTGGGCGC
GCCGACCGCCAGCAT	CGCTGCCGCCGCCGC	CTGCTACTGGGCGCG
CCGACCGCCAGCATG	GCTGCCGCCGCCGCC	TGCTACTGGGCGCGA
CGACCGCCAGCATGC	CTGCCGCCGCCGCCG	GCTACTGGGCGCGAG
GACCGCCAGCATGCT	TGCCGCCGCCGCCGC	CTACTGGGCGCGAGT
ACCGCCAGCATGCTG	GCCGCCGCCGCCGCT	TACTGGGCGCGAGTG
CCGCCAGCATGCTGC	CCGCCGCCGCCGCTG	ACTGGGCGCGAGTGG
CGCCAGCATGCTGCC	CGCCGCCGCCGCTGC	CTGGGCGCGAGTGGC
GCCAGCATGCTGCCG	GCCGCCGCCGCTGCT	TGGGCGCGAGTGGCG
CCAGCATGCTGCCGA	CCGCCGCCGCTGCTG	GGGCGCGAGTGGCGG
CAGCATGCTGCCGAG	CGCCGCCGCTGCTGC	GGCGCGAGTGGCGGC
AGCATGCTGCCGAGA	GCCGCCGCTGCTGCC	GCGCGAGTGGCGGCG
GCATGCTGCCGAGAG	CCGCCGCTGCTGCCG	CGCGAGTGGCGGCGG
CATGCTGCCGAGAGT	CGCCGCTGCTGCCGC	GCGAGTGGCGGCGGC
ATGCTGCCGAGAGTG	GCCGCTGCTGCCGCT	CGAGTGGCGGCGGCG
TGCTGCCGAGAGTGG	CCGCTGCTGCCGCTG	GAGTGGCGGCGGCGG
GCTGCCGAGAGTGGG	CGCTGCTGCCGCTGC	AGTGGCGGCGGCGGC
CTGCCGAGAGTGGGC	GCTGCTGCCGCTGCT	GTGGCGGCGGCGGCG
TGCCGAGAGTGGGCT	CTGCTGCCGCTGCTG	TGGCGGCGGCGGCGG
GCCGAGAGTGGGCTG	TGCTGCCGCTGCTGC	GGCGGCGGCGGCGGG
CCGAGAGTGGGCTGC	GCTGCCGCTGCTGCC	GCGGCGGCGGCGGGG
CGAGAGTGGGCTGCC	CTGCCGCTGCTGCCG	CGGCGGCGGCGGGGC
GAGAGTGGGCTGCCC	TGCCGCTGCTGCCGC	GGCGGCGGCGGGGCG
AGAGTGGGCTGCCCC	GCCGCTGCTGCCGCT	GCGGCGGCGGGGCGC
GAGTGGGCTGCCCCG	CCGCTGCTGCCGCTG	CGGCGGCGGGGCGCG
AGTGGGCTGCCCCGC	CGCTGCTGCCGCTGC	GGCGGCGGGGCGCGC
GTGGGCTGCCCCGCG	GCTGCTGCCGCTGCT	GCGGCGGGGCGCGCG
TGGGCTGCCCCGCGC	CTGCTGCCGCTGCTG	CGGCGGGGCGCGCGC
GGCGGGGCGCGCGCG	ACCCGAGCGCCTGGC	CCGCCGCGGTGGCCG
GCGGGGCGCGCGCGG	CCCGAGCGCCTGGCC	CGCCGCGGTGGCCGC
CGGGGCGCGCGCGGA	CCGAGCGCCTGGCCG	GCCGCGGTGGCCGCA
GGGGCGCGCGCGGAG	CGAGCGCCTGGCCGC	CCGCGGTGGCCGCAG
GGGCGCGCGCGGAGG	GAGCGCCTGGCCGCC	CGCGGTGGCCGCAGT
GGCGCGCGCGGAGGT	AGCGCCTGGCCGCCT	GCGGTGGCCGCAGTG
GCGCGCGCGGAGGTG	GCGCCTGGCCGCCTG	CGGTGGCCGCAGTGG
CGCGCGCGGAGGTGC	CGCCTGGCCGCCTGC	GGTGGCCGCAGTGGC
GCGCGCGGAGGTGCT	GCCTGGCCGCCTGCG	GTGGCCGCAGTGGCC
CGCGCGGAGGTGCTG	CCTGGCCGCCTGCGG	TGGCCGCAGTGGCCG
GCGCGGAGGTGCTGT	CTGGCCGCCTGCGGG	GGCCGCAGTGGCCGG
CGCGGAGGTGCTGTT	TGGCCGCCTGCGGGC	GCCGCAGTGGCCGGA
GCGGAGGTGCTGTTC	GGCCGCCTGCGGGCC	CCGCAGTGGCCGGAG
CGGAGGTGCTGTTCC	GCCGCCTGCGGGCCC	CGCAGTGGCCGGAGG
GGAGGTGCTGTTCCG	CCGCCTGCGGGCCCC	GCAGTGGCCGGAGGC
GAGGTGCTGTTCCGC	CGCCTGCGGGCCCCC	CAGTGGCCGGAGGCG
AGGTGCTGTTCCGCT	GCCTGCGGGCCCCCG	AGTGGCCGGAGGCGC
GGTGCTGTTCCGCTG	CCTGCGGGCCCCCGC	GTGGCCGGAGGCGCC
GTGCTGTTCCGCTGC	CTGCGGGCCCCCGCC	TGGCCGGAGGCGCCC
TGCTGTTCCGCTGCC	TGCGGGCCCCCGCCG	GGCCGGAGGCGCCCG
GCTGTTCCGCTGCCC	GCGGGCCCCCGCCGG	GCCGGAGGCGCCCGC
CTGTTCCGCTGCCCG	CGGGCCCCCGCCGGT	CCGGAGGCGCCCGCA
TGTTCCGCTGCCCGC	GGGCCCCCGCCGGTT	CGGAGGCGCCCGCAT
GTTCCGCTGCCCGCC	GGCCCCCGCCGGTTG	GGAGGCGCCCGCATG
TTCCGCTGCCCGCCC	GCCCCCGCCGGTTGC	GAGGCGCCCGCATGC
TCCGCTGCCCGCCCT	CCCCCGCCGGTTGCG	AGGCGCCCGCATGCC
CCGCTGCCCGCCCTG	CCCCGCCGGTTGCGC	GGCGCCCGCATGCCA
CGCTGCCCGCCCTGC	CCCGCCGGTTGCGCC	GCGCCCGCATGCCAT
GCTGCCCGCCCTGCA	CCCCCGGTTGCGCCG	CGCCCGCATGCCATG
CTGCCCGCCCTGCAC	CGCCGGTTGCGCCGC	GCCCGCATGCCATGC
TGCCCGCCCTGCACA	GCCGGTTGCGCCGCC	CCCGCATGCCATGCG
GCCCGCCCTGCACAC	CCGGTTGCGCCGCCC	CCGCATGCCATGCGC
CCCGCCCTGCACACC	CGGTTGCGCCGCCCG	CGCATGCCATGCGCG
CCGCCCTGCACACCC	GGTTGCGCCGCCCGC	GCATGCCATGCGCGG
CGCCCTGCACACCCG	GTTGCGCCGCCCGCC	CATGCCATGCGCGGA
GCCCTGCACACCCGA	TTGCGCCGCCCGCCG	ATGCCATGCGCGGAG
CCCTGCACACCCGAG	TGCGCCGCCCGCCGC	TGCCATGCGCGGAGC
CCTGCACACCCGAGC	GCGCCGCCCGCCGCG	GCCATGCGCGGAGCT
CTGCACACCCGAGCG	CGCCGCCCGCCGCGG	CCATGCGCGGAGCTC
TGCACACCCGAGCGC	GCCGCCCGCCGCGGT	CATGCGCGGAGCTCG
GCACACCCGAGCGCC	CCGCCCGCCGCGGTG	ATGCGCGGAGCTCGT
CACACCCGAGCGCCT	CGCCCGCCGCGGTGG	TGCGCGGAGCTCGTC
ACACCCGAGCGCCTG	GCCCGCCGCGGTGGC	GCGCGGAGCTCGTCC
CACCCGAGCGCCTGG	CCCGCCGCGGTGGCC	CGCGGAGCTCGTCCG
GCGGAGCTCGTCCGG	CGCCCGGCTGGAGGG	GCGGCCAGGGGCTGC
CGGAGCTCGTCCGCG	GCCCGGCTGGAGGGC	CGGCCAGGGGCTGCG
GGAGCTCGTCCGGGA	CCCGGCTGGAGGGCG	GGCCAGGGGCTGCGC
GAGCTCGTCCGGGAG	CCGGCTGGAGGGCGA	GCCAGGGGCTGCGCT
AGCTCGTCCGGGAGC	CGGCTGGAGGGCGAG	CCAGGGGCTGCGCTG
GCTCGTCCGGGAGCC	GGCTGGAGGGCGAGG	CAGGGGCTGCGCTGC
CTCGTCCGGGAGCCG	GCTGGAGGGCGAGGC	AGGGGCTGCGCTGCT
TCGTCCGGGAGCCGG	CTGGAGGGCGAGGCG	GGGGCTGCGCTGCTA
CGTCCGGGAGCCGGG	TGGAGGGCGAGGCGT	GGGCTGCGCTGCTAT
GTCCGGGAGCCGGGC	GGAGGGCGAGGCGTG	GGCTGCGCTGCTATC
TCCGGGAGCCGGGCT	GAGGGCGAGGCGTGC	GCTGCGCTGCTATCC
CCGGGAGCCGGGCTG	AGGGCGAGGCGTGCG	CTGCGCTGCTATCCC
CGGGAGCCGGGCTGC	GGGCGAGGCGTGCGG	TGCGCTGCTATCCCC
GGGAGCCGGGCTGCG	GGCGAGGCGTGCGGC	GCGCTGCTATCCCCA
GGAGCCGGGCTGCGG	GCGAGGCGTGCGGCG	CGCTGCTATCCCCAC
GAGCCGGGCTGCGGC	CGAGGCGTGCGGCGT	GCTGCTATCCCCACC
AGCCGGGCTGCGGCT	GAGGCGTGCGGCGTC	CTGCTATCCCCACCC
GCCGGGCTGCGGCTG	AGGCGTGCGGCGTCT	TGCTATCCCCACCCG
CCGGGCTGCGGCTGC	GGCGTGCGGCGTCTA	GCTATCCCCACCCGG
CGGGCTGCGGCTGCT	GCGTGCGGCGTCTAC	CTATCCCCACCCGGG
GGGCTGCGGCTGCTG	CGTGCGGCGTCTACA	TATCCCCACCCGGGC
GGCTGCGGCTGCTGC	GTGCGGCGTCTACAC	ATCCCCACCCGGGCT
GCTGCGGCTGCTGCT	TGCGGCGTCTACACC	TCCCCACCCGGGCTC
CTGCGGCTGCTGCTC	GCGGCGTCTACACCC	CCCCACCCGGGCTCC
TGCGGCTGCTGCTCG	CGGCGTCTACACCCC	CCCACCCGGGCTCCG
GCGGCTGCTGCTCGG	GGCGTCTACACCCCG	CCACCCGGGCTCCGA
CGGCTGCTGCTCGGT	GCGTCTACACCCCGC	CACCCGGGCTCCGAG
GGCTGCTGCTCGGTG	CGTCTACACCCCGCG	ACCCGGGCTCCGAGC
GCTGCTGCTCGGTGT	GTCTACACCCCGCGC	CCCGGGCTCCGAGCT
CTGCTGCTCGGTGTG	TCTACACCCCGCGCT	CCGGGCTCCGAGCTG
TGCTGCTCGGTGTGC	CTACACCCCGCGCTG	CGGGCTCCGAGCTGC
GCTGCTCGGTGTGCG	TACACCCCGCGCTGC	GGGCTCCGAGCTGCC
CTGCTCGGTGTGCGC	ACACCCCGCGCTGCG	GGCTCCGAGCTGCCC
TGCTCGGTGTGCGCC	CACCCCGCGCTGCGG	GCTCCGAGCTGCCCC
GCTCGGTGTGCGCCC	ACCCCGCGCTGCGGC	CTCCGAGCTGCCCCT
CTCGGTGTGCGCCCG	CCCCGCGCTGCGGCC	TCCGAGCTGCCCCTG
TCGGTGTGCGCCCGG	CCCGCGCTGCGGCCA	CCGAGCTGCCCCTGC
CGGTGTGCGCCCGGC	CCGCGCTGCGGCCAG	CGAGCTGCCCCTGCA
GGTGTGCGCCCGGCT	CGCGCTGCGGCCAGG	GAGCTGCCCCTGCAG
GTGTGCGCCCGGCTG	GCGCTGCGGCCAGGG	AGCTGCCCCTGCAGG
TGTGCGCCCGGCTGG	CGCTGCGGCCAGGGG	GCTGCCCCTGCAGGC
GTGCGCCCGGCTGGA	GCTGCGGCCAGGGGC	CTGCCCCTGCAGGCG
TGCGCCCGGCTGGAG	CTGCGGCCAGGGGCT	TGCCCCTGCAGGCGC
GCGCCCGGCTGGAGG	TGCGGCCAGGGGCTG	GCCCCTGCAGGCGCT
CCCCTGCAGGCGCTG	CCGGGACGCCGAGTA	ATGGCGATGACCACT
CCCTGCAGGCGCTGG	CGGGACGCCGAGTAT	TGGCGATGACCACTC
CCTGCAGGCGCTGGT	GGGACGCCGAGTATG	GGCGATGACCACTCA
CTGCAGGCGCTGGTC	GGACGCCGAGTATGG	GCGATGACCACTCAG
TGCAGGCGCTGGTCA	GACGCCGAGTATGGC	CGATGACCACTCAGA
GCAGGCGCTGGTCAT	ACGCCGAGTATGGCG	GATGACCACTCAGAA
CAGGCGCTGGTCATG	CGCCGAGTATGGCGC	ATGACCACTCAGAAG
AGGCGCTGGTCATGG	GCCGAGTATGGCGCC	TGACCACTCAGAAGG
GGCGCTGGTCATGGG	CCGAGTATGGCGCCA	GACCACTCAGAAGGA
GCGCTGGTCATGGGC	CGAGTATGGCGCCAG	ACCACTCAGAAGGAG
CGCTGGTCATGGGCG	GAGTATGGCGCCAGC	CCACTCAGAAGGAGG
GCTGGTCATGGGCGA	AGTATGGCGCCAGCC	CACTCAGAAGGAGGC
CTGGTCATGGGCGAG	GTATGGCGCCAGCCC	ACTCAGAAGGAGGCC
TGGTCATGGGCGAGG	TATGGCGCCAGCCCG	CTCAGAAGGAGGCCT
GGTCATGGGCGAGGG	ATGGCGCCAGCCCGG	TCAGAAGGAGGCCTG
GTCATGGGCGAGGGC	TGGCGCCAGCCCGGA	CAGAAGGAGGCCTGG
TCATGGGCGAGGGCA	GGCGCCAGCCCGGAG	AGAAGGAGGCCTGGT
CATGGGCGAGGGCAC	GCGCCAGCCCGGAGC	GAAGGAGGCCTGGTG
ATGGGCGAGGGCACT	CGCCAGCCCGGAGCA	AAGGAGGCCTGGTGG
TGGGCGAGGGCACTT	GCCAGCCCGGAGCAG	AGGAGGCCTGGTGGA
GGGCGAGGGCACTTG	CCAGCCCGGAGCAGG	GGAGGCCTGGTGGAG
GGCGAGGGCACTTGT	CAGCCCGGAGCAGGT	GAGGCCTGGTGGAGA
GCGAGGGCACTTGTG	AGCCCGGAGCAGGTT	AGGCCTGGTGGAGAA
CGAGGGCACTTGTGA	GCCCGGAGCAGGTTG	GGCCTGGTGGAGAAC
GAGGGCACTTGTGAG	CCCGGAGCAGGTTGC	GCCTGGTGGAGAACC
AGGGCACTTGTGAGA	CCGGAGCAGGTTGCA	CCTGGTGGAGAACCA
GGGCACTTGTGAGAA	CGGAGCAGGTTGCAG	CTGGTGGAGAACCAC
GGCACTTGTGAGAAG	GGAGCAGGTTGCAGA	TGGTGGAGAACCACG
GCACTTGTGAGAAGC	GAGCAGGTTGCAGAC	GGTGGAGAACCACGT
CACTTGTGAGAAGCG	AGCAGGTTGCAGACA	GTGGAGAACCACGTG
ACTTGTGAGAAGCGC	GCAGGTTGCAGACAA	TGGAGAACCACGTGG
CTTGTGAGAAGCGCC	CAGGTTGCAGACAAT	GGAGAACCACGTGGA
TTGTGAGAAGCGCCG	AGGTTGCAGACAATG	GAGAACCACGTGGAC
TGTGAGAAGCGCCGG	GGTTGCAGACAATGG	AGAACCACGTGGACA
GTGAGAAGCGCCGGG	GTTGCAGACAATGGC	GAACCACGTGGACAG
TGAGAAGCGCCGGGA	TTGCAGACAATGGCG	AACCACGTGGACAGC
GAGAAGCGCCGGGAC	TGCAGACAATGGCGA	ACCACGTGGACAGCA
AGAAGCGCCGGGACG	GCAGACAATGGCGAT	CCACGTGGACAGCAC
GAAGCGCCGGGACGC	CAGACAATGGCGATG	CACGTGGACAGCACC
AAGCGCCGGGACGCC	AGACAATGGCGATGA	ACGTGGACAGCACCA
AGCGCCGGGACGCCG	GACAATGGCGATGAC	CGTGGACAGCACCAT
GCGCCGGGACGCCGA	ACAATGGCGATGACC	GTGGACAGCACCATG
CGCCGGGACGCCGAG	CAATGGCGATGACCA	TGGACAGCACCATGA
GCCGGGACGCCGAGT	AATGGCGATGACCAC	GGACAGCACCATGAA
GACAGCACCATGAAC	GAAGCCCCTCAAGTC	AGAAGGTCACTGAGC
ACAGCACCATGAACA	AAGCCCCTCAAGTCG	GAAGGTCACTGAGCA
CAGCACCATGAACAT	AGCCCCTCAAGTCGG	AAGGTCACTGAGCAG
AGCACCATGAACATG	GCCCCTCAAGTCGGG	AGGTCACTGAGCAGC
GCACCATGAACATGT	CCCCTCAAGTCGGGT	GGTCACTGAGCAGCA
CACCATGAACATGTT	CCCTCAAGTCGGGTA	GTCACTGAGCAGCAC
ACCATGAACATGTTG	CCTCAAGTCGGGTAT	TCACTGAGCAGCACC
CCATGAACATGTTGG	CTCAAGTCGGGTATG	CACTGAGCAGCACCG
CATGAACATGTTGGG	TCAAGTCGGGTATGA	ACTGAGCAGCACCGG
ATGAACATGTTGGGC	CAAGTCGGGTATGAA	CTGAGCAGCACCGGC
TGAACATGTTGGGCG	AAGTCGGGTATGAAG	TGAGCAGCACCGGCA
GAACATGTTGGGCGG	AGTCGGGTATGAAGG	GAGCAGCACCGGCAG
AACATGTTGGGCGGG	GTCGGGTATGAAGGA	AGCAGCACCGGCAGA
ACATGTTGGGCGGGG	TCGGGTATGAAGGAG	GCAGCACCGGCAGAT
CATGTTGGGCGGGGG	CGGGTATGAAGGAGC	CAGCACCGGCAGATG
ATGTTGGGCGGGGGA	GGGTATGAAGGAGCT	AGCACCGGCAGATGG
TGTTGGGCGGGGGAG	GGTATGAAGGAGCTG	GCACCGGCAGATGGG
GTTGGGCGGGGGAGG	GTATGAAGGAGCTGG	CACCGGCAGATGGGC
TTGGGCGGGGGAGGC	TATGAAGGAGCTGGC	ACCGGCAGATGGGCA
TGGGCGGGGGAGGCA	ATGAAGGAGCTGGCC	CCGGCAGATGGGCAA
GGGCGGGGGAGGCAG	TGAAGGAGCTGGCCG	CGGCAGATGGGCAAG
GGCGGGGGAGGCAGT	GAAGGAGCTGGCCGT	GGCAGATGGGCAAGG
GCGGGGGAGGCAGTG	AAGGAGCTGGCCGTG	GCAGATGGGCAAGGG
CGGGGGAGGCAGTGC	AGGAGCTGGCCGTGT	CAGATGGGCAAGGGT
GGGGGAGGCAGTGCT	GGAGCTGGCCGTGTT	AGATGGGCAAGGGTG
GGGGAGGCAGTGCTG	GAGCTGGCCGTGTTC	GATGGGCAAGGGTGG
GGGAGGCAGTGCTGG	AGCTGGCCGTGTTCC	ATGGGCAAGGGTGGC
GGAGGCAGTGCTGGC	GCTGGCCGTGTTCCG	TGGGCPAGGGTGGCA
GAGGCAGTGCTGGCC	CTGGCCGTGTTCCGG	GGGCAAGGGTGGCAA
AGGCAGTGCTGGCCG	TGGCCGTGTTCCGGG	GGCAAGGGTGGCAAG
GGCAGTGCTGGCCGG	GGCCGTGTTCCGGGA	GCAAGGGTGGCAAGC
GCAGTGCTGGCCGGA	GCCGTGTTCCGGGAG	CAAGGGTGGCAAGCA
CAGTGCTGGCCGGAA	CCGTGTTCCGGGAGA	AAGGGTGGCAAGCAT
AGTGCTGGCCGGAAG	CGTGTTCCGGGAGAA	AGGGTGGCAAGCATC
GTGCTGGCCGGAAGC	GTGTTCCGGGAGAAG	GGGTGGCAAGCATCA
TGCTGGCCGGAAGCC	TGTTCCGGGAGAAGG	GGTGGCAAGCATCAC
GCTGGCCGGAAGCCC	GTTCCGGGAGAAGGT	GTGGCAAGCATCACC
CTGGCCGGAAGCCCC	TTCCGGGAGAAGGTC	TGGCAAGCATCACCT
TGGCCGGAAGCCCCT	TCCGGGAGAAGGTCA	GGCAAGCATCACCTT
GGCCGGAAGCCCCTC	CCGGGAGAAGGTCAC	GCAAGCATCACCTTG
GCCGGAAGCCCCTCA	CGGGAGAAGGTCACT	CAAGCATCACCTTGG
CCGGAAGCCCCTCAA	GGGAGAAGGTCACTG	AAGCATCACCTTGGC
CGGAAGCCCCTCAAG	GGAGAAGGTCACTGA	AGCATCACCTTGGCC
GGAAGCCCCTCAAGT	GAGAAGGTCACTGAG	GCATCACCTTGGCCT
CATCACCTTGGCCTG	TGCCAGGACTCCCTG	GGATCTCCACCATGC
ATCACCTTGGCCTGG	GCCAGGACTCCCTGC	GATCTCCACCATGCG
TCACCTTGGCCTCGA	CCAGGACTCCCTGCC	ATCTCCACCATGCGC
CACCTTGGCCTGGAG	CAGGACTCCCTGCCA	TCTCCACCATGCGCC
ACCTTGGCCTGGAGG	AGGACTCCCTGCCAA	CTCCACCATGCGCCT
CCTTGGCCTGGAGGA	GGACTCCCTGCCAAC	TCCACCATGCGCCTT
CTTGGCCTGGAGGAG	GACTCCCTGCCAACA	CCACCATGCGCCTTC
TTGGCCTGGAGGAGC	ACTCCCTGCCAACAG	CACCATGCGCCTTCC
TGGCCTGGAGGAGCC	CTCCCTGCCAACAGG	ACCATGCGCCTTCCG
GGCCTGGAGGAGCCC	TGCCTGCCAACAGGA	GGATGCGCCTTCCGG
GCCTGGAGGACCCCA	GCCTGCCAACAGGAA	CATGCGCCTTCCGGA
CCTGGAGGAGCCCAA	CCTGCCAACAGGAAC	ATGCGCCTTCCGGAT
CTGGAGGAGCCCAAG	CTGCCAACAGGAACT	TGCGCCTTCCGGATG
TGGAGGAGCCCAAGA	TGCCAACAGGAACTG	GCGCCTTCCGGATGA
GGAGGAGCCCAAGAA	GCCAACAGGAACTGG	CGCCTTCCGGATGAG
GAGGAGCCCAAGAAG	CCAACAGGAACTGGA	GCCTTCCGGATGAGC
AGGAGCCCAAGAAGC	CAACAGGAACTGGAC	CCTTCCGGATGAGCG
GGAGCCCAAGAAGCT	AACAGGAACTGGACC	CTTCCGGATGAGCGG
GAGCCCAAGAAGCTG	ACAGGAACTGGACCA	TTCCGGATGAGCGGG
AGCCCAAGAAGCTGC	CAGGAACTGGACCAG	TCCGGATGAGCGGGG
GCCCAAGAAGCTGCG	AGGAACTGGACCAGG	CCGGATGAGCGGGGC
CCCAAGAAGCTGCGA	GGAACTGGACCAGGT	CGGATGAGCGGGGCC
CCAAGAAGCTGCGAC	GAACTGGACCAGGTC	GGATGAGCGGGGCCC
CAAGAAGCTGCGACC	AACTGGACCAGGTCC	GATGAGCGGGGCCCT
AAGAAGCTGCGACCA	ACTGGACCAGGTCCT	ATGAGCGGGGCCCTC
AGAAGCTGCGACCAC	CTGGACCAGGTCCTG	TGAGCGGGGCCCTCT
GAAGCTGCGACCACC	TGGACCAGGTCCTGG	GAGCGGGGCCCTCTG
AAGCTGCGACCACCC	GGACCAGGTCCTGGA	AGCGGGGCCCTCTGG
AGCTGCGACCACCCC	GACCAGGTCCTGGAG	GCGGGGCCCTCTGGA
GCTGCGACCACCCCC	ACCAGGTCCTGGAGC	CGGGGCCCTCTGGAG
CTGCGACCACCCCCT	CCAGGTCCTGGAGCG	GGGGCCCTCTGGAGC
TGCGACCACCCCCTG	CAGGTCCTGGAGCGG	GGGCCCTCTGGAGCA
GCGACCACCCCCTGC	AGGTCCTGGAGCGGA	GGCCCTCTGGAGCAC
CGACCACCCCCTGCC	GGTCCTGGAGCGGAT	GCCCTCTGGAGCACC
GACCACCCCCTGCCA	GTCCTGGAGCGGATC	CCCTCTGGAGCACCT
ACCACCCCCTGCCAG	TCCTGGAGCGGATCT	CCTCTGGAGCACCTC
CCACCCCCTGCCAGG	CCTGGAGCGGATCTC	CTCTGGAGCACCTCT
CACCCCCTGCCAGGA	CTGGAGCGGATCTCC	TCTGGAGCACCTCTA
ACCCCCTGCCAGGAC	TGGAGCGGATCTCCA	CTGGAGCACCTCTAC
CCCCCTGCCAGGACT	GGAGCGGATCTCCAC	TGGAGCACCTCTACT
CCCCTGCCAGGACTC	GAGCGGATCTCCACC	GGAGCACCTCTACTC
CCCTGCCAGGACTCC	AGCGGATCTCCACCA	GAGCACCTCTACTCC
CCTGCCAGGACTCCC	GCGGATCTCCACCAT	AGCACCTCTACTCCC
CTGCCAGGACTCCCT	CGGATCTCCACCATG	GCACCTCTACTCCCT
CACCTCTACTCCCTG	GTACAACCTCAAACA	GGGAGTGCTGGTGTG
ACCTCTACTCCCTGC	TACAACCTCAAACAG	GGAGTGCTGGTGTGT
CCTCTACTCCCTGCA	ACAACCTCAAACAGT	GAGTGCTGGTGTGTG
CTCTACTCCCTGCAC	CAACCTCAAACAGTG	AGTGCTGGTGTGTGA
TCTACTCCCTGCACA	AACCTCAAACAGTGC	GTGCTGGTGTGTGAA
CTACTCCCTGCACAT	ACCTCAAACAGTGCA	TGCTGGTGTGTGAAC
TACTCCCTGCACATC	CCTCAAACAGTGCAA	GCTGGTGTGTGAACC
ACTCCCTGCACATCC	CTCAAACAGTGCAAG	CTGGTGTGTGAACCC
CTCCCTGCACATCCC	TCAAACAGTGCAAGA	TGGTGTGTGAACCCC
TCCCTGCACATCCCC	CAAACAGTGCAAGAT	GGTGTGTGAACCCCA
CCCTGCACATCCCCA	AAACAGTGCAAGATG	GTGTGTGAACCCCAA
CCTGCACATCCCCAA	AACAGTGCAAGATGT	TGTGTGAACCCCAAC
CTGCACATCCCCAAC	ACAGTGCAAGATGTC	GTGTGAACCCCAACA
TGCACATCCCCAACT	CAGTGCAAGATGTCT	TGTGAACCCCAACAC
GCACATCCCCAACTG	AGTGCAAGATGTCTC	GTGAACCCCAACACC
CACATCCCCAACTGT	GTGCAAGATGTCTCT	TGAACCCCAACACCG
ACATCCCCAACTGTG	TGCAAGATGTCTCTG	GAACCCCAACACCGG
CATCCCCAACTGTGA	GCAAGATGTCTCTGA	AACCCCAACACCGGG
ATCCCCAACTGTGAC	CAAGATGTCTCTGAA	ACCCCAACACCGGGA
TCCCCAACTGTGACA	AAGATGTCTCTGAAC	CCCCAACACCGGGAA
CCCCAACTGTGACAA	AGATGTCTCTGAACG	CCCAACACCGGGAAG
CCCAACTGTGACAAG	GATGTCTCTGAACGG	CCAACACCGGGAAGC
CCAACTGTGACAAGC	ATGTCTCTGAACGGG	CAACACCGGGAAGCT
CAACTGTGACAAGCA	TGTCTCTGAACGGGC	AACACCGGGAAGCTG
AACTGTGACAAGCAT	GTCTCTGAACGGGCA	ACACCGGGAAGCTGA
ACTGTGACAAGCATG	TCTCTGAACGGGCAG	CACCGGGAAGCTGAT
CTGTGACAAGCATGG	CTCTGAACGGGCAGC	ACCGGGAAGCTGATC
TGTGACAAGCATGGC	TCTGAACGGGCAGCG	CCGGGAAGCTGATCC
GTGACAAGCATGGCC	CTGAACGGGCAGCGT	CGGGAAGCTGATCCA
TGACAAGCATGGCCT	TGAACGGGCAGCGTG	GGGAAGCTGATCCAG
GACAAGCATGGCCTG	GAACGGGCAGCGTGG	GGAAGCTGATCCAGG
ACAAGCATGGCCTGT	AACGGGCAGCGTGGG	GAAGCTGATCCAGGG
CAAGCATGGCCTGTA	ACGGGCAGCGTGGGG	AAGCTGATCCAGGGA
AAGCATGGCCTGTAC	CGGGCAGCGTGGGGA	AGCTGATCCAGGGAG
AGCATGGCCTGTACA	GGGCAGCGTGGGGAG	GCTGATCCAGGGAGC
GCATGGCCTGTACAA	GGCAGCGTGGGGAGT	CTGATCCAGGGAGCC
CATGGCCTGTACAAC	GCAGCGTGGGGAGTG	TGATCCAGGGAGCCC
ATGGCCTGTACAACC	CAGCGTGGGGAGTGC	GATCCAGGGAGCCCC
TGGCCTGTACAACCT	AGCGTGGGGAGTGCT	ATCCAGGGAGCCCCC
GGCCTGTACAACCTC	GCGTGGGGAGTGCTG	TCCAGGGAGCCCCCA
GCCTGTACAACCTCA	CGTGGGGAGTGCTGG	CCAGGGAGCCCCCAC
CCTGTACAACCTCAA	GTGGGGAGTGCTGGT	CAGGGAGCCCCCACC
CTGTACAACCTCAAA	TGGGGAGTGCTGGTG	AGGGAGCCCCCACCA
TGTACAACCTCAAAC	GGGGAGTGCTGGTGT	GGGAGCCCCCACCAT
GGAGCCCCCACCATC	CAATGAGCAGCAGGA	AGTAGACCGCAGCCA
GAGCCCCCACCATCC	AATGAGCAGCAGGAG	GTAGACCGCAGCCAG
AGCCCCCACCATCCG	ATGAGCAGCAGGAGG	TAGACCGCAGCCAGC
GCCCCCACCATCCGG	TGAGCAGCAGGAGGC	AGACCGCAGCCAGCC
CCCCCACCATCCGGG	GAGCAGCAGGAGGCT	GACCGCAGCCAGCCG
CCCCACCATCCGGGG	AGCAGCAGGAGGCTT	ACCGCAGCCAGCCGG
CCCACCATCCGGGGG	GCAGCAGGAGGCTTG	CCGCAGCCAGCCGGT
CCACCATCCGGGGGG	CAGCAGGAGGCTTGC	CGCAGCCAGCCGGTG
CACCATCCGGGGGGA	AGCAGGAGGCTTGCG	GCAGCCAGCCGGTGC
ACCATCCGGGGGGAC	GCAGGAGGCTTGCGG	CAGCCAGCCGGTGCC
CCATCCGGGGGGACC	CAGGAGGCTTGCGGG	AGCCAGCCGGTGCCT
CATCCGGGGGGACCC	AGGAGGCTTGCGGGG	GCCAGCCGGTGCCTG
ATCCGGGGGGACCCC	GGAGGCTTGCGGGGT	CCAGCCGGTGCCTGG
TCCGGGGGGACCCCG	GAGGCTTGCGGGGTG	CAGCCGGTGCCTGGC
CCGGGGGGACCCCGA	AGGCTTGCGGGGTGC	AGCCGGTGCCTGGCG
CGGGGGGACCCCGAG	GGCTTGCGGGGTGCA	GCCGGTGCCTGGCGC
GGGGGGACCCCGAGT	GCTTGCGGGGTGCAC	CCGGTGCCTGGCGCC
GGGGGACCCCGAGTG	CTTGCGGGGTGCACA	CGGTGCCTGGCGCCC
GGGGACCCCGAGTGT	TTGCGGGGTGCACAC	GGTGCCTGGCGCCCC
GGGACCCCGAGTGTC	TGCGGGGTGCACACC	GTGCCTGGCGCCCCT
GGACCCCGAGTGTCA	GCGGGGTGCACACCC	TGCCTGGCGCCCCTG
GACCCCGAGTGTCAT	CGGGGTGCACACCCA	GCCTGGCGCCCCTGC
ACCCCGAGTGTCATC	GGGGTGCACACCCAG	CCTGGCGCCCCTGCC
CCCCGAGTGTCATCT	GGGTGCACACCCAGC	CTGGCGCCCCTGCCC
CCCGAGTGTCATCTC	GGTGCACACCCAGCG	TGGCGCCCCTGCCCC
CCGAGTGTCATCTCT	GTGCACACCCAGCGG	GGCGCCCCTGCCCCC
CGAGTGTCATCTCTT	TGCACACCCAGCGGA	GCGCCCCTGCCCCCC
GAGTGTCATCTCTTC	GCACACCCAGCGGAT	CGCCCCTGCCCCCCG
AGTGTCATCTCTTCT	CACACCCAGCGGATG	GCCCCTGCCCCCCGC
GTGTCATCTCTTCTA	ACACCCAGCGGATGC	CCCCTGCCCCCCGCC
TGTCATCTCTTCTAC	CACCCAGCGGATGCA	CCCTGCCCCCCGCCC
GTCATCTCTTCTACA	ACCCAGCGGATGCAG	CCTGCCCCCCGCCCC
TCATCTCTTCTACAA	CCCAGCGGATGCAGT	CTGCCCCCCGCCCCT
CATCTCTTCTACAAT	CCAGCGGATGCAGTA	TGCCCCCCGCCCCTC
ATCTCTTCTACAATG	CAGCGGATGCAGTAG	GCCCCCCGCCCCTCT
TCTCTTCTACAATGA	AGCGGATGCAGTAGA	CCCCCCGCCCCTCTC
CTCTTCTACAATGAG	GCGGATGCAGTAGAC	CCCCCGCCCCTCTCC
TCTTCTACAATGAGC	CGGATGCAGTAGACC	CCCCGCCCCTCTCCA
CTTCTACAATGAGCA	GGATGCAGTAGACCG	CCCGCCCCTCTCCAA
TTCTACAATGAGCAG	GATGCAGTAGACCGC	CCGCCCCTCTCCAAA
TCTACAATGAGCAGC	ATGCAGTAGACCGCA	CGCCCCTCTCCAAAC
CTACAATGAGCAGCA	TGCAGTAGACCGCAG	GCCCCTCTCCAAACA
TACAATGAGCAGCAG	GCAGTAGACCGCAGC	CCCCTCTCCAAACAC
ACAATGAGCAGCAGG	CAGTAGACCGCAGCC	CCCTCTCCAAACACC
CCTCTCCAAACACCG	GTGCTGGAGGATTTT	AAAGAGACCAGCACC
CTCTCCAAACACCGG	TGCTGGAGGATTTTC	AAGAGACCAGCACCG
TCTCCAAACACCGGC	GCTGGAGGATTTTCC	AGAGACCAGCACCGA
CTCCAAACACCGGCA	CTGGAGGATTTTCCA	GAGACCAGCACCGAG
TCCAAACACCGGCAG	TGGAGGATTTTCCAG	AGACCAGCACCGAGC
CCAAACACCGGCAGA	GGAGGATTTTCCAGT	GACCAGCACCGAGCT
CAAACACCGGCAGAA	GAGGATTTTCCAGTT	ACCAGCACCGAGCTC
AAACACCGGCAGAAA	AGGATTTTCCAGTTC	CCAGCACCGAGCTCG
AACACCGGCAGAAAA	GGATTTTCCAGTTCT	CAGCACCGAGCTCGG
ACACCGGCAGAAAAC	GATTTTCCAGTTCTG	AGCACCGAGCTCGGC
CACCGGCAGAAAACG	ATTTTCCAGTTCTGA	GCACCGAGCTCGGCA
ACCGGCAGAAAACGG	TTTTCCAGTTCTGAC	CACCGAGCTCGGCAC
CCGGCAGAAAACGGA	TTTCCAGTTCTGACA	ACCGAGCTCGGCACC
CGGCAGAAAACGGAG	TTCCAGTTCTGACAC	CCGAGCTCGGCACCT
GGCAGAAAACGGAGA	TCCAGTTCTGACACA	CGAGCTCGGCACCTC
GCAGAAAACGGAGAG	CCAGTTCTGACACAC	GAGCTCGGCACCTCC
CAGAAAACGGAGAGT	CAGTTCTGACACACG	AGCTCGGCACCTCCC
AGAAAACGGAGAGTG	AGTTCTGACACACGT	GCTCGGCACCTCCCC
GAAAACGGAGAGTGC	GTTCTGACACACGTA	CTCGGCACCTCCCCG
AAAACGGAGAGTGCT	TTCTGACACACGTAT	TCGGCACCTCCCCGG
AAACGGAGAGTGCTT	TCTGACACACGTATT	CGGCACCTCCCCGGC
AACGGAGAGTGCTTG	CTGACACACGTATTT	GGCACCTCCCCGGCC
ACGGAGAGTGCTTGG	TGACACACGTATTTA	GCACCTCCCCGGCCT
CGGAGAGTGCTTGGG	GACACACGTATTTAT	CACCTCCCCGGCCTC
GGAGAGTGCTTGGGT	ACACACGTATTTATA	ACCTCCCCGGCCTCT
GAGAGTGCTTGGGTG	CACACGTATTTATAT	CCTCCCCGGCCTCTC
AGAGTGCTTGGGTGG	ACACGTATTTATATT	CTCCCCGGCCTCTCT
GAGTGCTTGGGTGGT	CACGTATTTATATTT	TCCCCGGCCTCTCTC
AGTGCTTGGGTGGTG	ACGTATTTATATTTG	CCCCGGCCTCTCTCT
GTGCTTGGGTGGTGG	CGTATTTATATTTGG	CCCGGCCTCTCTCTT
TGCTTGGGTGGTGGG	GTATTTATATTTGGA	CCGGCCTCTCTCTTC
GCTTGGGTGGTGGGT	TATTTATATTTGGAA	CGGCCTCTCTCTTCC
CTTGGGTGGTGGGTG	ATTTATATTTGGAAA	GGCCTCTCTCTTCCC
TTGGGTGGTGGGTGC	TTTATATTTGGAAAG	GCCTCTCTCTTCCCA
TGGGTGGTGGGTGCT	TTATATTTGGAAAGA	CCTCTCTCTTCCCAG
GGGTGGTGGGTGCTG	TATATTTGGAAAGAG	CTCTCTCTTCCCAGC
GGTGGTGGGTGCTGG	ATATTTGGAAAGAGA	TCTCTCTTCCCAGCT
GTGGTGGGTGCTGGA	TATTTGGAAAGAGAC	CTCTCTTCCCAGCTG
TGGTGGGTGCTGGAG	ATTTGGAAAGAGACC	TCTCTTCCCAGCTGC
GGTGGGTGCTGGAGG	TTTGGAAAGAGACCA	CTCTTCCCAGCTGCA
GTGGGTGCTGGAGGA	TTGGAAAGAGACCAG	TCTTCCCAGCTGCAG
TGGGTGCTGGAGGAT	TGGAAAGAGACCAGC	CTTCCCAGCTGCAGA
GGGTGCTGGAGGATT	GGAAAGAGACCAGCA	TTCCCAGCTGCAGAT
GGTGCTGGAGGATTT	GAAAGAGACCAGCAC	TCCCAGCTGCAGATG
CCCAGCTGCAGATGC	GGAGGAAGGGGGTTG	GAGGGGGAAGAGAAA
CCAGCTGCAGATGCC	GAGGAAGGGGGTTGT	AGGGGGAAGAGAAAT
CAGCTGCAGATGCCA	AGGAAGGGGGTTGTG	GGGGGAAGAGAAATT
AGCTGCAGATGCCAC	GGAAGGGGGTTGTGG	GGGGAAGAGAAATTT
GCTGCAGATGCCACA	GAAGGGGGTTGTGGT	GGGAAGAGAAATTTT
CTGCAGATGCCACAC	AAGGGGGTTGTGGTC	GGAAGAGAAATTTTT
TGCAGATGCCACACC	AGGGGGTTGTGGTCG	GAAGAGAAATTTTTA
GCAGATGCCACACCT	GGGGGTTGTGGTCGG	AAGAGAAATTTTTAT
CAGATGCCACACCTG	GGGGTTGTGGTCGGG	AGAGAAATTTTTATT
AGATGCCACACCTGC	GGGTTGTGGTCGGGG	GAGAAATTTTTATTT
GATGCCACACCTGCT	GGTTGTGGTCGGGGA	AGAAATTTTTATTTT
ATGCCACACCTGCTC	GTTGTGGTCGGGGAG	GAAATTTTTATTTTT
TGCCACACCTGCTCC	TTGTGGTCGGGGAGC	AAATTTTTATTTTTG
GCCACACCTGCTCCT	TGTGGTCGGGGAGCT	AATTTTTATTTTTGA
CCACACCTGCTCCTT	GTGGTCGGGGAGCTG	ATTTTTATTTTTGAA
CACACCTGCTCCTTC	TGGTCGGGGAGCTGG	TTTTTATTTTTGAAC
ACACCTGCTCCTTCT	GGTCGGGGAGCTGGG	TTTTATTTTTGAACC
CACCTGCTCCTTCTT	GTCGGGGAGCTGGGG	TTTATTTTTGAACCC
ACCTGCTCCTTCTTG	TCGGGGAGCTGGGGT	TTATTTTTGAACCCC
CCTGCTCCTTCTTGC	CGGGGAGCTGGGGTA	TATTTTTGAACCCCT
CTGCTCCTTCTTGCT	GGGGAGCTGGGGTAC	ATTTTTGAACCCCTG
TGCTCCTTCTTGCTT	GGGAGCTGGGGTACA	TTTTTGAACCCCTGT
GCTCCTTCTTGCTTT	GGAGCTGGGGTACAG	TTTTGAACCCCTGTG
CTCCTTCTTGCTTTC	GAGCTGGGGTACAGG	TTTGAACCCCTGTGT
TCCTTCTTGCTTTCC	AGCTGGGGTACAGGT	TTGAACCCCTGTGTC
CCTTCTTGCTTTCCC	GCTGGGGTACAGGTT	TGAACCCCTGTGTCC
CTTCTTGCTTTCCCC	CTGGGGTACAGGTTT	GAACCCCTGTGTCCC
TTCTTGCTTTCCCCG	TGGGGTACAGGTTTG	AACCCCTGTGTCCCT
TCTTGCTTTCCCCGG	GGGGTACAGGTTTGG	ACCCCTGTGTCCCTT
CTTGCTTTCCCCGGG	GGGTACAGGTTTGGG	CCCCTGTGTCCCTTT
TTGCTTTCCCCGGGG	GGTACAGGTTTGGGG	CCCTGTGTCCCTTTT
TGCTTTCCCCGGGGG	GTACAGGTTTGGGGA	CCTGTGTCCCTTTTG
GCTTTCCCCGGGGGA	TACAGGTTTGGGGAG	CTGTGTCCCTTTTGC
CTTTCCCCGGGGGAG	ACAGGTTTGGGGAGG	TGTGTCCCTTTTGCA
TTTCCCCGGGGGAGG	CAGGTTTGGGGAGGG	GTGTCCCTTTTGCAT
TTCCCCGGGGGAGGA	AGGTTTGGGGAGGGG	TGTCCCTTTTGCATA
TCCCCGGGGGAGGAA	GGTTTGGGGAGGGGG	GTCCCTTTTGCATAA
CCCCGGGGGAGGAAG	GTTTGGGGAGGGGGA	TCCCTTTTGCATAAG
CCCGGGGGAGGAAGG	TTTGGGGAGGGGGAA	CCCTTTTGCATAAGA
CCGGGGGAGGAAGGG	TTGGGGAGGGGGAAG	CCTTTTGCATAAGAT
CGGGGGAGGAAGGGG	TGGGGAGGGGGAAGA	CTTTTGCATAAGATT
GGGGGAGGAAGGGGG	GGGGAGGGGGAAGAG	TTTTGCATAAGATTA
GGGGAGGAAGGGGGT	GGGAGGGGGAAGAGA	TTTGCATAAGATTAA
GGGAGGAAGGGGGTT	GGAGGGGGAAGAGAA	TTGCATAAGATTAAA
TGCATAAGATTAAAG
GCATAAGATTAAAGG
CATAAGATTAAAGGA
ATAAGATTAAAGGAA
TAAGATTAAAGGAAG
AAGATTAAAGGAAGG
AGATTAAAGGAAGGA
GATTAAAGGAAGGAA
ATTAAAGGAAGGAAA
TTAAAGGAAGGAAAA
TAAAGGAAGGAAAAG
AAAGGAAGGAAAAGT

EXAMPLE 7

Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:

CTCAGCGCCCAGCCG	TGGATTCCACAGCTT	TACTGTCGCCCCATC
TCAGCGCCCAGCCGC	GGATTCCACAGCTTC	ACTGTCGCCCCATCC
CAGCGCCCAGCCGCT	GATTCCACAGCTTCG	CTGTCGCCCCATCCC
AGCGCCCAGCCGCTT	ATTCCACAGCTTCGC	TGTCGCCCCATCCCT
GCGCCCAGCCGCTTC	TTCCACAGCTTCGCG	GTCGCCCCATCCCTG
CGCCCAGCCGCTTCC	TCCACAGCTTCGCGC	TCGCCCCATCCCTGC
GCCCAGCCGCTTCCT	CCACAGCTTCGCGCC	CGCCCCATCCCTGCG
CCCAGCCGCTTCCTG	CACAGCTTCGCGCCG	GCCCCATCCCTGCGC
CCAGCCGCTTCCTGC	ACAGCTTCGCGCCGT	CCCCATCCCTGCGCG
CAGCCGCTTCCTGCC	CAGCTTCGCGCCGTG	CCCATCCCTGCGCGC
AGCCGCTTCCTGCCT	AGCTTCGCGCCGTGT	CCATCCCTGCGCGCC
GCCGCTTCCTGCCTG	GCTTCGCGCCGTGTA	CATCCCTGCGCGCCC
CCGCTTCCTGCCTGG	CTTCGCGCCGTGTAC	ATCCCTGCGCGCCCA
CGCTTCCTGCCTGGA	TTCGCGCCGTGTACT	TCCCTGCGCGCCCAG
GCTTCCTGCCTGGAT	TCGCGCCGTGTACTG	CCCTGCGCGCCCAGC
CTTCCTGCCTGGATT	CGCGCCGTGTACTGT	CCTGCGCGCCCAGCC
TTCCTGCCTGGATTC	GCGCCGTGTACTGTC	CTGCGCGCCCAGCCT
TCCTGCCTGGATTCC	CGCCGTGTACTGTCG	TGCGCGCCCAGCCTG
CCTGCCTGGATTCCA	GCCGTGTACTGTCGC	GCGCGCCCAGCCTGC
CTGCCTGGATTCCAC	CCGTGTACTGTCGCC	CGCGCCCAGCCTGCC
TGCCTGGATTCCACA	CGTGTACTGTCGCCC	GCGCCCAGCCTGCCA
GCCTGGATTCCACAG	GTGTACTGTCGCCCC	CGCCCAGCCTGCCAA
CCTGGATTCCACAGC	TGTACTGTCGCCCCA	GCCCAGCCTGCCAAG
CTGGATTCCACAGCT	GTACTGTCGCCCCAT	CCCAGCCTGCCAAGC
CCAGCCTGCCAAGCA	GGGCGCGACCCACGC	CTGCTCCGCGGGCCG
CAGCCTGCCAAGCAG	GGCGCGACCCACGCT	TGCTCCGCGGGCCGC
AGCCTGCCAAGCAGC	GCGCGACCCACGCTC	GCTCCGCGGGCCGCC
GCCTGCCAAGCAGCG	CGCGACCCACGCTCT	CTCCGCGGGCCGCCG
CCTGCCAAGCAGCGT	GCGACCCACGCTCTG	TCCGCGGGCCGCCGG
CTGCCAAGCAGCGTG	CGACCCACGCTCTGG	CCGCGGGCCGCCGGT
TGCCAAGCAGCGTGC	GACCCACGCTCTGGG	CGCGGGCCGCCGGTG
GCCAAGCAGCGTGCC	ACCCACGCTCTGGGC	GCGGGCCGCCGGTGG
CCAAGCAGCGTGCCC	CCCACGCTCTGGGCC	CGGGCCGCCGGTGGC
CAAGCAGCGTGCCCC	CCACGCTCTGGGCCG	GGGCCGCCGGTGGCG
AAGCAGCGTGCCCCG	CACGCTCTGGGCCGC	GGCCGCCGGTGGCGC
AGCAGCGTGCCCCGG	ACGCTCTGGGCCGCT	GCCGCCGGTGGCGCG
GCAGCGTGCCCCGGT	CGCTCTGGGCCGCTG	CCGCCGGTGGCGCGG
CAGCGTGCCCCGGTT	GCTCTGGGCCGCTGC	CGCCGGTGGCGCGGG
AGCGTGCCCCGGTTG	CTCTGGGCCGCTGCG	GCCGGTGGCGCGGGC
GCGTGCCCCGGTTGC	TCTGGGCCGCTGCGC	CCGGTGGCGCGGGCT
CGTGCCCCGGTTGCA	CTGGGCCGCTGCGCT	CGGTGGCGCGGGCTG
GTGCCCCGGTTGCAG	TGGGCCGCTGCGCTG	GGTGGCGCGGGCTGG
TGCCCCGGTTGCAGG	GGGCCGCTGCGCTGA	GTGGCGCGGGCTGGC
GCCCCGGTTGCAGGC	GGCCGCTGCGCTGAC	TGGCGCGGGCTGGCG
CCCCGGTTGCAGGCG	GCCGCTGCGCTGACT	GGCGCGGGCTGGCGC
CCCGGTTGCAGGCGT	CCGCTGCGCTGACTC	GCGCGGGCTGGCGCG
CCGGTTGCAGGCGTC	CGCTGCGCTGACTCT	CGCGGGCTGGCGCGA
CGGTTGCAGGCGTCA	GCTGCGCTGACTCTG	GCGGGCTGGCGCGAG
GGTTGCAGGCGTCAT	CTGCGCTGACTCTGC	CGGGCTGGCGCGAGC
GTTGCAGGCGTCATG	TGCGCTGACTCTGCT	GGGCTGGCGCGAGCT
TTGCAGGCGTCATGC	GCGCTGACTCTGCTG	GGCTGGCGCGAGCTC
TGCAGGCGTCATGCA	CGCTGACTCTGCTGG	GCTGGCGCGAGCTCG
GCAGGCGTCATGCAG	GCTGACTCTGCTGGT	CTGGCGCGAGCTCGG
CAGGCGTCATGCAGC	CTGACTCTGCTGGTG	TGGCGCGAGCTCGGG
AGGCGTCATGCAGCG	TGACTCTGCTGGTGC	GGCGCGAGCTCGGGG
GGCGTCATGCAGCGG	GACTCTGCTGGTGCT	GCGCGAGCTCGGGGG
GCGTCATGCAGCGGG	ACTCTGCTGGTGCTG	CGCGAGCTCGGGGGG
CGTCATGCAGCGGGC	CTCTGCTGGTGCTGC	GCGAGCTCGGGGGGC
GTCATGCAGCGGGCG	TCTGCTGGTGCTGCT	CGAGCTCGGGGGGCT
TCATGCAGCGGGCGC	CTGCTGGTGCTGCTC	GAGCTCGGGGGGCTT
CATGCAGCGGGCGCG	TGCTGGTGCTGCTCC	AGCTCGGGGGGCTTG
ATGCAGCGGGCGCGA	GCTGGTGCTGCTCCG	GCTCGGGGGGCTTGG
TGCAGCGGGCGCGAC	CTGGTGCTGCTCCGC	CTCGGGGGGCTTGGG
GCAGCGGGCGCGACC	TGGTGCTGCTCCGCG	TCGGGGGGCTTGGGT
CAGCGGGCGCGACCC	GGTGCTGCTCCGCGG	CGGGGGGCTTGGGTC
AGCGGGCGCGACCCA	GTGCTGCTCCGCGGG	GGGGGGCTTGGGTCC
GCGGGCGCGACCCAC	TGCTGCTCCGCGGGC	GGGGGCTTGGGTCCC
CGGGCGCGACCCACG	GCTGCTCCGCGGGCC	GGGGCTTGGGTCCCG
GGGCTTGGGTCCCGT	CACTGGCCCAGTGCG	GTGCGCGAGCCGGGC
GGCTTGGGTCCCGTG	ACTGGCCCAGTGCGC	TGCGCGAGCCGGGCT
GCTTGGGTCCCGTGG	CTGGCCCAGTGCGCG	GCGCGAGCCGGGCTG
CTTGGGTCCCGTGGT	TGGCCCAGTGCGCGC	CGCGAGCCGGGCTGC
TTGGGTCCCGTGGTG	GGCCCAGTGCGCGCC	GCGAGCCGGGCTGCG
TGGGTCCCGTGGTGC	GCCCAGTGCGCGCCT	CGAGCCGGGCTGCGG
GGGTCCCGTGGTGCG	CCCAGTGCGCGCCTC	GAGCCGGGCTGCGGC
GGTCCCGTGGTGCGC	CCAGTGCGCGCCTCC	AGCCGGGCTGCGGCT
GTCCCGTGGTGCGCT	CAGTGCGCGCCTCCG	GCCGGGCTGCGGCTG
TCCCGTGGTGCGCTG	AGTGCGCGCCTCCGC	CCGGGCTGCGGCTGC
CCCGTGGTGCGCTGC	GTGCGCGCCTCCGCC	CGGGCTGCGGCTGCT
CCGTGGTGCGCTGCG	TGCGCGCCTCCGCCC	GGGCTGCGGCTGCTG
CGTGGTGCGCTGCGA	GCGCGCCTCCGCCCG	GGCTGCGGCTGCTGC
GTGGTGCGCTGCGAG	CGCGCCTCCGCCCGC	GCTGCGGCTGCTGCC
TGGTGCGCTGCGAGC	GCGCCTCCGCCCGCC	CTGCGGCTGCTGCCT
GGTGCGCTGCGAGCC	CGCCTCCGCCCGCCG	TGCGGCTGCTGCCTG
GTGCGCTGCGAGCCG	GCCTCCGCCCGCCGT	GCGGCTGCTGCCTGA
TGCGCTGCGAGCCGT	CCTCCGCCCGCCGTG	CGGCTGCTGCCTGAC
GCGCTGCGAGCCGTG	CTCCGCCCGCCGTGT	GGCTGCTGCCTGACG
CGCTGCGAGCCGTGC	TCCGCCCGCCGTGTG	GCTGCTGCCTGACGT
GCTGCGAGCCGTGCG	CCGCCCGCCGTGTGC	CTGCTGCCTGACGTG
CTGCGAGCCGTGCGA	CGCCCGCCGTGTGCG	TGCTGCCTGACGTGC
TGCGAGCCGTGCGAC	GCCCGCCGTGTGCGC	GCTGCCTGACGTGCG
GCGAGCCGTGCGACG	CCCGCCGTGTGCGCG	CTGCCTGACGTGCGC
CGAGCCGTGCGACGC	CCGCCGTGTGCGCGG	TGCCTGACGTGCGCA
GAGCCGTGCGACGCG	CGCCGTGTGCGCGGA	GCCTGACGTGCGCAC
AGCCGTGCGACGCGC	GCCGTGTGCGCGGAG	CCTGACGTGCGCACT
GCCGTGCGACGCGCG	CCGTGTGCGCGGAGC	CTGACGTGCGCACTG
CCGTGCGACGCGCGT	CGTGTGCGCGGAGCT	TGACGTGCGCACTGA
CGTGCGACGCGCGTG	GTGTGCGCGGAGCTG	GACGTGCGCACTGAG
GTGCGACGCGCGTGC	TGTGCGCGGAGCTGG	ACGTGCGCACTGAGC
TGCGACGCGCGTGCA	GTGCGCGGAGCTGGT	CGTGCGCACTGAGCG
GCGACGCGCGTGCAC	TGCGCGGAGCTGGTG	GTGCGCACTGAGCGA
CGACGCGCGTGCACT	GCGCGGAGCTGGTGC	TGCGCACTGAGCGAG
GACGCGCGTGCACTG	CGCGGAGCTGGTGCG	GCGCACTGAGCGAGG
ACGCGCGTGCACTGG	GCGGAGCTGGTGCGC	CGCACTGAGCGAGGG
CGCGCGTGCACTGGC	CGGAGCTGGTGCGCG	GCACTGAGCGAGGGC
GCGCGTGCACTGGCC	GGAGCTGGTGCGCGA	CACTGAGCGAGGGCC
CGCGTGCACTGGCCC	GAGCTGGTGCGCGAG	ACTGAGCGAGGGCCA
GCGTGCACTGGCCCA	AGCTGGTGCGCGAGC	CTGAGCGAGGGCCAG
CGTGCACTGGCCCAG	GCTGGTGCGCGAGCC	TGAGCGAGGGCCAGC
GTGCACTGGCCCAGT	CTGGTGCGCGAGCCG	GAGCGAGGGCCAGCC
TGCACTGGCCCAGTG	TGGTGCGCGAGCCGG	AGCGAGGGCCAGCCG
GCACTGGCCCAGTGC	GGTGCGCGAGCCGGG	GCGAGGGCCAGCCGT
CGAGGGCCAGCCGTG	GCCTTCGCTGCCAGC	GCGCTGCTGGACGGC
GAGGGCCAGCCGTGC	CCTTCGCTGCCAGCC	CGCTGCTGGACGGCC
AGGGCCAGCCGTGCG	CTTCGCTGCCAGCCG	GCTGCTGGACGGCCG
GGGCCAGCCGTGCGG	TTCGCTGCCAGCCGT	CTGCTGGACGGCCGC
GGCCAGCCGTGCGGC	TCGCTGCCAGCCGTC	TGCTGGACGGCCGCG
GCCAGCCGTGCGGCA	CGCTGCCAGCCGTCG	GCTGGACGGCCGCGG
CCAGCCGTGCGGCAT	GCTGCCAGCCGTCGC	CTGGACGGCCGCGGG
CAGCCGTGCGGCATC	CTGCCAGCCGTCGCC	TGGACGGCCGCGGGC
AGCCGTGCGGCATCT	TGCCAGCCGTCGCCC	GGACGGCCGCGGGCT
CCCGTGCGGCATCTA	GCCAGCCGTCGCCCG	GACGGCCGCGGGCTC
CCGTGCGGCATCTAC	CCAGCCGTCGCCCGA	ACGGCCGCGGGCTCT
CGTGCGGCATCTACA	CAGCCGTCGCCCGAC	CGGCCGCGGGCTCTG
GTGCGGCATCTACAC	AGCCGTCGCCCGACG	GGCCGCGGGCTCTGC
TGCGGCATCTACACC	GCCGTCGCCCGACGA	GCCGCGGGCTCTGCG
GCGGCATCTACACCG	CCGTCGCCCGACGAG	CCGCGGGCTCTGCGT
CGGCATCTACACCGA	CGTCGCCCGACGAGG	CGCGGGCTCTGCGTC
GGCATCTACACCGAG	GTCGCCCGACGAGGC	GCGGGCTCTGCGTCA
GCATCTACACCGAGC	TCGCCCGACGAGGCG	CGGGCTCTGCGTCAA
CATCTACACCGAGCG	CGCCCGACGAGGCGC	GGGCTCTGCGTCAAC
ATCTACACCGAGCGC	GCCCGACGAGGCGCG	GGCTCTGCGTCAACG
TCTACACCGAGCGCT	CCCGACGAGGCGCGA	GCTCTGCGTCAACGC
CTACACCGAGCGCTG	CCGACGAGGCGCGAC	CTCTGCGTCAACGCT
TACACCGAGCGCTGT	CGACGAGGCGCGACC	TCTGCGTCAACGCTA
ACACCGAGCGCTGTG	GACGAGGCGCGACCG	CTGCGTCAACGCTAG
CACCGAGCGCTGTGG	ACGAGGCGCGACCGC	TGCGTCAACGCTAGT
ACCGAGCGCTGTGGC	CGAGGCGCGACCGCT	GCGTCAACGCTAGTG
CCGAGCGCTGTGGCT	GAGGCGCGACCGCTG	CGTCAACGCTAGTGC
CGAGCGCTGTGGCTC	AGGCGCGACCGCTGC	GTCAACGCTAGTGCC
GAGCGCTGTGGCTCC	GGCGCGACCGCTGCA	TCAACGCTAGTGCCG
AGCGCTGTGGCTCCG	GCGCGACCGCTGCAG	CAACGCTAGTGCCGT
GCGCTGTGGCTCCGG	CGCGACCGCTGCAGG	AACGCTAGTGCCGTC
CGCTGTGGCTCCGGC	GCGACCGCTGCAGGC	ACGCTAGTGCCGTCA
GCTGTGGCTCCGGCC	CGACCGCTGCAGGCG	CGCTAGTGCCGTCAG
CTGTGGCTCCGGCCT	GACCGCTGCAGGCGC	GCTAGTGCCGTCAGC
TGTGGCTCCGGCCTT	ACCGCTGCAGGCGCT	CTAGTGCCGTCAGCC
GTGGCTCCGGCCTTC	CCGCTGCAGGCGCTG	TAGTGCCGTCAGCCG
TGGCTCCGGCCTTCG	CGCTGCAGGCGCTGC	AGTGCCGTCAGCCGC
GGCTCCGGCCTTCGC	GCTGCAGGCGCTGCT	GTGCCGTCAGCCGCC
GCTCCGGCCTTCGCT	CTGCAGGCGCTGCTG	TGCCGTCAGCCGCCT
CTCCGGCCTTCGCTG	TGCAGGCGCTGCTGG	GCCGTCAGCCGCCTG
TCCGGCCTTCGCTGC	GCAGGCGCTGCTGGA	CCGTCAGCCGCCTGC
CCGGCCTTCGCTGCC	CAGGCGCTGCTGGAC	CGTCAGCCGCCTGCG
CGGCCTTCGCTGCCA	AGGCGCTGCTGGACG	GTCAGCCGCCTGCGC
GGCCTTCGCTGCCAG	GGCGCTGCTGGACGG	TCAGCCGCCTGCGCG
CAGCCGCCTGCGCGC	GAAATGCTAGTGAGT	GAGAGCCCGTCCGTC
AGCCGCCTGCGCGCC	AAATGCTAGTGAGTC	AGAGCCCGTCCGTCT
GCCGCCTGCGCGCCT	AATGCTAGTGAGTCG	GAGCCCGTCCGTCTC
CCGCCTGCGCGCCTA	ATGCTAGTGAGTCGG	AGCCCGTCCGTCTCC
CGCCTGCGCGCCTAC	TGCTAGTGAGTCGGA	GCCCGTCCGTCTCCA
GCCTGCGCGCCTACC	GCTAGTGAGTCGGAG	CCCGTCCGTCTCCAG
CCTGCGCGCCTACCT	CTAGTGAGTCGGAGG	CCGTCCGTCTCCAGC
CTGCGCGCCTACCTG	TAGTGAGTCGGAGGA	CGTCCGTCTCCAGCA
TGCGCGCCTACCTGC	AGTGAGTCGGAGGAA	GTCCGTCTCCAGCAC
GCGCGCCTACCTGCT	GTGAGTCGGAGGAAG	TCCGTCTCCAGCACG
CGCGCCTACCTGCTG	TGAGTCGGAGGAAGA	CCGTCTCCAGCACGC
GCGCCTACCTGCTGC	GAGTCGGAGGAAGAC	CGTCTCCAGCACGCA
CGCCTACCTGCTGCC	AGTCGGAGGAAGACC	GTCTCCAGCACGCAC
GCCTACCTGCTGCCA	GTCGGAGGAAGACCG	TCTCCAGCACGCACC
CCTACCTGCTGCCAG	TCGGAGGAAGACCGC	CTCCAGCACGCACCG
CTACCTGCTGCCAGC	CGGAGGAAGACCGCA	TCCAGCACGCACCGG
TACCTGCTGCCAGCG	GGAGGAAGACCGCAG	CCAGCACGCACCGGG
ACCTGCTGCCAGCGC	GAGGAAGACCGCAGC	CAGCACGCACCGGGT
CCTGCTGCCAGCGCC	AGGAAGACCGCAGCG	AGCACGCACCGGGTG
CTGCTGCCAGCGCCG	GGAAGACCGCAGCGC	GCACGCACCGGGTGT
TGCTGCCAGCGCCGC	GAAGACCGCAGCGCC	CACGCACCGGGTGTC
GCTGCCAGCGCCGCC	AAGACCGCAGCGCCG	ACGCACCGGGTGTCT
CTGCCAGCGCCGCCA	AGACCGCAGCGCCGG	CGCACCGGGTGTCTG
TGCCAGCGCCGCCAG	GACCGCAGCGCCGGC	GCACCGGGTGTCTGA
GCCAGCGCCGCCAGC	ACCGCAGCGCCGGCA	CACCGGGTGTCTGAT
CCAGCGCCGCCAGCT	CCGCAGCGCCGGCAG	ACCGGGTGTCTGATC
CAGCGCCGCCAGCTC	CGCAGCGCCGGCAGT	CCGGGTGTCTGATCC
AGCGCCGCCAGCTCC	GCAGCGCCGGCAGTG	CGGGTGTCTGATCCC
GCGCCGCCAGCTCCA	CAGCGCCGGCAGTGT	GGGTGTCTGATCCCA
CGCCGCCAGCTCCAG	AGCGCCGGCAGTGTG	GGTGTCTGATCCCAA
GCCGCCAGCTCCAGG	GCGCCGGCAGTGTGG	GTGTCTGATCCCAAG
CCGCCAGCTCCAGGA	CGCCGGCAGTGTGGA	TGTCTGATCCCAAGT
CGCCAGCTCCAGGAA	GCCGGCAGTGTGGAG	GTCTGATCCCAAGTT
GCCAGCTCCAGGAAA	CCGGCAGTGTGGAGA	TCTGATCCCAAGTTC
CCAGCTCCAGGAAAT	CGGCAGTGTGGAGAG	CTGATCCCAAGTTCC
CAGCTCCAGGAAATG	GGCAGTGTGGAGAGC	TGATCCCAAGTTCCA
AGCTCCAGGAAATGC	GCAGTGTGGAGAGCC	GATCCCAAGTTCCAC
GCTCCAGGAAATGCT	CAGTGTGGAGAGCCC	ATCCCAAGTTCCACC
CTCCAGGAAATGCTA	AGTGTGGAGAGCCCG	TCCCAAGTTCCACCC
TCCAGGAAATGCTAG	GTGTGGAGAGCCCGT	CCCAAGTTCCACCCC
CCAGGAAATGCTAGT	TGTGGAGAGCCCGTC	CCAAGTTCCACCCCC
CAGGAAATGCTAGTG	GTGGAGAGCCCGTCC	CAAGTTCCACCCCCT
AGGAAATGCTAGTGA	TGGAGAGCCCGTCCG	AAGTTCCACCCCCTC
GGAAATGCTAGTGAG	GGAGAGCCCGTCCGT	AGTTCCACCCCCTCC
GTTCCACCCCCTCCA	ATGCTAAAGACAGCC	AGCACAGATACCCAG
TTCCACCCCCTCCAT	TGCTAAAGACAGCCA	GCACAGATACCCAGA
TCCACCCCCTCCATT	GCTAAAGACAGCCAG	CACAGATACCCAGAA
CCACCCCCTCCATTC	CTAAAGACAGCCAGC	ACAGATACCCAGAAC
CACCCCCTCCATTCA	TAAAGACAGCCAGCG	CAGATACCCAGAACT
ACCCCCTCCATTCAA	AAAGACAGCCAGCGC	AGATACCCAGAACTT
CCCCCTCCATTCAAA	AAGACAGCCAGCGCT	GATACCCAGAACTTC
CCCCTCCATTCAAAG	AGACAGCCAGCGCTA	ATACCCAGAACTTCT
CCCTCCATTCAAAGA	GACAGCCAGCGCTAC	TACCCAGAACTTCTC
CCTCCATTCAAAGAT	ACAGCCAGCGCTACA	ACCCAGAACTTCTCC
CTCCATTCAAAGATA	CAGCCAGCGCTACAA	CCCAGAACTTCTCCT
TCCATTCAAAGATAA	AGCCAGCGCTACAAA	CCAGAACTTCTCCTC
CCATTCAAAGATAAT	GCCAGCGCTACAAAG	CAGAACTTCTCCTCC
CATTCAAAGATAATC	CCAGCGCTACAAAGT	AGAACTTCTCCTCCG
ATTCAAAGATAATCA	CAGCGCTACAAAGTT	GAACTTCTCCTCCGA
TTCAAAGATAATCAT	AGCGCTACAAAGTTG	AACTTCTCCTCCGAG
TCAAAGATAATCATC	GCGCTACAAAGTTGA	ACTTCTCCTCCGAGT
CAAAGATAATCATCA	CGCTACAAAGTTGAC	CTTCTCCTCCGAGTC
AAAGATAATCATCAT	GCTACAAAGTTGACT	TTCTCCTCCGAGTCC
AAGATAATCATCATC	CTACAAAGTTGACTA	TCTCCTCCGAGTCCA
AGATAATCATCATCA	TACAAAGTTGACTAC	CTCCTCCGAGTCCAA
GATAATCATCATCAA	ACAAAGTTGACTACG	TCCTCCGAGTCCAAG
ATAATCATCATCAAG	CAAAGTTGACTACGA	CCTCCGAGTCCAAGC
TAATCATCATCAAGA	AAAGTTGACTACGAG	CTCCGAGTCCAAGCG
AATCATCATCAAGAA	AAGTTGACTACGAGT	TCCGAGTCCAAGCGG
ATCATCATCAAGAAA	AGTTGACTACGAGTC	CCGAGTCCAAGCGGG
TCATCATCAAGAAAG	GTTGACTACGAGTCT	CGAGTCCAAGCGGGA
CATCATCAAGAAAGG	TTGACTACGAGTCTC	GAGTCCAAGCGGGAG
ATCATCAAGAAAGGG	TGACTACGAGTCTCA	AGTCCAAGCGGGAGA
TCATCAAGAAAGGGC	GACTACGAGTCTCAG	GTCCAAGCGGGAGAC
CATCAAGAAAGGGCA	ACTACGAGTCTCAGA	TCCAAGCGGGAGACA
ATCAAGAAAGGGCAT	CTACGAGTCTCAGAG	CCAAGCGGGAGACAG
TCAAGAAAGGGCATG	TACGAGTCTCAGAGC	CAAGCGGGAGACAGA
CAAGAAAGGGCATGC	ACGAGTCTCAGAGCA	AAGCGGGAGACAGAA
AAGAAAGGGCATGCT	CGAGTCTCAGAGCAC	AGCGGGAGACAGAAT
AGAAAGGGCATGCTA	GAGTCTCAGAGCACA	GCGGGAGACAGAATA
GAAAGGGCATGCTAA	AGTCTCAGAGCACAG	CGGGAGACAGAATAT
AAAGGGCATGCTAAA	GTCTCAGAGCACAGA	GGGAGACAGAATATG
AAGGGCATGCTAAAG	TCTCAGAGCACAGAT	GGAGACAGAATATGG
AGGGCATGCTAAAGA	CTCAGAGCACAGATA	GAGACAGAATATGGT
GGGCATGCTAAAGAC	TCAGAGCACAGATAC	AGACAGAATATGGTC
GGCATGCTAAAGACA	CAGAGCACAGATACC	GACAGAATATGGTCC
GCATGCTAAAGACAG	AGAGCACAGATACCC	ACAGAATATGGTCCC
CATGCTAAAGACAGC	GAGCACAGATACCCA	CAGAATATGGTCCCT
AGAATATGGTCCCTG	ACCTGAAGTTCCTCA	CCCAACTGTGACAAG
GAATATGGTCCCTGC	CCTGAAGTTCCTCAA	CCAACTGTGACAAGA
AATATGGTCCCTGCC	CTGAAGTTCCTCAAT	CAACTGTGACAAGAA
ATATGGTCCCTGCCG	TGAAGTTCCTCAATG	AACTGTGACAAGAAC
TATGGTCCCTGCCGT	GAAGTTCCTCAATGT	ACTGTGACAAGAAGG
ATGGTCCCTGCCGTA	AAGTTCCTCAATGTG	CTGTGACAAGAAGGG
TGGTCCCTGCCGTAG	AGTTCCTCAATGTGC	TGTGACAAGAAGGGA
GGTCCCTGCCGTAGA	GTTCCTCAATGTGCT	GTGACAAGAAGGGAT
GTCCCTGCCGTAGAG	TTCCTCAATGTGCTG	TGACAAGAAGGGATT
TCCCTGCCGTAGAGA	TCCTCAATGTGCTGA	GACAAGAAGGGATTT
CCCTGCCGTAGAGAA	CCTCAATGTGCTGAG	ACAAGAAGGGATTTT
CCTGCCGTAGAGAAA	CTCAATGTGCTGAGT	CAAGAAGGGATTTTA
CTGCCGTAGAGAAAT	TCAATGTGCTGAGTC	AAGAAGGGATTTTAT
TGCCGTAGAGAAATG	CAATGTGCTGAGTCC	AGPAGGGATTTTATA
GCCGTAGAGAAATGG	AATGTGCTGAGTCCC	GAAGGGATTTTATAA
CCGTAGAGAAATGGA	ATGTGCTGAGTCCCA	AAGGGATTTTATAAG
CGTAGAGAAATGGAA	TGTGCTGAGTCCCAG	AGGGATTTTATAAGA
GTAGAGAAATGGAAG	GTGCTGAGTCCCAGG	GGGATTTTATAAGAA
TAGAGAAATGGAAGA	TGCTGAGTCCCAGGG	GGATTTTATAAGAAA
AGAGAAATGGAAGAC	GCTGAGTCCCAGGGG	GATTTTATAAGAAAA
GAGAAATGGAAGACA	CTGAGTCCCAGGGGT	ATTTTATAAGAAAAA
AGAAATGGAAGACAC	TGAGTCCCAGGGGTG	TTTTATAAGAAAAAG
GAAATGGAAGACACA	GAGTCCCAGGGGTGT	TTTATAAGAAAAAGC
AAATGGAAGACACAC	AGTCCCAGGGGTGTA	TTATAAGAAAAAGCA
AATGGAAGACACACT	GTCCCAGGGGTGTAC	TATAAGAAAAAGCAG
ATGGAAGACACACTG	TCCCAGGGGTGTACA	ATAAGAAAAAGCAGT
TGGAAGACACACTGA	CCCAGGGGTGTACAC	TAAGAAAAAGCAGTG
GGAAGACACACTGAA	CCAGGGGTGTACACA	AAGAAAAAGCAGTGT
GAAGACACACTGAAT	CAGGGGTGTACACAT	AGAAAAAGCAGTGTC
AAGACACACTGAATC	AGGGGTGTACACATT	GAAAAAGCAGTGTCG
AGACACACTGAATCA	GGGGTGTACACATTC	AAAAAGCAGTGTCGC
GACACACTGAATCAC	GGGTGTACACATTCC	AAAAGCAGTGTCGCC
ACACACTGAATCACC	GGTGTACACATTCCC	AAAGCAGTGTCGCCC
CACACTGAATCACCT	GTGTACACATTCCCA	AAGCAGTGTCGCCCT
ACACTGAATCACCTG	TGTACACATTCCCAA	AGCAGTGTCGCCCTT
CACTGAATCACCTGA	GTACACATTCCCAAC	GCAGTGTCGCCCTTC
ACTGAATCACCTGAA	TACACATTCCCAACT	CAGTGTCGCCCTTCC
CTGAATCACCTGAAG	ACACATTCCCAACTG	AGTGTCGCCCTTCCA
TGAATCACCTGAAGT	CACATTCCCAACTGT	GTGTCGCCCTTCCAA
GAATCACCTGAAGTT	ACATTCCCAACTGTG	TGTCGCCCTTCCAAA
AATCACCTGAAGTTC	CATTCCCAACTGTGA	GTCGCCCTTCCAAAG
ATCACCTGAAGTTCC	ATTCCCAACTGTGAC	TCGCCCTTCCAAAGG
TCACCTGAAGTTCCT	TTCCCAACTGTGACA	CGCCCTTCCAAAGGC
CACCTGAAGTTCCTC	TCCCAACTGTGACAA	GCCCTTCCAAAGGCA
CCCTTCCAAAGGCAG	AGTATGGGCAGCCTC	GACGTGCACTGCTAC
CCTTCCAAAGGCAGG	GTATGGGCAGCCTCT	ACGTGCACTGCTACA
CTTCCAAAGGCAGGA	TATGGGCAGCCTCTC	CGTGCACTGCTACAG
TTCCAAAGGCAGGAA	ATGGGCAGCCTCTCC	GTGCACTGCTACAGC
TCCAAAGGCAGGAAG	TGGGCAGCCTCTCCC	TGCACTGCTACAGCA
CCAAAGGCAGGAAGC	GGGCAGCCTCTCCCA	GCACTGCTACAGCAT
CAAAGGCAGGAAGCG	GGCAGCCTCTCCCAG	CACTGCTACAGCATG
AAAGGCAGGAAGCGG	GCAGCCTCTCCCAGG	ACTGCTACAGCATGC
AAGGCAGGAAGCGGG	CAGCCTCTCCCAGGC	CTGCTACAGCATGCA
AGGCAGGAAGCGGGG	AGCCTCTCCCAGGCT	TGCTACAGCATGCAG
GGCAGGAAGCGGGGC	GCCTCTCCCAGGCTA	GCTACAGCATGCAGA
GCAGGAAGCGGGGCT	CCTCTCCCAGGCTAC	CTACAGCATGCAGAG
CAGGAAGCGGGGCTT	CTCTCCCAGGCTACA	TACAGCATGCAGAGC
AGGAAGCGGGGCTTC	TCTCCCAGGCTACAC	ACAGCATGCAGAGCA
GGAAGCGGGGCTTCT	CTCCCAGGCTACACC	CAGCATGCAGAGCAA
GAAGCGGGGCTTCTG	TCCCAGGCTACACCA	AGCATGCAGAGCAAG
AAGCGGGGCTTCTGC	CCCAGGCTACACCAC	GCATGCAGAGCAAGT
AGCGGGGCTTCTGCT	CCAGGCTACACCACC	CATGCAGAGCAAGTA
GCGGGGCTTCTGCTG	CAGGCTACACCACCA	ATGCAGAGCAAGTAG
CGGGGCTTCTGCTGG	AGGCTACACCACCAA	TGCAGAGCAAGTAGA
GGGGCTTCTGCTGGT	GGCTACACCACCAAG	GCAGAGCAAGTAGAC
GGGCTTCTGCTGGTG	GCTACACCACCAAGG	CAGAGCAAGTAGACG
GGCTTCTGCTGGTGT	CTACACCACCAAGGG	AGAGCAAGTAGACGC
GCTTCTGCTGGTGTG	TACACCACCAAGGGG	GAGCAAGTAGACGCC
CTTCTGCTGGTGTGT	ACACCACCAAGGGGA	AGCAAGTAGACGCCT
TTCTGCTGGTGTGTG	CACCACCAAGGGGAA	GCAAGTAGACGCCTG
TCTGCTGGTGTGTGG	ACCACCAAGGGGAAG	CAAGTAGACGCCTGC
CTGCTGGTGTGTGGA	CCACCAAGGGGAAGG	AAGTAGACGCCTGCC
TGCTGGTGTGTGGAT	CACCAAGGGGAAGGA	AGTAGACGCCTGCCG
GCTGGTGTGTGGATA	ACCAAGGGGAAGGAG	GTAGACGCCTGCCGC
CTGGTGTGTGGATAA	CCAAGGGGAAGGAGG	TAGACGCCTGCCGCA
TGGTGTGTGGATAAG	CAAGGGGAAGGAGGA	AGACGCCTGCCGCAA
GGTGTGTGGATAAGT	AAGGGGAAGGAGGAC	GACGCCTGCCGCAAG
GTGTGTGGATAAGTA	AGGGGAAGGAGGACG	ACGCCTGCCGCAAGT
TGTGTGGATAAGTAT	GGGGAAGGAGGACGT	CGCCTGCCGCAAGTT
GTGTGGATAAGTATG	GGGAAGGAGGACGTG	GCCTGCCGCAAGTTA
TGTGGATAAGTATGG	GGAAGGAGGACGTGC	CCTGCCGCAAGTTAA
GTGGATAAGTATGGG	GAAGGAGGACGTGCA	CTGCCGCAAGTTAAT
TGGATAAGTATGGGC	AAGGAGGACGTGCAC	TGCCGCAAGTTAATG
GGATAAGTATGGGCA	AGGAGGACGTGCACT	GCCGCAAGTTAATGT
GATAAGTATGGGCAG	GGAGGACGTGCACTG	CCGCAAGTTAATGTG
ATAAGTATGGGCAGC	GAGGACGTGCACTGC	CGCAAGTTAATGTGG
TAAGTATGGGCAGCC	AGGACGTGCACTGCT	GCAAGTTAATGTGGA
AAGTATGGGCAGCCT	GGACGTGCACTGCTA	CAAGTTAATGTGGAG
AAGTTAATGTGGAGC	TGCCAAGGACATGAC	TTCTGTTTGTGGTGA
AGTTAATGTGGAGCT	GCCAAGGACATGACC	TCTGTTTGTGGTGAA
GTTAATGTGGAGCTC	CCAAGGACATGACCA	CTGTTTGTGGTGAAC
TTAATGTGGAGCTCA	CAAGGACATGACCAG	TGTTTGTGGTGAACT
TAATGTGGAGCTCAA	AAGGACATGACCAGC	GTTTGTGGTGAACTG
AATGTGGAGCTCAAA	AGGACATGACCAGCA	TTTGTGGTGAACTGA
ATGTGGAGCTCAAAT	GGACATGACCAGCAG	TTGTGGTGAACTGAT
TGTGGAGCTCAAATA	GACATGACCAGCAGC	TGTGGTGAACTGATT
GTGGAGCTCAAATAT	ACATGACCAGCAGCT	GTGGTGAACTGATTT
TGGAGCTCAAATATG	CATGACCAGCAGCTG	TGGTGAACTGATTTT
GGAGCTCAAATATGC	ATGACCAGCAGCTGG	GGTGAACTGATTTTT
GAGCTCAAATATGCC	TGACCAGCAGCTGGC	GTGAACTGATTTTTT
AGCTCAAATATGCCT	GACCAGCAGCTGGCT	TGAACTGATTTTTTT
GCTCAAATATGCCTT	ACCAGCAGCTGGCTA	GAACTGATTTTTTTT
CTCAAATATGCCTTA	CCAGCAGCTGGCTAC	AACTGATTTTTTTTA
TCAAATATGCCTTAT	CAGCAGCTGGCTACA	ACTGATTTTTTTTAA
CAAATATGCCTTATT	AGCAGCTGGCTACAG	CTGATTTTTTTTAAA
AAATATGCCTTATTT	GCAGCTGGCTACAGC	TGATTTTTTTTAAAC
AATATGCCTTATTTT	CAGCTGGCTACAGCC	GATTTTTTTTAAACC
ATATGCCTTATTTTG	AGCTGGCTACAGCCT	ATTTTTTTTAAACCA
TATGCCTTATTTTGC	GCTGGCTACAGCCTC	TTTTTTTTAAACCAA
ATGCCTTATTTTGCA	CTGGCTACAGCCTCG	TTTTTTTAAACCAAA
TGCCTTATTTTGCAC	TGGCTACAGCCTCGA	TTTTTTAAACCAAAG
GCCTTATTTTGCACA	GGCTACAGCCTCGAT	TTTTTAAACCAAAGT
CCTTATTTTGCACAA	GCTACAGCCTCGATT	TTTTAAACCAAAGTT
CTTATTTTGCACAAA	CTACAGCCTCGATTT	TTTAAACCAAAGTTT
TTATTTTGCACAAAA	TACAGCCTCGATTTA	TTAAACCAAAGTTTA
TATTTTGCACAAAAG	ACAGCCTCGATTTAT	TAAACCAAAGTTTAG
ATTTTGCACAAAAGA	CAGCCTCGATTTATA	AAACCAAAGTTTAGA
TTTTGCACAAAAGAC	AGCCTCGATTTATAT	AACCAAAGTTTAGAA
TTTGCACAAAAGACT	GCCTCGATTTATATT	ACCAAAGTTTAGAAA
TTGCACAAAAGACTG	CCTCGATTTATATTT	CCAAAGTTTAGAAAG
TGCACAAAAGACTGC	CTCGATTTATATTTC	CAAAGTTTAGAAAGA
GCACAAAAGACTGCC	TCGATTTATATTTCT	AAAGTTTAGAAAGAG
CACAAAAGACTGCCA	CGATTTATATTTCTG	AAGTTTAGAAAGAGG
ACAAAAGACTGCCAA	GATTTATATTTCTGT	AGTTTAGAAAGAGGT
CAAAAGACTGCCAAG	ATTTATATTTCTGTT	GTTTAGAAAGAGGTT
AAAAGACTGCCAAGG	TTTATATTTCTGTTT	TTTAGAAAGAGGTTT
AAAGACTGCCAAGGA	TTATATTTCTGTTTG	TTAGAAAGAGGTTTT
AAGACTGCCAAGGAC	TATATTTCTGTTTGT	TAGAAAGAGGTTTTT
AGACTGCCAAGGACA	ATATTTCTGTTTGTG	AGAAAGAGGTTTTTG
GACTGCCAAGGACAT	TATTTCTGTTTGTGG	GAAAGAGGTTTTTGA
ACTGCCAAGGACATG	ATTTCTGTTTGTGGT	AAAGAGGTTTTTGAA
CTGCCAAGGACATGA	TTTCTGTTTGTGGTG	AAGAGGTTTTTGAAA
AGAGGTTTTTGAAAT	AGCATCTTTTCACTT	TTTCTTGTCGCTTCC
GAGGTTTTTGAAATG	GCATCTTTTCACTTT	TTCTTGTCGCTTCCT
AGGTTTTTGAAATGC	CATCTTTTCACTTTC	TCTTGTCGCTTCCTA
GGTTTTTGAAATGCC	ATCTTTTCACTTTCC	CTTGTCGCTTCCTAT
GTTTTTGAAATGCCT	TCTTTTCACTTTCCA	TTGTCGCTTCCTATC
TTTTTGAAATGCCTA	CTTTTCACTTTCCAG	TGTCGCTTCCTATCA
TTTTGAAATGCCTAT	TTTTCACTTTCCAGT	GTCGCTTCCTATCAA
TTTGAAATGCCTATG	TTTCACTTTCCAGTA	TCGCTTCCTATCAAA
TTGAAATGCCTATGG	TTCACTTTCCAGTAG	CGCTTCCTATCAAAA
TGAAATGCCTATGGT	TCACTTTCCAGTAGT	GCTTCCTATCAAAAT
GAAATGCCTATGGTT	CACTTTCCAGTAGTC	CTTCCTATCAAAATA
AAATGCCTATGGTTT	ACTTTCCAGTAGTCA	TTCCTATCAAAATAT
AATGCCTATGGTTTC	CTTTCCAGTAGTCAG	TCCTATCAAAATATT
ATGCCTATGGTTTCT	TTTCCAGTAGTCAGC	CCTATCAAAATATTC
TGCCTATGGTTTCTT	TTCCAGTAGTCAGCA	CTATCAAAATATTCA
GCCTATGGTTTCTTT	TCCAGTAGTCAGCAA	TATCAAAATATTCAG
CCTATGGTTTCTTTG	CCAGTAGTCAGCAAA	ATCAAAATATTCAGA
CTATGGTTTCTTTGA	CAGTAGTCAGCAAAG	TCAAAATATTCAGAG
TATGGTTTCTTTGAA	AGTAGTCAGCAAAGA	CAAAATATTCAGAGA
ATGGTTTCTTTGAAT	GTAGTCAGCAAAGAG	AAAATATTCAGAGAC
TGGTTTCTTTGAATG	TAGTCAGCAAAGAGC	AAATATTCAGAGACT
GGTTTCTTTGAATGG	AGTCAGCAAAGAGCA	AATATTCAGAGACTC
GTTTCTTTGAATGGT	GTCAGCAAAGAGCAG	ATATTCAGAGACTCG
TTTCTTTGAATGGTA	TCAGCAAAGAGCAGT	TATTCAGAGACTCGA
TTCTTTGAATGGTAA	CAGCAAAGAGCAGTT	ATTCAGAGACTCGAG
TCTTTGAATGGTAAA	AGCAAAGAGCAGTTT	TTCAGAGACTCGAGC
CTTTGAATGGTAAAC	GCAAAGAGCAGTTTG	TCAGAGACTCGAGCA
TTTGAATGGTAAACT	CAAAGAGCAGTTTGA	CAGAGACTCGAGCAC
TTGAATGGTAAACTT	AAAGAGCAGTTTGAA	AGAGACTCGAGCACA
TGAATGGTAAACTTG	AAGAGCAGTTTGAAT	GAGACTCGAGCACAG
GAATGGTAAACTTGA	AGAGCAGTTTGAATT	AGACTCGAGCACAGC
AATGGTAAACTTGAG	GAGCAGTTTGAATTT	GACTCGAGCACAGCA
ATGGTAAACTTGAGC	AGCAGTTTGAATTTT	ACTCGAGCACAGCAC
TGGTAAACTTGAGCA	GCAGTTTGAATTTTC	CTCGAGCACAGCACC
GGTAAACTTGAGCAT	CAGTTTGAATTTTCT	TCGAGCACAGCACCC
GTAAACTTGAGCATC	AGTTTGAATTTTCTT	CGAGCACAGCACCCA
TAAACTTGAGCATCT	GTTTGAATTTTCTTG	GAGCACAGCACCCAG
AAACTTGAGCATCTT	TTTGAATTTTCTTGT	AGCACAGCACCCAGA
AACTTGAGCATCTTT	TTGAATTTTCTTGTC	GCACAGCACCCAGAC
ACTTGAGCATCTTTT	TGAATTTTCTTGTCG	CACAGCACCCAGACT
CTTGAGCATCTTTTC	GAATTTTCTTGTCGC	ACAGCACCCAGACTT
TTGAGCATCTTTTCA	AATTTTCTTGTCGCT	CAGCACCCAGACTTC
TGAGCATCTTTTCAC	ATTTTCTTGTCGCTT	AGCACCCAGACTTCA
GAGCATCTTTTCACT	TTTTCTTGTCGCTTC	GCACCCAGACTTCAT
CACCCAGACTTCATG	CGAAGCGGCCGACCA	CCTATGTAGAGAACA
ACCCAGACTTCATGC	GAAGCGGCCGACCAC	CTATGTAGAGAACAC
CCCAGACTTCATGCG	AAGCGGCCGACCACT	TATGTAGAGAACACG
CCAGACTTCATGCGC	AGCGGCCGACCACTG	ATGTAGAGAACACGC
CAGACTTCATGCGCC	GCGGCCGACCACTGA	TGTAGAGAACACGCT
AGACTTCATGCGCCC	CGGCCGACCACTGAC	GTAGAGAACACGCTT
GACTTCATGCGCCCG	GGCCGACCACTGACT	TAGAGAACACGCTTC
ACTTCATGCGCCCGT	GCCGACCACTGACTT	AGAGAACACGCTTCA
CTTCATGCGCCCGTG	CCGACCACTGACTTT	GAGAACACGCTTCAC
TTCATGCGCCCGTGG	CGACCACTGACTTTG	AGAACACGCTTCACC
TCATGCGCCCGTGGA	GACCACTGACTTTGT	GAACACGCTTCACCC
CATGCGCCCGTGGAA	ACCACTGACTTTGTG	AACACGCTTCACCCC
ATGCGCCCGTGGAAT	CCACTGACTTTGTGA	ACACGCTTCACCCCC
TGCGCCCGTGGAATG	CACTGACTTTGTGAC	CACGCTTCACCCCCA
GCGCCCGTGGAATGC	ACTGACTTTGTGACT	ACGCTTCACCCCCAC
CGCCCGTGGAATGCT	CTGACTTTGTGACTT	CGCTTCACCCCCACT
GCCCGTGGAATGCTC	TGACTTTGTGACTTA	GCTTCACCCCCACTC
CCCGTGGAATGCTCA	GACTTTGTGACTTAG	CTTCACCCCCACTCC
CCGTGGAATGCTCAC	ACTTTGTGACTTAGG	TTCACCCCCACTCCC
CGTGGAATGCTCACC	CTTTGTGACTTAGGC	TCACCCCCACTCCCC
GTGGAATGCTCACCA	TTTGTGACTTAGGCG	CACCCCCACTCCCCG
TGGAATGCTCACCAC	TTGTGACTTAGGCGG	ACCCCCACTCCCCGT
GGAATGCTCACCACA	TGTGACTTAGGCGGC	CCCCCACTCCCCGTA
GAATGCTCACCACAT	GTGACTTAGGCGGCT	CCCCACTCCCCGTAC
AATGCTCACCACATG	TGACTTAGGCGGCTG	CCCACTCCCCGTACA
ATGCTCACCACATGT	GACTTAGGCGGCTGT	CCACTCCCCGTACAG
TGCTCACCACATGTT	ACTTAGGCGGCTGTG	CACTCCCCGTACAGT
GCTCACCACATGTTG	CTTAGGCGGCTGTGT	ACTCCCCGTACAGTG
CTCACCACATGTTGG	TTAGGCGGCTGTGTT	CTCCCCGTACAGTGC
TCACCACATGTTGGT	TAGGCGGCTGTGTTG	TCCCCGTACAGTGCG
CACCACATGTTGGTC	AGGCGGCTGTGTTGC	CCCCGTACAGTGCGC
ACCACATGTTGGTCG	GGCGGCTGTGTTGCC	CCCGTACAGTGCGCA
CCACATGTTGGTCGA	GCGGCTGTGTTGCCT	CCGTACAGTGCGCAC
CACATGTTGGTCGAA	CGGCTGTGTTGCCTA	CGTACAGTGCGCACA
ACATGTTGGTCGAAG	GGCTGTGTTGCCTAT	GTACAGTGCGCACAG
CATGTTGGTCGAAGC	GCTGTGTTGCCTATG	TACAGTGCGCACAGG
ATGTTGGTCGAAGCG	CTGTGTTGCCTATGT	ACAGTGCGCACAGGC
TGTTGGTCGAAGCGG	TGTGTTGCCTATGTA	CAGTGCGCACAGGCT
GTTGGTCGAAGCGGC	GTGTTGCCTATGTAG	AGTGCGCACAGGCTT
TTGGTCGAAGCGGCC	TGTTGCCTATGTAGA	GTGCGCACAGGCTTT
TGGTCGAAGCGGCCG	GTTGCCTATGTAGAG	TGCGCACAGGCTTTA
GGTCGAAGCGGCCGA	TTGCCTATGTAGAGA	GCGCACAGGCTTTAT
GTCGAAGCGGCCGAC	TGCCTATGTAGAGAA	CGCACAGGCTTTATC
TCGAAGCGGCCGACC	GCCTATGTAGAGAAC	GCACAGGCTTTATCG
CACAGGCTTTATCGA	CCGGACATCCCAACG	GTGTCATTTCTGAAA
ACAGGCTTTATCGAG	CGGACATCCCAACGC	TGTCATTTCTGAAAC
CAGGCTTTATCGAGA	GGACATCCCAACGCA	GTCATTTCTGAAACA
AGGCTTTATCGAGAA	GACATCCCAACGCAT	TCATTTCTGAAACAA
GGCTTTATCGAGAAT	ACATCCCAACGCATG	CATTTCTGAAACAAG
GCTTTATCGAGAATA	CATCCCAACGCATGC	ATTTCTGAAACAAGG
CTTTATCGAGAATAG	ATCCCAACGCATGCT	TTTCTGAAACAAGGG
TTTATCGAGAATAGG	TCCCAACGCATGCTC	TTCTGAAACAAGGGC
TTATCGAGAATAGGA	CCCAACGCATGCTCC	TCTGAAACAAGGGCG
TATCGAGAATAGGAA	CCAACGCATGCTCCT	CTGAAACAAGGGCGT
ATCGAGAATAGGAAA	CAACGCATGCTCCTG	TGAAACAAGGGCGTG
TCGAGAATAGGAAAA	AACGCATGCTCCTGG	GAAACAAGGGCGTGG
CGAGAATAGGAAAAC	ACGCATGCTCCTGGA	AAACAAGGGCGTGGA
GAGAATAGGAAAACC	CGCATGCTCCTGGAG	AACAAGGGCGTGGAT
AGAATAGGAAAACCT	GCATGCTCCTGGAGC	ACAAGGGCGTGGATC
GAATAGGAAAACCTT	CATGCTCCTGGAGCT	CAAGGGCGTGGATCC
AATAGGAAAACCTTT	ATGCTCCTGGAGCTC	AAGGGCGTGGATCCC
ATAGGAAAACCTTTA	TGCTCCTGGAGCTCA	AGGGCGTGGATCCCT
TAGGAAAACCTTTAA	GCTCCTGGAGCTCAC	GGGCGTGGATCCCTC
AGGAAAACCTTTAAA	CTCCTGGAGCTCACA	GGCGTGGATCCCTCA
GGAAAACCTTTAAAC	TCCTGGAGCTCACAG	GCGTGGATCCCTCAA
GAAAACCTTTAAACC	CCTGGAGCTCACAGC	CGTGGATCCCTCAAC
AAAACCTTTAAACCC	CTGGAGCTCACAGCC	GTGGATCCCTCAACC
AAACCTTTAAACCCC	TGGAGCTCACAGCCT	TGGATCCCTCAACCA
AACCTTTAAACCCCG	GGAGCTCACAGCCTT	GGATCCCTCAACCAA
ACCTTTAAACCCCGG	GAGCTCACAGCCTTC	GATCCCTCAACCAAG
CCTTTAAACCCCGGT	AGCTCACAGCCTTCT	ATCCCTCAACCAAGA
CTTTAAACCCCGGTC	GCTCACAGCCTTCTG	TCCCTCAACCAAGAA
TTTAAACCCCGGTCA	CTCACAGCCTTCTGT	CCCTCAACCAAGAAG
TTAAACCCCGGTCAT	TCACAGCCTTCTGTG	CCTCAACCAAGAAGA
TAAACCCCGGTCATC	CACAGCCTTCTGTGG	CTCAACCAAGAAGAA
AAACCCCGGTCATCC	ACAGCCTTCTGTGGT	TCAACCAAGAAGAAT
AACCCCGGTCATCCG	CAGCCTTCTGTGGTG	CAACCAAGAAGAATG
ACCCCGGTCATCCGG	AGCCTTCTGTGGTGT	AACCAAGAAGAATGT
CCCCGGTCATCCGGA	GCCTTCTGTGGTGTC	ACCAAGAAGAATGTT
CCCGGTCATCCGGAC	CCTTCTGTGGTGTCA	CCAAGAAGAATGTTT
CCGGTCATCCGGACA	CTTCTGTGGTGTCAT	CAAGAAGAATGTTTA
CGGTCATCCGGACAT	TTCTGTGGTGTCATT	AAGAAGAATGTTTAT
GGTCATCCGGACATC	TCTGTGGTGTCATTT	AGAAGAATGTTTATG
GTCATCCGGACATCC	CTGTGGTGTCATTTC	GAAGAATGTTTATGT
TCATCCGGACATCCC	TGTGGTGTCATTTCT	AAGAATGTTTATGTC
CATCCGGACATCCCA	GTGGTGTCATTTCTG	AGAATGTTTATGTCT
ATCCGGACATCCCAA	TGGTGTCATTTCTGA	GAATGTTTATGTCTT
TCCGGACATCCCAAC	GGTGTCATTTCTGAA	AATGTTTATGTCTTC
ATGTTTATGTCTTCA	AGAAAATAAGGTGGA	AGAATGTTCTAGGGC
TGTTTATGTCTTCAA	GAAAATAAGGTGGAG	GAATGTTCTAGGGCA
GTTTATGTCTTCAAG	AAAATAAGGTGGAGT	AATGTTCTAGGGCAC
TTTATGTCTTCAAGT	AAATAAGGTGGAGTC	ATGTTCTAGGGCACT
TTATGTCTTCAAGTG	AATAAGGTGGAGTCC	TGTTCTAGGGCACTC
TATGTCTTCAAGTGA	ATAAGGTGGAGTCCT	GTTCTAGGGCACTCT
ATGTCTTCAAGTGAC	TAAGGTGGAGTCCTA	TTCTAGGGCACTCTG
TGTCTTCAAGTGACC	AAGGTGGAGTCCTAC	TCTAGGGCACTCTGG
GTCTTCAAGTGACCT	AGGTGGAGTCCTACT	CTAGGGCACTCTGGG
TCTTCAAGTGACCTG	GGTGGAGTCCTACTT	TAGGGCACTCTGGGA
CTTCAAGTGACCTGT	GTGGAGTCCTACTTG	AGGGCACTCTGGGAA
TTCAAGTGACCTGTA	TGGAGTCCTACTTGT	GGGCACTCTGGGAAC
TCAAGTGACCTGTAC	GGAGTCCTACTTGTT	GGCACTCTGGGAACC
CAAGTGACCTGTACT	GAGTCCTACTTGTTT	GCACTCTGGGAACCT
AAGTGACCTGTACTG	AGTCCTACTTGTTTA	CACTCTGGGAACCTA
AGTGACCTGTACTGC	GTCCTACTTGTTTAA	ACTCTGGGAACCTAT
GTGACCTGTACTGCT	TCCTACTTGTTTAAA	CTCTGGGAACCTATA
TGACCTGTACTGCTT	CCTACTTGTTTAAAA	TCTGGGAACCTATAA
GACCTGTACTGCTTG	CTACTTGTTTAAAAA	CTGGGAACCTATAAA
ACCTGTACTGCTTGG	TACTTGTTTAAAAAA	TGGGAACCTATAAAG
CCTGTACTGCTTGGG	ACTTGTTTAAAAAAT	GGGAACCTATAAAGG
CTGTACTGCTTGGGG	CTTGTTTAAAAAATA	GGAACCTATAAAGGC
TGTACTGCTTGGGGA	TTGTTTAAAAAATAT	GAACCTATAAAGGCA
GTACTGCTTGGGGAC	TGTTTAAAAAATATG	AACCTATAAAGGCAG
TACTGCTTGGGGACT	GTTTAAAAAATATGT	ACCTATAAAGGCAGG
ACTGCTTGGGGACTA	TTTAAAAAATATGTA	CCTATAAAGGCAGGT
CTGCTTGGGGACTAT	TTAAAAAATATGTAT	CTATAAAGGCAGGTA
TGCTTGGGGACTATT	TAAAAAATATGTATC	TATAAAGGCAGGTAT
GCTTGGGGACTATTG	AAAAAATATGTATCT	ATAAAGGCAGGTATT
CTTGGGGACTATTGG	AAAAATATGTATCTA	TAAAGGCAGGTATTT
TTGGGGACTATTGGA	AAAATATGTATCTAA	AAAGGCAGGTATTTC
TGGGGACTATTGGAG	AAATATGTATCTAAG	AAGGCAGGTATTTCG
GGGGACTATTGGAGA	AATATGTATCTAAGA	AGGCAGGTATTTCGG
GGGACTATTGGAGAA	ATATGTATCTAAGAA	GGCAGGTATTTCGGG
GGACTATTGGAGAAA	TATGTATCTAAGAAT	GCAGGTATTTCGGGC
GACTATTGGAGAAAA	ATGTATCTAAGAATG	CAGGTATTTCGGGCC
ACTATTGGAGAAAAT	TGTATCTAAGAATGT	AGGTATTTCGGGCCC
CTATTGGAGAAAATA	GTATCTAAGAATGTT	GGTATTTCGGGCCCT
TATTGGAGAAAATAA	TATCTAAGAATGTTC	GTATTTCGGGCCCTC
ATTGGAGAAAATAAG	ATCTAAGAATGTTCT	TATTTCGGGCCCTCC
TTGGAGAAAATAAGG	TCTAAGAATGTTCTA	ATTTCGGGCCCTCCT
TGGAGAAAATAAGGT	CTAAGAATGTTCTAG	TTTCGGGCCCTCCTC
GGAGAAAATAAGGTG	TAAGAATGTTCTAGG	TTCGGGCCCTCCTCT
GAGAAAATAAGGTGG	AAGAATGTTCTAGGG	TCGGGCCCTCCTCTT
CGGGCCCTCCTCTTC	GAAGGCCCAGGATGG	GACAGAGAGACGGGA
GGGCCCTCCTCTTCA	AAGGCCCAGGATGGC	ACAGAGAGACGGGAG
GGCCCTCCTCTTCAG	AGGCCCAGGATGGCT	CAGAGAGACGGGAGA
GCCCTCCTCTTCAGG	GGCCCAGGATGGCTT	AGAGAGACGGGAGAG
CCCTCCTCTTCAGGA	GCCCAGGATGGCTTT	GAGAGACGGGAGAGT
CCTCCTCTTCACGAA	CCCAGGATGGCTTTT	AGAGACGGGAGAGTC
CTCCTCTTCAGGAAT	CCAGGATGGCTTTTG	GAGACGGGAGAGTCA
TCCTCTTCAGGAATC	CAGGATGGCTTTTGC	AGACGGGAGAGTCAG
CCTCTTCAGGAATCT	AGGATGGCTTTTGCT	GACGGGAGAGTCAGC
CTCTTCAGGAATCTT	GGATGGCTTTTGCTG	ACGGGAGAGTCAGCC
TCTTCAGGAATCTTC	GATGGCTTTTGCTGC	CGGGAGAGTCAGCCT
CTTCAGGAATCTTCC	ATGGCTTTTGCTGCG	GGGAGAGTCAGCCTC
TTCAGGAATCTTCCT	TGGCTTTTGCTGCGG	GGAGAGTCAGCCTCC
TCAGGAATCTTCCTG	GGCTTTTGCTGCGGC	GAGAGTCAGCCTCCA
CAGGAATCTTCCTGA	GCTTTTGCTGCGGCC	AGAGTCAGCCTCCAC
AGGAATCTTCCTGAA	CTTTTGCTGCGGCCC	GAGTCAGCCTCCACA
GGAATCTTCCTGAAG	TTTTGCTGCGGCCCC	AGTCAGCCTCCACAT
GAATCTTCCTGAAGA	TTTGCTGCGGCCCCG	GTCAGCCTCCACATT
AATCTTCCTGAAGAC	TTGCTGCGGCCCCGT	TCAGCCTCCACATTC
ATCTTCCTGAAGACA	TGCTGCGGCCCCGTG	CAGCCTCCACATTCA
TCTTCCTGAAGACAT	GCTGCGGCCCCGTGG	AGCCTCCACATTCAG
CTTCCTGAAGACATG	CTGCGGCCCCGTGGG	GCCTCCACATTCAGA
TTCCTGAAGACATGG	TGCGGCCCCGTGGGG	CCTCCACATTCAGAG
TCCTGAAGACATGGC	GCGGCCCCGTGGGGT	CTCCACATTCAGAGG
CCTGAAGACATGGCC	CGGCCCCGTGGGGTA	TCCACATTCAGAGGC
CTGAAGACATGGCCC	GGCCCCGTGGGGTAG	CCACATTCAGAGGCA
TGAAGACATGGCCCA	GCCCCGTGGGGTAGG	CACATTCAGAGGCAT
GAAGACATGGCCCAG	CCCCGTGGGGTAGGA	ACATTCAGAGGCATC
AAGACATGGCCCAGT	CCCGTGGGGTAGGAG	CATTCAGAGGCATCA
AGACATGGCCCAGTC	CCGTGGGGTAGGAGG	ATTCAGAGGCATCAC
GACATGGCCCAGTCG	CGTGGGGTAGGAGGG	TTCAGAGGCATCACA
ACATGGCCCAGTCGA	GTGGGGTAGGAGGGA	TCAGAGGCATCACAA
CATGGCCCAGTCGAA	TGGGGTAGGAGGGAC	CAGAGGCATCACAAG
ATGGCCCAGTCGAAG	GGGGTAGGAGGGACA	AGAGGCATCACAAGT
TGGCCCAGTCGAAGG	GGGTAGGAGGGACAG	GAGGCATCACAAGTA
GGCCCAGTCGAAGGC	GGTAGGAGGGACAGA	AGGCATCACAAGTAA
GCCCAGTCGAAGGCC	GTAGGAGGGACAGAG	GGCATCACAAGTAAT
CCCAGTCGAAGGCCC	TAGGAGGGACAGAGA	GCATCACAAGTAATG
CCAGTCGAAGGCCCA	AGGAGGGACAGAGAG	CATCACAAGTAATGG
CAGTCGAAGGCCCAG	GGAGGGACAGAGAGA	ATCACAAGTAATGGC
AGTCGAAGGCCCAGG	GAGGGACAGAGAGAC	TCACAAGTAATGGCA
GTCGAAGGCCCAGGA	AGGGACAGAGAGACG	CACAAGTAATGGCAC
TCGAAGGCCCAGGAT	GGGACAGAGAGACGG	ACAAGTAATGGCACA
CGAAGGCCCAGGATG	GGACAGAGAGACGGG	CAAGTAATGGCACAA
AAGTAATGGCACAAT	TGTAGTTCAACAACT	TCTTTAAAGGCAAAG
AGTAATGGCACAATT	GTAGTTCAACAACTC	CTTTAAAGGCAAAGC
GTAATGGCACAATTC	TAGTTCAACAACTCA	TTTAAAGGCAAAGCT
TAATGGCACAATTCT	AGTTCAACAACTCAA	TTAAAGGCAAAGCTT
AATGGCACAATTCTT	GTTCAACAACTCAAG	TAAAGGCAAAGCTTT
ATGGCACAATTCTTC	TTCAACAACTCAAGA	AAAGGCAAAGCTTTA
TGGCACAATTCTTCG	TCAACAACTCAAGAC	AAGGCAAAGCTTTAT
GGCACAATTCTTCGG	CAACAACTCAAGACG	AGGCAAAGCTTTATT
GCACAATTCTTCGGA	AACAACTCAAGACGA	GGCAAAGCTTTATTT
CACAATTCTTCGGAT	ACAACTCAAGACGAA	GCAAAGCTTTATTTT
ACAATTCTTCGGATG	CAACTCAAGACGAAG	CAAAGCTTTATTTTC
CAATTCTTCGGATGA	AACTCAAGACGAAGC	AAAGCTTTATTTTCA
AATTCTTCGGATGAC	ACTCAAGACGAAGCT	AAGCTTTATTTTCAT
ATTCTTCGGATGACT	CTCAAGACGAAGCTT	AGCTTTATTTTCATC
TTCTTCGGATGACTG	TCAAGACGAAGCTTA	GCTTTATTTTCATCT
TCTTCGGATGACTGC	CAAGACGAAGCTTAT	CTTTATTTTCATCTC
CTTCGGATGACTGCA	AAGACGAAGCTTATT	TTTATTTTCATCTCT
TTCGGATGACTGCAG	AGACGAAGCTTATTT	TTATTTTCATCTCTC
TCGGATGACTGCAGA	GACGAAGCTTATTTC	TATTTTCATCTCTCA
CGGATGACTGCAGAA	ACGAAGCTTATTTCT	ATTTTCATCTCTCAT
GGATGACTGCAGAAA	CGAAGCTTATTTCTG	TTTTCATCTCTCATC
GATGACTGCAGAAAA	GAAGCTTATTTCTGA	TTTCATCTCTCATCT
ATGACTGCAGAAAAT	AAGCTTATTTCTGAG	TTCATCTCTCATCTT
TGACTGCAGAAAATA	AGCTTATTTCTGAGG	TCATCTCTCATCTTT
GACTGCAGAAAATAG	GCTTATTTCTGAGGA	CATCTCTCATCTTTT
ACTGCAGAAAATAGT	CTTATTTCTGAGGAT	ATCTCTCATCTTTTG
CTGCAGAAAATAGTG	TTATTTCTGAGGATA	TCTCTCATCTTTTGT
TGCAGAAAATAGTGT	TATTTCTGAGGATAA	CTCTCATCTTTTGTC
GCAGAAAATAGTGTT	ATTTCTGAGGATAAG	TCTCATCTTTTGTCC
CAGAAAATAGTGTTT	TTTCTGAGGATAAGC	CTCATCTTTTGTCCT
AGAAAATAGTGTTTT	TTCTGAGGATAAGCT	TCATCTTTTGTCCTC
GAAAATAGTGTTTTG	TCTGAGGATAAGCTC	CATCTTTTGTCCTCC
AAAATAGTGTTTTGT	CTGAGGATAAGCTCT	ATCTTTTGTCCTCCT
AAATAGTGTTTTGTA	TGAGGATAAGCTCTT	TCTTTTGTCCTCCTT
AATAGTGTTTTGTAG	GAGGATAAGCTCTTT	CTTTTGTCCTCCTTA
ATAGTGTTTTGTAGT	AGGATAAGCTCTTTA	TTTTGTCCTCCTTAG
TAGTGTTTTGTAGTT	GGATAAGCTCTTTAA	TTTGTCCTCCTTAGC
AGTGTTTTGTAGTTC	GATAAGCTCTTTAAA	TTGTCCTCCTTAGCA
GTGTTTTGTAGTTCA	ATAAGCTCTTTAAAG	TGTCCTCCTTAGCAC
TGTTTTGTAGTTCAA	TAAGCTCTTTAAAGG	GTCCTCCTTAGCACA
GTTTTGTAGTTCAAC	AAGCTCTTTAAAGGC	TCCTCCTTAGCACAA
TTTTGTAGTTCAACA	AGCTCTTTAAAGGCA	CCTCCTTAGCACAAT
TTTGTAGTTCAACAA	GCTCTTTAAAGGCAA	CTCCTTAGCACAATG
TTGTAGTTCAACAAC	CTCTTTAAAGGCAAA	TCCTTAGCACAATGT
CCTTAGCACAATGTA	GAGGAATGGCTTGCT	ATAGAGATTCACCCA
CTTAGCACAATGTAA	AGGAATGGCTTGCTG	TAGAGATTCACCCAT
TTAGCACAATGTAAA	GGAATGGCTTGCTGG	AGAGATTCACCCATG
TAGCACAATGTAAAA	GAATGGCTTGCTGGG	GAGATTCACCCATGT
AGCACAATGTAAAAA	AATGGCTTGCTGGGG	AGATTCACCCATGTT
GCACAATGTAAAAAA	ATGGCTTGCTGGGGA	GATTCACCCATGTTT
CACAATGTAAAAAAG	TGGCTTGCTGGGGAG	ATTCACCCATGTTTG
ACAATGTAAAAAAAG	GGCTTGCTGGGGAGC	TTCACCCATGTTTGT
CAATGTAAAAAAGAA	GCTTGCTGGGGAGCC	TCACCCATGTTTGTT
AATGTAAAAAAGAAT	CTTGCTGGGGAGCCC	CACCCATGTTTGTTG
ATGTAAAAAAGAATA	TTGCTGGGGAGCCCA	ACCCATGTTTGTTGA
TGTAPAAAAGAATAG	TGCTGGGGAGCCCAT	CCCATGTTTGTTGAA
GTAAAAAAGAATAGT	GCTGGGGAGCCCATC	CCATGTTTGTTGAAC
TAAAAAAGAATAGTA	CTGGGGAGCCCATCC	CATGTTTGTTGAACT
AAAAAAGAATAGTAA	TGGGGAGCCCATCCA	ATGTTTGTTGAACTT
AAAAAGAATAGTAAT	GGGGAGCCCATCCAG	TGTTTGTTGAACTTA
AAAAGAATAGTAATA	GGGAGCCCATCCAGG	GTTTGTTGAACTTAG
AAAGAATAGTAATAT	GGAGCCCATCCAGGA	TTTGTTGAACTTAGA
AAGAATAGTAATATC	GAGCCCATCCAGGAC	TTGTTGAACTTAGAG
AGAATAGTAATATCA	AGCCCATCCAGGACA	TGTTGAACTTAGAGT
GAATAGTAATATCAG	GCCCATCCAGGACAC	GTTGAACTTAGAGTC
AATAGTAATATCAGA	CCCATCCAGGACACT	TTGAACTTAGAGTCA
ATAGTAATATCAGAA	CCATCCAGGACACTG	TGAACTTAGAGTCAT
TAGTAATATCAGAAC	CATCCAGGACACTGG	GAACTTAGAGTCATT
AGTAATATCAGAACA	ATCCAGGACACTGGG	AACTTAGAGTCATTC
GTAATATCAGAACAG	TCCAGGACACTGGGA	ACTTAGAGTCATTCT
TAATATCAGAACAGG	CCAGGACACTGGGAG	CTTAGAGTCATTCTC
AATATCAGAACAGGA	CAGGACACTGGGAGC	TTAGAGTCATTCTCA
ATATCAGAACAGGAA	AGGACACTGGGAGCA	TAGAGTCATTCTCAT
TATCAGAACAGGAAG	GGACACTGGGAGCAC	AGAGTCATTCTCATG
ATCAGAACAGGAAGG	GACACTGGGAGCACA	GAGTCATTCTCATGC
TCAGAACAGGAAGGA	ACACTGGGAGCACAT	AGTCATTCTCATGCT
CAGAACAGGAAGGAG	CACTGGGAGCACATA	GTCATTCTCATGCTT
AGAACAGGAAGGAGG	ACTGGGAGCACATAG	TCATTCTCATGCTTT
GAACAGGAAGGAGGA	CTGGGAGCACATAGA	CATTCTCATGCTTTT
AACAGGAAGGAGGAA	TGGGAGCACATAGAG	ATTCTCATGCTTTTC
ACAGGAAGGAGGAAT	GGGAGCACATAGAGA	TTCTCATGCTTTTCT
CAGGAAGGAGGAATG	GGAGCACATAGAGAT	TCTCATGCTTTTCTT
AGGAAGGAGGAATGG	GAGCACATAGAGATT	CTCATGCTTTTCTTT
GGAAGGAGGAATGGC	AGCACATAGAGATTC	TCATGCTTTTCTTTA
GAAGGAGGAATGGCT	GCACATAGAGATTCA	CATGCTTTTCTTTAT
AAGGAGGAATGGCTT	CACATAGAGATTCAC	ATGCTTTTCTTTATA
AGGAGGAATGGCTTG	ACATAGAGATTCACC	TGCTTTTCTTTATAA
GGAGGAATGGCTTGC	CATAGAGATTCACCC	GCTTTTCTTTATAAT
CTTTTCTTTATAATT	TGTTAACATTGTATA	TACTAGATAATCCTA
TTTTCTTTATAATTC	GTTAACATTGTATAC	ACTAGATAATCCTAG
TTTCTTTATAATTCA	TTAACATTGTATACA	CTAGATAATCCTAGA
TTCTTTATAATTCAC	TAACATTGTATACAA	TAGATAATCCTAGAT
TCTTTATAATTCACA	AACATTGTATACAAC	AGATAATCCTAGATG
CTTTATAATTCACAC	ACATTGTATACAACA	GATAATCCTAGATGA
TTTATAATTCACACA	CATTGTATACAACAT	ATAATCCTAGATGAA
TTATAATTCACACAT	ATTGTATACAACATA	TAATCCTAGATGAAA
TATAATTCACACATA	TTGTATACAACATAG	AATCCTAGATGAAAT
ATAATTCACACATAT	TGTATACAACATAGC	ATCCTAGATGAAATG
TAATTCACACATATA	GTATACAACATAGCC	TCCTAGATGAAATGT
AATTCACACATATAT	TATACAACATAGCCC	CCTAGATGAAATGTT
ATTCACACATATATG	ATACAACATAGCCCC	CTAGATGAAATGTTA
TTCACACATATATGC	TACAACATAGCCCCA	TAGATGAAATGTTAG
TCACACATATATGCA	ACAACATAGCCCCAA	AGATGAAATGTTAGA
CACACATATATGCAG	CAACATAGCCCCAAA	GATGAAATGTTAGAG
ACACATATATGCAGA	AACATAGCCCCAAAT	ATGAAATGTTAGAGA
CACATATATGCAGAG	ACATAGCCCCAAATA	TGAAATGTTAGAGAT
ACATATATGCAGAGA	CATAGCCCCAAATAT	GAAATGTTAGAGATG
CATATATGCAGAGAA	ATAGCCCCAAATATA	AAATGTTAGAGATGC
ATATATGCAGAGAAG	TAGCCCCAAATATAG	AATGTTAGAGATGCT
TATATGCAGAGAAGA	AGCCCCAAATATAGT	ATGTTAGAGATGCTA
ATATGCAGAGAAGAT	GCCCCAAATATAGTA	TGTTAGAGATGCTAT
TATGCAGAGAAGATA	CCCCAAATATAGTAA	GTTAGAGATGCTATA
ATGCAGAGAAGATAT	CCCAAATATAGTAAG	TTAGAGATGCTATAT
TGCAGAGAAGATATG	CCAAATATAGTAAGA	TAGAGATGCTATATG
GCAGAGAAGATATGT	CAAATATAGTAAGAT	AGAGATGCTATATGA
CAGAGAAGATATGTT	AAATATAGTAAGATC	GAGATGCTATATGAT
AGAGAAGATATGTTC	AATATAGTAAGATCT	AGATGCTATATGATA
GAGAAGATATGTTCT	ATATAGTAAGATCTA	GATGCTATATGATAC
AGAAGATATGTTCTT	TATAGTAAGATCTAT	ATGCTATATGATACA
GAAGATATGTTCTTG	ATAGTAAGATCTATA	TGCTATATGATACAA
AAGATATGTTCTTGT	TAGTAAGATCTATAC	GCTATATGATACAAC
AGATATGTTCTTGTT	AGTAAGATCTATACT	CTATATGATACAACT
GATATGTTCTTGTTA	GTAAGATCTATACTA	TATATGATACAACTG
ATATGTTCTTGTTAA	TAAGATCTATACTAG	ATATGATACAACTGT
TATGTTCTTGTTAAC	AAGATCTATACTAGA	TATGATACAACTGTG
ATGTTCTTGTTAACA	AGATCTATACTAGAT	ATGATACAACTGTGG
TGTTCTTGTTAACAT	GATCTATACTAGATA	TGATACAACTGTGGC
GTTCTTGTTAACATT	ATCTATACTAGATAA	GATACAACTGTGGCC
TTCTTGTTAACATTG	TCTATACTAGATAAT	ATACAACTGTGGCCA
TCTTGTTAACATTGT	CTATACTAGATAATC	TACAACTGTGGCCAT
CTTGTTAACATTGTA	TATACTAGATAATCC	ACAACTGTGGCCATG
TTGTTAACATTGTAT	ATACTAGATAATCCT	CAACTGTGGCCATGA
AACTGTGGCCATGAC	GGCTGCTCTCCCGGA	AGGCTCAGGGAGACT
ACTGTGGCCATGACT	GCTGCTCTCCCGGAG	GGCTCAGGGAGACTC
CTGTGGCCATGACTG	CTGCTCTCCCGGAGG	GCTCAGGGAGACTCT
TGTGGCCATGACTGA	TGCTCTCCCGGAGGC	CTCAGGGAGACTCTG
GTGGCCATGACTGAG	GCTCTCCCGGAGGCC	TCAGGGAGACTCTGC
TGGCCATGACTGAGG	CTCTCCCGGAGGCCA	CAGGGAGACTCTGCC
GGCCATGACTGAGGA	TCTCCCGGAGGCCAA	AGGGAGACTCTGCCC
GCCATGACTGAGGAA	CTCCCGGAGGCCAAA	GGGAGACTCTGCCCT
CCATGACTGAGGAAA	TCCCGGAGGCCAAAC	GGAGACTCTGCCCTG
CATGACTGAGGAAAG	CCCGGAGGCCAAACC	GAGACTCTGCCCTGC
ATGACTGAGGAAAGG	CCGGAGGCCAAACCC	AGACTCTGCCCTGCT
TGACTGAGGAAAGGA	CGGAGGCCAAACCCA	GACTCTGCCCTGCTG
GACTGAGGAAAGGAG	GGAGGCCAAACCCAA	ACTCTGCCCTGCTGC
ACTGAGGAAAGGAGC	GAGGCCAAACCCAAG	CTCTGCCCTGCTGCA
CTGAGGAAAGGAGCT	AGGCCAAACCCAAGA	TCTGCCCTGCTGCAG
TGAGGAAAGGAGCTC	GGCCAAACCCAAGAA	CTGCCCTGCTGCAGA
GAGGAAAGGAGCTCA	GCCAAACCCAAGAAG	TGCCCTGCTGCAGAC
AGGAAAGGAGCTCAC	CCAAACCCAAGAAGG	GCCCTGCTGCAGACC
GGAAAGGAGCTCACG	CAAACCCAAGAAGGT	CCCTGCTGCAGACCT
GAAAGGAGCTCACGC	AAACCCAAGAAGGTC	CCTGCTGCAGACCTC
AAAGGAGCTCACGCC	AACCCAAGAAGGTCT	CTGCTGCAGACCTCG
AAGGAGCTCACGCCC	ACCCAAGAAGGTCTG	TGCTGCAGACCTCGG
AGGAGCTCACGCCCA	CCCAAGAAGGTCTGG	GCTGCAGACCTCGGT
GGAGCTCACGCCCAG	CCAAGAAGGTCTGGC	CTGCAGACCTCGGTG
GAGCTCACGCCCAGA	CAAGAAGGTCTGGCA	TGCAGACCTCGGTGT
AGCTCACGCCCAGAG	AAGAAGGTCTGGCAA	GCAGACCTCGGTGTG
GCTCACGCCCAGAGA	AGAAGGTCTGGCAAA	CAGACCTCGGTGTGG
CTCACGCCCAGAGAC	GAAGGTCTGGCAAAG	AGACCTCGGTGTGGA
TCACGCCCAGAGACT	AAGGTCTGGCAAAGT	GACCTCGGTGTGGAC
CACGCCCAGAGACTG	AGGTCTGGCAAAGTC	ACCTCGGTGTGGACA
ACGCCCAGAGACTGG	GGTCTGGCAAAGTCA	CCTCGGTGTGGACAC
CGCCCAGAGACTGGG	GTCTGGCAAAGTCAG	CTCGGTGTGGACACA
GCCCAGAGACTGGGC	TCTGGCAAAGTCAGG	TCGGTGTGGACACAC
CCCAGAGACTGGGCT	CTGGCAAAGTCAGGC	CGGTGTGGACACACG
CCAGAGACTGGGCTG	TGGCAAAGTCAGGCT	GGTGTGGACACACGC
CAGAGACTGGGCTGC	GGCAAAGTCAGGCTC	GTGTGGACACACGCT
AGAGACTGGGCTGCT	GCAAAGTCAGGCTCA	TGTGGACACACGCTG
GAGACTGGGCTGCTC	CAAAGTCAGGCTCAG	GTGGACACACGCTGC
AGACTGGGCTGCTCT	AAAGTCAGGCTCAGG	TGGACACACGCTGCA
GACTGGGCTGCTCTC	AAGTCAGGCTCAGGG	GGACACACGCTGCAT
ACTGGGCTGCTCTCC	AGTCAGGCTCAGGGA	GACACACGCTGCATA
CTGGGCTGCTCTCCC	GTCAGGCTCAGGGAG	ACACACGCTGCATAG
TGGGCTGCTCTCCCG	TCAGGCTCAGGGAGA	CACACGCTGCATAGA
GGGCTGCTCTCCCGG	CAGGCTCAGGGAGAC	ACACGCTGCATAGAG
CACGCTGCATAGAGC	ATTCTGCCTACCTAT	GGGGGAAAAGTATTT
ACGCTGCATAGAGCT	TTCTGCCTACCTATT	GGGGAAAAGTATTTT
CGCTGCATAGAGCTC	TCTGCCTACCTATTA	GGGAAAAGTATTTTT
GCTGCATAGAGCTCT	CTGCCTACCTATTAG	GGAAAAGTATTTTTG
CTGCATAGAGCTCTC	TGCCTACCTATTAGC	GAAAAGTATTTTTGA
TGCATAGAGCTCTCC	GCCTACCTATTAGCT	AAAAGTATTTTTGAG
GCATAGAGCTCTCCT	CCTACCTATTAGCTT	AAAGTATTTTTGAGA
CATAGAGCTCTCCTT	CTACCTATTAGCTTT	AAGTATTTTTGAGAA
ATAGAGCTCTCCTTG	TACCTATTAGCTTTT	AGTATTTTTGAGAAG
TAGAGCTCTCCTTGA	ACCTATTAGCTTTTC	GTATTTTTGAGAAGT
AGAGCTCTCCTTGAA	CCTATTAGCTTTTCT	TATTTTTGAGAAGTT
GAGCTCTCCTTGAAA	CTATTAGCTTTTCTT	ATTTTTGAGAAGTTT
AGCTCTCCTTGAAAA	TATTAGCTTTTCTTT	TTTTTGAGAAGTTTG
GCTCTCCTTGAAAAC	ATTAGCTTTTCTTTA	TTTTGAGAAGTTTGT
CTCTCCTTGAAAACA	TTAGCTTTTCTTTAT	TTTGAGAAGTTTGTC
TCTCCTTGAAAACAG	TAGCTTTTCTTTATT	TTGAGAAGTTTGTCT
CTCCTTGAAAACAGA	AGCTTTTCTTTATTT	TGAGAAGTTTGTCTT
TCCTTGAAAACAGAG	GCTTTTCTTTATTTT	GAGAAGTTTGTCTTG
CCTTGAAAACAGAGG	CTTTTCTTTATTTTT	AGAAGTTTGTCTTGC
CTTGAAAACAGAGGG	TTTTCTTTATTTTTT	GAAGTTTGTCTTGCA
TTGAAAACAGAGGGG	TTTCTTTATTTTTTT	AAGTTTGTCTTGCAA
TGAAAACAGAGGGGT	TTCTTTATTTTTTTA	AGTTTGTCTTGCAAT
GAAAACAGAGGGGTC	TCTTTATTTTTTTAA	GTTTGTCTTGCAATG
AAAACAGAGGGGTCT	CTTTATTTTTTTAAC	TTTGTCTTGCAATGT
AAACAGAGGGGTCTC	TTTATTTTTTTAACT	TTGTCTTGCAATGTA
AACAGAGGGGTCTCA	TTATTTTTTTAACTT	TGTCTTGCAATGTAT
ACAGAGGGGTCTCAA	TATTTTTTTAACTTT	GTCTTGCAATGTATT
CAGAGGGGTCTCAAG	ATTTTTTTAACTTTT	TCTTGCAATGTATTT
AGAGGGGTCTCAAGA	TTTTTTTAACTTTTT	CTTGCAATGTATTTA
GAGGGGTCTCAAGAC	TTTTTTAACTTTTTG	TTGCAATGTATTTAT
AGGGGTCTCAAGACA	TTTTTAACTTTTTGG	TGCAATGTATTTATA
GGGGTCTCAAGACAT	TTTTAACTTTTTGGG	GCAATGTATTTATAA
GGGTCTCAAGACATT	TTTAACTTTTTGGGG	CAATGTATTTATAAA
GGTCTCAAGACATTC	TTAACTTTTTGGGGG	AATGTATTTATAAAT
GTCTCAAGACATTCT	TAACTTTTTGGGGGG	ATGTATTTATAAATA
TCTCAAGACATTCTG	AACTTTTTGGGGGGA	TGTATTTATAAATAG
CTCAAGACATTCTGC	ACTTTTTGGGGGGAA	GTATTTATAAATAGT
TCAAGACATTCTGCC	CTTTTTGGGGGGAAA	TATTTATAAATAGTA
CAAGACATTCTGCCT	TTTTTGGGGGGAAAA	ATTTATAAATAGTAA
AAGACATTCTGCCTA	TTTTGGGGGGAAAAG	TTTATAAATAGTAAA
AGACATTCTGCCTAC	TTTGGGGGGAAAAGT	TTATAAATAGTAAAT
GACATTCTGCCTACC	TTGGGGGGAAAAGTA	TATAAATAGTAAATA
ACATTCTGCCTACCT	TGGGGGGAAAAGTAT	ATAAATAGTAAATAA
CATTCTGCCTACCTA	GGGGGGAAAAGTATT	TAAATAGTAAATAAA
AAATAGTAAATAAAG
AATAGTAAATAAAGT
ATAGTAAATAAAGTT
TAGTAAATAAAGTTT
AGTAAATAAAGTTTT
GTAAATAAAGTTTTT
TAAATAAAGTTTTTA
AAATAAAGTTTTTAC
AATAAAGTTTTTACC
ATAAAGTTTTTACCA
TAAAGTTTTTACCAT
AAAGTTTTTACCATT

EXAMPLE 8

Antisense oligonucleotides to IGF-I may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:

TTTTTTTTTTTTTTG	ATTTCATCCCAAATA	AAGTCTGGCTCCGGA
TTTTTTTTTTTTTGA	TTTCATCCCAAATAA	AGTCTGGCTCCGGAG
TTTTTTTTTTTTGAG	TTCATCCCAAATAAA	GTCTGGCTCCGGAGG
TTTTTTTTTTTGAGA	TCATCCCAAATAAAA	TCTGGCTCCGGAGGA
TTTTTTTTTTGAGAA	CATCCCAAATAAAAG	CTGGCTCCGGAGGAG
TTTTTTTTTGAGAAA	ATCCCAAATAAAAGG	TGGCTCCGGAGGAGG
TTTTTTTTGAGAAAG	TCCCAAATAAAAGGA	GGCTCCGGAGGAGGG
TTTTTTTGAGAAAGG	CCCAAATAAAAGGAA	GCTCCGGAGGAGGGT
TTTTTTGAGAAAGGG	CCAAATAAAAGGAAT	CTCCGGAGGAGGGTC
TTTTTGAGAAAGGGA	CAAATAAAAGGAATG	TCCGGAGGAGGGTCC
TTTTGAGAAAGGGAA	AAATAAAAGGAATGA	CCGGAGGAGGGTCCC
TTTGAGAAAGGGAAT	AATAAAAGGAATGAA	CGGAGGAGGGTCCCC
TTGAGAAAGGGAATT	ATAAAAGGAATGAAG	GGAGGAGGGTCCCCG
TGAGAAAGGGAATTT	TAAAAGGAATGAAGT	GAGGAGGGTCCCCGA
GAGAAAGGGAATTTC	AAAAGGAATGAAGTC	AGGAGGGTCCCCGAC
AGAAAGGGAATTTCA	AAAGGAATGAAGTCT	GGAGGGTCCCCGACC
GAAAGGGAATTTCAT	AAGGAATGAAGTCTG	GAGGOTCCCCGACCT
AAAGGGAATTTCATC	AGGAATGAAGTCTGG	AGGGTCCCCGACCTC
AAGGGAATTTCATCC	GGAATGAAGTCTGGC	GGGTCCCCGACCTCG
AGGGAATTTCATCCC	GAATGAAGTCTGGCT	GGTCCCCGACCTCGC
GGGAATTTCATCCCA	AATGAAGTCTGGCTC	GTCCCCGACCTCGCT
GGAATTTCATCCCAA	ATGAAGTCTGGCTCC	TCCCCGACCTCGCTG
GAATTTCATCCCAAA	TGAAGTCTGGCTCCG	CCCCGACCTCGCTGT
AATTTCATCCCAAAT	GAAGTCTGGCTCCGG	CCCGACCTCGCTGTG
CCGACCTCGCTGTGG	GCTCTGGCCGACGAG	TCCGCAACGACTATC
CGACCTCGCTGTGGG	CTCTGGCCGACGAGT	CCGCAACGACTATCA
GACCTCGCTGTGGGG	TCTGGCCGACGAGTG	CGCAACGACTATCAG
ACCTCGCTGTGGGGG	CTGGCCGACGAGTGG	GCAACGACTATCAGC
CCTCGCTGTGGGGGC	TGGCCGACGAGTGGA	CAACGACTATCAGCA
CTCGCTGTGGGGGCT	GGCCGACGAGTGGAG	AACGACTATCAGCAG
TCGCTGTGGGGGCTC	GCCGACGAGTGGAGA	ACGACTATCAGCAGC
CGCTGTGGGGGCTCC	CCGACGAGTGGAGAA	CGACTATCAGCAGCT
GCTGTGGGGGCTCCT	CGACGAGTGGAGATA	GACTATCAGCAGCTG
CTGTGGGGGCTCCTG	GACGAGTGGAGAAAT	ACTATCAGCAGCTGA
TGTGGGGGCTCCTGT	ACGAGTGGAGAAATC	CTATCAGCAGCTGAA
GTGGGGGCTCCTGTT	CGAGTGGAGAAATCT	TATCAGCAGCTGAAG
TGGGGGCTCCTGTTT	GAGTGGAGAAATCTG	ATCAGCAGCTGAAGC
GGGGGCTCCTGTTTC	AGTGGAGAAATCTGC	TCAGCAGCTGAAGCG
GGGGCTCCTGTTTCT	GTGGAGAAATCTGCG	CAGCAGCTGAAGCGC
GGGCTCCTGTTTCTC	TGGAGAAATCTGCGG	AGCAGCTGAAGCGCC
GGCTCCTGTTTCTCT	GGAGAAATCTGCGGG	GCAGCTGAAGCGCCT
GCTCCTGTTTCTCTC	GAGAAATCTGCGGGC	CAGCTGAAGCGCCTG
CTCCTGTTTCTCTCC	AGAAATCTGCGGGCC	AGCTGAAGCGCCTGG
TCCTGTTTCTCTCCG	GAAATCTGCGGGCCA	GCTGAAGCGCCTGGA
CCTGTTTCTCTCCGC	AAATCTGCGGGCCAG	CTGAAGCGCCTGGAG
CTGTTTCTCTCCGCC	AATCTGCGGGCCAGG	TGAAGCGCCTGGAGA
TGTTTCTCTCCGCCG	ATCTGCGGGCCAGGC	GAAGCGCCTGGAGAA
GTTTCTCTCCGCCGC	TCTGCGGGCCAGGCA	AAGCGCCTGGAGAAC
TTTCTCTCCGCCGCG	CTGCGGGCCAGGCAT	AGCGCCTGGAGAACT
TTCTCTCCGCCGCGC	TGCGGGCCAGGCATC	GCGCCTGGAGAACTG
TCTCTCCGCCGCGCT	GCGGGCCAGGCATCG	CGCCTGGAGAACTGC
CTCTCCGCCGCGCTC	CGGGCCAGGCATCGA	GCCTGGAGAACTGCA
TCTCCGCCGCGCTCT	GGGCCAGGCATCGAC	CCTGGAGAACTGCAC
CTCCGCCGCGCTCTC	GGCCAGGCATCGACA	CTGGAGAACTGCACG
TCCGCCGCGCTCTCG	GCCAGGCATCGACAT	TGGAGAACTGCACGG
CCGCCGCGCTCTCGC	CCAGGCATCGACATC	GGAGAACTGCACGGT
CGCCGCGCTCTCGCT	CAGGCATCGACATCC	GAGAACTGCACGGTG
GCCGCGCTCTCGCTC	AGGCATCGACATCCG	AGAACTGCACGGTGA
CCGCGCTCTCGCTCT	GGCATCGACATCCGC	GAACTGCACGGTGAT
CGCGCTCTCGCTCTG	GCATCGACATCCGCA	AACTGCACGGTGATC
GCGCTCTCGCTCTGG	CATCGACATCCGCAA	ACTGCACGGTGATCG
CGCTCTCGCTCTGGC	ATCGACATCCGCAAC	CTGCACGGTGATCGA
GCTCTCGCTCTGGCC	TCGACATCCGCAACG	TGCACGGTGATCGAG
CTCTCGCTCTGGCCG	CGACATCCGCAACGA	GCACGGTGATCGAGG
TCTCGCTCTGGCCGA	GACATCCGCAACGAC	CACGGTGATCGAGGG
CTCGCTCTGGCCGAC	ACATCCGCAACGACT	ACGGTGATCGAGGGC
TCGCTCTGGCCGACG	CATCCGCAACGACTA	CGGTGATCGAGGGCT
CGCTCTGGCCGACGA	ATCCGCAACGACTAT	GGTGATCGAGGGCTA
GTGATCGAGGGCTAC	GGACTACCGCAGCTA	AGTACTTGCTGCTGT
TGATCGAGGGCTACC	GACTACCGCAGCTAC	GTACTTGCTGCTGTT
GATCGAGGGCTACCT	ACTACCGCAGCTACC	TACTTGCTGCTGTTC
ATCGAGGGCTACCTC	CTACCGCAGCTACCG	ACTTGCTGCTGTTCC
TCGAGGGCTACCTCC	TACCGCAGCTACCGC	CTTGCTGCTGTTCCG
CGAGGGCTACCTCCA	ACCGCAGCTACCGCT	TTGCTGCTGTTCCGA
GAGGGCTACCTCCAC	CCGCAGCTACCGCTT	TGCTGCTGTTCCGAG
AGGGCTACCTCCACA	CGCAGCTACCGCTTC	GCTGCTGTTCCGAGT
GGGCTACCTCCACAT	GCAGCTACCGCTTCC	CTGCTGTTCCGAGTG
GGCTACCTCCACATC	CAGCTACCGCTTCCC	TGCTGTTCCGAGTGG
GCTACCTCCACATCC	AGCTACCGCTTCCCC	GCTGTTCCGAGTGGC
CTACCTCCACATCCT	GCTACCGCTTCCCCA	CTGTTCCGAGTGGCT
TACCTCCACATCCTG	CTACCGCTTCCCCAA	TGTTCCGAGTGGCTG
ACCTCCACATCCTGC	TACCGCTTCCCCAAG	GTTCCGAGTGGCTGG
CCTCCACATCCTGCT	ACCGCTTCCCCAAGC	TTCCGAGTGGCTGGC
CTCCACATCCTGCTC	CCGCTTCCCCAAGCT	TCCGAGTGGCTGGCC
TCCACATCCTGCTCA	CGCTTCCCCAAGCTC	CCGAGTGGCTGGCCT
CCACATCCTGCTCAT	GCTTCCCCAAGCTCA	CGAGTGGCTGGCCTC
CACATCCTGCTCATC	CTTCCCCAAGCTCAC	GAGTGGCTGGCCTCG
ACATCCTGCTCATCT	TTCCCCAAGCTCACG	AGTGGCTGGCCTCGA
CATCCTGCTCATCTC	TCCCCAAGCTCACGG	GTGGCTGGCCTCGAG
ATCCTGCTCATCTCC	CCCCAAGCTCACGGT	TGGCTGGCCTCGAGA
TCCTGCTCATCTCCA	CCCAAGCTCACGGTC	GGCTGGCCTCGAGAG
CCTGCTCATCTCCAA	CCAAGCTCACGGTCA	GCTGGCCTCGAGAGC
CTGCTCATCTCCAAG	CAAGCTCACGGTCAT	CTGGCCTCGAGAGCC
TGCTCATCTCCAAGG	AAGCTCACGGTCATT	TGGCCTCGAGAGCCT
GCTCATCTCCAAGGC	AGCTCACGGTCATTA	GGCCTCGAGAGCCTC
CTCATCTCCAAGGCC	GCTCACGGTCATTAC	GCCTCGAGAGCCTCG
TCATCTCCAAGGCCG	CTCACGGTCATTACC	CCTCGAGAGCCTCGG
CATCTCCAAGGCCGA	TCACGGTCATTACCG	CTCGAGAGCCTCGGA
ATCTCCAAGGCCGAG	CACGGTCATTACCGA	TCGAGAGCCTCGGAG
TCTCCAAGGCCGAGG	ACGGTCATTACCGAG	CGAGAGCCTCGGAGA
CTCCAAGGCCGAGGA	CGGTCATTACCGAGT	GAGAGCCTCGGAGAC
TCCAAGGCCGAGGAC	GGTCATTACCGAGTA	AGAGCCTCGGAGACC
CCAAGGCCGAGGACT	GTCATTACCGAGTAC	GAGCCTCGGAGACCT
CAAGGCCGAGGACTA	TCATTACCGAGTACT	AGCCTCGGAGACCTC
AAGGCCGAGGACTAC	CATTACCGAGTACTT	GCCTCGGAGACCTCT
AGGCCGAGGACTACC	ATTACCGAGTACTTG	CCTCGGAGACCTCTT
GGCCGAGGACTACCG	TTACCGAGTACTTGC	CTCGGAGACCTCTTC
GCCGAGGACTACCGC	TACCGAGTACTTGCT	TCGGAGACCTCTTCC
CCGAGGACTACCGCA	ACCGAGTACTTGCTG	CGGAGACCTCTTCCC
CGAGGACTACCGCAG	CCGAGTACTTGCTGC	GGAGACCTCTTCCCC
GAGGACTACCGCAGC	CGAGTACTTGCTGCT	GAGACCTCTTCCCCA
AGGACTACCGCAGCT	GAGTACTTGCTGCTG	AGACCTCTTCCCCAA
GACCTCTTCCCCAAC	CTACAACTACGCCCT	ATATTGGGCTTTACA
ACCTCTTCCCCAACC	TACAACTACGCCCTG	TATTGGGCTTTACAA
CCTCTTCCCCAACCT	ACAACTACGCCCTGG	ATTGGGCTTTACAAC
CTCTTCCCCAACCTC	CAACTACGCCCTGGT	TTGGGCTTTACAACC
TCTTCCCCAACCTCA	AACTACGCCCTGGTC	TGGGCTTTACAACCT
CTTCCCCAACCTCAC	ACTACGCCCTGGTCA	GGGCTTTACAACCTG
TTCCCCAACCTCACG	CTACGCCCTGGTCAT	GGCTTTACAACCTGA
TCCCCAACCTCACGG	TACGCCCTGGTCATC	GCTTTACAACCTGAG
CCCCAACCTCACGGT	ACGCCCTGGTCATCT	CTTTACAACCTGAGG
CCCAACCTCACGGTC	CGCCCTGGTCATCTT	TTTACAACCTGAGGA
CCAACCTCACGGTCA	GCCCTGGTCATCTTC	TTACAACCTGAGGAA
CAACCTCACGGTCAT	CCCTGGTCATCTTCG	TACAACCTGAGGAAC
AACCTCACGGTCATC	CCTGGTCATCTTCGA	ACAACCTGAGGAACA
ACCTCACGGTCATCC	CTGGTCATCTTCGAG	CAACCTGAGGAACAT
CCTCACGGTCATCCG	TGGTCATCTTCGAGA	AACCTGAGGAACATT
CTCACGGTCATCCGC	GGTCATCTTCGAGAT	ACCTGAGGAACATTA
TCACGGTCATCCGCG	GTCATCTTCGAGATG	CCTGAGGAACATTAC
CACGGTCATCCGCGG	TCATCTTCGAGATGA	CTGAGGAACATTACT
ACGGTCATCCGCGGC	CATCTTCGAGATGAC	TGAGGAACATTACTC
CGGTCATCCGCGGCT	ATCTTCGAGATGACC	GAGGAACATTACTCG
GGTCATCCGCGGCTG	TCTTCGAGATGACCA	AGGAACATTACTCGG
GTCATCCGCGGCTGG	CTTCGAGATGACCAA	GGAACATTACTCGGG
TCATCCGCGGCTGGA	TTCGAGATGACCAAT	GAACATTACTCGGGG
CATCCGCGGCTGGAA	TCGAGATGACCAATC	AACATTACTCGGGGG
ATCCGCGGCTGGAAA	CGAGATGACCAATCT	ACATTACTCGGGGGG
TCCGCGGCTGGAAAC	GAGATGACCAATCTC	CATTACTCGGGGGGC
CCGCGGCTGGAAACT	AGATGACCAATCTCA	ATTACTCGGGGGGCC
CGCGGCTGGAAACTC	GATGACCAATCTCAA	TTACTCGGGGGGCCA
GCGGCTGGAAACTCT	ATGACCAATCTCAAG	TACTCGGGGGGCCAT
CGGCTGGAAACTCTT	TGACCAATCTCAAGG	ACTCGGGGGGCCATC
GGCTGGAAACTCTTC	GACCAATCTCAAGGA	CTCGGGGGGCCATCA
GCTGGAAACTCTTCT	ACCAATCTCAAGGAT	TCGGGGGGCCATCAG
CTGGAAACTCTTCTA	CCAATCTCAAGGATA	CGGGGGGCCATCAGG
TGGAAACTCTTCTAC	CAATCTCAAGGATAT	GGGGGGCCATCAGGA
GGAAACTCTTCTACA	AATCTCAAGGATATT	GGGGGCCATCAGGAT
GAAACTCTTCTACAA	ATCTCAAGGATATTG	GGGGCCATCAGGATT
AAACTCTTCTACAAC	TCTCAAGGATATTGG	GGGCCATCAGGATTG
AACTCTTCTACAACT	CTCAAGGATATTGGG	GGCCATCAGGATTGA
ACTCTTCTACAACTA	TCAAGGATATTGGGC	GCCATCAGGATTGAG
CTCTTCTACAACTAC	CAAGGATATTGGGCT	CCATCAGGATTGAGA
TCTTCTACAACTACG	AAGGATATTGGGCTT	CATCAGGATTGAGAA
CTTCTACAACTACGC	AGGATATTGGGCTTT	ATCAGGATTGAGAAA
TTCTACAACTACGCC	GGATATTGGGCTTTA	TCAGGATTGAGAAAA
TCTACAACTACGCCC	GATATTGGGCTTTAC	CAGGATTGAGAAAAA
AGGATTGAGAAAAAT	CTGGTCCCTGATCCT	GGAATAAGCCCCCAA
GGATTGAGAAAAATG	TGGTCCCTGATCCTG	GAATAAGCCCCCAAA
GATTGAGAAAAATGC	GGTCCCTGATCCTGG	AATAAGCCCCCAAAG
ATTGAGAAAAATGCT	GTCCCTGATCCTGGA	ATAAGCCCCCAAAGG
TTGAGAAAAATGCTG	TCCCTGATCCTGGAT	TAAGCCCCCAAAGGA
TGAGAAAAATGCTGA	CCCTGATCCTGGATG	AAGCCCCCAAAGGAA
GAGAAAAATGCTGAC	CCTGATCCTGGATGC	AGCCCCCAAAGGAAT
AGAAAAATGCTGACC	CTGATCCTGGATGCG	GCCCCCAAAGGAATG
GAAAAATGCTGACCT	TGATCCTGGATGCGG	CCCCCAAAGGAATGT
AAAAATGCTGACCTC	GATCCTGGATGCGGT	CCCCAAAGGAATGTG
AAAATGCTGACCTCT	ATCCTGGATGCGGTG	CCCAAAGGAATGTGG
AAATGCTGACCTCTG	TCCTGGATGCGGTGT	CCAAAGGAATGTGGG
AATGCTGACCTCTGT	CCTGGATGCGGTGTC	CAAAGGAATGTGGGG
ATGCTGACCTCTGTT	CTGGATGCGGTGTCC	AAAGGAATGTGGGGA
TGCTGACCTCTGTTA	TGGATGCGGTGTCCA	AAGGAATGTGGGGAC
GCTGACCTCTGTTAC	GGATGCGGTGTCCAA	AGGAATGTGGGGACC
CTGACCTCTGTTACC	GATGCGGTGTCCAAT	GGAATGTGGGGACCT
TGACCTCTGTTACCT	ATGCGGTGTCCAATA	GAATGTGGGGACCTG
GACCTCTGTTACCTC	TGCGGTGTCCAATAA	AATGTGGGGACCTGT
ACCTCTGTTACCTCT	GCGGTGTCCAATAAC	ATGTGGGGACCTGTG
CCTCTGTTACCTCTC	CGGTGTCCAATAACT	TGTGGGGACCTGTGT
CTCTGTTACCTCTCC	GGTGTCCAATAACTA	GTGGGGACCTGTGTC
TCTGTTACCTCTCCA	GTGTCCAATAACTAC	TGGGGACCTGTGTCC
CTGTTACCTCTCCAC	TGTCCAATAACTACA	GGGGACCTGTGTCCA
TGTTACCTCTCCACT	GTCCAATAACTACAT	GGGACCTGTGTCCAG
GTTACCTCTCCACTG	TCCAATAACTACATT	GGACCTGTGTCCAGG
TTACCTCTCCACTGT	CCAATAACTACATTG	GACCTGTGTCCAGGG
TACCTCTCCACTGTG	CAATAACTACATTGT	ACCTGTGTCCAGGGA
ACCTCTCCACTGTGG	AATAACTACATTGTG	CCTGTGTCCAGGGAC
CCTCTCCACTGTGGA	ATAACTACATTGTGG	CTGTGTCCAGGGACC
CTCTCCACTGTGGAC	TAACTACATTGTGGG	TGTGTCCAGGGACCA
TCTCCACTGTGGACT	AACTACATTGTGGGG	GTGTCCAGGGACCAT
CTCCACTGTGGACTG	ACTACATTGTGGGGA	TGTCCAGGGACCATG
TCCACTGTGGACTGG	CTACATTGTGGGGAA	GTCCAGGGACCATGG
CCACTGTGGACTGGT	TACATTGTGGGGAAT	TCCAGGGACCATGGA
CACTGTGGACTGGTC	ACATTGTGGGGAATA	CCAGGGACCATGGAG
ACTGTGGACTGGTCC	CATTGTGGGGAATAA	CAGGGACCATGGAGG
CTGTGGACTGGTCCC	ATTGTGGGGAATAAG	AGGGACCATGGAGGA
TGTGGACTGGTCCCT	TTGTGGGGAATAAGC	GGGACCATGGAGGAG
GTGGACTGGTCCCTG	TGTGGGGAATAAGCC	GGACCATGGAGGAGA
TGGACTGGTCCCTGA	GTGGGGAATAAGCCC	GACCATGGAGGAGAA
GGACTGGTCCCTGAT	TGGGGAATAAGCCCC	ACCATGGAGGAGAAG
GACTGGTCCCTGATC	GGGGAATAAGCCCCC	CCATGGAGGAGAAGC
ACTGGTCCCTGATCC	GGGAATAAGCCCCCA	CATGGAGGAGAAGCC
ATGGAGGAGAAGCCG	GTACAACTACCGCTG	GCCCAAGCACGTGTG
TGGAGGAGAAGCCGA	TACAACTACCGCTGC	CCCAAGCACGTGTGG
GGAGGAGAAGCCGAT	ACAACTACCGCTGCT	CCAAGCACGTGTGGG
GAGGAGAAGCCGATG	CAACTACCGCTGCTG	CAAGCACGTGTGGGA
AGGAGAAGCCGATGT	AACTACCGCTGCTGG	AAGCACGTGTGGGAA
GGAGAAGCCGATGTG	ACTACCGCTGCTGGA	AGCACGTGTGGGAAG
GAGAAGCCGATGTGT	CTACCGCTGCTGGAC	GCACGTGTGGGAAGC
AGAAGCCGATGTGTG	TACCGCTGCTGGACC	CACGTGTGGGAAGCG
GAAGCCGATGTGTGA	ACCGCTGCTGGACCA	ACGTGTGGGAAGCGG
AAGCCGATGTGTGAG	CCGCTGCTGGACCAC	CGTGTGGGAAGCGGG
AGCCGATGTGTGAGA	CGCTGCTGGACCACA	GTGTGGGAAGCGGGC
GCCGATGTGTGAGAA	GCTGCTGGACCACAA	TGTGGGAAGCGGGCG
CCGATGTGTGAGAAG	CTGCTGGACCACAAA	GTGGGAAGCGGGCGT
CGATGTGTGAGAAGA	TGCTGGACCACAAAC	TGGGAAGCGGGCGTG
GATGTGTGAGAAGAC	GCTGGACCACAAACC	GGGAAGCGGGCGTGC
ATGTGTGAGAAGACC	CTGGACCACAAACCG	GGAAGCGGGCGTGCA
TGTGTGAGAAGACCA	TGGACCACAAACCGC	GAAGCGGGCGTGCAC
GTGTGAGAAGACCAC	GGACCACAAACCGCT	AAGCGGGCGTGCACC
TGTGAGAAGACCACC	GACCACAAACCGCTG	AGCGGGCGTGCACCG
GTGAGAAGACCACCA	ACCACAAACCGCTGC	GCGGGCGTGCACCGA
TGAGAAGACCACCAT	CCACAAACCGCTGCC	CGGGCGTGCACCGAG
GAGAAGACCACCATC	CACAAACCGCTGCCA	GGGCGTGCACCGAGA
AGAAGACCACCATCA	ACAAACCGCTGCCAG	GGCGTGCACCGAGAA
GAAGACCACCATCAA	CAAACCGCTGCCAGA	GCGTGCACCGAGAAC
AAGACCACCATCAAC	AAACCGCTGCCAGAA	CGTGCACCGAGAACA
AGACCACCATCAACA	AACCGCTGCCAGAAA	GTGCACCGAGAACAA
GACCACCATCAACAA	ACCGCTGCCAGAAAA	TGCACCGAGAACAAT
ACCACCATCAACAAT	CCGCTGCCAGAAAAT	GCACCGAGAACAATG
CCACCATCAACAATG	CGCTGCCAGAAAATG	CACCGAGAACAATGA
CACCATCAACAATGA	GCTGCCAGAAAATGT	ACCGAGAACAATGAG
ACCATCAACAATGAG	CTGCCAGAAAATGTG	CCGAGAACAATGAGT
CCATCAACAATGAGT	TGCCAGAAAATGTGC	CGAGAACAATGAGTG
CATCAACAATGAGTA	GCCAGAAAATGTGCC	GAGAACAATGAGTGC
ATCAACAATGAGTAC	CCAGAAAATGTGCCC	AGAACAATGAGTGCT
TCAACAATGAGTACA	CAGAAAATGTGCCCA	GAACAATGAGTGCTG
CAACAATGAGTACAA	AGAAAATGTGCCCAA	AACAATGAGTGCTGC
AACAATGAGTACAAC	GAAAATGTGCCCAAG	ACAATGAGTGCTGCC
ACAATGAGTACAACT	AAAATGTGCCCAAGC	CAATGAGTGCTGCCA
CAATGAGTACAACTA	AAATGTGCCCAAGCA	AATGAGTGCTGCCAC
AATGAGTACAACTAC	AATGTGCCCAAGCAC	ATGAGTGCTGCCACC
ATGAGTACAACTACC	ATGTGCCCAAGCACG	TGAGTGCTGCCACCC
TGAGTACAACTACCG	TGTGCCCAAGCACGT	GAGTGCTGCCACCCC
GAGTACAACTACCGC	GTGCCCAAGCACGTG	AGTGCTGCCACCCCG
AGTACAACTACCGCT	TGCCCAAGCACGTGT	GTGCTGCCACCCCGA
TGCTGCCACCCCGAG	CGACACGGCCTGTGT	TCTGTGTGCCTGCCT
GCTGCCACCCCGAGT	GACACGGCCTGTGTA	CTGTGTGCCTGCCTG
CTGCCACCCCGAGTG	ACACGGCCTGTGTAG	TGTGTGCCTGCCTGC
TGCCACCCCGAGTGC	CACGGCCTGTGTAGC	GTGTGCCTGCCTGCC
GCCACCCCGAGTGCC	ACGGCCTGTGTAGCT	TGTGCCTGCCTGCCC
CCACCCCGAGTGCCT	CGGCCTGTGTAGCTT	GTGCCTGCCTGCCCG
CACCCCGAGTGCCTG	GGCCTGTGTAGCTTG	TGCCTGCCTGCCCGC
ACCCCGAGTGCCTGG	GCCTGTGTAGCTTGC	GCCTGCCTGCCCGCC
CCCCGAGTGCCTGGG	CCTGTGTAGCTTGCC	CCTGCCTGCCCGCCC
CCCGAGTGCCTGGGC	CTGTGTAGCTTGCCG	CTGCCTGCCCGCCCA
CCGAGTGCCTGGGCA	TGTGTAGCTTGCCGC	TGCCTGCCCGCCCAA
CGAGTGCCTGGGCAG	GTGTAGCTTGCCGCC	GCCTGCCCGCCCAAC
GAGTGCCTGGGCAGC	TGTAGCTTGCCGCCA	CCTGCCCGCCCAACA
AGTGCCTGGGCAGCT	GTAGCTTGCCGCCAC	CTGCCCGCCCAACAC
GTGCCTGGGCAGCTG	TAGCTTGCCGCCACT	TGCCCGCCCAACACC
TGCCTGGGCAGCTGC	AGCTTGCCGCCACTA	GCCCGCCCAACACCT
GCCTGGGCAGCTGCA	GCTTGCCGCCACTAC	CCCGCCCAACACCTA
CCTGGGCAGCTGCAG	CTTGCCGCCACTACT	CCGCCCAACACCTAC
CTGGGCAGCTGCAGC	TTGCCGCCACTACTA	CGCCCAACACCTACA
TGGGCAGCTGCAGCG	TGCCGCCACTACTAC	GCCCAACACCTACAG
GGGCAGCTGCAGCGC	GCCGCCACTACTACT	CCCAACACCTACAGG
GGCAGCTGCAGCGCG	CCGCCACTACTACTA	CCAACACCTACAGGT
GCAGCTGCAGCGCGC	CGCCACTACTACTAT	CAACACCTACAGGTT
CAGCTGCAGCGCGCC	GCCACTACTACTATG	AACACCTACAGGTTT
AGCTGCAGCGCGCCT	CCACTACTACTATGC	ACACCTACAGGTTTG
GCTGCAGCGCGCCTG	CACTACTACTATGCC	CACCTACAGGTTTGA
CTGCAGCGCGCCTGA	ACTACTACTATGCCG	ACCTACAGGTTTGAG
TGCAGCGCGCCTGAC	CTACTACTATGCCGG	CCTACAGGTTTGAGG
GCAGCGCGCCTGACA	TACTACTATGCCGGT	CTACAGGTTTGAGGG
CAGCGCGCCTGACAA	ACTACTATGCCGGTG	TACAGGTTTGAGGGC
AGCGCGCCTGACAAC	CTACTATGCCGGTGT	ACAGGTTTGAGGGCT
GCGCGCCTGACAACG	TACTATGCCGGTGTC	CAGGTTTGAGGGCTG
CGCGCCTGACAACGA	ACTATGCCGGTGTCT	AGGTTTGAGGGCTGG
GCGCCTGACAACGAC	CTATGCCGGTGTCTG	GGTTTGAGGGCTGGC
CGCCTGACAACGACA	TATGCCGGTGTCTGT	GTTTGAGGGCTGGCG
GCCTGACAACGACAC	ATGCCGGTGTCTGTG	TTTGAGGGCTGGCGC
CCTGACAACGACACG	TGCCGGTGTCTGTGT	TTGAGGGCTGGCGCT
CTGACAACGACACGG	GCCGGTGTCTGTGTG	TGAGGGCTGGCGCTG
TGACAACGACACGGC	CCGGTGTCTGTGTGC	GAGGGCTGGCGCTGT
GACAACGACACGGCC	CGGTGTCTGTGTGCC	AGGGCTGGCGCTGTG
ACAACGACACGGCCT	GGTGTCTGTGTGCCT	GGGCTGGCGCTGTGT
CAACGACACGGCCTG	GTGTCTGTGTGCCTG	GGCTGGCGCTGTGTG
AACGACACGGCCTGT	TGTCTGTGTGCCTGC	GCTGGCGCTGTGTGG
ACGACACGGCCTGTG	GTCTGTGTGCCTGCC	CTGGCGCTGTGTGGA
TGGCGCTGTGTGGAC	CGAGAGCAGCGACTC	GCATGCAGGAGTGCC
GGCGCTGTGTGGACC	GAGAGCAGCGACTCC	CATGCAGGAGTGCCC
GCGCTGTGTGGACCG	AGAGCAGCGACTCCG	ATGCAGGAGTGCCCC
CGCTGTGTGGACCGT	GAGCAGCGACTCCGA	TGCAGGAGTGCCCCT
GCTGTGTGGACCGTG	AGCAGCGACTCCGAG	GCAGGAGTGCCCCTC
CTGTGTGGACCGTGA	GCAGCGACTCCGAGG	CAGGAGTGCCCCTCG
TGTGTGGACCGTGAC	CAGCGACTCCGAGGG	AGGAGTGCCCCTCGG
GTGTGGACCGTGACT	AGCGACTCCGAGGGG	GGAGTGCCCCTCGGG
TGTGGACCGTGACTT	GCGACTCCGAGGGGT	GAGTGCCCCTCGGGC
GTGGACCGTGACTTC	CGACTCCGAGGGGTT	AGTGCCCCTCGGGCT
TGGACCGTGACTTCT	GACTCCGAGGGGTTT	GTGCCCCTCGGGCTT
GGACCGTGACTTCTG	ACTCCGAGGGGTTTG	TGCCCCTCGGGCTTC
GACCGTGACTTCTGC	CTCCGAGGGGTTTGT	GCCCCTCGGGCTTCA
ACCGTGACTTCTGCG	TCCGAGGGGTTTGTG	CCCCTCGGGCTTCAT
CCGTGACTTCTGCGC	CCGAGGGGTTTGTGA	CCCTCGGGCTTCATC
CGTGACTTCTGCGCC	CGAGGGGTTTGTGAT	CCTCGGGCTTCATCC
GTGACTTCTGCGCCA	GAGGGGTTTGTGATC	CTCGGGCTTCATCCG
TGACTTCTGCGCCAA	AGGGGTTTGTGATCC	TCGGGCTTCATCCGC
GACTTCTGCGCCAAC	GGGGTTTGTGATCCA	CGGGCTTCATCCGCA
ACTTCTGCGCCAACA	GGGTTTGTGATCCAC	GGGCTTCATCCGCAA
CTTCTGCGCCAACAT	GGTTTGTGATCCACG	GGCTTCATCCGCAAC
TTCTGCGCCAACATC	GTTTGTGATCCACGA	GCTTCATCCGCAACG
TCTGCGCCAACATCC	TTTGTGATCCACGAC	CTTCATCCGCAACGG
CTGCGCCAACATCCT	TTGTGATCCACGACG	TTCATCCGCAACGGC
TGCGCCAACATCCTC	TGTGATCCACGACGG	TCATCCGCAACGGCA
GCGCCAACATCCTCA	GTGATCCACGACGGC	CATCCGCAACGGCAG
CGCCAACATCCTCAG	TGATCCACGACGGCG	ATCCGCAACGGCAGC
GCCAACATCCTCAGC	GATCCACGACGGCGA	TCCGCAACGGCAGCC
CCAACATCCTCAGCG	ATCCACGACGGCGAG	CCGCAACGGCAGCCA
CAACATCCTCAGCGC	TCCACGACGGCGAGT	CGCAACGGCAGCCAG
AACATCCTCAGCGCC	CCACGACGGCGAGTG	GCAACGGCAGCCAGA
ACATCCTCAGCGCCG	CACGACGGCGAGTGC	CAACGGCAGCCAGAG
CATCCTCAGCGCCGA	ACGACGGCGAGTGCA	AACGGCAGCCAGAGC
ATCCTCAGCGCCGAG	CGACGGCGAGTGCAT	ACGGCAGCCAGAGCA
TCCTCAGCGCCGAGA	GACGGCGAGTGCATG	CGGCAGCCAGAGCAT
CCTCAGCGCCGAGAG	ACGGCGAGTGCATGC	GGCAGCCAGAGCATG
CTCAGCGCCGAGAGC	CGGCGAGTGCATGCA	GCAGCCAGAGCATGT
TCAGCGCCGAGAGCA	GGCGAGTGCATGCAG	CAGCCAGAGCATGTA
CAGCGCCGAGAGCAG	GCGAGTGCATGCAGG	AGCCAGAGCATGTAC
AGCGCCGAGAGCAGC	CGAGTGCATGCAGGA	GCCAGAGCATGTACT
GCGCCGAGAGCAGCG	GAGTGCATGCAGGAG	CCAGAGCATGTACTG
CGCCGAGAGCAGCGA	AGTGCATGCAGGAGT	CAGAGCATGTACTGC
GCCGAGAGCAGCGAC	GTGCATGCAGGAGTG	AGAGCATGTACTGCA
CCGAGAGCAGCGACT	TGCATGCAGGAGTGC	GAGCATGTACTGCAT
AGCATGTACTGCATC	TGAGGAAGAAAAGAA	CTCAGATGCTCCAAG
GCATGTACTGCATCC	GAGGAAGAAAAGAAA	TCAGATGCTCCAAGG
CATGTACTGCATCCC	AGGAAGAAAAGAAAA	CAGATGCTCCAAGGA
ATGTACTGCATCCCT	GGAAGAAAAGAAAAC	AGATGCTCCAAGGAT
TGTACTGCATCCCTT	GAAGAAAAGAAAACA	GATGCTCCAAGGATG
GTACTGCATCCCTTG	AAGAAAAGAAAACAA	ATGCTCCAAGGATGC
TACTGCATCCCTTGT	AGAAAAGAAAACAAA	TGCTCCAAGGATGCA
ACTGCATCCCTTGTG	GAAAAGAAAACAAAG	GCTCCAAGGATGCAC
CTGCATCCCTTGTGA	AAAAGAAAACAAAGA	CTCCAAGGATGCACC
TGCATCCCTTGTGAA	AAAGAAAACAAAGAC	TCCAAGGATGCACCA
GCATCCCTTGTGAAG	AAGAAAACAAAGACC	CCAAGGATGCACCAT
CATCCCTTGTGAAGG	AGAAAACAAAGACCA	CAAGGATGCACCATC
ATCCCTTGTGAAGGT	GAAAACAAAGACCAT	AAGGATGCACCATCT
TCCCTTGTGAAGGTC	AAAACAAAGACCATT	AGGATGCACCATCTT
CCCTTGTGAAGGTCC	AAACAAAGACCATTG	GGATGCACCATCTTC
CCTTGTGAAGGTCCT	AACAAAGACCATTGA	GATGCACCATCTTCA
CTTGTGAAGGTCCTT	ACAAAGACCATTGAT	ATGCACCATCTTCAA
TTGTGAAGGTCCTTG	CAAAGACCATTGATT	TGCACCATCTTCAAG
TGTGAAGGTCCTTGC	AAAGACCATTGATTC	GCACCATCTTCAAGG
GTGAAGGTCCTTGCC	AAGACCATTGATTCT	CACCATCTTCAAGGG
TGAAGGTCCTTGCCC	AGACCATTGATTCTG	ACCATCTTCAAGGGC
GAAGGTCCTTGCCCG	GACCATTGATTCTGT	CCATCTTCAAGGGCA
AAGGTCCTTGCCCGA	ACCATTGATTCTGTT	CATCTTCAAGGGCAA
AGGTCCTTGCCCGAA	CCATTGATTCTGTTA	ATCTTCAAGGGCAAT
GGTCCTTGCCCGAAG	CATTGATTCTGTTAC	TCTTCAAGGGCAATT
GTCCTTGCCCGAAGG	ATTGATTCTGTTACT	CTTCAAGGGCAATTT
TCCTTGCCCGAAGGT	TTGATTCTGTTACTT	TTCAAGGGCAATTTG
CCTTGCCCGAAGGTC	TGATTCTGTTACTTC	TCAAGGGCAATTTGC
CTTGCCCGAAGGTCT	GATTCTGTTACTTCT	CAAGGGCAATTTGCT
TTGCCCGAAGGTCTG	ATTCTGTTACTTCTG	AAGGGCAATTTGCTC
TGCCCGAAGGTCTGT	TTCTGTTACTTCTGC	AGGGCAATTTGCTCA
GCCCGAAGGTCTGTG	TCTGTTACTTCTGCT	GGGCAATTTGCTCAT
CCCGAAGGTCTGTGA	CTGTTACTTCTGCTC	GGCAATTTGCTCATT
CCGAAGGTCTGTGAG	TGTTACTTCTGCTCA	GCAATTTGCTCATTA
CGAAGGTCTGTGAGG	GTTACTTCTGCTCAG	CAATTTGCTCATTAA
GAAGGTCTGTGAGGA	TTACTTCTGCTCAGA	AATTTGCTCATTAAC
AAGGTCTGTGAGGAA	TACTTCTGCTCAGAT	ATTTGCTCATTAACA
AGGTCTGTGAGGAAG	ACTTCTGCTCAGATG	TTTGCTCATTAACAT
GGTCTGTGAGGAAGA	CTTCTGCTCAGATGC	TTGCTCATTAACATC
GTCTGTGAGGAAGAA	TTCTGCTCAGATGCT	TGCTCATTAACATCC
TCTGTGAGGAAGAAA	TCTGCTCAGATGCTC	GCTCATTAACATCCG
CTGTGAGGAAGAAAA	CTGCTCAGATGCTCC	CTCATTAACATCCGA
TGTGAGGAAGAAAAG	TGCTCAGATGCTCCA	TCATTAACATCCGAC
GTGAGGAAGAAAAGA	GCTCAGATGCTCCAA	CATTAACATCCGACG
ATTAACATCCGACGG	CTTCATGGGGCTCAT	GCCATTCTCATGCCT
TTAACATCCGACGGG	TTCATGGGGCTCATC	CCATTCTCATGCCTT
TAACATCCGACGGGG	TCATGGGGCTCATCG	CATTCTCATGCCTTG
AACATCCGACGGGGG	CATGGGGCTCATCGA	ATTCTCATGCCTTGG
ACATCCGACGGGGGA	ATGGGGCTCATCGAG	TTCTCATGCCTTGGT
CATCCGACGGGGGAA	TGGGGCTCATCGAGG	TCTCATGCCTTGGTC
ATCCGACGGGGGAAT	GGGGCTCATCGAGGT	CTCATGCCTTGGTCT
TCCGACGGGGGAATA	GGGCTCATCGAGGTG	TCATGCCTTGGTCTC
CCGACGGGGGAATAA	GGCTCATCGAGGTGG	CATGCCTTGGTCTCC
CGACGGGGGAATAAC	GCTCATCGAGGTGGT	ATGCCTTGGTCTCCT
GACGGGGGAATAACA	CTCATCGAGGTGGTG	TGCCTTGGTCTCCTT
ACGGGGGAATAACAT	TCATCGAGGTGGTGA	GCCTTGGTCTCCTTG
CGGGGGAATAACATT	CATCGAGGTGGTGAC	CCTTGGTCTCCTTGT
GGGGGAATAACATTG	ATCGAGGTGGTGACG	CTTGGTCTCCTTGTC
GGGGAATAACATTGC	TCGAGGTGGTGACGG	TTGGTCTCCTTGTCC
GGGAATAACATTGCT	CGAGGTGGTGACGGG	TGGTCTCCTTGTCCT
GGAATAACATTGCTT	GAGGTGGTGACGGGC	GGTCTCCTTGTCCTT
GAATAACATTGCTTC	AGGTGGTGACGGGCT	GTCTCCTTGTCCTTC
AATAACATTGCTTCA	GGTGGTGACGGGCTA	TCTCCTTGTCCTTCC
ATAACATTGCTTCAG	GTGGTGACGGGCTAC	CTCCTTGTCCTTCCT
TAACATTGCTTCAGA	TGGTGACGGGCTACG	TCCTTGTCCTTCCTA
AACATTGCTTCAGAG	GGTGACGGGCTACGT	CCTTGTCCTTCCTAA
ACATTGCTTCAGAGC	GTGACGGGCTACGTG	CTTGTCCTTCCTAAA
CATTGCTTCAGAGCT	TGACGGGCTACGTGA	TTGTCCTTCCTAAAA
ATTGCTTCAGAGCTG	GACGGGCTACGTGAA	TGTCCTTCCTAAAAA
TTGCTTCAGAGCTGG	ACGGGCTACGTGAAG	GTCCTTCCTAAAAAA
TGCTTCAGAGCTGGA	CGGGCTACGTGAAGA	TCCTTCCTAAAAAAC
GCTTCAGAGCTGGAG	GGGCTACGTGAAGAT	CCTTCCTAAAAAACC
CTTCAGAGCTGGAGA	GGCTACGTGAAGATC	CTTCCTAAAAAACCT
TTCAGAGCTGGAGAA	GCTACGTGAAGATCC	TTCCTAAAAAACCTT
TCAGAGCTGGAGAAC	CTACGTGAAGATCCG	TCCTAAAAAACCTTC
CAGAGCTGGAGAACT	TACGTGAAGATCCGC	CCTAAAAAACCTTCG
AGAGCTGGAGAACTT	ACGTGAAGATCCGCC	CTAAAAAACCTTCGC
GAGCTGGAGAACTTC	CGTGAAQATCCGCCA	TAAAAAACCTTCGCC
AGCTGGAGAACTTCA	GTGAAGATCCGCCAT	AAAAAACCTTCGCCT
GCTGGAGAACTTCAT	TGAAGATCCGCCATT	AAAAACCTTCGCCTC
CTGGAGAACTTCATG	GAAGATCCGCCATTC	AAAACCTTCGCCTCA
TGGAGAACTTCATGG	AAGATCCGCCATTCT	AAACCTTCGCCTCAT
GGAGAACTTCATGGG	AGATCCGCCATTCTC	AACCTTCGCCTCATC
GAGAACTTCATGGGG	GATCCGCCATTCTCA	ACCTTCGCCTCATCC
AGAACTTCATGGGGC	ATCCGCCATTCTCAT	CCTTCGCCTCATCCT
GAACTTCATGGGGCT	TCCGCCATTCTCATG	CTTCGCCTCATCCTA
AACTTCATGGGGCTC	CCGCCATTCTCATGC	TTCGCCTCATCCTAG
ACTTCATGGGGCTCA	CGCCATTCTCATGCC	TCGCCTCATCCTAGG
CGCCTCATCCTAGGA	CTACGTCCTCGACAA	ACCACCGCAACCTGA
GCCTCATCCTAGGAG	TACGTCCTCGACAAC	CCACCGCAACCTGAC
CCTCATCCTAGGAGA	ACGTCCTCGACAACC	CACCGCAACCTGACC
CTCATCCTAGGAGAG	CGTCCTCGACAACCA	ACCGCAACCTGACCA
TCATCCTAGGAGAGG	GTCCTCGACAACCAG	CCGCAACCTGACCAT
CATCCTAGGAGAGGA	TCCTCGACAACCAGA	CGCAACCTGACCATC
ATCCTAGGAGAGGAG	CCTCGACAACCAGAA	GCAACCTGACCATCA
TCCTAGGAGAGGAGC	CTCGACAACCAGAAC	CAACCTGACCATCAA
CCTAGGAGAGGAGCA	TCGACAACCAGAACT	AACCTGACCATCAAA
CTAGGAGAGGAGCAG	CGACAACCAGAACTT	ACCTGACCATCAAAG
TAGGAGAGGAGCAGC	GACAACCAGAACTTG	CCTGACCATCAAAGC
AGGAGAGGAGCAGCT	ACAACCAGAACTTGC	CTGACCATCAAAGCA
GGAGAGGAGCAGCTA	CAACCAGAACTTGCA	TGACCATCAAAGCAG
GAGAGGAGCAGCTAG	AACCAGAACTTGCAG	GACCATCAAAGCAGG
AGAGGAGCAGCTAGA	ACCAGAACTTGCAGC	ACCATCAAAGCAGGG
GAGGAGCAGCTAGAA	CCAGAACTTGCAGCA	CCATCAAAGCAGGGA
AGGAGCAGCTAGAAG	CAGAACTTGCAGCAA	CATCAAAGCAGGGAA
GGAGCAGCTAGAAGG	AGAACTTGCAGCAAC	ATCAAAGCAGGGAAA
GAGCAGCTAGAAGGG	GAACTTGCAGCAACT	TCAAAGCAGGGAAAA
AGCAGCTAGAAGGGA	AACTTGCAGCAACTG	CAAAGCAGGGAAAAT
GCAGCTAGAAGGGAA	ACTTGCAGCAACTGT	AAAGCAGGGAAAATG
CAGCTAGAAGGGAAT	CTTGCAGCAACTGTG	AAGCAGGGAAAATGT
AGCTAGAAGGGAATT	TTGCAGCAACTGTGG	AGCAGGGAAAATGTA
GCTAGAAGGGAATTA	TGCAGCAACTGTGGG	GCAGGGAAAATGTAC
CTAGAAGGGAATTAC	GCAGCAACTGTGGGA	CAGGGAAAATGTACT
TAGAAGGGAATTACT	CAGCAACTGTGGGAC	AGGGAAAATGTACTT
AGAAGGGAATTACTC	AGCAACTGTGGGACT	GGGAAAATGTACTTT
GAAGGGAATTACTCC	GCAACTGTGGGACTG	GGAAAATGTACTTTG
AAGGGAATTACTCCT	CAACTGTGGGACTGG	GAAAATGTACTTTGC
AGGGAATTACTCCTT	AACTGTGGGACTGGG	AAAATGTACTTTGCT
GGGAATTACTCCTTC	ACTGTGGGACTGGGA	AAATGTACTTTGCTT
GGAATTACTCCTTCT	CTGTGGGACTGGGAC	AATGTACTTTGCTTT
GAATTACTCCTTCTA	TGTGGGACTGGGACC	ATGTACTTTGCTTTC
AATTACTCCTTCTAC	GTGGGACTGGGACCA	TGTACTTTGCTTTCA
ATTACTCCTTCTACG	TGGGACTGGGACCAC	GTACTTTGCTTTCAA
TTACTCCTTCTACGT	GGGACTGGGACCACC	TACTTTGCTTTCAAT
TACTCCTTCTACGTC	GGACTGGGACCACCG	ACTTTGCTTTCAATC
ACTCCTTCTACGTCC	GACTGGGACCACCGC	CTTTGCTTTCAATCC
CTCCTTCTACGTCCT	ACTGGGACCACCGCA	TTTGCTTTCAATCCC
TCCTTCTACGTCCTC	CTGGGACCACCGCAA	TTGCTTTCAATCCCA
CCTTCTACGTCCTCG	TGGGACCACCGCAAC	TGCTTTCAATCCCAA
CTTCTACGTCCTCGA	GGGACCACCGCAACC	GCTTTCAATCCCAAA
TTCTACGTCCTCGAC	GGACCACCGCAACCT	CTTTCAATCCCAAAT
TCTACGTCCTCGACA	GACCACCGCAACCTG	TTTCAATCCCAAATT
TTCAATCCCAAATTA	AGTGACGGGGACTAA	CCAGGAACAACGGGG
TCAATCCCAAATTAT	GTGACGGGGACTAAA	CAGGAACAACGGGGA
CAATCCCAAATTATG	TGACGGGGACTAAAG	AGGAACAACGGGGAG
AATCCCAAATTATGT	GACGGGGACTAAAGG	GGAACAACGGGGAGA
ATCCCAAATTATGTG	ACGGGGACTAAAGGG	GAACAACGGGGAGAG
TCCCAAATTATGTGT	CGGGGACTAAAGGGC	AACAACGGGGAGAGA
CCCAAATTATGTGTT	GGGGACTAAAGGGCG	ACAACGGGGAGAGAG
CCAAATTATGTGTTT	GGGACTAAAGGGCGC	CAACGGGGAGAGAGC
CAAATTATGTGTTTC	GGACTAAAGGGCGCC	AACGGGGAGAGAGCC
AAATTATGTGTTTCC	GACTAAAGGGCGCCA	ACGGGGAGAGAGCCT
AATTATGTGTTTCCG	ACTAAAGGGCGCCAA	CGGGGAGAGAGCCTC
ATTATGTGTTTCCGA	CTAAAGGGCGCCAAA	GGGGAGAGAGCCTCC
TTATGTGTTTCCGAA	TAAAGGGCGCCAAAG	GGGAGAGAGCCTCCT
TATGTGTTTCCGAAA	AAAGGGCGCCAAAGC	GGAGAGAGCCTCCTG
ATGTGTTTCCGAAAT	AAGGGCGCCAAAGCA	GAGAGAGCCTCCTGT
TGTGTTTCCGAAATT	AGGGCGCCAAAGCAA	AGAGAGCCTCCTGTG
GTGTTTCCGAAATTT	GGGCGCCAAAGCAAA	GAGAGCCTCCTGTGA
TGTTTCCGAAATTTA	GGCGCCAAAGCAAAG	AGAGCCTCCTGTGAA
GTTTCCGAAATTTAC	GCGCCAAAGCAAAGG	GAGCCTCCTGTGAAA
TTTCCGAAATTTACC	CGCCAAAGCAAAGGG	AGCCTCCTGTGAAAG
TTCCGAAATTTACCG	GCCAAAGCAAAGGGG	GCCTCCTGTGAAAGT
TCCGAAATTTACCGC	CCAAAGCAAAGGGGA	CCTCCTGTGAAAGTG
CCGAAATTTACCGCA	CAAAGCAAAGGGGAC	CTCCTGTGAAAGTGA
CGAAATTTACCGCAT	AAAGCAAAGGGGACA	TCCTGTGAAAGTGAC
GAAATTTACCGCATG	AAGCAAAGGGGACAT	CCTGTGAAAGTGACG
AAATTTACCGCATGG	AGCAAAGGGGACATA	CTGTGAAAGTGACGT
AATTTACCGCATGGA	GCAAAGGGGACATAA	TGTGAAAGTGACGTC
ATTTACCGCATGGAG	CAAAGGGGACATAAA	GTGAAAGTGACGTCC
TTTACCGCATGGAGG	AAAGGGGACATAAAC	TGAAAGTGACGTCCT
TTACCGCATGGAGGA	AAGGGGACATAAACA	GAAAGTGACGTCCTG
TACCGCATGGAGGAA	AGGGGACATAAACAC	AAAGTGACGTCCTGC
ACCGCATGGAGGAAG	GGGGACATAAACACC	AAGTGACGTCCTGCA
CCGCATGGAGGAAGT	GGGACATAAACACCA	AGTGACGTCCTGCAT
CGCATGGAGGAAGTG	GGACATAAACACCAG	GTGACGTCCTGCATT
GCATGGAGGAAGTGA	GACATAAACACCAGG	TGACGTCCTGCATTT
CATGGAGGAAGTGAC	ACATAAACACCAGGA	GACGTCCTGCATTTC
ATGGAGGAAGTGACG	CATAAACACCAGGAA	ACGTCCTGCATTTCA
TGGAGGAAGTGACGG	ATAAACACCAGGAAC	CGTCCTGCATTTCAC
GGAGGAAGTGACGGG	TAAACACCAGGAACA	GTCCTGCATTTCACC
GAGGAAGTGACGGGG	AAACACCAGGAACAA	TCCTGCATTTCACCT
AGGAAGTGACGGGGA	AACACCAGGAACAAC	CCTGCATTTCACCTC
GGAAGTGACGGGGAC	ACACCAGGAACAACG	CTGCATTTCACCTCC
GAAGTGACGGGGACT	CACCAGGAACAACGG	TGCATTTCACCTCCA
AAGTGACGGGGACTA	ACCAGGAACAACGGG	GCATTTCACCTCCAC
CATTTCACCTCCACC	CTGGCACCGGTACCG	TCACCGTTTACTACA
ATTTCACCTCCACCA	TGGCACCGGTACCGG	CACCGTTTACTACAA
TTTCACCTCCACCAC	GGCACCGGTACCGGC	ACCGTTTACTACAAG
TTCACCTCCACCACC	GCACCGGTACCGGCC	CCGTTTACTACAAGG
TCACCTCCACCACCA	CACCGGTACCGGCCC	CGTTTACTACAAGGA
CACCTCCACCACCAC	ACCGGTACCGGCCCC	GTTTACTACAAGGAA
ACCTCCACCACCACG	CCGGTACCGGCCCCC	TTTACTACAAGGAAG
CCTCCACCACCACGT	CGGTACCGGCCCCCT	TTACTACAAGGAAGC
CTCCACCACCACGTC	GGTACCGGCCCCCTG	TACTACAAGGAAGCA
TCCACCACCACGTCG	GTACCGGCCCCCTGA	ACTACAAGGAAGCAC
CCACCACCACGTCGA	TACCGGCCCCCTGAC	CTACAAGGAAGCACC
CACCACCACGTCGAA	ACCGGCCCCCTGACT	TACAAGGAAGCACCC
ACCACCACGTCGAAG	CCGGCCCCCTGACTA	ACAAGGAAGCACCCT
CCACCACGTCGAAGA	CGGCCCCCTGACTAC	CAAGGAAGCACCCTT
CACCACGTCGAAGAA	GGCCCCCTGACTACA	AAGGAAGCACCCTTT
ACCACGTCGAAGAAT	GCCCCCTGACTACAG	AGGAAGCACCCTTTA
CCACGTCGAAGAATC	CCCCCTGACTACAGG	GGAAGCACCCTTTAA
CACGTCGAAGAATCG	CCCCTGACTACAGGG	GAAGCACCCTTTAAG
ACGTCGAAGAATCGC	CCCTGACTACAGGGA	AAGCACCCTTTAAGA
CGTCGAAGAATCGCA	CCTGACTACAGGGAT	AGCACCCTTTAAGAA
GTCGAAGAATCGCAT	CTGACTACAGGGATC	GCACCCTTTAAGAAT
TCGAAGAATCGCATC	TGACTACAGGGATCT	CACCCTTTAAGAATG
CGAAGAATCGCATCA	GACTACAGGGATCTC	ACCCTTTAAGAATGT
GAAGAATCGCATCAT	ACTACAGGGATCTCA	CCCTTTAAGAATGTC
AAGAATCGCATCATC	CTACAGGGATCTCAT	CCTTTAAGAATGTCA
AGAATCGCATCATCA	TACAGGGATCTCATC	CTTTAAGAATGTCAC
GAATCGCATCATCAT	ACAGGGATCTCATCA	TTTAAGAATGTCACA
AATCGCATCATCATA	CAGGGATCTCATCAG	TTAAGAATGTCACAG
ATCGCATCATCATAA	AGGGATCTCATCAGC	TAAGAATGTCACAGA
TCGCATCATCATAAC	GGGATCTCATCAGCT	AAGAATGTCACAGAG
CGCATCATCATAACC	GGATCTCATCAGCTT	AGAATGTCACAGAGT
GCATCATCATAACCT	GATCTCATCAGCTTC	GAATGTCACAGAGTA
CATCATCATAACCTG	ATCTCATCAGCTTCA	AATGTCACAGAGTAT
ATCATCATAACCTGG	TCTCATCAGCTTCAC	ATGTCACAGAGTATG
TCATCATAACCTGGC	CTCATCAGCTTCACC	TGTCACAGAGTATGA
CATCATAACCTGGCA	TCATCAGCTTCACCG	GTCACAGAGTATGAT
ATCATAACCTGGCAC	CATCAGCTTCACCGT	TCACAGAGTATGATG
TCATAACCTGGCACC	ATCAGCTTCACCGTT	CACAGAGTATGATGG
CATAACCTGGCACCG	TCAGCTTCACCGTTT	ACAGAGTATGATGGG
ATAACCTGGCACCGG	CAGCTTCACCGTTTA	CAGAGTATGATGGGC
TAACCTGGCACCGGT	AGCTTCACCGTTTAC	AGAGTATGATGGGCA
AACCTGGCACCGGTA	GCTTCACCGTTTACT	GAGTATGATGGGCAG
ACCTGGCACCGGTAC	CTTCACCGTTTACTA	AGTATGATGGGCAGG
CCTGGCACCGGTACC	TTCACCGTTTACTAC	GTATGATGGGCAGGA
TATGATGGGCAGGAT	GGACGTGGACCTCCC	TACTACATGGGCTGA
ATGATGGGCAGGATG	GACGTGGACCTCCCG	ACTACATGGGCTGAA
TGATGGGCAGGATGC	ACGTGGACCTCCCGC	CTACATGGGCTGAAG
GATGGGCAGGATGCC	CGTGGACCTCCCGCC	TACATGGGCTGAAGC
ATGGGCAGGATGCCT	GTGGACCTCCCGCCC	ACATGGGCTGAAGCC
TGGGCAGGATGCCTG	TGGACCTCCCGCCCA	CATGGGCTGAAGCCC
GGGCAGGATGCCTGC	GGACCTCCCGCCCAA	ATGGGCTGAAGCCCT
GGCAGGATGCCTGCG	GACCTCCCGCCCAAC	TGGGCTGAAGCCCTG
GCAGGATGCCTGCGG	ACCTCCCGCCCAACA	GGGCTGAAGCCCTGG
CAGGATGCCTGCGGC	CCTCCCGCCCAACAA	GGCTGAAGCCCTGGA
AGGATGCCTGCGGCT	CTCCCGCCCAACAAG	GCTGAAGCCCTGGAC
GGATGCCTGCGGCTC	TCCCGCCCAACAAGG	CTGAAGCCCTGGACT
GATGCCTGCGGCTCC	CCCGCCCAACAAGGA	TGAAGCCCTGGACTC
ATGCCTGCGGCTCCA	CCGCCCAACAAGGAC	GAAGCCCTGGACTCA
TGCCTGCGGCTCCAA	CGCCCAACAAGGACG	AAGCCCTGGACTCAG
GCCTGCGGCTCCAAC	GCCCAACAAGGACGT	AGCCCTGGACTCAGT
CCTGCGGCTCCAACA	CCCAACAAGGACGTG	GCCCTGGACTCAGTA
CTGCGGCTCCAACAG	CCAACAAGGACGTGG	CCCTGGACTCAGTAC
TGCGGCTCCAACAGC	CAACAAGGACGTGGA	CCTGGACTCAGTACG
GCGGCTCCAACAGCT	AACAAGGACGTGGAG	CTGGACTCAGTACGC
CGGCTCCAACAGCTG	ACAAGGACGTGGAGC	TGGACTCAGTACGCC
GGCTCCAACAGCTGG	CAAGGACGTGGAGCC	GGACTCAGTACGCCG
GCTCCAACAGCTGGA	AAGGACGTGGAGCCC	GACTCAGTACGCCGT
CTCCAACAGCTGGAA	AGGACGTGGAGCCCG	ACTCAGTACGCCGTT
TCCAACAGCTGGAAC	GGACGTGGAGCCCGG	CTCAGTACGCCGTTT
CCAACAGCTGGAACA	GACGTGGAGCCCGGC	TCAGTACGCCGTTTA
CAACAGCTGGAACAT	ACGTGGAGCCCGGCA	CAGTACGCCGTTTAC
AACAGCTGGAACATG	CGTGGAGCCCGGCAT	AGTACGCCGTTTACG
ACAGCTGGAACATGG	GTGGAGCCCGGCATC	GTACGCCGTTTACGT
CAGCTGGAACATGGT	TGGAGCCCGGCATCT	TACGCCGTTTACGTC
AGCTGGAACATGGTG	GGAGCCCGGCATCTT	ACGCCGTTTACGTCA
GCTGGAACATGGTGG	GAGCCCGGCATCTTA	CGCCGTTTACGTCAA
CTGGAACATGGTGGA	AGCCCGGCATCTTAC	GCCGTTTACGTCAAG
TGGAACATGGTGGAC	GCCCGGCATCTTACT	CCGTTTACGTCAAGG
GGAACATGGTGGACG	CCCGGCATCTTACTA	CGTTTACGTCAAGGC
GAACATGGTGGACGT	CCGGCATCTTACTAC	GTTTACGTCAAGGCT
AACATGGTGGACGTG	CGGCATCTTACTACA	TTTACGTCAAGGCTG
ACATGGTGGACGTGG	GGCATCTTACTACAT	TTACGTCAAGGCTGT
CATGGTGGACGTGGA	GCATCTTACTACATG	TACGTCAAGGCTGTG
ATGGTGGACGTGGAC	CATCTTACTACATGG	ACGTCAAGGCTGTGA
TGGTGGACGTGGACC	ATCTTACTACATGGG	CGTCAAGGCTGTGAC
GGTGGACGTGGACCT	TCTTACTACATGGGC	GTCAAGGCTGTGACC
GTGGACGTGGACCTC	CTTACTACATGGGCT	TCAAGGCTGTGACCC
TGGACGTGGACCTCC	TTACTACATGGGCTG	CAAGGCTGTGACCCT
AAGGCTGTGACCCTC	GGCCAAGAGTGAGAT	CTTCCATTCCCTTGG
AGGCTGTGACCCTCA	GCCAAGAGTGAGATC	TTCCATTCCCTTGGA
GGCTGTGACCCTCAC	CCAAGAGTGAGATCT	TCCATTCCCTTGGAC
GCTGTGACCCTCACC	CAAGAGTGAGATCTT	CCATTCCCTTGGACG
CTGTGACCCTCACCA	AAGAGTGAGATCTTG	CATTCCCTTGGACGT
TGTGACCCTCACCAT	AGAGTGAGATCTTGT	ATTCCCTTGGACGTT
GTGACCCTCACCATG	GAGTGAGATCTTGTA	TTCCCTTGGACGTTC
TGACCCTCACCATGG	AGTGAGATCTTGTAC	TCCCTTGGACGTTCT
GACCCTCACCATGGT	GTGAGATCTTGTACA	CCCTTGGACGTTCTT
ACCCTCACCATGGTG	TGAGATCTTGTACAT	CCTTGGACGTTCTTT
CCCTCACCATGGTGG	GAGATCTTGTACATT	CTTGGACGTTCTTTC
CCTCACCATGGTGGA	AGATCTTGTACATTC	TTGGACGTTCTTTCA
CTCACCATGGTGGAG	GATCTTGTACATTCG	TGGACGTTCTTTCAG
TCACCATGGTGGAGA	ATCTTGTACATTCGC	GGACGTTCTTTCAGC
CACCATGGTGGAGAA	TCTTGTACATTCGCA	GACGTTCTTTCAGCA
ACCATGGTGGAGAAC	CTTGTACATTCGCAC	ACGTTCTTTCAGCAT
CCATGGTGGAGAACG	TTGTACATTCGCACC	CGTTCTTTCAGCATC
CATGGTGGAGAACGA	TGTACATTCGCACCA	GTTCTTTCAGCATCG
ATGGTGGAGAACGAC	GTACATTCGCACCAA	TTCTTTCAGCATCGA
TGGTGGAGAACGACC	TACATTCGCACCAAT	TCTTTCAGCATCGAA
GGTGGAGAACGACCA	ACATTCGCACCAATG	CTTTCAGCATCGAAC
GTGGAGAACGACCAT	CATTCGCACCAATGC	TTTCAGCATCGAACT
TGGAGAACGACCATA	ATTCGCACCAATGCT	TTCAGCATCGAACTC
GGAGAACGACCATAT	TTCGCACCAATGCTT	TCAGCATCGAACTCC
GAGAACGACCATATC	TCGCACCAATGCTTC	CAGCATCGAACTCCT
AGAACGACCATATCC	CGCACCAATGCTTCA	AGCATCGAACTCCTC
GAACGACCATATCCG	GCACCAATGCTTCAG	GCATCGAACTCCTCT
AACGACCATATCCGT	CACCAATGCTTCAGT	CATCGAACTCCTCTT
ACGACCATATCCGTG	ACCAATGCTTCAGTT	ATCGAACTCCTCTTC
CGACCATATCCGTGG	CCAATGCTTCAGTTC	TCGAACTCCTCTTCT
GACCATATCCGTGGG	CAATGCTTCAGTTCC	CGAACTCCTCTTCTC
ACCATATCCGTGGGG	AATGCTTCAGTTCCT	GAACTCCTCTTCTCA
CCATATCCGTGGGGC	ATGCTTCAGTTCCTT	AACTCCTCTTCTCAG
CATATCCGTGGGGCC	TGCTTCAGTTCCTTC	ACTCCTCTTCTCAGT
ATATCCGTGGGGCCA	GCTTCAGTTCCTTCC	CTCCTCTTCTCAGTT
TATCCGTGGGGCCAA	CTTCAGTTCCTTCCA	TCCTCTTCTCAGTTA
ATCCGTGGGGCCAAG	TTCAGTTCCTTCCAT	CCTCTTCTCAGTTAA
TCCGTGGGGCCAAGA	TCAGTTCCTTCCATT	CTCTTCTCAGTTAAT
CCGTGGGGCCAAGAG	CAGTTCCTTCCATTC	TCTTCTCAGTTAATC
CGTGGGGCCAAGAGT	AGTTCCTTCCATTCC	CTTCTCAGTTAATCG
GTGGGGCCAAGAGTG	GTTCCTTCCATTCCC	TTCTCAGTTAATCGT
TGGGGCCAAGAGTGA	TTCCTTCCATTCCCT	TCTCAGTTAATCGTG
GGGGCCAAGAGTGAG	TCCTTCCATTCCCTT	CTCAGTTAATCGTGA
GGGCCAAGAGTGAGA	CCTTCCATTCCCTTG	TCAGTTAATCGTGAA
CAGTTAATCGTGAAG	CCTGAGTTACTACAT	GCTACCTTTACCGGC
AGTTAATCGTGAAGT	CTGAGTTACTACATT	CTACCTTTACCGGCA
GTTAATCGTGAAGTG	TGAGTTACTACATTG	TACCTTTACCGGCAC
TTAATCGTGAAGTGG	GAGTTACTACATTGT	ACCTTTACCGGCACA
TAATCGTGAAGTGGA	AGTTACTACATTGTG	CCTTTACCGGCACAA
AATCGTGAAGTGGAA	GTTACTACATTGTGC	CTTTACCGGCACAAT
ATCGTGAAGTGGAAC	TTACTACATTGTGCG	TTTACCGGCACAATT
TCGTGAAGTGGAACC	TACTACATTGTGCGC	TTACCGGCACAATTA
CGTGAAGTGGAACCC	ACTACATTGTGCGCT	TACCGGCACAATTAC
GTGAAGTGGAACCCT	CTACATTGTGCGCTG	ACCGGCACAATTACT
TGAAGTGGAACCCTC	TACATTGTGCGCTGG	CCGGCACAATTACTG
GAAGTGGAACCCTCC	ACATTGTGCGCTGGC	CGGCACAATTACTGC
AAGTGGAACCCTCCC	CATTGTGCGCTGGCA	GGCACAATTACTGCT
AGTGGAACCCTCCCT	ATTGTGCGCTGGCAG	GCACAATTACTGCTC
GTGGAACCCTCCCTC	TTGTGCGCTGGCAGC	CACAATTACTGCTCC
TGGAACCCTCCCTCT	TGTGCGCTGGCAGCG	ACAATTACTGCTCCA
GGAACCCTCCCTCTC	GTGCGCTGGCAGCGG	CAATTACTGCTCCAA
GAACCCTCCCTCTCT	TGCGCTGGCAGCGGC	AATTACTGCTCCAAA
AACCCTCCCTCTCTG	GCGCTGGCAGCGGCA	ATTACTGCTCCAAAG
ACCCTCCCTCTCTGC	CGCTGGCAGCGGCAG	TTACTGCTCCAAAGA
CCCTCCCTCTCTGCC	GCTGGCAGCGGCAGC	TACTGCTCCAAAGAC
CCTCCCTCTCTGCCC	CTGGCAGCGGCAGCC	ACTGCTCCAAAGACA
CTCCCTCTCTGCCCA	TGGCAGCGGCAGCCT	CTGCTCCAAAGACAA
TCCCTCTCTGCCCAA	GGCAGCGGCAGCCTC	TGCTCCAAAGACAAA
CCCTCTCTGCCCAAC	GCAGCGGCAGCCTCA	GCTCCAAAGACAAAA
CCTCTCTGCCCAACG	CAGCGGCAGCCTCAG	CTCCAAAGACAAAAT
CTCTCTGCCCAACGG	AGCGGCAGCCTCAGG	TCCAAAGACAAAATC
TCTCTGCCCAACGGC	GCGGCAGCCTCAGGA	CCAAAGACAAAATCC
CTCTGCCCAACGGCA	CGGCAGCCTCAGGAC	CAAAGACAAAATCCC
TCTGCCCAACGGCAA	GGCAGCCTCAGGACG	AAAGACAAAATCCCC
CTGCCCAACGGCAAC	GCAGCCTCAGGACGG	AAGACAAAATCCCCA
TGCCCAACGGCAACC	CAGCCTCAGGACGGC	AGACAAAATCCCCAT
GCCCAACGGCAACCT	AGCCTCAGGACGGCT	GACAAAATCCCCATC
CCCAACGGCAACCTG	GCCTCAGGACGGCTA	ACAAAATCCCCATCA
CCAACGGCAACCTGA	CCTCAGGACGGCTAC	CAAAATCCCCATCAG
CAACGGCAACCTGAG	CTCAGGACGGCTACC	AAAATCCCCATCAGG
AACGGCAACCTGAGT	TCAGGACGGCTACCT	AAATCCCCATCAGGA
ACGGCAACCTGAGTT	CAGGACGGCTACCTT	AATCCCCATCAGGAA
CGGCAACCTGAGTTA	AGGACGGCTACCTTT	ATCCCCATCAGGAAG
GGCAACCTGAGTTAC	GGACGGCTACCTTTA	TCCCCATCAGGAAGT
GCAACCTGAGTTACT	GACGGCTACCTTTAC	CCCCATCAGGAAGTA
CAACCTGAGTTACTA	ACGGCTACCTTTACC	CCCATCAGGAAGTAT
AACCTGAGTTACTAC	CGGCTACCTTTACCG	CCATCAGGAAGTATG
ACCTGAGTTACTACA	GGCTACCTTTACCGG	CATCAGGAAGTATGC
ATCAGGAAGTATGCC	AGAGAACCCCAAGAC	GCTGCGCCTGCCCCA
TCAGGAAGTATGCCG	GAGAACCCCAAGACT	CTGCGCCTGCCCCAA
CAGGAAGTATGCCGA	AGAACCCCAAGACTG	TGCGCCTGCCCCAAA
AGGAAGTATGCCGAC	GAACCCCAAGACTGA	GCGCCTGCCCCAAAA
GGAAGTATGCCGACG	AACCCCAAGACTGAG	CGCCTGCCCCAAAAC
GAAGTATGCCGACGG	ACCCCAAGACTGAGG	GCCTGCCCCAAAACT
AAGTATGCCGACGGC	CCCCAAGACTGAGGT	CCTGCCCCAAAACTG
AGTATGCCGACGGCA	CCCAAGACTGAGGTG	CTGCCCCAAAACTGA
GTATGCCGACGGCAC	CCAAGACTGAGGTGT	TGCCCCAAAACTGAA
TATGCCGACGGCACC	CAAGACTGAGGTGTG	GCCCCAA.AACTGAAG
ATGCCGACGGCACCA	AAGACTGAGGTGTGT	CCCCAAAACTGAAGC
TGCCGACGGCACCAT	AGACTGAGGTGTGTG	CCCAAAACTGAAGCC
GCCGACGGCACCATC	GACTGAGGTGTGTGG	CCAAAACTGAAGCCG
CCGACGGCACCATCG	ACTGAGGTGTGTGGT	CAAAACTGAAGCCGA
CGACGGCACCATCGA	CTGAGGTGTGTGGTG	AAAACTGAAGCCGAG
GACGGCACCATCGAC	TGAGGTGTGTGGTGG	AAACTGAAGCCGAGA
ACGGCACCATCGACA	GAGGTGTGTGGTGGG	AACTGAAGCCGAGAA
CGGCACCATCGACAT	AGGTGTGTGGTGGGG	ACTGAAGCCGAGAAG
GGCACCATCGACATT	GGTGTGTGGTGGGGA	CTGAAGCCGAGAAGC
GCACCATCGACATTG	GTGTGTGGTGGGGAG	TGAAGCCGAGAAGCA
CACCATCGACATTGA	TGTGTGGTGGGGAGA	GAAGCCGAGAAGCAG
ACCATCGACATTGAG	GTGTGGTGGGGAGAA	AAGCCGAGAAGCAGG
CCATCGACATTGAGG	TGTGGTGGGGAGAAA	AGCCGAGAAGCAGGC
CATCGACATTGAGGA	GTGGTGGGGAGAAAG	GCCGAGAAGCAGGCC
ATCGACATTGAGGAG	TGGTGGGGAGAAAGG	CCGAGAAGCAGGCCG
TCGACATTGAGGAGG	GGTGGGGAGAAAGGG	CGAGAAGCAGGCCGA
CGACATTGAGGAGGT	GTGGGGAGAAAGGGC	GAGAAGCAGGCCGAG
GACATTGAGGAGGTC	TGGGGAGAAAGGGCC	AGAAGCAGGCCGAGA
ACATTGAGGAGGTCA	GGGGAGAAAGGGCCT	GAAGCAGGCCGAGAA
CATTGAGGAGGTCAC	GGGAGAAAGGGCCTT	AAGCAGGCCGAGAAG
ATTGAGGAGGTCACA	GGAGAAAGGGCCTTG	AGCAGGCCGAGAAGG
TTGAGGAGGTCACAG	GAGAAAGGGCCTTGC	GCAGGCCGAGAAGGA
TGAGGAGGTCACAGA	AGAAAGGGCCTTGCT	CAGGCCGAGAAGGAG
GAGGAGGTCACAGAG	GAAAGGGCCTTGCTG	AGGCCGAGAAGGAGG
AGGAGGTCACAGAGA	AAAGGGCCTTGCTGC	GGCCGAGAAGGAGGA
GGAGGTCACAGAGAA	AAGGGCCTTGCTGCG	GCCGAGAAGGAGGAG
GAGGTCACAGAGAAC	AGGGCCTTGCTGCGC	CCGAGAAGGAGGAGG
AGGTCACAGAGAACC	GGGCCTTGCTGCGCC	CGAGAAGGAGGAGGC
GGTCACAGAGAACCC	GGCCTTGCTGCGCCT	GAGAAGGAGGAGGCT
GTCACAGAGAACCCC	GCCTTGCTGCGCCTG	AGAAGGAGGAGGCTG
TCACAGAGAACCCCA	CCTTGCTGCGCCTGC	GAAGGAGGAGGCTGA
CACAGAGAACCCCAA	CTTGCTGCGCCTGCC	AAGGAGGAGGCTGAA
ACAGAGAACCCCAAG	TTGCTGCGCCTGCCC	AGGAGGAGGCTGAAT
CAGAGAACCCCAAGA	TGCTGCGCCTGCCCC	GGAGGAGGCTGAATA
GAGGAGGCTGAATAC	CTCCATCTTCGTGCC	TGCAAGTGGCCAACA
AGGAGGCTGAATACC	TCCATCTTCGTGCCC	GCAAGTGGCCAACAC
GGAGGCTGAATACCG	CCATCTTCGTGCCCA	CAAGTGGCCAACACC
GAGGCTGAATACCGC	CATCTTCGTGCCCAG	AAGTGGCCAACACCA
AGGCTGAATACCGCA	ATCTTCGTGCCCAGA	AGTGGCCAACACCAC
GGCTGAATACCGCAA	TCTTCGTGCCCAGAC	GTGGCCAACACCACC
GCTGAATACCGCAAA	CTTCGTGCCCAGACC	TGGCCAACACCACCA
CTGAATACCGCAAAG	TTCGTGCCCAGACCT	GGCCAACACCACCAT
TGAATACCGCAAAGT	TCGTGCCCAGACCTG	GCCAACACCACCATG
GAATACCGCAAAGTC	CGTGCCCAGACCTGA	CCAACACCACCATGT
AATACCGCAAAGTCT	GTGCCCAGACCTCAA	CAACACCACCATGTC
ATACCGCAAAGTCTT	TGCCCAGACCTGAAA	AACACCACCATGTCC
TACCGCAAAGTCTTT	GCCCAGACCTGAAAG	ACACCACCATGTCCA
ACCGCAAAGTCTTTG	CCCAGACCTGAAAGG	CACCACCATGTCCAG
CCGCAAAGTCTTTGA	CCAGACCTGAAAGGA	ACCACCATGTCCAGC
CGCAAAGTCTTTGAG	CAGACCTGAAAGGAA	CCACCATGTCCAGCC
GCAAAGTCTTTGAGA	AGACCTGAAAGGAAG	CACCATGTCCAGCCG
CAAAGTCTTTGAGAA	GACCTGAAAGGAAGC	ACCATGTCCAGCCGA
AAAGTCTTTGAGAAT	ACCTGAAAGGAAGCG	CCATGTCCAGCCGAA
AAGTCTTTGAGAATT	CCTGAAAGGAAGCGG	CATGTCCAGCCGAAG
AGTCTTTGAGAATTT	CTGAAAGGAAGCGGA	ATGTCCAGCCGAAGC
GTCTTTGAGAATTTC	TGAAAGGAAGCGGAG	TGTCCAGCCGAAGCA
TCTTTGAGAATTTCC	GAAAGGAAGCGGAGA	GTCCAGCCGAAGCAG
CTTTGAGAATTTCCT	AAAGGAAGCGGAGAG	TCCAGCCGAAGCAGG
TTTGAGAATTTCCTG	AAGGAAGCGGAGAGA	CCAGCCGAAGCAGGA
TTGAGAATTTCCTGC	AGGAAGCGGAGAGAT	CAGCCGAAGCAGGAA
TGAGAATTTCCTGCA	GGAAGCGGAGAGATG	AGCCGAAGCAGGAAC
GAGAATTTCCTGCAC	GAAGCGGAGAGATGT	GCCGAAGCAGGAACA
AGAATTTCCTGCACA	AAGCGGAGAGATGTC	CCGAAGCAGGAACAC
GAATTTCCTGCACAA	AGCGGAGAGATGTCA	CGAAGCAGGAACACC
AATTTCCTGCACAAC	GCGGAGAGATGTCAT	GAAGCAGGAACACCA
ATTTCCTGCACAACT	CGGAGAGATGTCATG	AAGCAGGAACACCAC
TTTCCTGCACAACTC	GGAGAGATGTCATGC	AGCAGGAACACCACG
TTCCTGCACAACTCC	GAGAGATGTCATGCA	GCAGGAACACCACGG
TCCTGCACAACTCCA	AGAGATGTCATGCAA	CAGGAACACCACGGC
CCTGCACAACTCCAT	GAGATGTCATGCAAG	AGGAACACCACGGCC
CTGCACAACTCCATC	AGATGTCATGCAAGT	GGAACACCACGGCCG
TGCACAACTCCATCT	GATGTCATGCAAGTG	GAACACCACGGCCGC
GCACAACTCCATCTT	ATGTCATGCAAGTGG	AACACCACGGCCGCA
CACAACTCCATCTTC	TGTCATGCAAGTGGC	ACACCACGGCCGCAG
ACAACTCCATCTTCG	GTCATGCAAGTGGCC	CACCACGGCCGCAGA
CAACTCCATCTTCGT	TCATGCAAGTGGCCA	ACCACGGCCGCAGAC
AACTCCATCTTCGTG	CATGCAAGTGGCCAA	CCACGGCCGCAGACA
ACTCCATCTTCGTGC	ATGCAAGTGGCCAAC	CACGGCCGCAGACAC
ACGGCCGCAGACACC	GACAGAGTACCCTTT	GAACTGTCATTTCTA
CGGCCGCAGACACCT	ACAGAGTACCCTTTC	AACTGTCATTTCTAA
GGCCGCAGACACCTA	CAGAGTACCCTTTCT	ACTGTCATTTCTAAC
GCCGCAGACACCTAC	AGAGTACCCTTTCTT	CTGTCATTTCTAACC
CCGCAGACACCTACA	GAGTACCCTTTCTTT	TGTCATTTCTAACCT
CGCAGACACCTACAA	AGTACCCTTTCTTTG	GTCATTTCTAACCTT
GCAGACACCTACAAC	GTACCCTTTCTTTGA	TCATTTCTAACCTTC
CAGACACCTACAACA	TACCCTTTCTTTGAG	CATTTCTAACCTTCG
AGACACCTACAACAT	ACCCTTTCTTTGAGA	ATTTCTAACCTTCGG
GACACCTACAACATC	CCCTTTCTTTGAGAG	TTTCTAACCTTCGGC
ACACCTACAACATCA	CCTTTCTTTGAGAGC	TTCTAACCTTCGGCC
CACCTACAACATCAC	CTTTCTTTGAGAGCA	TCTAACCTTCGGCCT
ACCTACAACATCACC	TTTCTTTGAGAGCAG	CTAACCTTCGGCCTT
CCTACAACATCACCG	TTCTTTGAGAGCAGA	TAACCTTCGGCCTTT
CTACAACATCACCGA	TCTTTGAGAGCAGAG	AACCTTCGGCCTTTC
TACAACATCACCGAC	CTTTGAGAGCAGAGT	ACCTTCGGCCTTTCA
ACAACATCACCGACC	TTTGAGAGCAGAGTG	CCTTCGGCCTTTCAC
CAACATCACCGACCC	TTGAGAGCAGAGTGG	CTTCGGCCTTTCACA
AACATCACCGACCCG	TGAGAGCAGAGTGGA	TTCGGCCTTTCACAT
ACATCACCGACCCGG	GAGAGCAGAGTGGAT	TCGGCCTTTCACATT
CATCACCGACCCGGA	AGAGCAGAGTGGATA	CGGCCTTTCACATTG
ATCACCGACCCGGAA	GAGCAGAGTGGATAA	GGCCTTTCACATTGT
TCACCGACCCGGAAG	AGCAGAGTGGATAAC	GCCTTTCACATTGTA
CACCGACCCGGAAGA	GCAGAGTGGATAACA	CCTTTCACATTGTAC
ACCGACCCGGAAGAG	CAGAGTGGATAACAA	CTTTCACATTGTACC
CCGACCCGGAAGAGC	AGAGTGGATAACAAG	TTTCACATTGTACCG
CGACCCGGAAGAGCT	GAGTGGATAACAAGG	TTCACATTGTACCGC
GACCCGGAAGAGCTG	AGTGGATAACAAGGA	TCACATTGTACCGCA
ACCCGGAAGAGCTGG	GTGGATAACAAGGAG	CACATTGTACCGCAT
CCCGGAAGAGCTGGA	TGGATAACAAGGAGA	ACATTGTACCGCATC
CCGGAAGAGCTGGAG	GGATAACAAGGAGAG	CATTGTACCGCATCG
CGGAAGAGCTGGAGA	GATAACAAGGAGAGA	ATTGTACCGCATCGA
GGAAGAGCTGGAGAC	ATAACAAGGAGAGAA	TTGTACCGCATCGAT
GAAGAGCTGGAGACA	TAACAAGGAGAGAAC	TGTACCGCATCGATA
AAGAGCTGGAGACAG	AACAAGGAGAGAACT	GTACCGCATCGATAT
AGAGCTGGAGACAGA	ACAAGGAGAGAACTG	TACCGCATCGATATC
GAGCTGGAGACAGAG	CAAGGAGAGAACTGT	ACCGCATCGATATCC
AGCTGGAGACAGAGT	AAGGAGAGAACTGTC	CCGCATCGATATCCA
GCTGGAGACAGAGTA	AGGAGAGAACTGTCA	CGCATCGATATCCAC
CTGGAGACAGAGTAC	GGAGAGAACTGTCAT	GCATCGATATCCACA
TGGAGACAGAGTACC	GAGAGAACTGTCATT	CATCGATATCCACAG
GGAGACAGAGTACCC	AGAGAACTGTCATTT	ATCGATATCCACAGC
GAGACAGAGTACCCT	GAGAACTGTCATTTC	TCGATATCCACAGCT
AGACAGAGTACCCTT	AGAACTGTCATTTCT	CGATATCCACAGCTG
GATATCCACAGCTGC	CGCCTCCAACTTCGT	CAGATGACATTCCTG
ATATCCACAGCTGCA	GCCTCCAACTTCGTC	AGATGACATTCCTGG
TATCCACAGCTGCAA	CCTCCAACTTCGTCT	GATGACATTCCTGGG
ATCCACAGCTGCAAC	CTCCAACTTCGTCTT	ATGACATTCCTGGGC
TCCACAGCTGCAACC	TCCAACTTCGTCTTT	TGACATTCCTGGGCC
CCACAGCTGCAACCA	CCAACTTCGTCTTTG	GACATTCCTGGGCCA
CACAGCTGCAACCAC	CAACTTCGTCTTTGC	ACATTCCTGGGCCAG
ACAGCTGCAACCACG	AACTTCGTCTTTGCA	CATTCCTGGGCCAGT
CAGCTGCAACCACGA	ACTTCGTCTTTGCAA	ATTCCTGGGCCAGTG
AGCTGCAACCACGAG	CTTCGTCTTTGCAAG	TTCCTGGGCCAGTGA
GCTGCAACCACGAGG	TTCGTCTTTGCAAGG	TCCTGGGCCAGTGAC
CTGCAACCACGAGGC	TCGTCTTTGCAAGGA	CCTGGGCCAGTGACC
TGCAACCACGAGGCT	CGTCTTTGCAAGGAC	CTGGGCCAGTGACCT
GCAACCACGAGGCTG	GTCTTTGCAAGGACT	TGGGCCAGTGACCTG
CAACCACGAGGCTGA	TCTTTGCAAGGACTA	GGGCCAGTGACCTGG
AACCACGAGGCTGAG	CTTTGCAAGGACTAT	GGCCAGTGACCTGGG
ACCACGAGGCTGAGA	TTTGCAAGGACTATG	GCCAGTGACCTGGGA
CCACGAGGCTGAGAA	TTGCAAGGACTATGC	CCAGTGACCTGGGAG
CACGAGGCTGAGAAG	TGCAAGGACTATGCC	CAGTGACCTGGGAGC
ACGAGGCTGAGAAGC	GCAAGGACTATGCCC	AGTGACCTGGGAGCC
CGAGGCTGAGAAGCT	CAAGGACTATGCCCG	GTGACCTGGGAGCCA
GAGGCTGAGAAGCTG	AAGGACTATGCCCGC	TGACCTGGGAGCCAA
AGGCTGAGAAGCTGG	AGGACTATGCCCGCA	GACCTGGGAGCCAAG
GGCTGAGAAGCTGGG	GGACTATGCCCGCAG	ACCTGGGAGCCAAGG
GCTGAGAAGCTGGGC	GACTATGCCCGCAGA	CCTGGGAGCCAAGGC
CTGAGAAGCTGGGCT	ACTATGCCCGCAGAA	CTGGGAGCCAAGGCC
TGAGAAGCTGGGCTG	CTATGCCCGCAGAAG	TGGGAGCCAAGGCCT
GAGAAGCTGGGCTGC	TATGCCCGCAGAAGG	GGGAGCCAAGGCCTG
AGAAGCTGGGCTGCA	ATGCCCGCAGAAGGA	GGAGCCAAGGCCTGA
GAAGCTGGGCTGCAG	TGCCCGCAGAAGGAG	GAGCCAAGGCCTGAA
AAGCTGGGCTGCAGC	GCCCGCAGAAGGAGC	AGCCAAGGCCTGAAA
AGCTGGGCTGCAGCG	CCCGCAGAAGGAGCA	GCCAAGGCCTGAAAA
GCTGGGCTGCAGCGC	CCGCAGAAGGAGCAG	CCAAGGCCTGAAAAC
CTGGGCTGCAGCGCC	CGCAGAAGGAGCAGA	CAAGGCCTGAAAACT
TGGGCTGCAGCGCCT	GCAGAAGGAGCAGAT	AAGGCCTGAAAACTC
GGGCTGCAGCGCCTC	CAGAAGGAGCAGATG	AGGCCTGAAAACTCC
GGCTGCAGCGCCTCC	AGAAGGAGCAGATGA	GGCCTGAAAACTCCA
GCTGCAGCGCCTCCA	GAAGGAGCAGATGAC	GCCTGAAAACTCCAT
CTGCAGCGCCTCCAA	AAGGAGCAGATGACA	CCTGAAAACTCCATC
TGCAGCGCCTCCAAC	AGGAGCAGATGACAT	CTGAAAACTCCATCT
GCAGCGCCTCCAACT	GGAGCAGATGACATT	TGAAAACTCCATCTT
CAGCGCCTCCAACTT	GAGCAGATGACATTC	GAAAACTCCATCTTT
AGCGCCTCCAACTTC	AGCAGATGACATTCC	AAAACTCCATCTTTT
GCGCCTCCAACTTCG	GCAGATGACATTCCT	AAACTCCATCTTTTT
AACTCCATCTTTTTA	ATTGATTCTAATGTA	ATCAGCGAGAATGTG
ACTCCATCTTTTTAA	TTGATTCTAATGTAT	TCAGCGAGAATGTGT
CTCCATCTTTTTAAA	TGATTCTAATGTATG	CAGCGAGAATGTGTG
TCCATCTTTTTAAAG	GATTCTAATGTATGA	AGCGAGAATGTGTGT
CCATCTTTTTAAAGT	ATTCTAATGTATGAA	GCGAGAATGTGTGTC
CATCTTTTTAAAGTG	TTCTAATGTATGAAA	CGAGAATGTGTGTCC
ATCTTTTTAAAGTGG	TCTAATGTATGAAAT	GAGAATGTGTGTCCA
TCTTTTTAAAGTGGC	CTAATGTATGAAATA	AGAATGTGTGTCCAG
CTTTTTAAAGTGGCC	TAATGTATGAAATAA	GAATGTGTGTCCAGA
TTTTTAAAGTGGCCG	AATGTATGAAATAAA	AATGTGTGTCCAGAC
TTTTAAAGTGGCCGG	ATGTATGAAATAAAA	ATGTGTGTCCAGACA
TTTAAAGTGGCCGGA	TGTATGAAATAAAAT	TGTGTGTCCAGACAG
TTAAAGTGGCCGGAA	GTATGAAATAAAATA	GTGTGTCCAGACAGG
TAAAGTGGCCGGAAC	TATGAAATAAAATAC	TGTGTCCAGACAGGA
AAAGTGGCCGGAACC	ATGAAATAAAATACG	GTGTCCAGACAGGAA
AAGTGGCCGGAACCT	TGAAATAAAATACGG	TGTCCAGACAGGAAT
AGTGGCCGGAACCTG	GAAATAAAATACGGA	GTCCAGACAGGAATA
GTGGCCGGAACCTGA	AAATAAAATACGGAT	TCCAGACAGGAATAC
TGGCCGGAACCTGAG	AATAAAATACGGATC	CCAGACAGGAATACA
GGCCGGAACCTGAGA	ATAAAATACGGATCA	CAGACAGGAATACAG
GCCGGAACCTGAGAA	TAAAATACGGATCAC	AGACAGGAATACAGG
CCGGAACCTGAGAAT	AAAATACGGATCACA	GACAGGAATACAGGA
CGGAACCTGAGAATC	AAATACGGATCACAA	ACAGGAATACAGGAA
GGAACCTGAGAATCC	AATACGGATCACAAG	CAGGAATACAGGAAG
GAACCTGAGAATCCC	ATACGGATCACAAGT	AGGAATACAGGAAGT
AACCTGAGAATCCCA	TACGGATCACAAGTT	GGAATACAGGAAGTA
ACCTGAGAATCCCAA	ACGGATCACAAGTTG	GAATACAGGAAGTAT
CCTGAGAATCCCAAT	CGGATCACAAGTTGA	AATACAGGAAGTATG
CTGAGAATCCCAATG	GGATCACAAGTTGAG	ATACAGGAAGTATGG
TGAGAATCCCAATGG	GATCACAAGTTGAGG	TACAGGAAGTATGGA
GAGAATCCCAATGGA	ATCACAAGTTGAGGA	ACAGGAAGTATGGAG
AGAATCCCAATGGAT	TCACAAGTTGAGGAT	CAGGAAGTATGGAGG
GAATCCCAATGGATT	CACAAGTTGAGGATC	AGGAAGTATGGAGGG
AATCCCAATGGATTG	ACAAGTTGAGGATCA	GGAAGTATGGAGGGG
ATCCCAATGGATTGA	CAAGTTGAGGATCAG	GAAGTATGGAGGGGC
TCCCAATGGATTGAT	AAGTTGAGGATCAGC	AAGTATGGAGGGGCC
CCCAATGGATTGATT	AGTTGAGGATCAGCG	AGTATGGAGGGGCCA
CCAATGGATTGATTC	GTTGAGGATCAGCGA	GTATGGAGGGGCCAA
CAATGGATTGATTCT	TTGAGGATCAGCGAG	TATGGAGGGGCCAAG
AATGGATTGATTCTA	TGAGGATCAGCGAGA	ATGGAGGGGCCAAGC
ATGGATTGATTCTAA	GAGGATCAGCGAGAA	TGGAGGGGCCAAGCT
TGGATTGATTCTAAT	AGGATCAGCGAGAAT	GGAGGGGCCAAGCTA
GGATTGATTCTAATG	GGATCAGCGAGAATG	GAGGGGCCAAGCTAA
GATTGATTCTAATGT	GATCAGCGAGAATGT	AGGGGCCAAGCTAAA
GGGGCCAAGCTAAAC	GATTCAGGCCACATC	CTGTGTTCTTCTATG
GGGCCAAGCTAAACC	ATTCAGGCCACATCT	TGTGTTCTTCTATGT
GGCCAAGCTAAACCG	TTCAGGCCACATCTC	GTGTTCTTCTATGTC
GCCAAGCTAAACCGG	TCAGGCCACATCTCT	TGTTCTTCTATGTCC
CCAAGCTAAACCGGC	CAGGCCACATCTCTC	GTTCTTCTATGTCCA
CAAGCTAAACCGGCT	AGGCCACATCTCTCT	TTCTTCTATGTCCAG
AAGCTAAACCGGCTA	GGCCACATCTCTCTC	TCTTCTATGTCCAGG
AGCTAAACCGGCTAA	GCCACATCTCTCTCT	CTTCTATGTCCAGGC
GCTAAACCGGCTAAA	CCACATCTCTCTCTG	TTCTATGTCCAGGCC
CTAAACCGGCTAAAC	CACATCTCTCTCTGG	TCTATGTCCAGGCCA
TAAACCGGCTAAACC	ACATCTCTCTCTGGG	CTATGTCCAGGCCAA
AAACCGGCTAAACCC	CATCTCTCTCTGGGA	TATGTCCAGGCCAAA
AACCGGCTAAACCCG	ATCTCTCTCTGGGAA	ATGTCCAGGCCAAAA
ACCGGCTAAACCCGG	TCTCTCTCTGGGAAT	TGTCCAGGCCAAAAC
CCGGCTAAACCCGGG	CTCTCTCTGGGAATG	GTCCAGGCCAAAACA
CGGCTAAACCCGGGG	TCTCTCTGGGAATGG	TCCAGGCCAAAACAG
GGCTAAACCCGGGGA	CTCTCTGGGAATGGG	CCAGGCCAAAACAGG
GCTAAACCCGGGGAA	TCTCTGGGAATGGGT	CAGGCCAAAACAGGA
CTAAACCCGGGGAAC	CTCTGGGAATGGGTC	AGGCCAAAACAGGAT
TAAACCCGGGGAACT	TCTGGGAATGGGTCG	GGCCAAAACAGGATA
AAACCCGGGGAACTA	CTGGGAATGGGTCGT	GCCAAAACAGGATAT
AACCCGGGGAACTAC	TGGGAATGGGTCGTG	CCAAAACAGGATATG
ACCCGGGGAACTACA	GGGAATGGGTCGTGG	CAAAACAGGATATGA
CCCGGGGAACTACAC	GGAATGGGTCGTGGA	AAAACAGGATATGAA
CCGGGGAACTACACA	GAATGGGTCGTGGAC	AAACAGGATATGAAA
CGGGGAACTACACAG	AATGGGTCGTGGACA	AACAGGATATGAAAA
GGGGAACTACACAGC	ATGGGTCGTGGACAG	ACAGGATATGAAAAC
GGGAACTACACAGCC	TGGGTCGTGGACAGA	CAGGATATGAAAACT
GGAACTACACAGCCC	GGGTCGTGGACAGAT	AGGATATGAAAACTT
GAACTACACAGCCCG	GGTCGTGGACAGATC	GGATATGAAAACTTC
AACTACACAGCCCGG	GTCGTGGACAGATCC	GATATGAAAACTTCA
ACTACACAGCCCGGA	TCGTGGACAGATCCT	ATATGAAAACTTCAT
CTACACAGCCCGGAT	CGTGGACAGATCCTG	TATGAAAACTTCATC
TACACAGCCCGGATT	GTGGACAGATCCTGT	ATGAAAACTTCATCC
ACACAGCCCGGATTC	TGGACAGATCCTGTG	TGAAAACTTCATCCA
CACAGCCCGGATTCA	GGACAGATCCTGTGT	GAAAACTTCATCCAT
ACAGCCCGGATTCAG	GACAGATCCTGTGTT	AAAACTTCATCCATC
CAGCCCGGATTCAGG	ACAGATCCTGTGTTC	AAACTTCATCCATCT
AGCCCGGATTCAGGC	CAGATCCTGTGTTCT	AACTTCATCCATCTG
GCCCGGATTCAGGCC	AGATCCTGTGTTCTT	ACTTCATCCATCTGA
CCCGGATTCAGGCCA	GATCCTGTGTTCTTC	CTTCATCCATCTGAT
CCGGATTCAGGCCAC	ATCCTGTGTTCTTCT	TTCATCCATCTGATC
CGGATTCAGGCCACA	TCCTGTGTTCTTCTA	TCATCCATCTGATCA
GGATTCAGGCCACAT	CCTGTGTTCTTCTAT	CATCCATCTGATCAT
ATCCATCTGATCATC	GGGAGGGTTGGTGAT	ATAACAGCAGGCTGG
TCCATCTGATCATCG	GGAGGGTTGGTGATT	TAACAGCAGGCTGGG
CCATCTGATCATCGC	GAGGGTTGGTGATTA	AACAGCAGGCTGGGG
CATCTGATCATCGCT	AGGGTTGGTGATTAT	ACAGCAGGCTGGGGA
ATCTGATCATCGCTC	GGGTTGGTGATTATG	CAGCAGGCTGGGGAA
TCTGATCATCGCTCT	GGTTGGTGATTATGC	AGCAGGCTGGGGAAT
CTGATCATCGCTCTG	GTTGGTGATTATGCT	GCAGGCTGGGGAATG
TGATCATCGCTCTGC	TTGGTGATTATGCTG	CAGGCTGGGGAATGG
GATCATCGCTCTGCC	TGGTGATTATGCTGT	AGGCTGGGGAATGGA
ATCATCGCTCTGCCC	GGTGATTATGCTGTA	GGCTGGGGAATGGAG
TCATCGCTCTGCCCG	GTGATTATGCTGTAC	GCTGGGGAATGGAGT
CATCGCTCTGCCCGT	TGATTATGCTGTACG	CTGGGGAATGGAGTG
ATCGCTCTGCCCGTC	GATTATGCTGTACGT	TGGGGAATGGAGTGC
TCGCTCTGCCCGTCG	ATTATGCTGTACGTC	GGGGAATGGAGTGCT
CGCTCTGCCCGTCGC	TTATGCTGTACGTCT	GGGAATGGAGTGCTG
GCTCTGCCCGTCGCT	TATGCTGTACGTCTT	GGAATGGAGTGCTGT
CTCTGCCCGTCGCTG	ATGCTGTACGTCTTC	GAATGGAGTGCTGTA
TCTGCCCGTCGCTGT	TGCTGTACGTCTTCC	AATGGAGTGCTGTAT
CTGCCCGTCGCTGTC	GCTGTACGTCTTCCA	ATGGAGTGCTGTATG
TGCCCGTCGCTGTCC	CTGTACGTCTTCCAT	TGGAGTGCTGTATGC
GCCCGTCGCTGTCCT	TGTACGTCTTCCATA	GGAGTGCTGTATGCC
CCCGTCGCTGTCCTG	GTACGTCTTCCATAG	GAGTGCTGTATGCCT
CCGTCGCTGTCCTGT	TACGTCTTCCATAGA	AGTGCTGTATGCCTC
CGTCGCTGTCCTGTT	ACGTCTTCCATAGAA	GTGCTGTATGCCTCT
GTCGCTGTCCTGTTG	CGTCTTCCATAGAAA	TGCTGTATGCCTCTG
TCGCTGTCCTGTTGA	GTCTTCCATAGAAAG	GCTGTATGCCTCTGT
CGCTGTCCTGTTGAT	TCTTCCATAGAPAGA	CTGTATGCCTCTGTG
GCTGTCCTGTTGATC	CTTCCATAGAAAGAG	TGTATGCCTCTGTGA
CTGTCCTGTTGATCG	TTCCATAGAAAGAGA	GTATGCCTCTGTGAA
TGTCCTGTTGATCGT	TCCATAGAAAGAGAA	TATGCCTCTGTGAAC
GTCCTGTTGATCGTG	CCATAGAAAGAGAAA	ATGCCTCTGTGAACC
TCCTGTTGATCGTGG	CATAGAAAGAGAAAT	TGCCTCTGTGAACCC
CCTGTTGATCGTGGG	ATAGAAAGAGAAATA	GCCTCTGTGAACCCG
CTGTTGATCGTGGGA	TAGAAAGAGAAATAA	CCTCTGTGAACCCGG
TGTTGATCGTGGGAG	AGAAAGAGPAATAAC	CTCTGTGAACCCGGA
GTTGATCGTGGGAGG	GAAAGAGAAATAACA	TCTGTGAACCCGGAG
TTGATCGTGGGAGGG	AAAGAGAAATAACAG	CTGTGAACCCGGAGT
TGATCGTGGGAGGGT	AAGAGAAATAACAGC	TGTGAACCCGGAGTA
GATCGTGGGAGGGTT	AGAGAAATAACAGCA	GTGAACCCGGAGTAC
ATCGTGGGAGGGTTG	GAGAAATAACAGCAG	TGAACCCGGAGTACT
TCGTGGGAGGGTTGG	AGAAATAACAGCAGG	GAACCCGGAGTACTT
CGTGGGAGGGTTGGT	GAAATAACAGCAGGC	AACCCGGAGTACTTC
GTGGGAGGGTTGGTG	AAATAACAGCAGGCT	ACCCGGAGTACTTCA
TGGGAGGGTTGGTGA	AATAACAGCAGGCTG	CCCGGAGTACTTCAG
CCGGAGTACTTCAGC	GGAGGTGGCTCGGGA	AGGGGTCGTTTGGGA
CGGAGTACTTCAGCG	GAGGTGGCTCGGGAG	GGGGTCGTTTGGGAT
GGAGTACTTCAGCGC	AGGTGGCTCGGGAGA	GGGTCGTTTGGGATG
GAGTACTTCAGCGCT	GGTGGCTCGGGAGAA	GGTCGTTTGGGATGG
AGTACTTCAGCGCTG	GTGGCTCGGGAGAAG	GTCGTTTGGGATGGT
GTACTTCAGCGCTGC	TGGCTCGGGAGAAGA	TCGTTTGGGATGGTC
TACTTCAGCGCTGCT	GGCTCGGGAGAAGAT	CGTTTGGGATGGTCT
ACTTCAGCGCTGCTG	GCTCGGGAGAAGATC	GTTTGGGATGGTCTA
CTTCAGCGCTGCTGA	CTCGGGAGAAGATCA	TTTGGGATGGTCTAT
TTCAGCGCTGCTGAT	TCGGGAGAAGATCAC	TTGGGATGGTCTATG
TCAGCGCTGCTGATG	CGGGAGAAGATCACC	TGGGATGGTCTATGA
CAGCGCTGCTGATGT	GGGAGAAGATCACCA	GGGATGGTCTATGAA
AGCGCTGCTGATGTG	GGAGAAGATCACCAT	GGATGGTCTATGAAG
GCGCTGCTGATGTGT	GAGAAGATCACCATG	GATGGTCTATGAAGG
CGCTGCTGATGTGTA	AGAAGATCACCATGA	ATGGTCTATGAAGGA
GCTGCTGATGTGTAC	GAAGATCACCATGAG	TGGTCTATGAAGGAG
CTGCTGATGTGTACG	AAGATCACCATGAGC	GGTCTATGAAGGAGT
TGCTGATGTGTACGT	AGATCACCATGAGCC	GTCTATGAAGGAGTT
GCTGATGTGTACGTT	GATCACCATGAGCCG	TCTATGAAGGAGTTG
CTGATGTGTACGTTC	ATCACCATGAGCCGG	CTATGAAGGAGTTGC
TGATGTGTACGTTCC	TCACCATGAGCCGGG	TATGAAGGAGTTGCC
GATGTGTACGTTCCT	CACCATGAGCCGGGA	ATGAAGGAGTTGCCA
ATGTGTACGTTCCTG	ACCATGAGCCGGGAA	TGAAGGAGTTGCCAA
TGTGTACGTTCCTGA	CCATGAGCCGGGAAC	GAAGGAGTTGCCAAG
GTGTACGTTCCTGAT	CATGAGCCGGGAACT	AAGGAGTTGCCAAGG
TGTACGTTCCTGATG	ATGAGCCGGGAACTT	AGGAGTTGCCAAGGG
GTACGTTCCTGATGA	TGAGCCGGGAACTTG	GGAGTTGCCAAGGGT
TACGTTCCTGATGAG	GAGCCGGGAACTTGG	GAGTTGCCAAGGGTG
ACGTTCCTGATGAGT	AGCCGGGAACTTGGG	AGTTGCCAAGGGTGT
CGTTCCTGATGAGTG	GCCGGGAACTTGGGC	GTTGCCAAGGGTGTG
GTTCCTGATGAGTGG	CCGGGAACTTGGGCA	TTGCCAAGGGTGTGG
TTCCTGATGAGTGGG	CGGGAACTTGGGCAG	TGCCAAGGGTGTGGT
TCCTGATGAGTGGGA	GGGAACTTGGGCAGG	GCCAAGGGTGTGGTG
CCTGATGAGTGGGAG	GGAACTTGGGCAGGG	CCAAGGGTGTGGTGA
CTGATGAGTGGGAGG	GAACTTGGGCAGGGG	CAAGGGTGTGGTGAA
TGATGAGTGGGAGGT	AACTTGGGCAGGGGT	AAGGGTGTGGTGAAA
GATGAGTGGGAGGTG	ACTTGGGCAGGGGTC	AGGGTGTGGTGAAAG
ATGAGTGGGAGGTGG	CTTGGGCAGGGGTCG	GGGTGTGGTGAAAGA
TGAGTGGGAGGTGGC	TTGGGCAGGGGTCGT	GGTGTGGTGAAAGAT
GAGTGGGAGGTGGCT	TGGGCAGGGGTCGTT	GTGTGGTGAAAGATG
AGTGGGAGGTGGCTC	GGGCAGGGGTCGTTT	TGTGGTGAAAGATGA
GTGGGAGGTGGCTCG	GGCAGGGGTCGTTTG	GTGGTGAAAGATGAA
TGGGAGGTGGCTCGG	GCAGGGGTCGTTTGG	TGGTGAAAGATGAAC
GGGAGGTGGCTCGGG	CAGGGGTCGTTTGGG	GGTGAAAGATGAACC
GTGAAAGATGAACCT	CGAGGCCGCAAGCAT	CTTCTGTGATGAAGG
TGAAAGATGAACCTG	GAGGCCGCAAGCATG	TTCTGTGATGAAGGA
GAAAGATGAACCTGA	AGGCCGCAAGCATGC	TCTGTGATGAAGGAG
AAAGATGAACCTGAA	GGCCGCAAGCATGCG	CTGTGATGAAGGAGT
AAGATGAACCTGAAA	GCCGCAAGCATGCGT	TGTGATGAAGGAGTT
AGATGAACCTGAAAC	CCGCAAGCATGCGTG	GTGATGAAGGAGTTC
GATGAACCTGAAACC	CGCAAGCATGCGTGA	TGATGAAGGAGTTCA
ATGAACCTGAAACCA	GCAAGCATGCGTGAG	GATGAAGGAGTTCAA
TGAACCTGAAACCAG	CAAGCATGCGTGAGA	ATGAAGGAGTTCAAT
GAACCTGAAACCAGA	AAGCATGCGTGAGAG	TGAAGGAGTTCAATT
AACCTGAAACCAGAG	AGCATGCGTGAGAGG	GAAGGAGTTCAATTG
ACCTGAAACCAGAGT	GCATGCGTGAGAGGA	AAGGAGTTCAATTGT
CCTGAAACCAGAGTG	CATGCGTGAGAGGAT	AGGAGTTCAATTGTC
CTGAAACCAGAGTGG	ATGCGTGAGAGGATT	GGAGTTCAATTGTCA
TGAAACCAGAGTGGC	TGCGTGAGAGGATTG	GAGTTCAATTGTCAC
GAAACCAGAGTGGCC	GCGTGAGAGGATTGA	AGTTCAATTGTCACC
AAACCAGAGTGGCCA	CGTGAGAGGATTGAG	GTTCAATTGTCACCA
AACCAGAGTGGCCAT	GTGAGAGGATTGAGT	TTCAATTGTCACCAT
ACCAGAGTGGCCATT	TGAGAGGATTGAGTT	TCAATTGTCACCATG
CCAGAGTGGCCATTA	GAGAGGATTGAGTTT	CAATTGTCACCATGT
CAGAGTGGCCATTAA	AGAGGATTGAGTTTC	AATTGTCACCATGTG
AGAGTGGCCATTAAA	GAGGATTGAGTTTCT	ATTGTCACCATGTGG
GAGTGGCCATTAAAA	AGGATTGAGTTTCTC	TTGTCACCATGTGGT
AGTGGCCATTAAAAC	GGATTGAGTTTCTCA	TGTCACCATGTGGTG
GTGGCCATTAAAACA	GATTGAGTTTCTCAA	GTCACCATGTGGTGC
TGGCCATTAAAACAG	ATTGAGTTTCTCAAC	TCACCATGTGGTGCG
GGCCATTAAAACAGT	TTGAGTTTCTCAACG	CACCATGTGGTGCGA
GCCATTAAAACAGTG	TGAGTTTCTCAACGA	ACCATGTGGTGCGAT
CCATTAAAACAGTGA	GAGTTTCTCAACGAA	CCATGTGGTGCGATT
CATTAAAACAGTGAA	AGTTTCTCAACGAAG	CATGTGGTGCGATTG
ATTAAAACAGTGAAC	GTTTCTCAACGAAGC	ATGTGGTGCGATTGC
TTAAAACAGTGAACG	TTTCTCAACGAAGCT	TGTGGTGCGATTGCT
TAAAACAGTGAACGA	TTCTCAACGAAGCTT	GTGGTGCGATTGCTG
AAAACAGTGAACGAG	TCTCAACGAAGCTTC	TGGTGCGATTGCTGG
AAACAGTGAACGAGG	CTCAACGAAGCTTCT	GGTGCGATTGCTGGG
AACAGTGAACGAGGC	TCAACGAAGCTTCTG	GTGCGATTGCTGGGT
ACAGTGAACGAGGCC	CAACGAAGCTTCTGT	TGCGATTGCTGGGTG
CAGTGAACGAGGCCG	AACGAAGCTTCTGTG	GCGATTGCTGGGTGT
AGTGAACGAGGCCGC	ACGAAGCTTCTGTGA	CGATTGCTGGGTGTG
GTGAACGAGGCCGCA	CGAAGCTTCTGTGAT	GATTGCTGGGTGTGG
TGAACGAGGCCGCAA	GAAGCTTCTGTGATG	ATTGCTGGGTGTGGT
GAACGAGGCCGCAAG	AAGCTTCTGTGATGA	TTGCTGGGTGTGGTG
AACGAGGCCGCAAGC	AGCTTCTGTGATGAA	TGCTGGGTGTGGTGT
ACGAGGCCGCAAGCA	GCTTCTGTGATGAAG	GCTGGGTGTGGTGTC
CTGGGTGTGGTGTCC	ACTGATGACACGGGG	GGCCAGAAATGGAGA
TGGGTGTGGTGTCCC	CTGATGACACGGGGC	GCCAGAAATGGAGAA
GGGTGTGGTGTCCCA	TGATGACACGGGGCG	CCAGAAATGGAGAAT
GGTGTGGTGTCCCAA	GATGACACGGGGCGA	CAGAAATGGAGAATA
GTGTGGTGTCCCAAG	ATGACACGGGGCGAT	AGAAATGGAGAATAA
TGTGGTGTCCCAAGG	TGACACGGGGCGATC	GAAATGGAGAATAAT
GTGGTGTCCCAAGGC	GACACGGGGCGATCT	AAATGGAGAATAATC
TGGTGTCCCAAGGCC	ACACGGGGCGATCTC	AATGGAGAATAATCC
GGTGTCCCAAGGCCA	CACGGGGCGATCTCA	ATGGAGAATAATCCA
GTGTCCCAAGGCCAG	ACGGGGCGATCTCAA	TGGAGAATAATCCAG
TGTCCCAAGGCCAGC	CGGGGCGATCTCAAA	GGAGAATAATCCAGT
GTCCCAAGGCCAGCC	GGGGCGATCTCAAAA	GAGAATAATCCAGTC
TCCCAAGGCCAGCCA	GGGCGATCTCAAAAG	AGAATAATCCAGTCC
CCCAAGGCCAGCCAA	GGCGATCTCAAAAGT	GAATAATCCAGTCCT
CCAAGGCCAGCCAAC	GCGATCTCAAAAGTT	AATAATCCAGTCCTA
CAAGGCCAGCCAACA	CGATCTCAAAAGTTA	ATAATCCAGTCCTAG
AAGGCCAGCCAACAC	GATCTCAAAAGTTAT	TAATCCAGTCCTAGC
AGGCCAGCCAACACT	ATCTCAAAAGTTATC	AATCCAGTCCTAGCA
GGCCAGCCAACACTG	TCTCAAAAGTTATCT	ATCCAGTCCTAGCAC
GCCAGCCAACACTGG	CTCAAAAGTTATCTC	TCCAGTCCTAGCACC
CCAGCCAACACTGGT	TCAAAAGTTATCTCC	CCAGTCCTAGCACCT
CAGCCAACACTGGTC	CAAAAGTTATCTCCG	CAGTCCTAGCACCTC
AGCCAACACTGGTCA	AAAAGTTATCTCCGG	AGTCCTAGCACCTCC
GCCAACACTGGTCAT	AAAGTTATCTCCGGT	GTCCTAGCACCTCCA
CCAACACTGGTCATC	AAGTTATCTCCGGTC	TCCTAGCACCTCCAA
CAACACTGGTCATCA	AGTTATCTCCGGTCT	CCTAGCACCTCCAAG
AACACTGGTCATCAT	GTTATCTCCGGTCTC	CTAGCACCTCCAAGC
ACACTGGTCATCATG	TTATCTCCGGTCTCT	TAGCACCTCCAAGCC
CACTGGTCATCATGG	TATCTCCGGTCTCTG	AGCACCTCCAAGCCT
ACTGGTCATCATGGA	ATCTCCGGTCTCTGA	GCACCTCCAAGCCTG
CTGGTCATCATGGAA	TCTCCGGTCTCTGAG	CACCTCCAAGCCTGA
TGGTCATCATGGAAC	CTCCGGTCTCTGAGG	ACCTCCAAGCCTGAG
GGTCATCATGGAACT	TCCGGTCTCTGAGGC	CCTCCAAGCCTGAGC
GTCATCATGGAACTG	CCGGTCTCTGAGGCC	CTCCAAGCCTGAGCA
TCATCATGGAACTGA	CGGTCTCTGAGGCCA	TCCAAGCCTGAGCAA
CATCATGGAACTGAT	GGTCTCTGAGGCCAG	CCAAGCCTGAGCAAG
ATCATGGAACTGATG	GTCTCTGAGGCCAGA	CAAGCCTGAGCAAGA
TCATGGAACTGATGA	TCTCTGAGGCCAGAA	AAGCCTGAGCAAGAT
CATGGAACTGATGAC	CTCTGAGGCCAGAAA	AGCCTGAGCAAGATG
ATGGAACTGATGACA	TCTGAGGCCAGAAAT	GCCTGAGCAAGATGA
TGGAACTGATGACAC	CTGAGGCCAGAAATG	CCTGAGCAAGATGAT
GGAACTGATGACACG	TGAGGCCAGAAATGG	CTGAGCAAGATGATT
GAACTGATGACACGG	GAGGCCAGAAATGGA	TGAGCAAGATGATTC
AACTGATGACACGGG	AGGCCAGAAATGGAG	GAGCAAGATGATTCA
AGCAAGATGATTCAG	ATACCTCAACGCCAA	GGAATTGCATGGTAG
GCAAGATGATTCAGA	TACCTCAACGCCAAT	GAATTGCATGGTAGC
CAAGATGATTCAGAT	ACCTCAACGCCAATA	AATTGCATGGTAGCC
AAGATGATTCAGATG	CCTCAACGCCAATAA	ATTGCATGGTAGCCG
AGATGATTCAGATGG	CTCAACGCCAATAAG	TTGCATGGTAGCCGA
GATGATTCAGATGGC	TCAACGCCAATAAGT	TGCATGGTAGCCGAA
ATGATTCAGATGGCC	CAACGCCAATAAGTT	GCATGGTAGCCGAAG
TGATTCAGATGGCCG	AACGCCAATAAGTTC	CATGGTAGCCGAAGA
GATTCAGATGGCCGG	ACGCCAATAAGTTCG	ATGGTAGCCGAAGAT
ATTCAGATGGCCGGA	CGCCAATAAGTTCGT	TGGTAGCCGAAGATT
TTCAGATGGCCGGAG	GCCAATAAGTTCGTC	GGTAGCCGAAGATTT
TCAGATGGCCGGAGA	CCAATAAGTTCGTCC	GTAGCCGAAGATTTC
CAGATGGCCGGAGAG	CAATAAGTTCGTCCA	TAGCCGAAGATTTCA
AGATGGCCGGAGAGA	AATAAGTTCGTCCAC	AGCCGAAGATTTCAC
GATGGCCGGAGAGAT	ATAAGTTCGTCCACA	GCCGAAGATTTCACA
ATGGCCGGAGAGATT	TAAGTTCGTCCACAG	CCGAAGATTTCACAG
TGGCCGGAGAGATTG	AAGTTCGTCCACAGA	CGAAGATTTCACAGT
GGCCGGAGAGATTGC	AGTTCGTCCACAGAG	GAAGATTTCACAGTC
GCCGGAGAGATTGCA	GTTCGTCCACAGAGA	AAGATTTCACAGTCA
CCGGAGAGATTGCAG	TTCGTCCACAGAGAC	AGATTTCACAGTCAA
CGGAGAGATTGCAGA	TCGTCCACAGAGACC	GATTTCACAGTCAAA
GGAGAGATTGCAGAC	CGTCCACAGAGACCT	ATTTCACAGTCAAAA
GAGAGATTGCAGACG	GTCCACAGAGACCTT	TTTCACAGTCAAAAT
AGAGATTGCAGACGG	TCCACAGAGACCTTG	TTCACAGTCAAAATC
GAGATTGCAGACGGC	CCACAGAGACCTTGC	TCACAGTCAAAATCG
AGATTGCAGACGGCA	CACAGAGACCTTGCT	CACAGTCAAAATCGG
GATTGCAGACGGCAT	ACAGAGACCTTGCTG	ACAGTCAAAATCGGA
ATTGCAGACGGCATG	CAGAGACCTTGCTGC	CAGTCAAAATCGGAG
TTGCAGACGGCATGG	AGAGACCTTGCTGCC	AGTCAAAATCGGAGA
TGCAGACGGCATGGC	GAGACCTTGCTGCCC	GTCAAAATCGGAGAT
GCAGACGGCATGGCA	AGACCTTGCTGCCCG	TCAAAATCGGAGATT
CAGACGGCATGGCAT	GACCTTGCTGCCCGG	CAAAATCGGAGATTT
AGACGGCATGGCATA	ACCTTGCTGCCCGGA	AAAATCGGAGATTTT
GACGGCATGGCATAC	CCTTGCTGCCCGGAA	AAATCGGAGATTTTG
ACGGCATGGCATACC	CTTGCTGCCCGGAAT	AATCGGAGATTTTGG
CGGCATGGCATACCT	TTGCTGCCCGGAATT	ATCGGAGATTTTGGT
GGCATGGCATACCTC	TGCTGCCCGGAATTG	TCGGAGATTTTGGTA
GCATGGCATACCTCA	GCTGCCCGGAATTGC	CGGAGATTTTGGTAT
CATGGCATACCTCAA	CTGCCCGGAATTGCA	GGAGATTTTGGTATG
ATGGCATACCTCAAC	TGCCCGGAATTGCAT	GAGATTTTGGTATGA
TGGCATACCTCAACG	GCCCGGAATTGCATG	AGATTTTGGTATGAC
GGCATACCTCAACGC	CCCGGAATTGCATGG	GATTTTGGTATGACG
GCATACCTCAACGCC	CCGGAATTGCATGGT	ATTTTGGTATGACGC
CATACCTCAACGCCA	CGGAATTGCATGGTA	TTTTGGTATGACGCG
TTTGGTATGACGCGA	AGGAGGCAAAGGGCT	CCCTCAAGGATGGAG
TTGGTATGACGCGAG	GGAGGCAAAGGGCTG	CCTCAAGGATGGAGT
TGGTATGACGCGAGA	GAGGCAAAGGGCTGC	CTCAAGGATGGAGTC
GGTATGACGCGAGAT	AGGCAAAGGGCTGCT	TCAAGGATGGAGTCT
GTATGACGCGAGATA	GGCAAAGGGCTGCTG	CAAGGATGGAGTCTT
TATGACGCGAGATAT	GCAAAGGGCTGCTGC	AAGGATGGAGTCTTC
ATGACGCGAGATATC	CAAAGGGCTGCTGCC	AGGATGGAGTCTTCA
TGACGCGAGATATCT	AAAGGGCTGCTGCCC	GGATGGAGTCTTCAC
GACGCGAGATATCTA	AAGGGCTGCTGCCCG	GATGGAGTCTTCACC
ACGCGAGATATCTAT	AGGGCTGCTGCCCGT	ATGGAGTCTTCACCA
CGCGAGATATCTATG	GGGCTGCTGCCCGTG	TGGAGTCTTCACCAC
GCGAGATATCTATGA	GGCTGCTGCCCGTGC	GGAGTCTTCACCACT
CGAGATATCTATGAG	GCTGCTGCCCGTGCG	GAGTCTTCACCACTT
GAGATATCTATGAGA	CTGCTGCCCGTGCGC	AGTCTTCACCACTTA
AGATATCTATGAGAC	TGCTGCCCGTGCGCT	GTCTTCACCACTTAC
GATATCTATGAGACA	GCTGCCCGTGCGCTG	TCTTCACCACTTACT
ATATCTATGAGACAG	CTGCCCGTGCGCTGG	CTTCACCACTTACTC
TATCTATGAGACAGA	TGCCCGTGCGCTGGA	TTCACCACTTACTCG
ATCTATGAGACAGAC	GCCCGTGCGCTGGAT	TCACCACTTACTCGG
TCTATGAGACAGACT	CCCGTGCGCTGGATG	CACCACTTACTCGGA
CTATGAGACAGACTA	CCGTGCGCTGGATGT	ACCACTTACTCGGAC
TATGAGACAGACTAT	CGTGCGCTGGATGTC	CCACTTACTCGGACG
ATGAGACAGACTATT	GTGCGCTGGATGTCT	CACTTACTCGGACGT
TGAGACAGACTATTA	TGCGCTGGATGTCTC	ACTTACTCGGACGTC
GAGACAGACTATTAC	GCGCTGGATGTCTCC	CTTACTCGGACGTCT
AGACAGACTATTACC	CGCTGGATGTCTCCT	TTACTCGGACGTCTG
GACAGACTATTACCG	GCTGGATGTCTCCTG	TACTCGGACGTCTGG
ACAGACTATTACCGG	CTGGATGTCTCCTGA	ACTCGGACGTCTGGT
CAGACTATTACCGGA	TGGATGTCTCCTGAG	CTCGGACGTCTGGTC
AGACTATTACCGGAA	GGATGTCTCCTGAGT	TCGGACGTCTGGTCC
GACTATTACCGGAAA	GATGTCTCCTGAGTC	CGGACGTCTGGTCCT
ACTATTACCGGAAAG	ATGTCTCCTGAGTCC	GGACGTCTGGTCCTT
CTATTACCGGAAAGG	TGTCTCCTGAGTCCC	GACGTCTGGTCCTTC
TATTACCGGAAAGGA	GTCTCCTGAGTCCCT	ACGTCTGGTCCTTCG
ATTACCGGAAAGGAG	TCTCCTGAGTCCCTC	CGTCTGGTCCTTCGG
TTACCGGAAAGGAGG	CTCCTGAGTCCCTCA	GTCTGGTCCTTCGGG
TACCGGAAAGGAGGC	TCCTGAGTCCCTCAA	TCTGGTCCTTCGGGG
ACCGGAAAGGAGGCA	CCTGAGTCCCTCAAG	CTGGTCCTTCGGGGT
CCGGAAAGGAGGCAA	CTGAGTCCCTCAAGG	TGGTCCTTCGGGGTC
CGGAAAGGAGGCAAA	TGAGTCCCTCAAGGA	GGTCCTTCGGGGTCG
GGAAAGGAGGCAAAG	GAGTCCCTCAAGGAT	GTCCTTCGGGGTCGT
GAAAGGAGGCAAAGG	AGTCCCTCAAGGATG	TCCTTCGGGGTCGTC
AAAGGAGGCAAAGGG	GTCCCTCAAGGATGG	CCTTCGGGGTCGTCC
AAGGAGGCAAAGGGC	TCCCTCAAGGATGGA	CTTCGGGGTCGTCCT
TTCGGGGTCGTCCTC	CTACCAGGGCTTGTC	AGGGCGGCCTTCTGG
TCGGGGTCGTCCTCT	TACCAGGGCTTGTCC	GGGCGGCCTTCTGGA
CGGGGTCGTCCTCTG	ACCAGGGCTTGTCCA	GGCGGCCTTCTGGAC
GGGGTCGTCCTCTGG	CCAGGGCTTGTCCAA	GCGGCCTTCTGGACA
GGGTCGTCCTCTGGG	CAGGGCTTGTCCAAC	CGGCCTTCTGGACAA
GGTCGTCCTCTGGGA	AGGGCTTGTCCAACG	GGCCTTCTGGACAAG
GTCGTCCTCTGGGAG	GGGCTTGTCCAACGA	GCCTTCTGGACAAGC
TCGTCCTCTGGGAGA	GGCTTGTCCAACGAG	CCTTCTGGACAAGCC
CGTCCTCTGGGAGAT	GCTTGTCCAACGAGC	CTTCTGGACAAGCCA
GTCCTCTGGGAGATC	CTTGTCCAACGAGCA	TTCTGGACAAGCCAG
TCCTCTGGGAGATCG	TTGTCCAACGAGCAA	TCTGGACAAGCCAGA
CCTCTGGGAGATCGC	TGTCCAACGAGCAAG	CTGGACAAGCCAGAC
CTCTGGGAGATCGCC	GTCCAACGAGCAAGT	TGGACAAGCCAGACA
TCTGGGAGATCGCCA	TCCAACGAGCAAGTC	GGACAAGCCAGACAA
CTGGGAGATCGCCAC	CCAACGAGCAAGTCC	GACAAGCCAGACAAC
TGGGAGATCGCCACA	CAACGAGCAAGTCCT	ACAAGCCAGACAACT
GGGAGATCGCCACAC	AACGAGCAAGTCCTT	CAAGCCAGACAACTG
GGAGATCGCCACACT	ACGAGCAAGTCCTTC	AAGCCAGACAACTGT
GAGATCGCCACACTG	CGAGCAAGTCCTTCG	AGCCAGACAACTGTC
AGATCGCCACACTGG	GAGCAAGTCCTTCGC	GCCAGACAACTGTCC
GATCGCCACACTGGC	AGCAAGTCCTTCGCT	CCAGACAACTGTCCT
ATCGCCACACTGGCC	GCAAGTCCTTCGCTT	CAGACAACTGTCCTG
TCGCCACACTGGCCG	CAAGTCCTTCGCTTC	AGACAACTGTCCTGA
CGCCACACTGGCCGA	AAGTCCTTCGCTTCG	GACAACTGTCCTGAC
GCCACACTGGCCGAG	AGTCCTTCGCTTCGT	ACAACTGTCCTGACA
CCACACTGGCCGAGC	GTCCTTCGCTTCGTC	CAACTGTCCTGACAT
CACACTGGCCGAGCA	TCCTTCGCTTCGTCA	AACTGTCCTGACATG
ACACTGGCCGAGCAG	CCTTCGCTTCGTCAT	ACTGTCCTGACATGC
CACTGGCCGAGCAGC	CTTCGCTTCGTCATG	CTGTCCTGACATGCT
ACTGGCCGAGCAGCC	TTCGCTTCGTCATGG	TGTCCTGACATGCTG
CTGGCCGAGCAGCCC	TCGCTTCGTCATGGA	GTCCTGACATGCTGT
TGGCCGAGCAGCCCT	CGCTTCGTCATGGAG	TCCTGACATGCTGTT
GGCCGAGCAGCCCTA	GCTTCGTCATGGAGG	CCTGACATGCTGTTT
GCCGAGCAGCCCTAC	CTTCGTCATGGAGGG	CTGACATGCTGTTTG
CCGAGCAGCCCTACC	TTCGTCATGGAGGGC	TGACATGCTGTTTGA
CGAGCAGCCCTACCA	TCGTCATGGAGGGCG	GACATGCTGTTTGAA
GAGCAGCCCTACCAG	CGTCATGGAGGGCGG	ACATGCTGTTTGAAC
AGCAGCCCTACCAGG	GTCATGGAGGGCGGC	CATGCTGTTTGAACT
GCAGCCCTACCAGGG	TCATGGAGGGCGGCC	ATGCTGTTTGAACTG
CAGCCCTACCAGGGC	CATGGAGGGCGGCCT	TGCTGTTTGAACTGA
AGCCCTACCAGGGCT	ATGGAGGGCGGCCTT	GCTGTTTGAACTGAT
GCCCTACCAGGGCTT	TGGAGGGCGGCCTTC	CTGTTTGAACTGATG
CCCTACCAGGGCTTG	GGAGGGCGGCCTTCT	TGTTTGAACTGATGC
CCTACCAGGGCTTGT	GAGGGCGGCCTTCTG	GTTTGAACTGATGCG
TTTGAACTGATGCGC	GCCTTCCTTCCTGGA	AGCCTGGCTTCCGGG
TTGAACTGATGCGCA	CCTTCCTTCCTGGAG	GCCTGGCTTCCGGGA
TGAACTGATGCGCAT	CTTCCTTCCTGGAGA	CCTGGCTTCCGGGAG
GAACTGATGCGCATG	TTCCTTCCTGGAGAT	CTGGCTTCCGGGAGG
AACTGATGCGCATGT	TCCTTCCTGGAGATC	TGGCTTCCGGGAGGT
ACTGATGCGCATGTG	CCTTCCTGGAGATCA	GGCTTCCGGGAGGTC
CTGATGCGCATGTGC	CTTCCTGGAGATCAT	GCTTCCGGGAGGTCT
TGATGCGCATGTGCT	TTCCTGGAGATCATC	CTTCCGGGAGGTCTC
GATGCGCATGTGCTG	TCCTGGAGATCATCA	TTCCGGGAGGTCTCC
ATGCGCATGTGCTGG	CCTGGAGATCATCAG	TCCGGGAGGTCTCCT
TGCGCATGTGCTGGC	CTGGAGATCATCAGC	CCGGGAGGTCTCCTT
GCGCATGTGCTGGCA	TGGAGATCATCAGCA	CGGGAGGTCTCCTTC
CGCATGTGCTGGCAG	GGAGATCATCAGCAG	GGGAGGTCTCCTTCT
GCATGTGCTGGCAGT	GAGATCATCAGCAGC	GGAGGTCTCCTTCTA
CATGTGCTGGCAGTA	AGATCATCAGCAGCA	GAGGTCTCCTTCTAC
ATGTGCTGGCAGTAT	GATCATCAGCAGCAT	AGGTCTCCTTCTACT
TGTGCTGGCAGTATA	ATCATCAGCAGCATC	GGTCTCCTTCTACTA
GTGCTGGCAGTATAA	TCATCAGCAGCATCA	GTCTCCTTCTACTAC
TGCTGGCAGTATAAC	CATCAGCAGCATCAA	TCTCCTTCTACTACA
GCTGGCAGTATAACC	ATCAGCAGCATCAAA	CTCCTTCTACTACAG
CTGGCAGTATAACCC	TCAGCAGCATCAAAG	TCCTTCTACTACAGC
TGGCAGTATAACCCC	CAGCAGCATCAAAGA	CCTTCTACTACAGCG
GGCAGTATAACCCCA	AGCAGCATCAAAGAG	CTTCTACTACAGCGA
GCAGTATAACCCCAA	GCAGCATCAAAGAGG	TTCTACTACAGCGAG
CAGTATAACCCCAAG	CAGCATCAAAGAGGA	TCTACTACAGCGAGG
AGTATAACCCCAAGA	AGCATCAAAGAGGAG	CTACTACAGCGAGGA
GTATAACCCCAAGAT	GCATCAAAGAGGAGA	TACTACAGCGAGGAG
TATAACCCCAAGATG	CATCAAAGAGGAGAT	ACTACAGCGAGGAGA
ATAACCCCAAGATGA	ATCAAAGAGGAGATG	CTACAGCGAGGAGAA
TAACCCCAAGATGAG	TCAAAGAGGAGATGG	TACAGCGAGGAGAAC
AACCCCAAGATGAGG	CAAAGAGGAGATGGA	ACAGCGAGGAGAACA
ACCCCAAGATGAGGC	AAAGAGGAGATGGAG	CAGCGAGGAGAACAA
CCCCAAGATGAGGCC	AAGAGGAGATGGAGC	AGCGAGGAGAACAAG
CCCAAGATGAGGCCT	AGAGGAGATGGAGCC	GCGAGGAGAACAAGC
CCAAGATGAGGCCTT	GAGGAGATGGAGCCT	CGAGGAGAACAAGCT
CAAGATGAGGCCTTC	AGGAGATGGAGCCTG	GAGGAGAACAAGCTG
AAGATGAGGCCTTCC	GGAGATGGAGCCTGG	AGGAGAACAAGCTGC
AGATGAGGCCTTCCT	GAGATGGAGCCTGGC	GGAGAACAAGCTGCC
GATGAGGCCTTCCTT	AGATGGAGCCTGGCT	GAGAACAAGCTGCCC
ATGAGGCCTTCCTTC	GATGGAGCCTGGCTT	AGAACAAGCTGCCCG
TGAGGCCTTCCTTCC	ATGGAGCCTGGCTTC	GAACAAGCTGCCCGA
GAGGCCTTCCTTCCT	TGGAGCCTGGCTTCC	AACAAGCTGCCCGAG
AGGCCTTCCTTCCTG	GGAGCCTGGCTTCCG	ACAAGCTGCCCGAGC
GGCCTTCCTTCCTGG	GAGCCTGGCTTCCGG	CAAGCTGCCCGAGCC
AAGCTGCCCGAGCCG	GGAGAGCGTCCCCCT	CACTGCCCGACAGAC
AGCTGCCCGAGCCGG	GAGAGCGTCCCCCTG	ACTGCCCGACAGACA
GCTGCCCGAGCCGGA	AGAGCGTCCCCCTGG	CTGCCCGACAGACAC
CTGCCCGAGCCGGAG	GAGCGTCCCCCTGGA	TGCCCGACAGACACT
TGCCCGAGCCGGAGG	AGCGTCCCCCTGGAC	GCCCGACAGACACTC
GCCCGAGCCGGAGGA	GCGTCCCCCTGGACC	CCCGACAGACACTCA
CCCGAGCCGGAGGAG	CGTCCCCCTGGACCC	CCGACAGACACTCAG
CCGAGCCGGAGGAGC	GTCCCCCTGGACCCC	CGACAGACACTCAGG
CGAGCCGGAGGAGCT	TCCCCCTGGACCCCT	GACAGACACTCAGGA
GAGCCGGAGGAGCTG	CCCCCTGGACCCCTC	ACAGACACTCAGGAC
AGCCGGAGGAGCTGG	CCCCTGGACCCCTCG	CAGACACTCAGGACA
GCCGGAGGAGCTGGA	CCCTGGACCCCTCGG	AGACACTCAGGACAC
CCGGAGGAGCTGGAC	CCTGGACCCCTCGGC	GACACTCAGGACACA
CGGAGGAGCTGGACC	CTGGACCCCTCGGCC	ACACTCAGGACACAA
GGAGGAGCTGGACCT	TGGACCCCTCGGCCT	CACTCAGGACACAAG
GAGGAGCTGGACCTG	GGACCCCTCGGCCTC	ACTCAGGACACAAGG
AGGAGCTGGACCTGG	GACCCCTCGGCCTCC	CTCAGGACACAAGGC
GGAGCTGGACCTGGA	ACCCCTCGGCCTCCT	TCAGGACACAAGGCC
GAGCTGGACCTGGAG	CCCCTCGGCCTCCTC	CAGGACACAAGGCCG
AGCTGGACCTGGAGC	CCCTCGGCCTCCTCG	AGGACACAAGGCCGA
GCTGGACCTGGAGCC	CCTCGGCCTCCTCGT	GGACACAAGGCCGAG
CTGGACCTGGAGCCA	CTCGGCCTCCTCGTC	GACACAAGGCCGAGA
TGGACCTGGAGCCAG	TCGGCCTCCTCGTCC	ACACAAGGCCGAGAA
GGACCTGGAGCCAGA	CGGCCTCCTCGTCCT	CACAAGGCCGAGAAC
GACCTGGAGCCAGAG	GGCCTCCTCGTCCTC	ACAAGGCCGAGAACG
ACCTGGAGCCAGAGA	GCCTCCTCGTCCTCC	CAAGGCCGAGAACGG
CCTGGAGCCAGAGAA	CCTCCTCGTCCTCCC	AAGGCCGAGAACGGC
CTGGAGCCAGAGAAC	CTCCTCGTCCTCCCT	AGGCCGAGAACGGCC
TGGAGCCAGAGAACA	TCCTCGTCCTCCCTG	GGCCGAGAACGGCCC
GGAGCCAGAGAACAT	CCTCGTCCTCCCTGC	GCCGAGAACGGCCCC
GAGCCAGAGAACATG	CTCGTCCTCCCTGCC	CCGAGAACGGCCCCG
AGCCAGAGAACATGG	TCGTCCTCCCTGCCA	CGAGAACGGCCCCGG
GCCAGAGAACATGGA	CGTCCTCCCTGCCAC	GAGAACGGCCCCGGC
CCAGAGAACATGGAG	GTCCTCCCTGCCACT	AGAACGGCCCCGGCC
CAGAGAACATGGAGA	TCCTCCCTGCCACTG	GAACGGCCCCGGCCC
AGAGAACATGGAGAG	CCTCCCTGCCACTGC	AACGGCCCCGGCCCT
GAGAACATGGAGAGC	CTCCCTGCCACTGCC	ACGGCCCCGGCCCTG
AGAACATGGAGAGCG	TCCCTGCCACTGCCC	CGGCCCCGGCCCTGG
GAACATGGAGAGCGT	CCCTGCCACTGCCCG	GGCCCCGGCCCTGGG
AACATGGAGAGCGTC	CCTGCCACTGCCCGA	GCCCCGGCCCTGGGG
ACATGGAGAGCGTCC	CTGCCACTGCCCGAC	CCCCGGCCCTGGGGT
CATGGAGAGCGTCCC	TGCCACTGCCCGACA	CCCGGCCCTGGGGTG
ATGGAGAGCGTCCCC	GCCACTGCCCGACAG	CCGGCCCTGGGGTGC
TGGAGAGCGTCCCCC	CCACTGCCCGACAGA	CGGCCCTGGGGTGCT
GGCCCTGGGGTGCTG	GCCTTACGCCCACAT	TGCCGCTGCCCCAGT
GCCCTGGGGTGCTGG	CCTTACGCCCACATG	GCCGCTGCCCCAGTC
CCCTGGGGTGCTGGT	CTTACGCCCACATGA	CCGCTGCCCCAGTCT
CCTGGGGTGCTGGTC	TTACGCCCACATGAA	CGCTGCCCCAGTCTT
CTGGGGTGCTGGTCC	TACGCCCACATGAAC	GCTGCCCCAGTCTTC
TGGGGTGCTGGTCCT	ACGCCCACATGAACG	CTGCCCCAGTCTTCG
GGGGTGCTGGTCCTC	CGCCCACATGAACGG	TGCCCCAGTCTTCGA
GGGTGCTGGTCCTCC	GCCCACATGAACGGG	GCCCCAGTCTTCGAC
GGTGCTGGTCCTCCG	CCCACATGAACGGGG	CCCCAGTCTTCGACC
GTGCTGGTCCTCCGC	CCACATGAACGGGGG	CCCAGTCTTCGACCT
TGCTGGTCCTCCGCG	CACATGAACGGGGGC	CCAGTCTTCGACCTG
GCTGGTCCTCCGCGC	ACATGAACGGGGGCC	CAGTCTTCGACCTGC
CTGGTCCTCCGCGCC	CATGAACGGGGGCCG	AGTCTTCGACCTGCT
TGGTCCTCCGCGCCA	ATGAACGGGGGCCGC	GTCTTCGACCTGCTG
GGTCCTCCGCGCCAG	TGAACGGGGGCCGCA	TCTTCGACCTGCTGA
GTCCTCCGCGCCAGC	GAACGGGGGCCGCAA	CTTCGACCTGCTGAT
TCCTCCGCGCCAGCT	AACGGGGGCCGCAAG	TTCGACCTGCTGATC
CCTCCGCGCCAGCTT	ACGGGGGCCGCAAGA	TCGACCTGCTGATCC
CTCCGCGCCAGCTTC	CGGGGGCCGCAAGAA	CGACCTGCTGATCCT
TCCGCGCCAGCTTCG	GGGGGCCGCAAGAAC	GACCTGCTGATCCTT
CCGCGCCAGCTTCGA	GGGGCCGCAAGAACG	ACCTGCTGATCCTTG
CGCGCCAGCTTCGAC	GGGCCGCAAGAACGA	CCTGCTGATCCTTGG
GCGCCAGCTTCGACG	GGCCGCAAGAACGAG	CTGCTGATCCTTGGA
CGCCAGCTTCGACGA	GCCGCAAGAACGAGC	TGCTGATCCTTGGAT
GCCAGCTTCGACGAG	CCGCAAGAACGAGCG	GCTGATCCTTGGATC
CCAGCTTCGACGAGA	CGCAAGAACGAGCGG	CTGATCCTTGGATCC
CAGCTTCGACGAGAG	GCAAGAACGAGCGGG	TGATCCTTGGATCCT
AGCTTCGACGAGAGA	CAAGAACGAGCGGGC	GATCCTTGGATCCTG
GCTTCGACGAGAGAC	AAGAACGAGCGGGCC	ATCCTTGGATCCTGA
CTTCGACGAGAGACA	AGAACGAGCGGGCCT	TCCTTGGATCCTGAA
TTCGACGAGAGACAG	GAACGAGCGGGCCTT	CCTTGGATCCTGAAT
TCGACGAGAGACAGC	AACGAGCGGGCCTTG	CTTGGATCCTGAATC
CGACGAGAGACAGCC	ACGAGCGGGCCTTGC	TTGGATCCTGAATCT
GACGAGAGACAGCCT	CGAGCGGGCCTTGCC	TGGATCCTGAATCTG
ACGAGAGACAGCCTT	GAGCGGGCCTTGCCG	GGATCCTGAATCTGT
CGAGAGACAGCCTTA	AGCGGGCCTTGCCGC	GATCCTGAATCTGTG
GAGAGACAGCCTTAC	GCGGGCCTTGCCGCT	ATCCTGAATCTGTGC
AGAGACAGCCTTACG	CGGGCCTTGCCGCTG	TCCTGAATCTGTGCA
GAGACAGCCTTACGC	GGGCCTTGCCGCTGC	CCTGAATCTGTGCAA
AGACAGCCTTACGCC	GGCCTTGCCGCTGCC	CTGAATCTGTGCAAA
GACAGCCTTACGCCC	GCCTTGCCGCTGCCC	TGAATCTGTGCAAAC
ACAGCCTTACGCCCA	CCTTGCCGCTGCCCC	GAATCTGTGCAAACA
CAGCCTTACGCCCAC	CTTGCCGCTGCCCCA	AATCTGTGCAAACAG
AGCCTTACGCCCACA	TTGCCGCTGCCCCAG	ATCTGTGCAAACAGT
TCTGTGCAAACAGTA	GGGAGAGAGAGTTTT	CAGTGGATCTTCAGT
CTGTGCAAACAGTAA	GGAGAGAGAGTTTTA	AGTGGATCTTCAGTT
TGTGCAAACAGTAAC	GAGAGAGAGTTTTAA	GTGGATCTTCAGTTC
GTGCAAACAGTAACG	AGAGAGAGTTTTAAC	TGGATCTTCAGTTCT
TGCAAACAGTAACGT	GAGAGAGTTTTAACA	GGATCTTCAGTTCTG
GCAAACAGTAACGTG	AGAGAGTTTTAACAA	GATCTTCAGTTCTGC
CAAACAGTAACGTGT	GAGAGTTTTAACAAT	ATCTTCAGTTCTGCC
AAACAGTAACGTGTG	AGAGTTTTAACAATC	TCTTCAGTTCTGCCC
AACAGTAACGTGTGC	GAGTTTTAACAATCC	CTTCAGTTCTGCCCT
ACAGTAACGTGTGCG	AGTTTTAACAATCCA	TTCAGTTCTGCCCTT
CAGTAACGTGTGCGC	GTTTTAACAATCCAT	TCAGTTCTGCCCTTG
AGTAACGTGTGCGCA	TTTTAACAATCCATT	CAGTTCTGCCCTTGC
GTAACGTGTGCGCAC	TTTAACAATCCATTC	AGTTCTGCCCTTGCT
TAACGTGTGCGCACG	TTAACAATCCATTCA	GTTCTGCCCTTGCTG
AACGTGTGCGCACGC	TAACAATCCATTCAC	TTCTGCCCTTGCTGC
ACGTGTGCGCACGCG	AACAATCCATTCACA	TCTGCCCTTGCTGCC
CGTGTGCGCACGCGC	ACAATCCATTCACAA	CTGCCCTTGCTGCCC
GTGTGCGCACGCGCA	CAATCCATTCACAAG	TGCCCTTGCTGCCCG
TGTGCGCACGCGCAG	AATCCATTCACAAGC	GCCCTTGCTGCCCGC
GTGCGCACGCGCAGC	ATCCATTCACAAGCC	CCCTTGCTGCCCGCG
TGCGCACGCGCAGCG	TCCATTCACAAGCCT	CCTTGCTGCCCGCGG
GCGCACGCGCAGCGG	CCATTCACAAGCCTC	CTTGCTGCCCGCGGG
CGCACGCGCAGCGGG	CATTCACAAGCCTCC	TTGCTGCCCGCGGGA
GCACGCGCAGCGGGG	ATTCACAAGCCTCCT	TGCTGCCCGCGGGAG
CACGCGCAGCGGGGT	TTCACAAGCCTCCTG	GCTGCCCGCGGGAGA
ACGCGCAGCGGGGTG	TCACAAGCCTCCTGT	CTGCCCGCGGGAGAC
CGCGCAGCGGGGTGG	CACAAGCCTCCTGTA	TGCCCGCGGGAGACA
GCGCAGCGGGGTGGG	ACAAGCCTCCTGTAC	GCCCGCGGGAGACAG
CGCAGCGGGGTGGGG	CAAGCCTCCTGTACC	CCCGCGGGAGACAGC
GCAGCGGGGTGGGGG	AAGCCTCCTGTACCT	CCGCGGGAGACAGCT
CAGCGGGGTGGGGGG	AGCCTCCTGTACCTC	CGCGGGAGACAGCTT
AGCGGGGTGGGGGGG	GCCTCCTGTACCTCA	GCGGGAGACAGCTTC
GCGGGGTGGGGGGGG	CCTCCTGTACCTCAG	CGGGAGACAGCTTCT
CGGGGTGGGGGGGGA	CTCCTGTACCTCAGT	GGGAGACAGCTTCTC
GGGGTGGGGGGGGAG	TCCTGTACCTCAGTG	GGAGACAGCTTCTCT
GGGTGGGGGGGGAGA	CCTGTACCTCAGTGG	GAGACAGCTTCTCTG
GGTGGGGGGGGAGAG	CTGTACCTCAGTGGA	AGACAGCTTCTCTGC
GTGGGGGGGGAGAGA	TGTACCTCAGTGGAT	GACAGCTTCTCTGCA
TGGGGGGGGAGAGAG	GTACCTCAGTGGATC	ACAGCTTCTCTGCAG
GGGGGGGGAGAGAGA	TACCTCAGTGGATCT	CAGCTTCTCTGCAGT
GGGGGGGAGAGAGAG	ACCTCAGTGGATCTT	AGCTTCTCTGCAGTA
GGGGGGAGAGAGAGT	CCTCAGTGGATCTTC	GCTTCTCTGCAGTAA
GGGGGAGAGAGAGTT	CTCAGTGGATCTTCA	CTTCTCTGCAGTAAA
GGGGAGAGAGAGTTT	TCAGTGGATCTTCAG	TTCTCTGCAGTAAAA
TCTCTGCAGTAAAAC	CAAGCAGCTTTTTAT	CCTTTAAGAACCTTA
CTCTGCAGTAAAACA	AAGCAGCTTTTTATT	CTTTAAGAACCTTAA
TCTGCAGTAAAACAC	AGCAGCTTTTTATTC	TTTAAGAACCTTAAT
CTGCAGTAAAACACA	GCAGCTTTTTATTCC	TTAAGAACCTTAATG
TGCAGTAAAACACAT	CAGCTTTTTATTCCC	TAAGAACCTTAATGA
GCAGTAAAACACATT	AGCTTTTTATTCCCT	AAGAACCTTAATGAC
CAGTAAAACACATTT	GCTTTTTATTCCCTG	AGAACCTTAATGACA
AGTAAAACACATTTG	CTTTTTATTCCCTGC	GAACCTTAATGACAA
GTAAAACACATTTGG	TTTTTATTCCCTGCC	AACCTTAATGACAAC
TAAAACACATTTGGG	TTTTATTCCCTGCCC	ACCTTAATGACAACA
AAAACACATTTGGGA	TTTATTCCCTGCCCA	CCTTAATGACAACAC
AAACACATTTGGGAT	TTATTCCCTGCCCAA	CTTAATGACAACACT
AACACATTTGGGATG	TATTCCCTGCCCAAA	TTAATGACAACACTT
ACACATTTGGGATGT	ATTCCCTGCCCAAAC	TAATGACAACACTTA
CACATTTGGGATGTT	TTCCCTGCCCAAACC	AATGACAACACTTAA
ACATTTGGGATGTTC	TCCCTGCCCAAACCC	ATGACAACACTTAAT
CATTTGGGATGTTCC	CCCTGCCCAAACCCT	TGACAACACTTAATA
ATTTGGGATGTTCCT	CCTGCCCAAACCCTT	GACAACACTTAATAG
TTTGGGATGTTCCTT	CTGCCCAAACCCTTA	ACAACACTTAATAGC
TTGGGATGTTCCTTT	TGCCCAAACCCTTAA	CAACACTTAATAGCA
TGGGATGTTCCTTTT	GCCCAAACCCTTAAC	AACACTTAATAGCAA
GGGATGTTCCTTTTT	CCCAAACCCTTAACT	ACACTTAATAGCAAC
GGATGTTCCTTTTTT	CCAAACCCTTAACTG	CACTTAATAGCAACA
GATGTTCCTTTTTTC	CAAACCCTTAACTGA	ACTTAATAGCAACAG
ATGTTCCTTTTTTCA	AAACCCTTAACTGAC	CTTAATAGCAACAGA
TGTTCCTTTTTTCAA	AACCCTTAACTGACA	TTAATAGCAACAGAG
GTTCCTTTTTTCAAT	ACCCTTAACTGACAT	TAATAGCAACAGAGC
TTCCTTTTTTCAATA	CCCTTAACTGACATG	AATAGCAACAGAGCA
TCCTTTTTTCAATAT	CCTTAACTGACATGG	ATAGCAACAGAGCAC
CCTTTTTTCAATATG	CTTAACTGACATGGG	TAGCAACAGAGCACT
CTTTTTTCAATATGC	TTAACTGACATGGGC	AGCAACAGAGCACTT
TTTTTTCAATATGCA	TAACTGACATGGGCC	GCAACAGAGCACTTG
TTTTTCAATATGCAA	AACTGACATGGGCCT	CAACAGAGCACTTGA
TTTTCAATATGCAAG	ACTGACATGGGCCTT	AACAGAGCACTTGAG
TTTCAATATGCAAGC	CTGACATGGGCCTTT	ACAGAGCACTTGAGA
TTCAATATGCAAGCA	TGACATGGGCCTTTA	CAGAGCACTTGAGAA
TCAATATGCAAGCAG	GACATGGGCCTTTAA	AGAGCACTTGAGAAC
CAATATGCAAGCAGC	ACATGGGCCTTTAAG	GAGCACTTGAGAACC
AATATGCAAGCAGCT	CATGGGCCTTTAAGA	AGCACTTGAGAACCA
ATATGCAAGCAGCTT	ATGGGCCTTTAAGAA	GCACTTGAGAACCAG
TATGCAAGCAGCTTT	TGGGCCTTTAAGAAC	CACTTGAGAACCAGT
ATGCAAGCAGCTTTT	GGGCCTTTAAGAACC	ACTTGAGAACCAGTC
TGCAAGCAGCTTTTT	GGCCTTTAAGAACCT	CTTGAGAACCAGTCT
GCAAGCAGCTTTTTA	GCCTTTAAGAACCTT	TTGAGAACCAGTCTC
TGAGAACCAGTCTCC	CCTTTCTCTCTCCTC	CAAGTCCAGCTGGGA
GAGAACCAGTCTCCT	CTTTCTCTCTCCTCT	AAGTCCAGCTGGGAA
AGAACCAGTCTCCTC	TTTCTCTCTCCTCTC	AGTCCAGCTGGGAAG
GAACCAGTCTCCTCA	TTCTCTCTCCTCTCT	GTCCAGCTGGGAAGC
AACCAGTCTCCTCAC	TCTCTCTCCTCTCTG	TCCAGCTGGGAAGCC
ACCAGTCTCCTCACT	CTCTCTCCTCTCTGC	CCAGCTGGGAAGCCC
CCAGTCTCCTCACTC	TCTCTCCTCTCTGCT	CAGCTGGGAAGCCCT
CAGTCTCCTCACTCT	CTCTCCTCTCTGCTT	AGCTGGGAAGCCCTT
AGTCTCCTCACTCTG	TCTCCTCTCTGCTTC	GCTGGGAAGCCCTTT
GTCTCCTCACTCTGT	CTCCTCTCTGCTTCA	CTGGGAAGCCCTTTT
TCTCCTCACTCTGTC	TCCTCTCTGCTTCAT	TGGGAAGCCCTTTTT
CTCCTCACTCTGTCC	CCTCTCTGCTTCATA	GGGAAGCCCTTTTTA
TCCTCACTCTGTCCC	CTCTCTGCTTCATAA	GGAAGCCCTTTTTAT
CCTCACTCTGTCCCT	TCTCTGCTTCATAAC	GAAGCCCTTTTTATC
CTCACTCTGTCCCTG	CTCTGCTTCATAACG	AAGCCCTTTTTATCA
TCACTCTGTCCCTGT	TCTGCTTCATAACGG	AGCCCTTTTTATCAG
CACTCTGTCCCTGTC	CTGCTTCATAACGGA	GCCCTTTTTATCAGT
ACTCTGTCCCTGTCC	TGCTTCATAACGGAA	CCCTTTTTATCAGTT
CTCTGTCCCTGTCCT	GCTTCATAACGGAAA	CCTTTTTATCAGTTT
TCTGTCCCTGTCCTT	CTTCATAACGGAAAA	CTTTTTATCAGTTTG
CTGTCCCTGTCCTTC	TTCATAACGGAAAAA	TTTTTATCAGTTTGA
TGTCCCTGTCCTTCC	TCATAACGGAAAAAT	TTTTATCAGTTTGAG
GTCCCTGTCCTTCCC	CATAACGGAAAAATA	TTTATCAGTTTGAGG
TCCCTGTCCTTCCCT	ATAACGGAAAAATAA	TTATCAGTTTGAGGA
CCCTGTCCTTCCCTG	TAACGGAAAAATAAT	TATCAGTTTGAGGAA
CCTGTCCTTCCCTGT	AACGGAAAAATAATT	ATCAGTTTGAGGAAG
CTGTCCTTCCCTGTT	ACGGAAAAATAATTG	TCAGTTTGAGGAAGT
TGTCCTTCCCTGTTC	CGGAAAAATAATTGC	CAGTTTGAGGAAGTG
GTCCTTCCCTGTTCT	GGAAAAATAATTGCC	AGTTTGAGGAAGTGG
TCCTTCCCTGTTCTC	GAAAAATAATTGCCA	GTTTGAGGAAGTGGC
CCTTCCCTGTTCTCC	AAAAATAATTGCCAC	TTTGAGGAAGTGGCT
CTTCCCTGTTCTCCC	AAAATAATTGCCACA	TTGAGGAAGTGGCTG
TTCCCTGTTCTCCCT	AAATAATTGCCACAA	TGAGGAAGTGGCTGT
TCCCTGTTCTCCCTT	AATAATTGCCACAAG	GAGGAAGTGGCTGTC
CCCTGTTCTCCCTTT	ATAATTGCCACAAGT	AGGAAGTGGCTGTCC
CCTGTTCTCCCTTTC	TAATTGCCACAAGTC	GGAAGTGGCTGTCCC
CTGTTCTCCCTTTCT	AATTGCCACAAGTCC	GAAGTGGCTGTCCCT
TGTTCTCCCTTTCTC	ATTGCCACAAGTCCA	AAGTGGCTGTCCCTG
GTTCTCCCTTTCTCT	TTGCCACAAGTCCAG	AGTGGCTGTCCCTGT
TTCTCCCTTTCTCTC	TGCCACAAGTCCAGC	GTGGCTGTCCCTGTG
TCTCCCTTTCTCTCT	GCCACAAGTCCAGCT	TGGCTGTCCCTGTGG
CTCCCTTTCTCTCTC	CCACAAGTCCAGCTG	GGCTGTCCCTGTGGC
TCCCTTTCTCTCTCC	CACAAGTCCAGCTGG	GCTGTCCCTGTGGCC
CCCTTTCTCTCTCCT	ACAAGTCCAGCTGGG	CTGTCCCTGTGGCCC
TGTCCCTGTGGCCCC	CCGTGGGTCATTACA	CTTTATCTTTCACCT
GTCCCTGTGGCCCCA	CGTGGGTCATTACAA	TTTATCTTTCACCTT
TCCCTGTGGCCCCAT	GTGGGTCATTACAAA	TTATCTTTCACCTTT
CCCTGTGGCCCCATC	TGGGTCATTACAAAA	TATCTTTCACCTTTC
CCTGTGGCCCCATCC	GGGTCATTACAAAAA	ATCTTTCACCTTTCT
CTGTGGCCCCATCCA	GGTCATTACAAAAAA	TCTTTCACCTTTCTA
TGTGGCCCCATCCAA	GTCATTACAAAAAAA	CTTTCACCTTTCTAG
GTGGCCCCATCCAAC	TCATTACAAAAAAAC	TTTCACCTTTCTAGG
TGGCCCCATCCAACC	CATTACAAAAAAACA	TTCACCTTTCTAGGG
GGCCCCATCCAACCA	ATTACAAAAAAACAC	TCACCTTTCTAGGGA
GCCCCATCCAACCAC	TTACAAAAAAACACG	CACCTTTCTAGGGAC
CCCCATCCAACCACT	TACAAAAAAACACGT	ACCTTTCTAGGGACA
CCCATCCAACCACTG	ACAAAAAAACACGTG	CCTTTCTAGGGACAT
CCATCCAACCACTGT	CAAAAAAACACGTGG	CTTTCTAGGGACATG
CATCCAACCACTGTA	AAAAAAACACGTGGA	TTTCTAGGGACATGA
ATCCAACCACTGTAC	AAAAAACACGTGGAG	TTCTAGGGACATGAA
TCCAACCACTGTACA	AAAAACACGTGGAGA	TCTAGGGACATGAAA
CCAACCACTGTACAC	AAAACACGTGGAGAT	CTAGGGACATGAAAT
CAACCACTGTACACA	AAACACGTGGAGATG	TAGGGACATGAAATT
AACCACTGTACACAC	AACACGTGGAGATGG	AGGGACATGAAATTT
ACCACTGTACACACC	ACACGTGGAGATGGA	GGGACATGAAATTTA
CCACTGTACACACCC	CACGTGGAGATGGAA	GGACATGAAATTTAC
CACTGTACACACCCG	ACGTGGAGATGGAAA	GACATGAAATTTACA
ACTGTACACACCCGC	CGTGGAGATGGAAAT	ACATGAAATTTACAA
CTGTACACACCCGCC	GTGGAGATGGAAATT	CATGAAATTTACAAA
TGTACACACCCGCCT	TGGAGATGGAAATTT	ATGAAATTTACAAAG
GTACACACCCGCCTG	GGAGATGGAAATTTT	TGAAATTTACAAAGG
TACACACCCGCCTGA	GAGATGGAAATTTTT	GAAATTTACAAAGGG
ACACACCCGCCTGAC	AGATGGAAATTTTTA	AAATTTACAAAGGGC
CACACCCGCCTGACA	GATGGAAATTTTTAC	AATTTACAAAGGGCC
ACACCCGCCTGACAC	ATGGAAATTTTTACC	ATTTACAAAGGGCCA
CACCCGCCTGACACC	TGGAAATTTTTACCT	TTTACAAAGGGCCAT
ACCCGCCTGACACCG	GGAAATTTTTACCTT	TTACAAAGGGCCATC
CCCGCCTGACACCGT	GAAATTTTTACCTTT	TACAAAGGGCCATCG
CCGCCTGACACCGTG	AAATTTTTACCTTTA	ACAAAGGGCCATCGT
CGCCTGACACCGTGG	AATTTTTACCTTTAT	CAAAGGGCCATCGTT
GCCTGACACCGTGGG	ATTTTTACCTTTATC	AAAGGGCCATCGTTC
CCTGACACCGTGGGT	TTTTTACCTTTATCT	AAGGGCCATCGTTCA
CTGACACCGTGGGTC	TTTTACCTTTATCTT	AGGGCCATCGTTCAT
TGACACCGTGGGTCA	TTTACCTTTATCTTT	GGGCCATCGTTCATC
GACACCGTGGGTCAT	TTACCTTTATCTTTC	GGCCATCGTTCATCC
ACACCGTGGGTCATT	TACCTTTATCTTTCA	GCCATCGTTCATCCA
CACCGTGGGTCATTA	ACCTTTATCTTTCAC	CCATCGTTCATCCAA
ACCGTGGGTCATTAC	CCTTTATCTTTCACC	CATCGTTCATCCAAG
ATCGTTCATCCAAGG	GCCAAAATCCTGAAC	CTCGTGTCCGGAGGC
TCGTTCATCCAAGGC	CCAAAATCCTGAACT	TCGTGTCCGGAGGCA
CGTTCATCCAAGGCT	CAAAATCCTGAACTT	CGTGTCCGGAGGCAT
GTTCATCCAAGGCTG	AAAATCCTGAACTTT	GTGTCCGGAGGCATG
TTCATCCAAGGCTGT	AAATCCTGAACTTTC	TGTCCGGAGGCATGG
TCATCCAAGGCTGTT	AATCCTGAACTTTCT	GTCCGGAGGCATGGG
CATCCAAGGCTGTTA	ATCCTGAACTTTCTC	TCCGGAGGCATGGGT
ATCCAAGGCTGTTAC	TCCTGAACTTTCTCC	CCGGAGGCATGGGTG
TCCAAGGCTGTTACC	CCTGAACTTTCTCCC	CGGAGGCATGGGTGA
CCAAGGCTGTTACCA	CTGAACTTTCTCCCT	GGAGGCATGGGTGAG
CAAGGCTGTTACCAT	TGAACTTTCTCCCTC	GAGGCATGGGTGAGC
AAGGCTGTTACCATT	GAACTTTCTCCCTCA	AGGCATGGGTGAGCA
AGGCTGTTACCATTT	AACTTTCTCCCTCAT	GGCATGGGTGAGCAT
GGCTGTTACCATTTT	ACTTTCTCCCTCATC	GCATGGGTGAGCATG
GCTGTTACCATTTTA	CTTTCTCCCTCATCG	CATGGGTGAGCATGG
CTGTTACCATTTTAA	TTTCTCCCTCATCGG	ATGGGTGAGCATGGC
TGTTACCATTTTAAC	TTCTCCCTCATCGGC	TGGGTGAGCATGGCA
GTTACCATTTTAACG	TCTCCCTCATCGGCC	GGGTGAGCATGGCAG
TTACCATTTTAACGC	CTCCCTCATCGGCCC	GGTGAGCATGGCAGC
TACCATTTTAACGCT	TCCCTCATCGGCCCG	GTGAGCATGGCAGCT
ACCATTTTAACGCTG	CCCTCATCGGCCCGG	TGAGCATGGCAGCTG
CCATTTTAACGCTGC	CCTCATCGGCCCGGC	GAGCATGGCAGCTGG
CATTTTAACGCTGCC	CTCATCGGCCCGGCG	AGCATGGCAGCTGGT
ATTTTAACGCTGCCT	TCATCGGCCCGGCGC	GCATGGCAGCTGGTT
TTTTAACGCTGCCTA	CATCGGCCCGGCGCT	CATGGCAGCTGGTTG
TTTAACGCTGCCTAA	ATCGGCCCGGCGCTG	ATGGCAGCTGGTTGC
TTAACGCTGCCTAAT	TCGGCCCGGCGCTGA	TGGCAGCTGGTTGCT
TAACGCTGCCTAATT	CGGCCCGGCGCTGAT	GGCAGCTGGTTGCTC
AACGCTGCCTAATTT	GGCCCGGCGCTGATT	GCAGCTGGTTGCTCC
ACGCTGCCTAATTTT	GCCCGGCGCTGATTC	CAGCTGGTTGCTCCA
CGCTGCCTAATTTTG	CCCGGCGCTGATTCC	AGCTGGTTGCTCCAT
GCTGCCTAATTTTGC	CCGGCGCTGATTCCT	GCTGGTTGCTCCATT
CTGCCTAATTTTGCC	CGGCGCTGATTCCTC	CTGGTTGCTCCATTT
TGCCTAATTTTGCCA	GGCGCTGATTCCTCG	TGGTTGCTCCATTTG
GCCTAATTTTGCCAA	GCGCTGATTCCTCGT	GGTTGCTCCATTTGA
CCTAATTTTGCCAAA	CGCTGATTCCTCGTG	GTTGCTCCATTTGAG
CTAATTTTGCCAAAA	GCTGATTCCTCGTGT	TTGCTCCATTTGAGA
TAATTTTGCCAAAAT	CTGATTCCTCGTGTC	TGCTCCATTTGAGAG
AATTTTGCCAAAATC	TGATTCCTCGTGTCC	GCTCCATTTGAGAGA
ATTTTGCCAAAATCC	GATTCCTCGTGTCCG	CTCCATTTGAGAGAC
TTTTGCCAAAATCCT	ATTCCTCGTGTCCGG	TCCATTTGAGAGACA
TTTGCCAAAATCCTG	TTCCTCGTGTCCGGA	CCATTTGAGAGACAC
TTGCCAAAATCCTGA	TCCTCGTGTCCGGAG	CATTTGAGAGACACG
TGCCAAAATCCTGAA	CCTCGTGTCCGGAGG	ATTTGAGAGACACGC
TTTGAGAGACACGCT	CTGCTGTGCTGCTCA	CTGACTAGATTATTA
TTGAGAGACACGCTG	TGCTGTGCTGCTCAA	TGACTAGATTATTAT
TGAGAGACACGCTGG	GCTGTGCTGCTCAAG	GACTAGATTATTATT
GAGAGACACGCTGGC	CTGTGCTGCTCAAGG	ACTAGATTATTATTT
AGAGACACGCTGGCG	TGTGCTGCTCAAGGC	CTAGATTATTATTTG
GAGACACGCTGGCGA	GTGCTGCTCAAGGCC	TAGATTATTATTTGG
AGACACGCTGGCGAC	TGCTGCTCAAGGCCA	AGATTATTATTTGGG
GACACGCTGGCGACA	GCTGCTCAAGGCCAC	GATTATTATTTGGGG
ACACGCTGGCGACAC	CTGCTCAAGGCCACA	ATTATTATTTGGGGG
CACGCTGGCGACACA	TGCTCAAGGCCACAG	TTATTATTTGGGGGA
ACGCTGGCGACACAC	GCTCAAGGCCACAGG	TATTATTTGGGGGAA
CGCTGGCGACACACT	CTCAAGGCCACAGGC	ATTATTTGGGGGAAC
GCTGGCGACACACTC	TCAAGGCCACAGGCA	TTATTTGGGGGAACT
CTGGCGACACACTCC	CAAGGCCACAGGCAC	TATTTGGGGGAACTG
TGGCGACACACTCCG	AAGGCCACAGGCACA	ATTTGGGGGAACTGG
GGCGACACACTCCGT	AGGCCACAGGCACAC	TTTGGGGGAACTGGA
GCGACACACTCCGTC	GGCCACAGGCACACA	TTGGGGGAACTGGAC
CGACACACTCCGTCC	GCCACAGGCACACAG	TGGGGGAACTGGACA
GACACACTCCGTCCA	CCACAGGCACACAGG	GGGGGAACTGGACAC
ACACACTCCGTCCAT	CACAGGCACACAGGT	GGGGAACTGGACACA
CACACTCCGTCCATC	ACAGGCACACAGGTC	GGGAACTGGACACAA
ACACTCCGTCCATCC	CAGGCACACAGGTCT	GGAACTGGACACAAT
CACTCCGTCCATCCG	AGGCACACAGGTCTC	GAACTGGACACAATA
ACTCCGTCCATCCGA	GGCACACAGGTCTCA	AACTGGACACAATAG
CTCCGTCCATCCGAC	GCACACAGGTCTCAT	ACTGGACACAATAGG
TCCGTCCATCCGACT	CACACAGGTCTCATT	CTGGACACAATAGGT
CCGTCCATCCGACTG	ACACAGGTCTCATTG	TGGACACAATAGGTC
CGTCCATCCGACTGC	CACAGGTCTCATTGC	GGACACAATAGGTCT
GTCCATCCGACTGCC	ACAGGTCTCATTGCT	GACACAATAGGTCTT
TCCATCCGACTGCCC	CAGGTCTCATTGCTT	ACACAATAGGTCTTT
CCATCCGACTGCCCC	AGGTCTCATTGCTTC	CACAATAGGTCTTTC
CATCCGACTGCCCCT	GGTCTCATTGCTTCT	ACAATAGGTCTTTCT
ATCCGACTGCCCCTG	GTCTCATTGCTTCTG	CAATAGGTCTTTCTC
TCCGACTGCCCCTGC	TCTCATTGCTTCTGA	AATAGGTCTTTCTCT
CCGACTGCCCCTGCT	CTCATTGCTTCTGAC	ATAGGTCTTTCTCTC
CGACTGCCCCTGCTG	TCATTGCTTCTGACT	TAGGTCTTTCTCTCA
GACTGCCCCTGCTGT	CATTGCTTCTGACTA	AGGTCTTTCTCTCAG
ACTGCCCCTGCTGTG	ATTGCTTCTGACTAG	GGTCTTTCTCTCAGT
CTGCCCCTGCTGTGC	TTGCTTCTGACTAGA	GTCTTTCTCTCAGTG
TGCCCCTGCTGTGCT	TGCTTCTGACTAGAT	TCTTTCTCTCAGTGA
GCCCCTGCTGTGCTG	GCTTCTGACTAGATT	CTTTCTCTCAGTGAA
CCCCTGCTGTGCTGC	CTTCTGACTAGATTA	TTTCTCTCAGTGAAG
CCCTGCTGTGCTGCT	TTCTGACTAGATTAT	TTCTCTCAGTGAAGG
CCTGCTGTGCTGCTC	TCTGACTAGATTATT	TCTCTCAGTGAAGGT
CTCTCAGTGAAGGTG
TCTCAGTGAAGGTGG
CTCAGTGAAGGTGGG
TCAGTGAAGGTGGGG
CAGTGAAGGTGGGGA
AGTGAAGGTGGGGAG
GTGAAGGTGGGGAGA
TGAAGGTGGGGAGAA
GAAGGTGGGGAGAAG
AAGGTGGGGAGAAGC
AGGTGGGGAGAAGCT
GGTGGGGAGAAGCTG
GTGGGGAGAAGCTGA
TGGGGAGAAGCTGAA
GGGGAGAAGCTGAAC
GGGAGAAGCTGAACC
GGAGAAGCTGAACCG
GAGAAGCTGAACCGG
AGAAGCTGAACCGGC

EXAMPLE 9

Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR.AS (antisense: 5′-ATCTCTCCGCTTCCTTTC-3′; (<400>10); ref 13) and IGFR.S (sense control: 5′-GAAAGGAAGCGGAGAGAT-3′; (<400>11); ref 13) IGF-I binding to the cell monolayers was then measured as ¹²⁵I-IGF-I.

EXAMPLE 10

The results of this experiment are shown in FIGS. 7 and 8.

HaCaT cells were initially plated in DMEM with 10% v/v serum, then AS oligo experiments were performed in complete “Keratinocyte-SFM” (Gibco) to exclude the influence of exogenous IGFBPs. Oligos were synthesised as phosphorothioate (nuclease-resistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, 5′-GCGCCCGCTGCATGACGCCTGCAAC-3′ (IGFBP-3 start codon); controls: AS2NS, 5′-CGGAGATGCCGCATGCCAGCGCAGG-3′; AS4,

5′-AGGCGGCTGACGGCACTA-3′; AS4NS, 5′-GACAGCGTCGGAGCGATC-3′; IGFRAS, 5′-ATCTCTCCGCTTCCTTTC-3′;

IGFRS, 5′-GAAAGGAAGCGGAGAGAT-3′. Oligos to IGFBP-3 were based on the published sequence of Spratt et al [12]. AS oligos were added to HaCaT monolayers in 0.5 ml medium in 24-well plates at the concentrations and addition frequencies indicated. IGFBP-3 measured in cell-conditioned medium using a dot-blot assay, adapted from the Western ligand blot method of Hossenlopp et al [11], in which 100 μl of conditioned medium was applied to nitrocellulose filters with a vacuum dot-blot apparatus. After drying the membranes at 37° C., relative amounts of IGFBP are determined by ¹²⁵I-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in FIG. 7, where duplicate wells were measured as shown) were analysed and corrected for changes in cell number per well. Relative cell number per well was determined using an amido black dye method, developed specifically for cultured monolayers of HaCaT cells [14]. Cell numbers differed by less than 10% after treatment. For oligos to the IGF receptor, receptor quantitation in intact HaCaT monolayers was by overnight incubation with ¹²⁵I-IGF-I (30,000 cpm/well) at 4° C.

EXAMPLE 11

Experiments involving ribozymes are generally conducted as described in Internaitonal Patent Application No. WO 89/05852 and in Haselhoff and Gerlach [8]. Ribozymes are constructed with a hybridising region which is complementary in nucleotide sequence to at least part of a target RNA which, in this case, encodes IGFBP-2. Activity of ribozymes is measurable on, for example, Northern blots or using animal models such as in the nude mouse model (15; 16) or the “flaky skin” mouse model (17; 18).

EXAMPLE 12

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 13

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 14

The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 15

Twenty-one antisense oligonucleotides targeted to mRNA sequences enducing the IGF-1 receptor, and four random oligonucleotides were synthesized. The antisense oligonucleotides are C5-propynyl-dU, dC 15 mer phosphorothioate oligodeoxyribonucleotides. In these oligonucleotides, a phosphorothioate backbone replaces the phosphodiester backbone of naturally occurring DNA. The positions of the 21 sequence specific antisense oligonucleotides relative to the IGF-1 receptor mRNA structure are shown in FIG. 9.

EXAMPLE 16

Experiments were performed to determine the uptake of the antisense oligonucleotides of Example 15 into keratinocytes. Cells of the differentiated human keratinocyte cell line, HaCaT, were incubated for 24 hours in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% (w/v) fetal calf serum (FCS) containing fluorescently labelled oligonucleotide (R451, a randomized sequence oligonucleotide, 30 nM) and cytofectin GSV (2 μg/ml, Glen Research, 44901 Falcon Place, Sterling, Va. 20166, Cat. No. 70-3815-78). Cells were then transferred to oligonucleotide-free medium and fluorescence microcopy and phase contrast images of the cells were obtained. FIG. 10 shows fluorescence microscopy (Panel A) and phase contrast (Panel B) images of uptake of fluorescently labelled oligonucleotide in the majority of cells in a HaCaT monolayer. The degree of uptake obtained with the cationic lipid cytofectin was far greater than the uptake obtained with the next best lipid tried, Tfx-50.

A further experiment was performed to assess the uptake and toxicity associated with the use of cytofectin GSV over five days. Confluent HaCaT keratinocytes were incubated in DMEM containing fluorescently labelled oligonucleotide R451 (30 nM or 100 nM) plus cytofectin GSV (2 μg/ml or 5 μg/ml) over 120 hours, viewed by fluorescence microscopy, tryptan blue stained, and counted. The graphs in FIG. 11 depict uptake (Panel A) and toxicity (Panel B). The proportion of cells containing oligonucleotide remained high over the 120 hour period. The combination of 30 nM oligonucleotide and 2 μg/ml GSV provided optimal uptake and minimal toxicity.

EXAMPLE 17

The twenty-one oligonucleotides of Example 15 were then screened for their ability to inhibit IGF-I receptor mRNA levels in HaCaT cells, in accordance with the teachings herein. HaCaT cells were grown to 90% confluence in DMEM supplemented with 10% (v/v) FCS. Antisense oligonucleotides (30 nM) were completed with cytofectin GSV (2 μg/ml) and added to the cells in the presence of serum. HaCaT keratinocytes were treated with the oligonucleotide/GSV complexes or randomized sequence oligonucleotides (R451, R766), liposome alone (GSV), or were left untreated (UT). Duplicate treatments were performed. Repeat additions of the oligonucleotides/GSV complex were performed at 24, 48 and 76 hours following the first addition. Total RNA was isolated as per the RNAzolB protocol (Biotecx Laboratories, Inc. 6023 South Loop East, Houston, Tex. 77033) 96 hours following the first addition.

IGF-I receptor mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA levels were simultaneously determined by a ribonuclease (RNase) protection assay. The RNase Protection Assay kit, in vitro transcription kit, and IGF-I receptor and GAPDH DNA templates were obtained from Ambion, Inc. (2130 Woodward St., Houston, Tex. 78744). The amount of IGF-I receptor mRNA in any given sample was expressed as the amount of IGF-I receptor mRNA relative to the amount of GAPDH mRNA. Each oligonucleotide was tested in at least two separate experiments.

FIG. 12 depicts representative results of the screening process. Panel A shows an electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase protection. Molecular weight markers are shown on the right hand side. The full-length probe is shown on the left hand side; G-probe indicates the IGF-I receptor probe. GAPDH protected fragments (G) are seen at 316 bases and IGF-I protected fragments (I) are seen at 276 bases. Exhibit E, Panel B provides a graph indicating the relative level of IGF-I receptor mRNA following each treatment.

The results obtaining from the above screening assays are summarized in FIG. 13. The graph depicts the relative level of IGF-I receptor mRNA after treatment with oligonucleotides complementary to the human IGF-I receptor mRNA (26-86), four randomized sequence oligonucleotides (R1, R4, R7, R9), liposome alone (GSV), or no treatment (UT). Asterisks indicate a significant different in relative IGF-I receptor mRNA as compared to GSV treated cells (n=4-10, p<0.05).

As demonstrated in FIG. 13, treatment with eighteen of the twenty-one oligonucleotides resulted in a significant different in levels of IGF-I receptor mRNA relative to GSV treated cells. Three of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to less than 35% of GSV-treated cells. These antisense oligonucleotides have the following sequences, presented in the 5′ to 3′ direction:

#27 UCCGGAGCCAGACUU
#64 CACAGUUGCUGCAAG
#78 UCUCCGCUUCCUUUC

As further demonstrated in FIG. 13, six of the antisense oligonucleotides tested in the screening assay reduce IGF-I receptor mRNA to between 35 and 50% of GSV-treated cells. These antisense oligonucleotides have the following sequences, presented in the 5′ to 3′ direction:

#28 AGCCCCCACAGCGAG
#32 GCCUUGGAGAUGAGC
#40 UAACAGAGGUCAGCA
#42 GGAUCAGGGACCAGU
#46 CGGCAAGCUACACAG
#50 GGCAGGCAGGCACAC

EXAMPLE 19

Another experiment was performed demonstrating that antisense oligonucleotides targeted to genetic sequences encoding the IGF0I receptor and that reduce IGF-I receptor mRNA levels also inhibit the IGF-I receptor level on the surface of the treated cultured keratinocytes. HaCaT cells were grown to confluence in 24-well plates in DMEM containing 10% (v/v) FCS. Oligodeoxynucleotide and cytofectin GSV were mixed together in serum-free DMEM, and incubated at room temperature for 10 minutes before being diluted ten-fold in medium and placed on the cells. Cells were incubated for 72 hours with 30 nM random sequence or antisense oligonucleotide and 2 μm/ml GSV, or with GSV alone in DMEM containing 10% (v/v) FCS with solutions replaced every 24 hours. This was followed by incubation with oligonucleotide/GSV in serum-free DMEM for 48 hours. All incubations were performed at 37° C. Cells were washed twice with 1 ml cold PBS. Serum-free DMEM containing 10⁻¹⁰M ¹²⁵I-IGF-I was added with or without the IGF-I analogue, des (1-3) IGF-I, at 10⁻¹¹M to 10⁻⁷M. Cells were incubated at 4° C. for 17 hours with gentle shaking, then washed three times with 1 ml cold PBS and lysed in 250 μl 0.5M NaOH/0.1% (v/v) Triton X-100 at room temperature for 4 hours. Specific binding of the solubilised cell extract was measured using a gamma counter. As shown in FIG. 14, treatment of HaCaT keratinocytes with oligonucleotide reduced cell surface IGF-I receptor levels to 30% of levels in untreated keratinocytes or in keratinocytes treated with liposome alone or a random oligonucleotide, R766. As shown in FIG. 15, treatment with oligonucleotide #27 also significantly reduced cell surface IGF-I receptor levels relative to untreated keratinocytes or treatment with liposome alone or random nucleotide R451. As demonstrated in Example 17, oligonucleotides #64 and #27 reduce IGF-I receptor mRNA levels in cultured keratinocytes to less than 35% of GSV-treated cells. Accordingly, the ability of an oligonucleotide to reduce IGF-I receptor mRNA levels in correlated with its ability to reduce cell surface IGF-I receptor levels.

The forgoing Examples demonstrate that antisense oligonucleotides targeted to the IGF-I receptor can be delivered to human keratinocytes in vitro, can inhibit IGF-I receptor mRNA levels in human keratinocytes in vitro, and that inhibition of mRNA levels is correlated with reduction of cell surface IGF-I receptor levels.

EXAMPLE 19

Further experiments demonstrated the efficacy of antisense oligonucleotides targeted to the IGF-I receptor in an in vivo model of psoriasis. An animal model of psoriasis is the human psoriatic skin xenograft model. The skin used in this model contains the true disease state. In this model, reduction in epidermal thickness of psoriatic grafts in response to treatment is positively correlated with efficacy of treatment. Both normal and psoriatic human skin were grated into a thymic (nude) mice in accordance with a thymic (nude) mice in accordance with the methods of Baker et al (1992) Brit. J. Dermatol. 126:105 and Nanney et al (1992) J. Invest. Dermatol, 92:296. Successful grafting was achieved, as demonstrated in FIG. 16, which shows hemotoxylin and eosin (H&E) stained sections of a 49-day old psoriatic human skin graft (Panel B) compared to the histology of the skin graft prior to grafting (Panel A). The histological features of psoriasis present in the pregraft section (e.g., parakeratosis, acanthosis and pronounced rete ridges) are present in the grafts more than seven weeks post grafting.

Using the model, oligonucleotide uptake was measured in epidermal keratinocytes in vivo after intradermal injection. Fluorescently labelled oligonucleotide (R451, 50 μl, 10 μM injection) was intradermally injected into psoriatic and normal skin grafts on a thymic mice. Live confocal microscopy and fluorescence microscopy of fixed sections was then employed.

Using both techniques, oligonucleotide was found to localize in the nucleus of over 90% of basal keratinocytes. FIG. 17 shows the nuclear localization of oligonucleotide in psoriatic skin cells using conventional fluorescence microscopy of a graft that was removed and sectioned after 24 hours.

After establishing oligonucleotide uptake in the in vivo model, a small number of pilots experiments were performed to determine a schedule for treatment of grated mice with antisense oligonucleotides targeted to genetic sequences encoding the IGF-I receptor. The treatment schedule was finalized as follows:

		Volume
Graft		of	ODN	Duration of
Number	Treatment	Injection	Concentration	Treatment
1-3	Vehicle (PBS)	50 μl	—	20 days
4-6	RandomODN#R451	50 μl	10 μM	20 days
7-9	ODN#27	50 μl	10 μM	20 days
10-12	ODN#74	50 μl	10 μM	20 days
13-15	ODN#50	50 μl	10 μM	20 days

As determined above, oligonucleotide #27 (ODN #27) reduced IGF-I receptor mRNA in vitro to less than 35% of GSV-treated cells. Oligonucleotide #50 (ODN#50) reduced IGF-I receptor mRNA in vitro to between 35 and 50% of GSV-treated cells. Oligonucleotide #74 (ODN #74) was not inhibitory to IGF-I receptor mRNA in vitro. In the in vivo model, each mouse received two grafts. Random oligonucleotide or vehicle was injected intradermally in one graft and acted as a control. The second graft was injected with the targeted oligonucleotide. Each graft received an injection every second day for the duration of the treatment.

Histology of representative grafts from each treatment type are shown in FIGS. 18(a)-(d) and 19(a)-(d). Each sheet shows three images of H&E stained sections: the pregraft histology, the control treated graft, and the targeted oligonucleotide treated graft. FIGS. 18(a)-(d) are shown at 100× magnification; FIGS. 19(a)-(d) are shown at 400× magnification. The total cross sectional area of epidermis of each graft was assessed using MCID analysis software. The pooled results from all of the treated grafts are shown in FIG. 20.

As shown in FIGS. 18(a)-(d) and 19(a)-(d), the vehicle-treated (control) grafts were marginally thinner than the pregraft sections. The degree of regression in these experiments (ie., less than 10%) is not significant. A similar amount of marginal thinning of epidermis compared to pregraft also occurred in pilot experiments in which psoriatic grafts were not injected, and thsu it is unlikely that the vehicle itself has any effect. Histological features of psoriasis present in skin samples prior to grafting (clubbing of rete ridges, parakeratosis, acanthosis) were present in these grafts.

The random oliognucleotide treated grafts varied in epidermal thickness after 20 days of treatment. Grafts were either a similar thickness to the pregraft histology, or marginally thinner. Random oligonucleotide treated grafts were in each case significantly thicker than their targeted oligonucleotide treated pairs.

As shown in FIG. 20, the targeted oligonucleotide treated grafts were significantly thinner than the pregraft sections and showed less parakeratosis and clubbing of rete ridges. Antisense oligonucleotides which were effective at reducing IGF-I receptor mRNA levels in vitro (#27 and #50) produced greatere epidermal thinning than an oligonucleotide which was not inhibitory to IGF-I receptor mRNA in vitro (#74). Accordingly, there is a direct correlation between the ability of an oligonucleotide targeted to the IGF-I receptor to inhibit IGF-I receptor mRNA levels in vitro and the efficacy of the oligonucleotide as an anti-psoriasis agent in an in vivo model.

EXAMPLE 20

Another experiment demonstrated that treatment of psoriatic grafts with an oligonucleotide targeted to a genetic sequence encoding the IGF-I receptor results in inhibition of proliferation. Pregrafts from psoriatic patients, control grafts treated with R4541, and grafts treated with oligonucleotide #27 were obtained as described in Example 19. An antibody to the cell cycle-specific nuclear antigen Ki67 was used to immunohistochemically detect actively dividing cells and tereby assess proliferation. The αKi67 antibody (DAKO, Glostrup, Denmark) recognizes the Ki67 antigen transiently expressed in nuclei of proliferating cells during late G₁, S, M and G₂ phases of the cycle and thsu provides a marker for proliferation. Pregraft and graft sections were immunohistochemically processed by standard methods using αKi67 (according to the manufacturer's instructions), peroxidase-conjugated anti-rabbit second stage antibody, and a chromogenic peroxidase substrate.

The results of this experiment are presented in FIG. 21 as immunohistochemical sections at 100× magnification. The top panel of FIG. 21 depicts a pregraft section obtained from a psoriatic patient. The epidermis is thicker than normal and nucleic are evident in the stratum corneum. Ki67 positive cells, appearing as brown dots, are evidence in the basal and suprabasal layers, and indicate actively proliferating cells. The control (R450-treated) graft in the bottom panel of FIG. 21 also exhibits evidence of proliferation, including parakeratosis and Ki67-positive cells appearing as brown-staining nuclei. The center panel of FIG. 21 exhibits the oligonucleotide #27-treated graft. This graft exhibits significantly reduced proliferation as evidenced by normal (thin) epidermis, lack of invaginations, and substantial loss of Ki67-positive cells.

These results indicate that treatment of human psoriatic grafts with an oligonucleotide targeted to mRNA encoding the IGF-I receptor results in inhibition of epidermal proliferation.

EXAMPLE 21

Topical formulations of complexes of oligonucleotides with cytofectin GSV in aqueous or methylcellulose gel formulations were prepared and assessed for uptake of the oligonucleotide by keratinocytes in vivo. The topical formulations contained oligonucleotides complexed with cytofectin GSV in an aqueous solution or methylcellulose carrier, as taught herein. With both aqueous and methylcellulose gel formulations, locatlization of oligonucleotide R451 to nuclei and cytoplasm of keratinocytes in normal human skin grafts on nuce mice was observed. FIG. 22 shows an image from confocal microscopy demonstrating oligonucleotide locatlization in the nuclei and cytoplasm of keratinocytes in normal human skin grafts after topical application of fluroescently labeled oligonucleotide (10 μM R451) complexed with cytofectin GSV (10 μg/ml). FIG. 23 shows an image from confocal microscopy demonstrating that topical application of the same oligonucleotide/GSV concentrations in a 3% (w/v) methylcellulose gel produced similar uptake in the target keratinocyte population. Using an aqueous formulation of oligonucleotide/GSV complexes, penetration of oligonucleotide into the viable epidermis was observed, whereas application of formulations of oliognucleotide complexed with other cationic lipids resulted in localization of oligonucleotide in the stratum corneum.

EXAMPLE 22

Thirteen antisense oligonucleotides targeted to IGFBP-3 were synthesized. The antisense oligonucleotides are C5-propynyl-dU, Dc15 mer phosphorothioate oligodeoxyribonucleotides. FIG. 24 attached hereto is a schematic diagram indicating the position of the thirteen oligonucleotides relative to the IGFBP-3 mRNA structure.

These oligonucleotides were screened for their ability to inhibit IGFBP-3 mRNA levels of HaCaT cells in accordance with the teachings herein. HaCaT cells were grown to 90% confluence in DMEM supplemented with 10% (v/v) FCS, then placed in complete keratinocyte serum free medium (KSFM, Gibco), which has a defined amount of EGF, for 24 hours. Oligonucleotides (30 nM or 100 nM) were complexed with GSV cytofectin (2 μg/ml) and added to cells in complete KSFM to allow oligonucleotides to enter the nucleus before removal of EGF. Repeat additions were performed at three hours (in serum free DMEM, which releases the EGF inhibition of IGFBP-3 mRNA) and again after another 24 hours. HaCaT cells were also treated with randomized sequence oligonucleotides (R121, R451, R766 and R961), liposome alone (GSV) or were left untreated (UT). Total RNA was isolated as described in Example 17, 24 hours after the last treatment. Total RNA (15 μg) was analyzed by Northern analysis and phosphoroimager quantitation for IGFBP-3 and GADPH mRNA. IGFBP-3 mRNA is expressed as the amount of IGFBP-3 mRNA relative to the amount of GAPDH mRNA.

FIGS. 25(a)-(d) provide graphs which depict results in this screening process. In these graphs, R1 and R12 refer to R121; R4, R4(0) and R45 rfer to R451; R7, R7(0) and R76 refer to R766; and R9 and R96 refer to R961. The values were standardized to GSV-treated cells, and data was pooled and statistically analyzed by ANOVA followed by Domet's test to compare each treatment to GSV-treated cells. The pooled data are presented as a bar graph in FIG. 26. As demonstrated, at a concentration of 30 nM, treatment of HaCaT cells with 8 of the 12 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells. At a concentration of 100 nM, treatment with 9 fo the 13 targeted oligonucleotides tested resulted in a statistically significant reduction in levels of IGFBP-3 mRNA relative to GSV-treated cells.

These experiments demonstrate that antisense oligonucleotides targeted to genetic sequences encoding IGFBP-3 can inhibit IGFBP-3 mRNA levels in human keratinocytes in vitro.

EXAMPLE 23

IGF-I receptor is a potent mitotic signalling molecule for keratinocytes and the human receptor elicits separate intracellular signals that prevent apoptosis (19). It is proposed in accordance with the present invention that inactivation of IGF-I receptors in epidermal keratinocytes will achieve three important outcomes in subsequent UV treatment of lesions:

• • (i) Acute epidermal hyperplasia following UV has been suggested to increase the risk of keratinocyte carcinogenic transformation (22). By reducing IGF-I receptor expression in the epidermis, the incidence of epidermal hyperplasia following UV exposure is likely to be reduced leading to an overall acceleration in normalization of the lesion and reduced carcinogenic risk.
  • ii) Inhibition of anti-apoptotic action of IGF-I receptor will enhance the reversal of epidermal thickening and accelerate normalization of differentiation. Topical or injected IGF-I receptor antisense as adjunctive treatment will increase apoptosis in the epidermal layer thereby enhancing the reduction in acanthosis observed in UV treatments.
  • iii) Survival of keratinocytes, ie. those which evade apoptosis is likely to occur when cells have damaged DNA. Such mutations may be in the tumor suppressor region. Consequently, the use of antisense therapy will result in less frequent selection of mutated keratinocytes and therefore reduced incidence of basal cell carcinomas and squamous.

Accordingly, antisense therapy, especially against IGF-I-receptor is useful in combination with UV therapy in the treatment of epidermal hyperplasia.

EXAMPLE 24

HaCaT cells were treated with antisense oligonucleotides directed to IGF-I receptor mRNA. Levels of IGF-I receptor mRNA were then monitored. In essence, confluent HaCaT cells were treated every 24 hours for four days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, R451 and R766). FIG. 27(a) is a photographic representation showing representative RNase protection assay gel showing IGF-I receptor (IGFR) and GAPDH mRNA in untreated or treated HaCaT cells. FIG. 27(b) is a densitometric quantification of IGF-I receptor mRNA in a HaCaT cells following treatment with IGF-I receptor specific oligonucleotides (solid black) random sequence oligonucleotides (horizontal striped bar) or GSV alone (shaded bar) compared to untreated cells (UT, vertical striped bar).

EXAMPLE 25

In this example, reduction in total cellular IGF-I receptor protein was monitored following antisense oligonucleotide treatment. Confluence HaCaT cells were treated with 24 hours for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific AONS (#27, #50 and #64) or the random sequence oligonucleotide, R451. Total cellular protein was isolated and analysed for IGF-I receptor by SDS PAGE followed by western blotting with antibody specific for the human IGF-I receptor. FIG. 28(a) shows duplicate treated cellular extracts following the IGF-I receptor at the predicted size of 110 kD. FIG. 28(b) is a densitometric quantification of IGF-I receptor protein.

EXAMPLE 26

The reduction in IGF-I receptor numbers was determined on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were tranfected with IGF-I receptor specific AONs #27, #50, #64, a random sequence oligonucleotides (R451) or following treatment with GSV a lipid alone every 24 hours for 4 days. Competition binding assays using ¹²⁵I-IGF-I and the receptor-specific analogue, des(1-3)IGF-I were performed. Results are shown in FIG. 29.

EXAMPLE 27

In this example, the apoptotic protecting effects of IGF-I receptor on keratinocyte cells was tested by following the reduction in keratino cell numbers following antisense oligonucleotide treatment. HaCaT cells, initially at 40% confluence, were transfected with the IGF-I receptor specific AON #64, control sequences R451 and 6414 or treated with GSV a lipid alone every 24 hours for 2 days. The cell number was measured in culture wells using a dye binding assay. The results are presented in FIG. 30. The results clearly confirm that the IGF-I receptor exhibits an anti-apoptotic effect. By reducing IGF-I receptor levels using antisense oligonucleotide treatment, the anti-apoptotic effect is interrupted and apoptosis results in the reduction in keratinocyte cell number. Results are shown in FIG. 30.

EXAMPLE 28

This example shows a reversal of epidermal hyperplasia in psoriatic human skin grafts on nude mice following intradermal injection with antisense oligonucleotides. Grafted psoriasis lesions were injected with IGF-I receptor specific AONs, a random sequence oligonucleotide in PBS, or with PBS alone, every 2 days for 20 days, then analysed histologically. The results are shown in FIG. 31. In FIG. 31(a), donor A graft treated with AON #50 showing epidermal thinning compared with the pregraft and control (PBS) treated graft and donor graft treated with AON #27 showing epidermal thinning compared with pregraft and control (R451) treated graft. In FIG. 31(b), the mean epidermal cross-sectional area over the full width of grafts is shown as determined by digital image analysis. The results show that epidermal hyperplasia is reversed following the intradermal injection of antisense oligonucleotides.

EXAMPLE 29

FIG. 32 shows the reversal of epidermal hyperplasia correlating with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides. FIG. 32(a) shows a psoriasis lesion prior to grafting and after grafting and treatment with IGF-I receptor specific oligonucleotide #27 (AON #27) or random sequence (R451) immunostained with antibodies to Ki67 to identify proliferating cells. Proliferating cells are indicated by a dark brown nucleus (arrows). FIG. 32(b) shows the same lesion prior to grafting and after oligonucleotide treatment as in FIG. 32(a) but subjected to in situ hybridisation with ³⁵S-labelled cRNA probe complementary to the human IGF-I receptor mRNA. The presence of IGF-I receptor mRNA is indicated by silver grains which are almost eliminated in the epidermis of the lesion treated with IGF-I receptor specific oligonucleotide # 27 (AON #27). This experiment shows that reversal of epidermal hyperplasia correlates with reduced IGF-I receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides.

EXAMPLE 30

FIG. 33 treatment with oligonucleotides. HaCaT cell monolayers were grown to 90% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for two days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Total RNA was isolated and analysed for IGF-I receptor and GAPDH mRNA using a commercially available ribonuclease protection assay kit. The results show a reduction in IGF-I receptor mRNA in the HaCaT keratinocyte cells.

EXAMPLE 31

FIG. 34 treatment with oligonucleotides. HaCaT cell monolayers were grown to 90% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 4 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide. Cells were lysed in a buffer containing 50 mM HEPES, 150 mM NaCl, 10% v/v glycerol, 1 v/v Trison X-100 and 100 μg/ml aprotinin on ice for 30 minutes, then 30 μg of lysate was loaded onto a denaturing 7% w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane. Membranes were then incubated with anti-IGF-I receptor antibodies C20 (available from Santa Cruz Biotechnology Inc., Santa Cruz, Calif.) for 1 hour at room temperature and developed using the Vistra ECF western blotting kit (Amersham). The results shown in FIG. 34 confirm that IGF-I receptor protein is reduced in HaCaT keratinocytes following treatment with oligonucleotides.

EXAMPLE 32

This example shows a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. The results are shown in FIG. 35. HaCaT cell monolayers were grown at 40% confluence in DMEM containing 10% fetal calf serum treated every 24 hours for 3 days with 2 μg/ml GSV lipid alone (GSV) or complexed with 15 nM oligonucleotide. Cell numbers were then measured every 24 hours using the amido black dye binding assay [32]. Results show that HaCaT keratino cells decrease in number following treatment with oligonucleotides due to a reduction in the anti-apoptotic effect of the IGF-I receptor.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

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Claims

1-44. (canceled)

45. A method for ameliorating a proliferative or inflammatory skin disorder in a mammal, the method comprising contacting a cell in proliferating or inflamed skin with an effective amount of a nucleic acid molecule, or a chemical modification thereof, wherein the modification produces a modified nucleic acid molecule that has the same length and nucleotide sequence as the nucleic acid molecule prior to modification, and wherein the nucleic acid molecule or modified nucleic acid molecule inhibits growth-factor-mediated cell proliferation or inflammation.

46. The method of claim 45 wherein the proliferative or inflammatory skin disorder is mediated by a growth factor, wherein the growth factor is selected from the group consisting of insulin-like growth factor I (IGF), keratinocyte growth factor (KGF), transforming growth factor (TGF), tumor necrosis factor (TNF), interleukin (IL), basic fibroblast growth factor (bFGF), and a combination thereof.

47. The method of claim 45, wherein the proliferative or inflammatory skin disorder is selected from the group consisting of psoriasis, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths, and a cancer of the skin.

48. The method of claim 45, wherein the nucleic acid molecule or modified nucleic acid molecule reduces the level of an IGF, IGF receptor, or IGF-binding protein in the mammal.

49. The method of claim 45, wherein the nucleic acid molecule or modified nucleic acid molecule is an antisense molecule that reduces the expression of a gene encoding IGF, IGF receptor, or IGF-binding protein.

50. A method for ameliorating a disease in a mammal, the method comprising contacting a cell in the diseased tissue with an effective amount of a nucleic acid molecule, or a chemical modification thereof, wherein the modification produces a modified nucleic acid molecule that has the same length and nucleotide sequence as the nucleic acid molecule prior to modification, and wherein the nucleic acid molecule or modified nucleic acid molecule is capable of inhibiting growth-factor-mediated cell proliferation or inflammation.

51. The method of claim 50, wherein the disease is selected from the group consisting of a hyperneovascular condition, neovascular condition of the retina, neovascular condition of the retina, neovascular condition of the skin, growth-factor-mediated disease, a sclerotic disease, kidney disease, hyper-proliferation of vascular endothelial cells, and hyperplasia.

52. The method of claim 50, wherein the nucleic acid molecule or modified nucleic acid molecule reduces the level of an IGF, IGF receptor, or IGF-binding protein in the mammal.

53. The method of claim 50, wherein the nucleic acid molecule or modified nucleic acid molecule is an antisense molecule that reduces the expression of a gene encoding IGF, IGF receptor, or IGF-binding protein.