CA2376284A1 - A method for the prophylaxis and/or treatment of medical disorders - Google Patents

A method for the prophylaxis and/or treatment of medical disorders Download PDF

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CA2376284A1
CA2376284A1 CA002376284A CA2376284A CA2376284A1 CA 2376284 A1 CA2376284 A1 CA 2376284A1 CA 002376284 A CA002376284 A CA 002376284A CA 2376284 A CA2376284 A CA 2376284A CA 2376284 A1 CA2376284 A1 CA 2376284A1
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nucleic acid
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Christopher John Wraight
George Arthur Werther
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Murdoch Childrens Research Institute
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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.</SDO AB>

Description

A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF
MEDICAL DISORDERS
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 Garners 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
Figure 1 is a representation of the nucleotide sequence of IGFBP-2.
LOCUS HSIGFBP2 1433 by RNA PRI 31-JAN-1990 S DEFINITIONHuman mRNA for insulin-like growth factor binding protein (IGFBP-2) KEYWORDS insulin-like growth factor binding protein.

SOURCE human ORGANISM Homo Sapiens IO 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 1S 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 ZO source 1. .1433 /organism="Homo Sapiens"

/dev stage="fetal"

/tissue type="liver"

misc eature 1416. .1420 f _ /note="pot. polyadenylation signal"
ZS

polyA site 1433 /note="polyadenylation site"

CDS 118. .1104 /note="precursor polypeptide; (AA -39 to 289); NCBI
gi:

3O 33010. "

/codon start=1 /translation="MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARAEVLFR

CPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGEACG

VYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAEYGASPEQVADNGDDHSEGG

KKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHLYSLHIPNCDKHGLYNLKQCK

MSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEACGVHTQRMQ"

(<400>21) CDS 118. .234 4O /note="signal peptide; (AA -39 to -1); NCBI gi: 33011."

/codon start=1 /translation="MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARA"

(<400>22) CDS 235. .1101 4S /note="mature IGFBP-2; (AA 1 to 289); NCBI gi: 33012."

/codon start=1 /translation="EVLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVR

EPGCGCCSVCARLEGEACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAE

YGASPEQVADNGDDHSEGGLVENHVDSTMNMLGGGGSAGRKPLKSGMKELAVFREKVT

SO EQHRQMGKGGKHHLGLEEPKKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHLY

SLHIPNCDKHGLYNLKQCKMSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNE

QQEACGVHTQRMQ" (<400>23) BASE COUNT 239 a 466 c 501 g 227 t ORIGIN
SS

_ '7 _ HSIGFBP2 Length: 1433 May 11, 1994 10:06 Type: N Check: 6232 ..
Figure 2 is a representation of the nucleotide sequence of IGFBP-3.
S
LOCUS HUMGFIBPA 2474 by ss-mRNA PRI 15-JUN-1990 DEFINITION Human growth hormone-dependent insulin-like growth factor-binding protein mRNA, complete cds.

1~ 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.
1S 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 COMMENT NCBI gi: 183115 FEATURES Location/Qualifiers mRNA <1. .2474 ZS /note="GFIBP mRNA"
CDS 110. .985 /gene="IGFBP1"
/note="insulin-like growth factor-binding protein; NCBI
gi: 183116."
/codon start=1 /translation="MQRARPTLWAAALTLLVLLRGPPVARAGASSGGLGPWRCEPCD
ARALAQCAPPPAVCAELVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPSPDEAR
PLQALLDGRGLCVNASAVSRLRAYLLPAPPAPGNASESEEDRSAGSVESPSVSSTHRV
SDPKFHPLHSKIIIIKKGHAKDSQRYKVDYESQSTDTQNFSSESKRETEYGPCRREME

TKGKEDVHCYSMQSK" (<400>24>) source 1. .2474 /organism="Homo sapiens"
BASE COUNT 597 a 646 c 651 g 580 t HUMGFIBPA Length: 2474 May 11, 1994 10:00 Type: N Check: 9946 ..
4S Figure 3 is a representation of the nucleotide sequence of IGF-1-receptor.
LOCUS HSIGFIRR 4989 by RNA PRI 28-MAR-1991 DEFINITION Human mRNA for insulin-like growth factor I receptor $0 KEYWORDS glycoprotein; insulin receptor;
insulin-like growth factor I receptor; membrane glycoprotein;
receptor; tyrosine kinase.
SOURCE human _g_ ORGANISM
Homo sapiens Eukaryota;
Animalia;
Metazoa;
Chordata;
Vertebrata;
Mammalia;

Theria; Eutheria; Primates; Haplorhini; Catarrhini;
Hominidae.

REFERENCE1 (bases 1 to 4989) AUTHORSUllrich,A., ., Gray, A., Tam,A.W., Yang-Feng,T., Tsubokawa,M

Collins,C., Henzel,W., Bon,T.L., Kathuria,S., Chen,E., Jakobs,S., Francke,U., Ramachandran,J.
and Fujita-Yamaguchi,Y.

TITLE Insulin-like growth factor I receptor primarycomparison structure:

with insulin receptor suggests structural dererminants that define 1~ functional specificity JOURNALEMBO 5, 2503-2512 (1986) J.

STANDARDfull automatic gi:

FEATURES Location/Qualifiers IS source 1. .4989 /organism="Homo sapiens"

/tissue type="placenta"

/clone lib="(lamda)gtl0"

/clone="(lambda)IGF-1-R.85, (lambda)IGF-1-R.76"

sig~eptide 32. .121 mat 122. .4132 peptide /note="IGF-I receptor"

misc_ feature 122. .2251 /note="alpha-subunit (AA 1 - 710)"

25 misc_ feature 182. .190 /note="pot.N-linked glycosylation 23)"
site (AA 21 -misc_ feature 335. .343 /note="pot.N-linked glycostlation 74)"
site (AA 72 -misc_ feature 434. .442 /note="pot.N-linked glycostlation - 107)"
site (AA 105 misc_ feature 761. .769 /note="pot.N-linked glycostlation - 216)"
site (AA 214 misc_ feature 971. .979 /note="pot.N-linked glycostlation - 286)"
site (AA 284 35 misc_ feature 1280. .1288 /note="pot.N-linked glycostlation - 389)"
site (AA 387 misc_ feature 1343. .1351 /note="pot.N-linked glycosylation - 410)"
site (AA 408 misc feature 1631. .1639 _ /note="pot.N-linked glycostlation - 506)"
site (AA 504 misc_ feature 1850. .1858 /note="pot.N-linked glycosylation - 579)"
site (AA 577 misc_ feature 1895. .1903 /note="pot.N-linked glycosylation - 594)"
site (AA 592 45 misc_ feature 1949. .1957 /note="pot.N-linked glycosylation - 612)"
site (AA 610 misc_ feature 2240. .2251 /note="putative proreceptor processing707 -site (AA

710)"

$0 misc_ feature 2252. .4132 /note="beta-subunit (AA 711 - 1337)"

misc_ feature 2270. .2278 /note="pot.N-linked glycosylation - 719]"
site (AA 717 misc_ feature 2297. .2305 $S /note="pot.N-linked glycosylation - 728)"
site (AA 726 misc_ feature 2321. .2329 /note="pot.N-linked glycosylation 736)"
site (AA 734 -misc_ feature 2729. .2737 /note="pot.N-linked glycosylation(AA 870 - 872)"
site misc_ feature 2768. .2776 /note="pot.N-linked glycosylation(AA 883 - 885)"
site misc_ feature 2837. .2908 /note="transmembrane region 929)"
(AA 906 -misc_ feature 2918. .2926 /note="pot.N-linked glycosylation(AA 933 - 935)"
site misc feature 3047. .3049 10_ /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)"

15misc_ 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 20 0"

BASE 1216 a 1371 c 1320 g 1082 t COUNT

ORIGIN

HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N Check: 133 ..
Figure 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 O.S~.M and S~,M;
* no oligonucleotide added.
Figure 4B is a graphical representation of a scanning imaging desitometry of Western ligand blot (Figure 4A), showing relative band intensities of IGFBP-3 and the 24kDa IGFBP-4 after treatment with phosphorothioate oligonucleotides;
* no oligonucleotide added.
Figure 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 O.S~,M compared with several control oligonucleotides at O.S~.M.
(a) oligonucleotide BP3AS2NS; (b) oligonucleotide BP3AS4; (c) oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.

Figure 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (Figure SA), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in Figure SA, showing IGFBP-3 band intensities expressed as a percentage of the average band intensity from conditioned medium of cells not treated with oligonucleotide.
Figure 6 is a graphical representation showing inhibition of IGF-I binding by antisense oligonucleotides to IGF-I receptor. IGFR.AS: antisense; IGFR.S: sense.
Figure 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.
Figure 8 is a graphical representation showing optimization of IGFBP-3 antisense oligonucleotide concentration as determined by relative IGFBP-3 concentration in culture medium.
Figure 9 is a diagramatic representation of a map of IGF-1 Receptor mRNA and position of target ODNs.
Figure 10 is a photographical representation showing Lipid-mediated uptake of oligonucleotide in keratinocytes. HaCaT keratinocytes were incubated for 24 hours in medium (DMEM plus 10% v/v FCS) containing fluorescently labelled ODN (R451, 30 nM) and cytofectin GSV (2 ~g/ml). The cells were then transferred to ODN-free medium and fluorescence microscopy (a) and phase contrast (b) images of the cells were obtained.
Figure 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.

Figure 12 is a graphical representation of an IGF-1 Receptor mRNA in ODN
treated (30nM) HaCaT cells (2~cg/ml GSV). HaCaT keratinocytes were treated for 96 hours with 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 (I) are seen at 276 bases.
(B) Relative level of IGF-I receptor mRNA following each treatment is shown.
Figure 13 is a graphical representation of an IGF-1 receptor mRNA in ODN
treated (30nM) HaCaT cells (2,ug/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=8121, R4=8451, R7=8766, 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).
Figure 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 ~cg/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-'°M 'z5I-IGF-I was added with or without the IGF-I
analogue, des (1-3) IGF-I, at 10-'°M to 10-'M. 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 ,u1 O.SM
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 y counter.
Figure 15 is a graphical representation of the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes.
Figure 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.
Figure 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 ,u1, 10 ~cM). The graft was removed and sectioned after 24 hours, then viewed using confocal microscopy.
Figure 18(a) is a photographical representation of Pregraft, Donor JH, Donor JH, PBS
treated, SO~cI, Donor JH, #50 treated, SO,uI, lO,uM.
Figure 18(b) is a photographical representation of Donor LB, pregraft, Donor LB, PBS
treated (SO~cI), Donor LB, #74 treated (SO,uI, lO,uM).

Figure 18(c) is a photographical representation of Donor PW, pregraft, Donor PW, R451 treated (50,u1, lO~cM), Donor LB, #74 treated (50,u1, lO,uM).
Figure 18(d) is a photographical representation of Donor GM, pregraft, Donor GB, 8451 treated (50,u1, lO,uM), Donor GM, #27 treated (50,u1, lO,uM).
Figure 19(a) is a photographical representation showing Donor JH pregraft, Donor JH PBS
treated 50,u1, Donor JH #50 treated 50,u1, lO,uM.
Figure 19(b) is a photographical representation Donor LB pregraft, Donor LB
PBS treated 50,u1, Donor LB #74 treated 50,u1, lO,uM.
Figure 19(c) is a photographical representational showing Donor PW pregraft, Donor PW
r451 treated 501, lO,uM, Donor PW #74 treated 50~c1, IO~cM.
Figure 19(d) is a photographical representation showing Donor GM pregraft, Donor GM
8451 treated 501, 10~M, Donor #27 treated 50,u1, 10~M.
Figure 20 is a graphical representation showing suppression of psoriasis after treatment with oligonucleotide (quantification). Oligonucleotide (50 ,u1, lO,uM) 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) Figure 21 is a photographic representation of ahKi-67 imunobiological binding.
Figure 22 is a photographical representation showing penetration of oligonucleotide into human skin after topical treatment. Fluorescently labelled oligonucleotide (10 ~cM R451) was applied topically after formulation with cytofectin GSV (10 ,ug/ml) and viewed using confocal microscopy.
Figure 23 is a photographical representation showing penetration of oligonucleotide into human skin after application of topical gel formation. Fluorescently labelled oligonucleotide (10 ,uM R451) was applied topically after complexing with cytofectin GSV (10 ,ug/ml) and formulation into 3 % methylcellulose gel. Image was obtained using confocal microscopy.
Figure 24 is a graphical representation showing IGFBP-3 mRNA.
Figure 25(a) is a graphical representation showing IGFBP-3 mRNA in AON treated ( 100nM) HaCaT cells (2,ug/ml GSV).
Figure 25(b) is a graphical representation showing IGFBP-3 mRNA levels of AON
treated (100nm) HaCaT cells (2~cg/ml GSV).
Figure 25(c) is a graphical representation showing IGFBP-3 mRNA in AON treated (30nM) HaCaT cells (2~cg/ml GSV).
Figure 25(d) is a graphical representation showing IGFBP-3 mRNA in AON treated (30nM) HaCaT cells (2,ug/ml GSV).
Figure 26(a) is a graphical representation showing IGFBP-3 mRNA in ODN treated (30nM) HaCaT cells (2,ug/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-ODNs; R1, R4, R7 and R9=randomised ODNs (R1=8121, R4=8451, R7=8766, 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).
Figure 26(b) is a graphical representation showing IGFBP-3 mRNA in ODN treated (100nM) HaCaT cells (2,ug/ml GSV). HaCaT keratinocytes were treated for 51 hours with 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 (Rl-R121, R4=8451, R7=8766, 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).
Figure 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 ,ug/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I
receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, 8451 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 8451 and 8766, 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 t SEM. A one-way ANOVA followed by Tukey's (1) test was performed; 1 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), 8766 (n=9), and 8451, GSV and untreated (n=10).
S
Figure 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 ,ug/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I
receptor specific AONs (#27, #50 and #64) or the random sequence oligonucleotide, 8451.
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). GfV, GSV lipid alone; UT, untreated; 8451, random sequence oligonucleotide;
64, S0, 27, IGF-I receptor-specific AONs.
Figure 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 (-1-), #50 (-x-), #64 (---~---), a random sequence oligonucleotide 8451 (-o-), or treated with GSV lipid alone (--~--) every 24 h for four days (untreated cells, --~--). Competition binding assays using l2sl_IGF-I
and the receptor-specific analogue, des(1-3)IGF-I, were performed (inset);
plotted values are means t standard error. The mean values were then subjected to Scatchard analysis.
Figure 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 8451 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. 1 indicates a significant difference between cells treated with AON #64 and all of the control treatments (p < 0.001).
Figure 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: 8451, 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.
Figure 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 ,um.
Figure 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 ,ug/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, Texas).
Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, California).
Figure 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 ~g/ml GSV lipid alone (GSV) or complexed with 30 nM
oligonucleotide.
Cells were lyased in a buffer containing 50 mM HEPES, 150 mM NaCI, 10 % v/v gycerol, 1 % v/v Triton X-100 and 100 ~g/ml aprotinin on ice for 30 mins, then 30 ,ug of lysate was loaded onto a denaturing 7 % w/v polyacrylamide gel followed by transfer onto an Immobilon-P membrane (Millipore, Bedford, Massachusetts). Membranes were incubated with the anti-IGF-I receptor antibody C20 (Sanra Cruz Biotechnology Inc., Santa Cruz, California, 25 ng/ml in 150 mM NaCI, 10 mM Tris-HCI, 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, California).

Figure 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 ,ug/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-a (TGFa), tumour necrosis factor-a (TNFa), 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:
(r) 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 1 S 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 Figures 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 S 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 S 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 1 S 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.

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 COZ 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].

Cells were grown to 4 days post confluence in 2cm2 wells with daily medium changes of Keratinocyte-SFM, then the medium was changed to DMEM (Cytosystems, Australia), with the following additions: 25mM Hepes, 0.19% w/v, sodium bicarbonate, 0.03% w/v glutamine (Sigma Chemical Co, USA), SOILT/ml penicillin and SO~g/ml streptomycin (Flow Laboratories).
After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in O.SmI 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 ~.Ci/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 (200~1/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).

HaCaT conditioned medium (2501) was concentrated by adding 7501 cold ethanol, incubating at -20°C for 2 hours and centrifuging at 16,OOOg 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 (0.45mm, Schleicher and Schuell, Dassel, Germany) in a buffer containing 25mM Tris, 192mM glycine and 20% v/v methanol. IGFBPs were then visualised by the procedure of Hossenlopp et al [ 11 ], using ['ZSI]-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.

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 25mer 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 24mer complementary to the exon 1/intron 1 splice site;
BP3AS4, 5'-AGG CGG CTG ACG GCA CTA -3'(<400>6), an l8mer 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 l8mer sense control sequence equivalent to the start codon region; BP3AS2NS, S'- CGG AGA TGC CGC ATG CCA GCG CAG G -3' (<400>8), a 25mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, 5'- GAC AGC GTC GGA GCG
ATC -3' (<400>9), an l8mer 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 2cm2 wells with daily medium changes of O.SmI
Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte-SFM
for a further 4 days. Daily additions of O.SmI fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 5~1 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%.

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, SpM and O.SpM, was tested.
Two S 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 Figures 4A and 4B, all oligonucleotides at SpM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately SO%
compared to the sense control (Figure 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 O.SpM. 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 O.SpM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at O.SpM. As shown in Figures SA and SB, BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately SO% 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 O.SpM, compared to untreated cells.
Of possible significance is the fact that this control oligonucleotide, BP3AS2NS, like BP3AS2 itself, has the highest potential Tm 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.

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

TTCGGGGCGAGGGAG GCAGGGCCGTGCACC CGCGCCGCGCTGCCG

TCGGGGCGAGGGAGG CAGGGCCGTGCACCT GCGCCGCGCTGCCGA

CGGGGCGAGGGAGGA AGGGCCGTGCACCTG CGCCGCGCTGCCGAC

GGGGCGAGGGAGGAG GGGCCGTGCACCTGC GCCGCGCTGCCGACC

GGGCGAGGGAGGAGG GGCCGTGCACCTGCC CCGCGCTGCCGACCG

GCGAGGGAGGAGGAA CCGTGCACCTGCCCG GCGCTGCCGACCGCC

CGAGGGAGGAGGAAG CGTGCACCTGCCCGC CGCTGCCGACCGCCA

GAGGGAGGAGGAAGA GTGCACCTGCCCGCC GCTGCCGACCGCCAG

AGGGAGGAGGAAGAA TGCACCTGCCCGCCC CTGCCGACCGCCAGC

GGAGGAGGAAGAAGC CACCTGCCCGCCCGC GCCGACCGCCAGCAT

GAGGAGGAAGAAGCG ACCTGCCCGCCCGCC CCGACCGCCAGCATG

AGGAGGAAGAAGCGG CCTGCCCGCCCGCCC CGACCGCCAGCATGC

GGAGGAAGAAGCGGA CTGCCCGCCCGCCCG GACCGCCAGCATGCT

AGGAAGAAGCGGAGG GCCCGCCCGCCCGCT CCGCCAGCATGCTGC

GGAAGAAGCGGAGGA CCCGCCCGCCCGCTC CGCCAGCATGCTGCC

GAAGAAGCGGAGGAG CCGCCCGCCCGCTCG GCCAGCATGCTGCCG

AAGAAGCGGAGGAGG CGCCCGCCCGCTCGC CCAGCATGCTGCCGA

GAAGCGGAGGAGGCG CCCGCCCGCTCGCTC AGCATGCTGCCGAGA

AAGCGGAGGAGGCGG CCGCCCGCTCGCTCG GCATGCTGCCGAGAG

AGCGGAGGAGGCGGC CGCCCGCTCGCTCGC CATGCTGCCGAGAGT

GCGGAGGAGGCGGCT GCCCGCTCGCTCGCT ATGCTGCCGAGAGTG

GGAGGAGGCGGCTCC CCGCTCGCTCGCTCG GCTGCCGAGAGTGGG

GAGGAGGCGGCTCCC CGCTCGCTCGCTCGC CTGCCGAGAGTGGGC

AGGAGGCGGCTCCCG GCTCGCTCGCTCGCC TGCCGAGAGTGGGCT

GGAGGCGGCTCCCGC CTCGCTCGCTCGCCC GCCGAGAGTGGGCTG

AGGCGGCTCCCGCTC CGCTCGCTCGCCCGC CGAGAGTGGGCTGCC

GGCGGCTCCCGCTCG GCTCGCTCGCCCGCC GAGAGTGGGCTGCCC

GCGGCTCCCGCTCGC CTCGCTCGCCCGCCG AGAGTGGGCTGCCCC

CGGCTCCCGCTCGCA TCGCTCGCCCGCCGC GAGTGGGCTGCCCCG

GCTCCCGCTCGCAGG GCTCGCCCGCCGCGC GTGGGCTGCCCCGCG

CTCCCGCTCGCAGGG CTCGCCCGCCGCGCC TGGGCTGCCCCGCGC

TCCCGCTCGCAGGGC TCGCCCGCCGCGCCG GGGCTGCCCCGCGCT

CCCGCTCGCAGGGCC CGCCCGCCGCGCCGC GGCTGCCCCGCGCTG

CGCTCGCAGGGCCGT CCCGCCGCGCCGCGC CTGCCCCGCGCTGCC

GCTCGCAGGGCCGTG CCGCCGCGCCGCGCT TGCCCCGCGCTGCCG

CTCGCAGGGCCGTGC CGCCGCGCCGCGCTG GCCCCGCGCTGCCGC

TCGCAGGGCCGTGCA GCCGCGCCGCGCTGC CCCCGCGCTGCCGCT

CCCGCGCTGCCGCTG CTGCTGCTACTGGGC CTGTTCCGCTGCCCG

CCGCGCTGCCGCTGC TGCTGCTACTGGGCG TGTTCCGCTGCCCGC

CGCGCTGCCGCTGCC GCTGCTACTGGGCGC GTTCCGCTGCCCGCC

GCGCTGCCGCTGCCG CTGCTACTGGGCGCG TTCCGCTGCCCGCCC

CGCTGCCGCTGCCGC TGCTACTGGGCGCGA TCCGCTGCCCGCCCT

GCTGCCGCTGCCGCC GCTACTGGGCGCGAG CCGCTGCCCGCCCTG

CTGCCGCTGCCGCCG CTACTGGGCGCGAGT CGCTGCCCGCCCTGC

TGCCGCTGCCGCCGC TACTGGGCGCGAGTG GCTGCCCGCCCTGCA

GCCGCTGCCGCCGCC ACTGGGCGCGAGTGG CTGCCCGCCCTGCAC

CGCTGCCGCCGCCGC TGGGCGCGAGTGGCG GCCCGCCCTGCACAC

GCTGCCGCCGCCGCC GGGCGCGAGTGGCGG CCCGCCCTGCACACC

CTGCCGCCGCCGCCG GGCGCGAGTGGCGGC CCGCCCTGCACACCC

TGCCGCCGCCGCCGC GCGCGAGTGGCGGCG CGCCCTGCACACCCG

CCGCCGCCGCCGCTG GCGAGTGGCGGCGGC CCCTGCACACCCGAG

CGCCGCCGCCGCTGC CGAGTGGCGGCGGCG CCTGCACACCCGAGC

GCCGCCGCCGCTGCT GAGTGGCGGCGGCGG CTGCACACCCGAGCG

CCGCCGCCGCTGCTG AGTGGCGGCGGCGGC TGCACACCCGAGCGC

GCCGCCGCTGCTGCC TGGCGGCGGCGGCGG CACACCCGAGCGCCT

CCGCCGCTGCTGCCG GGCGGCGGCGGCGGG ACACCCGAGCGCCTG

CGCCGCTGCTGCCGC GCGGCGGCGGCGGGG CACCCGAGCGCCTGG

GCCGCTGCTGCCGCT CGGCGGCGGCGGGGC ACCCGAGCGCCTGGC

CGCTGCTGCCGCTGC GCGGCGGCGGGGCGC CCGAGCGCCTGGCCG

GCTGCTGCCGCTGCT CGGCGGCGGGGCGCG CGAGCGCCTGGCCGC

CTGCTGCCGCTGCTG GGCGGCGGGGCGCGC GAGCGCCTGGCCGCC

TGCTGCCGCTGCTGC GCGGCGGGGCGCGCG AGCGCCTGGCCGCCT

CTGCCGCTGCTGCCG ' GGCGGGGCGCGCGCG CGCCTGGCCGCCTGC

TGCCGCTGCTGCCGC GCGGGGCGCGCGCGG GCCTGGCCGCCTGCG

GCCGCTGCTGCCGCT CGGGGCGCGCGCGGA CCTGGCCGCCTGCGG

CCGCTGCTGCCGCTG GGGGCGCGCGCGGAG CTGGCCGCCTGCGGG

GCTGCTGCCGCTGCT GGCGCGCGCGGAGGT GGCCGCCTGCGGGCC

CTGCTGCCGCTGCTG GCGCGCGCGGAGGTG GCCGCCTGCGGGCCC

TGCTGCCGCTGCTGC CGCGCGCGGAGGTGC CCGCCTGCGGGCCCC

GCTGCCGCTGCTGCT GCGCGCGGAGGTGCT CGCCTGCGGGCCCCC

TGCCGCTGCTGCTGC GCGCGGAGGTGCTGT CCTGCGGGCCCCCGC

GCCGCTGCTGCTGCT CGCGGAGGTGCTGTT CTGCGGGCCCCCGCC

CCGCTGCTGCTGCTG GCGGAGGTGCTGTTC TGCGGGCCCCCGCCG

CGCTGCTGCTGCTGC CGGAGGTGCTGTTCC GCGGGCCCCCGCCGG

CTGCTGCTGCTGCTA GAGGTGCTGTTCCGC GGGCCCCCGCCGGTT

TGCTGCTGCTGCTAC AGGTGCTGTTCCGCT GGCCCCCGCCGGTTG

GCTGCTGCTGCTACT GGTGCTGTTCCGCTG GCCCCCGCCGGTTGC

CTGCTGCTGCTACTG GTGCTGTTCCGCTGC CCCCCGCCGGTTGCG

GCTGCTGCTACTGGG GCTGTTCCGCTGCCC CCCGCCGGTTGCGCC

CCGCCGGTTGCGCCG ATGCCATGCGCGGAG TGCGCCCGGCTGGAG

CGCCGGTTGCGCCGC TGCCATGCGCGGAGC GCGCCCGGCTGGAGG

GCCGGTTGCGCCGCC GCCATGCGCGGAGCT CGCCCGGCTGGAGGG

CCGGTTGCGCCGCCC CCATGCGCGGAGCTC GCCCGGCTGGAGGGC

CGGTTGCGCCGCCCG CATGCGCGGAGCTCG CCCGGCTGGAGGGCG

GGTTGCGCCGCCCGC ATGCGCGGAGCTCGT CCGGCTGGAGGGCGA

GTTGCGCCGCCCGCC TGCGCGGAGCTCGTC CGGCTGGAGGGCGAG

TTGCGCCGCCCGCCG GCGCGGAGCTCGTCC GGCTGGAGGGCGAGG

TGCGCCGCCCGCCGC CGCGGAGCTCGTCCG GCTGGAGGGCGAGGC

CGCCGCCCGCCGCGG CGGAGCTCGTCCGGG TGGAGGGCGAGGCGT

GCCGCCCGCCGCGGT GGAGCTCGTCCGGGA GGAGGGCGAGGCGTG

CCGCCCGCCGCGGTG GAGCTCGTCCGGGAG GAGGGCGAGGCGTGC

CGCCCGCCGCGGTGG AGCTCGTCCGGGAGC AGGGCGAGGCGTGCG

CCCGCCGCGGTGGCC CTCGTCCGGGAGCCG GGCGAGGCGTGCGGC

CCGCCGCGGTGGCCG TCGTCCGGGAGCCGG GCGAGGCGTGCGGCG

CGCCGCGGTGGCCGC CGTCCGGGAGCCGGG CGAGGCGTGCGGCGT

GCCGCGGTGGCCGCA GTCCGGGAGCCGGGC GAGGCGTGCGGCGTC

CGCGGTGGCCGCAGT CCGGGAGCCGGGCTG GGCGTGCGGCGTCTA

GCGGTGGCCGCAGTG CGGGAGCCGGGCTGC GCGTGCGGCGTCTAC

CGGTGGCCGCAGTGG GGGAGCCGGGCTGCG CGTGCGGCGTCTACA

GGTGGCCGCAGTGGC GGAGCCGGGCTGCGG GTGCGGCGTCTACAC

TGGCCGCAGTGGCCG AGCCGGGCTGCGGCT GCGGCGTCTACACCC

GGCCGCAGTGGCCGG GCCGGGCTGCGGCTG CGGCGTCTACACCCC

GCCGCAGTGGCCGGA CCGGGCTGCGGCTGC GGCGTCTACACCCCG

CCGCAGTGGCCGGAG CGGGCTGCGGCTGCT GCGTCTACACCCCGC

GCAGTGGCCGGAGGC GGCTGCGGCTGCTGC GTCTACACCCCGCGC

CAGTGGCCGGAGGCG GCTGCGGCTGCTGCT TCTACACCCCGCGCT

AGTGGCCGGAGGCGC CTGCGGCTGCTGCTC CTACACCCCGCGCTG

GTGGCCGGAGGCGCC TGCGGCTGCTGCTCG TACACCCCGCGCTGC

GGCCGGAGGCGCCCG CGGCTGCTGCTCGGT CACCCCGCGCTGCGG

GCCGGAGGCGCCCGC GGCTGCTGCTCGGTG ACCCCGCGCTGCGGC

CCGGAGGCGCCCGCA GCTGCTGCTCGGTGT CCCCGCGCTGCGGCC

CGGAGGCGCCCGCAT CTGCTGCTCGGTGTG CCCGCGCTGCGGCCA

GAGGCGCCCGCATGC GCTGCTCGGTGTGCG CGCGCTGCGGCCAGG

AGGCGCCCGCATGCC CTGCTCGGTGTGCGC GCGCTGCGGCCAGGG

GGCGCCCGCATGCCA TGCTCGGTGTGCGCC CGCTGCGGCCAGGGG

GCGCCCGCATGCCAT GCTCGGTGTGCGCCC GCTGCGGCCAGGGGC

GCCCGCATGCCATGC TCGGTGTGCGCCCGG TGCGGCCAGGGGCTG

CCCGCATGCCATGCG CGGTGTGCGCCCGGC GCGGCCAGGGGCTGC

CCGCATGCCATGCGC GGTGTGCGCCCGGCT CGGCCAGGGGCTGCG

CGCATGCCATGCGCG GTGTGCGCCCGGCTG GGCCAGGGGCTGCGC

CATGCCATGCGCGGA GTGCGCCCGGCTGGA CCAGGGGCTGCGCTG

CAGGGGCTGCGCTGC CTGGTCATGGGCGAG GCCAGCCCGGAGCAG

AGGGGCTGCGCTGCT TGGTCATGGGCGAGG CCAGCCCGGAGCAGG

GGGGCTGCGCTGCTA GGTCATGGGCGAGGG CAGCCCGGAGCAGGT

GGGCTGCGCTGCTAT GTCATGGGCGAGGGC AGCCCGGAGCAGGTT

GGCTGCGCTGCTATC TCATGGGCGAGGGCA GCCCGGAGCAGGTTG

GCTGCGCTGCTATCC CATGGGCGAGGGCAC CCCGGAGCAGGTTGC

CTGCGCTGCTATCCC ATGGGCGAGGGCACT CCGGAGCAGGTTGCA

TGCGCTGCTATCCCC TGGGCGAGGGCACTT CGGAGCAGGTTGCAG

GCGCTGCTATCCCCA GGGCGAGGGCACTTG GGAGCAGGTTGCAGA

GCTGCTATCCCCACC GCGAGGGCACTTGTG AGCAGGTTGCAGACA

CTGCTATCCCCACCC CGAGGGCACTTGTGA GCAGGTTGCAGACAA

TGCTATCCCCACCCG GAGGGCACTTGTGAG CAGGTTGCAGACAAT

GCTATCCCCACCCGG AGGGCACTTGTGAGA AGGTTGCAGACAATG

TATCCCCACCCGGGC GGCACTTGTGAGAAG GTTGCAGACAATGGC
.

ATCCCCACCCGGGCT GCACTTGTGAGAAGC TTGCAGACAATGGCG

TCCCCACCCGGGCTC CACTTGTGAGAAGCG TGCAGACAATGGCGA

CCCCACCCGGGCTCC ACTTGTGAGAAGCGC GCAGACAATGGCGAT

CCACCCGGGCTCCGA TTGTGAGAAGCGCCG AGACAATGGCGATGA

CACCCGGGCTCCGAG TGTGAGAAGCGCCGG GACAATGGCGATGAC

ACCCGGGCTCCGAGC GTGAGAAGCGCCGGG ACAATGGCGATGACC

CCCGGGCTCCGAGCT TGAGAAGCGCCGGGA CAATGGCGATGACCA

CGGGCTCCGAGCTGC AGAAGCGCCGGGACG ATGGCGATGACCACT

GGGCTCCGAGCTGCC GAAGCGCCGGGACGC TGGCGATGACCACTC

GGCTCCGAGCTGCCC AAGCGCCGGGACGCC GGCGATGACCACTCA

GCTCCGAGCTGCCCC AGCGCCGGGACGCCG GCGATGACCACTCAG

TCCGAGCTGCCCCTG CGCCGGGACGCCGAG GATGACCACTCAGAA

CCGAGCTGCCCCTGC GCCGGGACGCCGAGT ATGACCACTCAGAAG

CGAGCTGCCCCTGCA CCGGGACGCCGAGTA TGACCACTCAGAAGG

GAGCTGCCCCTGCAG CGGGACGCCGAGTAT GACCACTCAGAAGGA

GCTGCCCCTGCAGGC GGACGCCGAGTATGG CCACTCAGAAGGAGG

CTGCCCCTGCAGGCG GACGCCGAGTATGGC CACTCAGAAGGAGGC

TGCCCCTGCAGGCGC ACGCCGAGTATGGCG ACTCAGAAGGAGGCC

GCCCCTGCAGGCGCT CGCCGAGTATGGCGC CTCAGAAGGAGGCCT

CCCTGCAGGCGCTGG CCGAGTATGGCGCCA CAGAAGGAGGCCTGG

CCTGCAGGCGCTGGT CGAGTATGGCGCCAG AGAAGGAGGCCTGGT

CTGCAGGCGCTGGTC GAGTATGGCGCCAGC GAAGGAGGCCTGGTG

TGCAGGCGCTGGTCA AGTATGGCGCCAGCC AAGGAGGCCTGGTGG

CAGGCGCTGGTCATG TATGGCGCCAGCCCG GGAGGCCTGGTGGAG

AGGCGCTGGTCATGG ATGGCGCCAGCCCGG GAGGCCTGGTGGAGA

GGCGCTGGTCATGGG TGGCGCCAGCCCGGA AGGCCTGGTGGAGAA

GCGCTGGTCATGGGC GGCGCCAGCCCGGAG GGCCTGGTGGAGAAC

GCTGGTCATGGGCGA CGCCAGCCCGGAGCA CCTGGTGGAGAACCA

CTGGTGGAGAACCAC AGTGCTGGCCGGAAG CGGGAGAAGGTCACT

TGGTGGAGAACCACG GTGCTGGCCGGAAGC GGGAGAAGGTCACTG

GGTGGAGAACCACGT TGCTGGCCGGAAGCC GGAGAAGGTCACTGA

GTGGAGAACCACGTG GCTGGCCGGAAGCCC GAGAAGGTCACTGAG

TGGAGAACCACGTGG CTGGCCGGAAGCCCC AGAAGGTCACTGAGC

GGAGAACCACGTGGA TGGCCGGAAGCCCCT GAAGGTCACTGAGCA

GAGAACCACGTGGAC GGCCGGAAGCCCCTC AAGGTCACTGAGCAG

AGAACCACGTGGACA GCCGGAAGCCCCTCA AGGTCACTGAGCAGC

GAACCACGTGGACAG CCGGAAGCCCCTCAA GGTCACTGAGCAGCA

ACCACGTGGACAGCA GGAAGCCCCTCAAGT TCACTGAGCAGCACC

CCACGTGGACAGCAC GAAGCCCCTCAAGTC CACTGAGCAGCACCG

CACGTGGACAGCACC AAGCCCCTCAAGTCG ACTGAGCAGCACCGG

ACGTGGACAGCACCA AGCCCCTCAAGTCGG CTGAGCAGCACCGGC

GTGGACAGCACCATG CCCCTCAAGTCGGGT GAGCAGCACCGGCAG

TGGACAGCACCATGA CCCTCAAGTCGGGTA AGCAGCACCGGCAGA

GGACAGCACCATGAA CCTCAAGTCGGGTAT GCAGCACCGGCAGAT

GACAGCACCATGAAC CTCAAGTCGGGTATG CAGCACCGGCAGATG

CAGCACCATGAACAT CAAGTCGGGTATGAA GCACCGGCAGATGGG

AGCACCATGAACATG AAGTCGGGTATGAAG CACCGGCAGATGGGC

GCACCATGAACATGT AGTCGGGTATGAAGG ACCGGCAGATGGGCA

CACCATGAACATGTT GTCGGGTATGAAGGA CCGGCAGATGGGCAA

CCATGAACATGTTGG CGGGTATGAAGGAGC GGCAGATGGGCAAGG

CATGAACATGTTGGG GGGTATGAAGGAGCT GCAGATGGGCAAGGG

ATGAACATGTTGGGC GGTATGAAGGAGCTG CAGATGGGCAAGGGT

TGAACATGTTGGGCG GTATGAAGGAGCTGG AGATGGGCAAGGGTG

AACATGTTGGGCGGG ATGAAGGAGCTGGCC ATGGGCAAGGGTGGC

ACATGTTGGGCGGGG TGAAGGAGCTGGCCG TGGGCAAGGGTGGCA

CATGTTGGGCGGGGG GAAGGAGCTGGCCGT GGGCAAGGGTGGCAA

ATGTTGGGCGGGGGA AAGGAGCTGGCCGTG GGCAAGGGTGGCAAG

GTTGGGCGGGGGAGG GGAGCTGGCCGTGTT CAAGGGTGGCAAGCA

TTGGGCGGGGGAGGC GAGCTGGCCGTGTTC AAGGGTGGCAAGCAT

TGGGCGGGGGAGGCA AGCTGGCCGTGTTCC AGGGTGGCAAGCATC

GGGCGGGGGAGGCAG GCTGGCCGTGTTCCG GGGTGGCAAGCATCA

GCGGGGGAGGCAGTG TGGCCGTGTTCCGGG GTGGCAAGCATCACC

CGGGGGAGGCAGTGC GGCCGTGTTCCGGGA TGGCAAGCATCACCT

GGGGGAGGCAGTGCT GCCGTGTTCCGGGAG GGCAAGCATCACCTT

GGGGAGGCAGTGCTG CCGTGTTCCGGGAGA GCAAGCATCACCTTG

GGAGGCAGTGCTGGC GTGTTCCGGGAGAAG AAGCATCACCTTGGC

GAGGCAGTGCTGGCC TGTTCCGGGAGAAGG AGCATCACCTTGGCC

AGGCAGTGCTGGCCG GTTCCGGGAGAAGGT GCATCACCTTGGCCT

GGCAGTGCTGGCCGG TTCCGGGAGAAGGTC CATCACCTTGGCCTG

CAGTGCTGGCCGGAA CCGGGAGAAGGTCAC TCACCTTGGCCTGGA

CACCTTGGCCTGGAG CCCTGCCAACAGGAA CTTCCGGATGAGCGG

ACCTTGGCCTGGAGG CCTGCCAACAGGAAC TTCCGGATGAGCGGG

CCTTGGCCTGGAGGA CTGCCAACAGGAACT TCCGGATGAGCGGGG

CTTGGCCTGGAGGAG TGCCAACAGGAACTG CCGGATGAGCGGGGC

TTGGCCTGGAGGAGC GCCAACAGGAACTGG CGGATGAGCGGGGCC

TGGCCTGGAGGAGCC CCAACAGGAACTGGA GGATGAGCGGGGCCC

GGCCTGGAGGAGCCC CAACAGGAACTGGAC GATGAGCGGGGCCCT

GCCTGGAGGAGCCCA AACAGGAACTGGACC ATGAGCGGGGCCCTC

CCTGGAGGAGCCCAA ACAGGAACTGGACCA TGAGCGGGGCCCTCT

TGGAGGAGCCCAAGA AGGAACTGGACCAGG AGCGGGGCCCTCTGG

GGAGGAGCCCAAGAA GGAACTGGACCAGGT GCGGGGCCCTCTGGA

GAGGAGCCCAAGAAG GAACTGGACCAGGTC CGGGGCCCTCTGGAG

AGGAGCCCAAGAAGC AACTGGACCAGGTCC GGGGCCCTCTGGAGC

GAGCCCAAGAAGCTG CTGGACCAGGTCCTG GGCCCTCTGGAGCAC

AGCCCAAGAAGCTGC TGGACCAGGTCCTGG GCCCTCTGGAGCACC

GCCCAAGAAGCTGCG GGACCAGGTCCTGGA CCCTCTGGAGCACCT

CCCAAGAAGCTGCGA GACCAGGTCCTGGAG CCTCTGGAGCACCTC

CAAGAAGCTGCGACC CCAGGTCCTGGAGCG TCTGGAGCACCTCTA

AAGAAGCTGCGACCA CAGGTCCTGGAGCGG CTGGAGCACCTCTAC

AGAAGCTGCGACCAC AGGTCCTGGAGCGGA TGGAGCACCTCTACT

GAAGCTGCGACCACC GGTCCTGGAGCGGAT GGAGCACCTCTACTC

AGCTGCGACCACCCC TCCTGGAGCGGATCT AGCACCTCTACTCCC

GCTGCGACCACCCCC CCTGGAGCGGATCTC GCACCTCTACTCCCT

CTGCGACCACCCCCT CTGGAGCGGATCTCC CACCTCTACTCCCTG

TGCGACCACCCCCTG TGGAGCGGATCTCCA ACCTCTACTCCCTGC

CGACCACCCCCTGCC GAGCGGATCTCCACC CTCTACTCCCTGCAC

GACCACCCCCTGCCA AGCGGATCTCCACCA TCTACTCCCTGCACA

ACCACCCCCTGCCAG GCGGATCTCCACCAT CTACTCCCTGCACAT

CCACCCCCTGCCAGG CGGATCTCCACCATG TACTCCCTGCACATC

ACCCCCTGCCAGGAC GATCTCCACCATGCG CTCCCTGCACATCCC

CCCCCTGCCAGGACT ATCTCCACCATGCGC TCCCTGCACATCCCC

CCCCTGCCAGGACTC TCTCCACCATGCGCC CCCTGCACATCCCCA

CCCTGCCAGGACTCC CTCCACCATGCGCCT CCTGCACATCCCCAA

CTGCCAGGACTCCCT CCACCATGCGCCTTC TGCACATCCCCAACT

TGCCAGGACTCCCTG CACCATGCGCCTTCC GCACATCCCCAACTG

GCCAGGACTCCCTGC ACCATGCGCCTTCCG CACATCCCCAACTGT

CCAGGACTCCCTGCC CCATGCGCCTTCCGG ~ACATCCCCAACTGTG

AGGACTCCCTGCCAA ATGCGCCTTCCGGAT ATCCCCAACTGTGAC

GGACTCCCTGCCAAC TGCGCCTTCCGGATG TCCCCAACTGTGACA

GACTCCCTGCCAACA GCGCCTTCCGGATGA CCCCAACTGTGACAA

ACTCCCTGCCAACAG CGCCTTCCGGATGAG CCCAACTGTGACAAG

TCCCTGCCAACAGGA CCTTCCGGATGAGCG CAACTGTGACAAGCA

AACTGTGACAAGCAT AACGGGCAGCGTGGG ATCCAGGGAGCCCCC

ACTGTGACAAGCATG ACGGGCAGCGTGGGG TCCAGGGAGCCCCCA

CTGTGACAAGCATGG CGGGCAGCGTGGGGA CCAGGGAGCCCCCAC

TGTGACAAGCATGGC GGGCAGCGTGGGGAG CAGGGAGCCCCCACC

GTGACAAGCATGGCC GGCAGCGTGGGGAGT AGGGAGCCCCCACCA

TGACAAGCATGGCCT GCAGCGTGGGGAGTG GGGAGCCCCCACCAT

GACAAGCATGGCCTG CAGCGTGGGGAGTGC GGAGCCCCCACCATC

ACAAGCATGGCCTGT AGCGTGGGGAGTGCT GAGCCCCCACCATCC

CAAGCATGGCCTGTA GCGTGGGGAGTGCTG AGCCCCCACCATCCG

AGCATGGCCTGTACA GTGGGGAGTGCTGGT CCCCCACCATCCGGG

GCATGGCCTGTACAA TGGGGAGTGCTGGTG CCCCACCATCCGGGG

CATGGCCTGTACAAC GGGGAGTGCTGGTGT CCCACCATCCGGGGG

ATGGCCTGTACAACC GGGAGTGCTGGTGTG CCACCATCCGGGGGG

GGCCTGTACAACCTC GAGTGCTGGTGTGTG ACCATCCGGGGGGAC

GCCTGTACAACCTCA AGTGCTGGTGTGTGA CCATCCGGGGGGACC

CCTGTACAACCTCAA GTGCTGGTGTGTGAA CATCCGGGGGGACCC

CTGTACAACCTCAAA TGCTGGTGTGTGAAC ATCCGGGGGGACCCC

GTACAACCTCAA~CA CTGGTGTGTGAACCC CCGGGGGGACCCCGA

TACAACCTCAAACAG TGGTGTGTGAACCCC CGGGGGGACCCCGAG

ACAACCTCAAACAGT GGTGTGTGAACCCCA GGGGGGACCCCGAGT

CAACCTCAAACAGTG GTGTGTGAACCCCAA GGGGGACCCCGAGTG

ACCTCAAACAGTGCA GTGTGAACCCCAACA GGGACCCCGAGTGTC

CCTCAAACAGTGCAA TGTGAACCCCAACAC GGACCCCGAGTGTCA

CTCAAACAGTGCAAG GTGAACCCCAACACC GACCCCGAGTGTCAT

TCAAACAGTGCAAGA TGAACCCCAACACCG ACCCCGAGTGTCATC

AAACAGTGCAAGATG AACCCCAACACCGGG CCCGAGTGTCATCTC

AACAGTGCAAGATGT ACCCCAACACCGGGA CCGAGTGTCATCTCT

ACAGTGCAAGATGTC CCCCAACACCGGGAA CGAGTGTCATCTCTT

CAGTGCAAGATGTCT CCCAACACCGGGAAG GAGTGTCATCTCTTC

GTGCAAGATGTCTCT CAACACCGGGAAGCT GTGTCATCTCTTCTA

TGCAAGATGTCTCTG AACACCGGGAAGCTG TGTCATCTCTTCTAC

GCAAGATGTCTCTGA ACACCGGGAAGCTGA GTCATCTCTTCTACA

CAAGATGTCTCTGAA CACCGGGAAGCTGAT TCATCTCTTCTACAA

AGATGTCTCTGAACG CCGGGAAGCTGATCC ATCTCTTCTACAATG

GATGTCTCTGAACGG CGGGAAGCTGATCCA TCTCTTCTACAATGA

ATGTCTCTGAACGGG GGGAAGCTGATCCAG CTCTTCTACAATGAG

TGTCTCTGAACGGGC GGAAGCTGATCCAGG TCTTCTACAATGAGC

TCTCTGAACGGGCAG AAGCTGATCCAGGGA TTCTACAATGAGCAG

CTCTGAACGGGCAGC AGCTGATCCAGGGAG TCTACAATGAGCAGC

TCTGAACGGGCAGCG GCTGATCCAGGGAGC CTACAATGAGCAGCA

CTGAACGGGCAGCGT CTGATCCAGGGAGCC TACAATGAGCAGCAG

GAACGGGCAGCGTGG GATCCAGGGAGCCCC CAATGAGCAGCAGGA

AATGAGCAGCAGGAG GCAGCCAGCCGGTGC GCAGAAAACGGAGAG

ATGAGCAGCAGGAGG CAGCCAGCCGGTGCC CAGAAAACGGAGAGT

TGAGCAGCAGGAGGC AGCCAGCCGGTGCCT AGAAAACGGAGAGTG

GAGCAGCAGGAGGCT GCCAGCCGGTGCCTG GAAAACGGAGAGTGC

AGCAGCAGGAGGCTT CCAGCCGGTGCCTGG AAAACGGAGAGTGCT

GCAGCAGGAGGCTTG CAGCCGGTGCCTGGC AAACGGAGAGTGCTT

CAGCAGGAGGCTTGC AGCCGGTGCCTGGCG AACGGAGAGTGCTTG

AGCAGGAGGCTTGCG GCCGGTGCCTGGCGC ACGGAGAGTGCTTGG

GCAGGAGGCTTGCGG CCGGTGCCTGGCGCC CGGAGAGTGCTTGGG

AGGAGGCTTGCGGGG GGTGCCTGGCGCCCC GAGAGTGCTTGGGTG

GGAGGCTTGCGGGGT GTGCCTGGCGCCCCT AGAGTGCTTGGGTGG

GAGGCTTGCGGGGTG TGCCTGGCGCCCCTG GAGTGCTTGGGTGGT

AGGCTTGCGGGGTGC GCCTGGCGCCCCTGC AGTGCTTGGGTGGTG

GCTTGCGGGGTGCAC CTGGCGCCCCTGCCC TGCTTGGGTGGTGGG

CTTGCGGGGTGCACA TGGCGCCCCTGCCCC GCTTGGGTGGTGGGT

TTGCGGGGTGCACAC GGCGCCCCTGCCCCC CTTGGGTGGTGGGTG

TGCGGGGTGCACACC GCGCCCCTGCCCCCC TTGGGTGGTGGGTGC

CGGGGTGCACACCCA GCCCCTGCCCCCCGC GGGTGGTGGGTGCTG

GGGGTGCACACCCAG CCCCTGCCCCCCGCC GGTGGTGGGTGCTGG

GGGTGCACACCCAGC CCCTGCCCCCCGCCC GTGGTGGGTGCTGGA

GGTGCACACCCAGCG CCTGCCCCCCGCCCC TGGTGGGTGCTGGAG

TGCACACCCAGCGGA TGCCCCCCGCCCCTC GTGGGTGCTGGAGGA

GCACACCCAGCGGAT GCCCCCCGCCCCTCT TGGGTGCTGGAGGAT

CACACCCAGCGGATG CCCCCCGCCCCTCTC GGGTGCTGGAGGATT

ACACCCAGCGGATGC CCCCCGCCCCTCTCC GGTGCTGGAGGATTT

ACCCAGCGGATGCAG CCCGCCCCTCTCCAA TGCTGGAGGATTTTC

CCCAGCGGATGCAGT CCGCCCCTCTCCAAA GCTGGAGGATTTTCC

CCAGCGGATGCAGTA CGCCCCTCTCCAAAC CTGGAGGATTTTCCA

CAGCGGATGCAGTAG GCCCCTCTCCAAACA TGGAGGATTTTCCAG

GCGGATGCAGTAGAC CCCTCTCCAAACACC GAGGATTTTCCAGTT

CGGATGCAGTAGACC CCTCTCCAAACACCG AGGATTTTCCAGTTC

GGATGCAGTAGACCG CTCTCCAAACACCGG GGATTTTCCAGTTCT

GATGCAGTAGACCGC TCTCCAAACACCGGC GATTTTCCAGTTCTG

TGCAGTAGACCGCAG TCCAAACACCGGCAG TTTTCCAGTTCTGAC

GCAGTAGACCGCAGC CCAAACACCGGCAGA TTTCCAGTTCTGACA

CAGTAGACCGCAGCC CAAACACCGGCAGAA TTCCAGTTCTGACAC

AGTAGACCGCAGCCA AAACACCGGCAGAAA TCCAGTTCTGACACA

TAGACCGCAGCCAGC ACACCGGCAGAAAAC CAGTTCTGACACACG

AGACCGCAGCCAGCC CACCGGCAGAAAACG AGTTCTGACACACGT

GACCGCAGCCAGCCG ACCGGCAGAAAACGG GTTCTGACACACGTA

ACCGCAGCCAGCCGG CCGGCAGAAAACGGA TTCTGACACACGTAT

CGCAGCCAGCCGGTG GGCAGAAAACGGAGA CTGACACACGTATTT

TGACACACGTATTTA CCCGGCCTCTCTCTT TCCCCGGGGGAGGAA

GACACACGTATTTAT CCGGCCTCTCTCTTC CCCCGGGGGAGGAAG

ACACACGTATTTATA CGGCCTCTCTCTTCC CCCGGGGGAGGAAGG

CACACGTATTTATAT GGCCTCTCTCTTCCC CCGGGGGAGGAAGGG

ACACGTATTTATATT GCCTCTCTCTTCCCA CGGGGGAGGAAGGGG

CACGTATTTATATTT CCTCTCTCTTCCCAG GGGGGAGGAAGGGGG

ACGTATTTATATTTG CTCTCTCTTCCCAGC GGGGAGGAAGGGGGT

CGTATTTATATTTGG TCTCTCTTCCCAGCT GGGAGGAAGGGGGTT

GTATTTATATTTGGA CTCTCTTCCCAGCTG GGAGGAAGGGGGTTG

ATTTATATTTGGAAA CTCTTCCCAGCTGCA AGGAAGGGGGTTGTG

TTTATATTTGGAAAG TCTTCCCAGCTGCAG GGAAGGGGGTTGTGG

TTATATTTGGAAAGA CTTCCCAGCTGCAGA GAAGGGGGTTGTGGT

TATATTTGGAAAGAG TTCCCAGCTGCAGAT AAGGGGGTTGTGGTC

TATTTGGAAAGAGAC CCCAGCTGCAGATGC GGGGGTTGTGGTCGG

ATTTGGAAAGAGACC CCAGCTGCAGATGCC GGGGTTGTGGTCGGG

TTTGGAAAGAGACCA CAGCTGCAGATGCCA GGGTTGTGGTCGGGG

TTGGAAAGAGACCAG AGCTGCAGATGCCAC GGTTGTGGTCGGGGA

GGAAAGAGACCAGCA CTGCAGATGCCACAC TTGTGGTCGGGGAGC

GAAAGAGACCAGCAC TGCAGATGCCACACC TGTGGTCGGGGAGCT

AAAGAGACCAGCACC GCAGATGCCACACCT GTGGTCGGGGAGCTG

AAGAGACCAGCACCG CAGATGCCACACCTG TGGTCGGGGAGCTGG

GAGACCAGCACCGAG GATGCCACACCTGCT GTCGGGGAGCTGGGG

AGACCAGCACCGAGC ATGCCACACCTGCTC TCGGGGAGCTGGGGT

GACCAGCACCGAGCT TGCCACACCTGCTCC CGGGGAGCTGGGGTA

ACCAGCACCGAGCTC GCCACACCTGCTCCT GGGGAGCTGGGGTAC

CAGCACCGAGCTCGG CACACCTGCTCCTTC GGAGCTGGGGTACAG

AGCACCGAGCTCGGC ACACCTGCTCCTTCT GAGCTGGGGTACAGG

GCACCGAGCTCGGCA CACCTGCTCCTTCTT AGCTGGGGTACAGGT

CACCGAGCTCGGCAC ACCTGCTCCTTCTTG GCTGGGGTACAGGTT

CCGAGCTCGGCACCT CTGCTCCTTCTTGCT TGGGGTACAGGTTTG

CGAGCTCGGCACCTC TGCTCCTTCTTGCTT GGGGTACAGGTTTGG

GAGCTCGGCACCTCC GCTCCTTCTTGCTTT GGGTACAGGTTTGGG

AGCTCGGCACCTCCC CTCCTTCTTGCTTTC GGTACAGGTTTGGGG

CTCGGCACCTCCCCG CCTTCTTGCTTTCCC TACAGGTTTGGGGAG

TCGGCACCTCCCCGG CTTCTTGCTTTCCCC ACAGGTTTGGGGAGG

CGGCACCTCCCCGGC TTCTTGCTTTCCCCG CAGGTTTGGGGAGGG

GGCACCTCCCCGGCC TCTTGCTTTCCCCGG AGGTTTGGGGAGGGG

CACCTCCCCGGCCTC TTGCTTTCCCCGGGG GTTTGGGGAGGGGGA

ACCTCCCCGGCCTCT TGCTTTCCCCGGGGG TTTGGGGAGGGGGAA

CCTCCCCGGCCTCTC GCTTTCCCCGGGGGA TTGGGGAGGGGGAAG

CTCCCCGGCCTCTCT CTTTCCCCGGGGGAG TGGGGAGGGGGAAGA

CCCCGGCCTCTCTCT TTCCCCGGGGGAGGA GGGAGGGGGAAGAGA

GGAGGGGGAAGAGAA AGATTAAAGGAAGGA

GAGGGGGAAGAGAAA GATTAAAGGAAGGAA

AGGGGGAAGAGAAAT ATTAAAGGAAGGAAA

GGGGGAAGAGAAATT TTAAAGGAAGGAAAA

GGGGAAGAGAAATTT TAAAGGAAGGAAAAG

GGGAAGAGAAATTTT AAAGGAAGGAAAAGT

GGAAGAGAAATTTTT

GAAGAGAAATTTTTA

AAGAGAAATTTTTAT

GAGAAATTTTTATTT

AGAAATTTTTATTTT

GAAATTTTTATTTTT

AAATTTTTATTTTTG

ATTTTTATTTTTGAA

TTTTTATTTTTGAAC

TTTTATTTTTGAACC

TTTATTTTTGAACCC

TATTTTTGAACCCCT

ATTTTTGAACCCCTG

TTTTTGAACCCCTGT

TTTTGAACCCCTGTG

TTGAACCCCTGTGTC

TGAACCCCTGTGTCC

GAACCCCTGTGTCCC

AACCCCTGTGTCCCT

CCCCTGTGTCCCTTT

CCCTGTGTCCCTTTT

CCTGTGTCCCTTTTG

CTGTGTCCCTTTTGC

GTGTCCCTTTTGCAT

TGTCCCTTTTGCATA

GTCCCTTTTGCATAA

TCCCTTTTGCATAAG

CCTTTTGCATAAGAT

CTTTTGCATAAGATT

TTTTGCATAAGATTA

TTTGCATAAGATTAA

TGCATAAGATTAAAG

GCATAAGATTAAAGG

CATAAGATTAAAGGA

ATAAGATTAAAGGAA

AAGATTAAAGGAAGG

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

TCAGCGCCCAGCCGC CCGTGTACTGTCGCC CAGCGTGCCCCGGTT

CAGCGCCCAGCCGCT CGTGTACTGTCGCCC AGCGTGCCCCGGTTG

GCGCCCAGCCGCTTC TGTACTGTCGCCCCA CGTGCCCCGGTTGCA

CGCCCAGCCGCTTCC GTACTGTCGCCCCAT GTGCCCCGGTTGCAG

GCCCAGCCGCTTCCT TACTGTCGCCCCATC TGCCCCGGTTGCAGG

CCCAGCCGCTTCCTG ACTGTCGCCCCATCC GCCCCGGTTGCAGGC

CAGCCGCTTCCTGCC TGTCGCCCCATCCCT CCCGGTTGCAGGCGT

AGCCGCTTCCTGCCT GTCGCCCCATCCCTG CCGGTTGCAGGCGTC

GCCGCTTCCTGCCTG TCGCCCCATCCCTGC CGGTTGCAGGCGTCA

CCGCTTCCTGCCTGG CGCCCCATCCCTGCG GGTTGCAGGCGTCAT

GCTTCCTGCCTGGAT CCCCATCCCTGCGCG TTGCAGGCGTCATGC

CTTCCTGCCTGGATT CCCATCCCTGCGCGC TGCAGGCGTCATGCA

TTCCTGCCTGGATTC CCATCCCTGCGCGCC GCAGGCGTCATGCAG

TCCTGCCTGGATTCC CATCCCTGCGCGCCC CAGGCGTCATGCAGC

CTGCCTGGATTCCAC TCCCTGCGCGCCCAG GGCGTCATGCAGCGG

TGCCTGGATTCCACA CCCTGCGCGCCCAGC GCGTCATGCAGCGGG

GCCTGGATTCCACAG CCTGCGCGCCCAGCC CGTCATGCAGCGGGC

CCTGGATTCCACAGC CTGCGCGCCCAGCCT GTCATGCAGCGGGCG

TGGATTCCACAGCTT GCGCGCCCAGCCTGC CATGCAGCGGGCGCG

GGATTCCACAGCTTC CGCGCCCAGCCTGCC ATGCAGCGGGCGCGA

GATTCCACAGCTTCG GCGCCCAGCCTGCCA TGCAGCGGGCGCGAC

ATTCCACAGCTTCGC CGCCCAGCCTGCCAA GCAGCGGGCGCGACC

TCCACAGCTTCGCGC CCCAGCCTGCCAAGC AGCGGGCGCGACCCA

CCACAGCTTCGCGCC CCAGCCTGCCAAGCA GCGGGCGCGACCCAC

CACAGCTTCGCGCCG CAGCCTGCCAAGCAG CGGGCGCGACCCACG

ACAGCTTCGCGCCGT AGCCTGCCAAGCAGC GGGCGCGACCCACGC

AGCTTCGCGCCGTGT CCTGCCAAGCAGCGT GCGCGACCCACGCTC

GCTTCGCGCCGTGTA CTGCCAAGCAGCGTG CGCGACCCACGCTCT

CTTCGCGCCGTGTAC TGCCAAGCAGCGTGC GCGACCCACGCTCTG

TTCGCGCCGTGTACT GCCAAGCAGCGTGCC CGACCCACGCTCTGG

CGCGCCGTGTACTGT CAAGCAGCGTGCCCC ACCCACGCTCTGGGC

GCGCCGTGTACTGTC AAGCAGCGTGCCCCG CCCACGCTCTGGGCC

CGCCGTGTACTGTCG AGCAGCGTGCCCCGG CCACGCTCTGGGCCG

CACGCTCTGGGCCGC GGTGGCGCGGGCTGG CGAGCCGTGCGACGC

ACGCTCTGGGCCGCT GTGGCGCGGGCTGGC GAGCCGTGCGACGCG

CGCTCTGGGCCGCTG TGGCGCGGGCTGGCG AGCCGTGCGACGCGC

GCTCTGGGCCGCTGC GGCGCGGGCTGGCGC GCCGTGCGACGCGCG

CTCTGGGCCGCTGCG GCGCGGGCTGGCGCG CCGTGCGACGCGCGT

TCTGGGCCGCTGCGC CGCGGGCTGGCGCGA CGTGCGACGCGCGTG

CTGGGCCGCTGCGCT GCGGGCTGGCGCGAG GTGCGACGCGCGTGC

TGGGCCGCTGCGCTG CGGGCTGGCGCGAGC TGCGACGCGCGTGCA

GGGCCGCTGCGCTGA GGGCTGGCGCGAGCT GCGACGCGCGTGCAC

GCCGCTGCGCTGACT GCTGGCGCGAGCTCG GACGCGCGTGCACTG

CCGCTGCGCTGACTC CTGGCGCGAGCTCGG ACGCGCGTGCACTGG

CGCTGCGCTGACTCT TGGCGCGAGCTCGGG CGCGCGTGCACTGGC

GCTGCGCTGACTCTG GGCGCGAGCTCGGGG GCGCGTGCACTGGCC

TGCGCTGACTCTGCT CGCGAGCTCGGGGGG GCGTGCACTGGCCCA

GCGCTGACTCTGCTG GCGAGCTCGGGGGGC CGTGCACTGGCCCAG

CGCTGACTCTGCTGG CGAGCTCGGGGGGCT GTGCACTGGCCCAGT

GCTGACTCTGCTGGT GAGCTCGGGGGGCTT TGCACTGGCCCAGTG

TGACTCTGCTGGTGC GCTCGGGGGGCTTGG CACTGGCCCAGTGCG

GACTCTGCTGGTGCT CTCGGGGGGCTTGGG ACTGGCCCAGTGCGC

ACTCTGCTGGTGCTG TCGGGGGGCTTGGGT CTGGCCCAGTGCGCG

CTCTGCTGGTGCTGC CGGGGGGCTTGGGTC TGGCCCAGTGCGCGC

CTGCTGGTGCTGCTC GGGGGCTTGGGTCCC GCCCAGTGCGCGCCT

TGCTGGTGCTGCTCC GGGGCTTGGGTCCCG CCCAGTGCGCGCCTC

GCTGGTGCTGCTCCG GGGCTTGGGTCCCGT CCAGTGCGCGCCTCC

CTGGTGCTGCTCCGC GGCTTGGGTCCCGTG CAGTGCGCGCCTCCG

GGTGCTGCTCCGCGG CTTGGGTCCCGTGGT GTGCGCGCCTCCGCC

GTGCTGCTCCGCGGG TTGGGTCCCGTGGTG TGCGCGCCTCCGCCC

TGCTGCTCCGCGGGC TGGGTCCCGTGGTGC GCGCGCCTCCGCCCG

GCTGCTCCGCGGGCC GGGTCCCGTGGTGCG CGCGCCTCCGCCCGC

TGCTCCGCGGGCCGC GTCCCGTGGTGCGCT CGCCTCCGCCCGCCG

GCTCCGCGGGCCGCC TCCCGTGGTGCGCTG GCCTCCGCCCGCCGT

CTCCGCGGGCCGCCG CCCGTGGTGCGCTGC CCTCCGCCCGCCGTG

TCCGCGGGCCGCCGG CCGTGGTGCGCTGCG CTCCGCCCGCCGTGT

CGCGGGCCGCCGGTG GTGGTGCGCTGCGAG CCGCCCGCCGTGTGC

GCGGGCCGCCGGTGG TGGTGCGCTGCGAGC CGCCCGCCGTGTGCG

CGGGCCGCCGGTGGC GGTGCGCTGCGAGCC GCCCGCCGTGTGCGC

GGGCCGCCGGTGGCG GTGCGCTGCGAGCCG CCCGCCGTGTGCGCG

GCCGCCGGTGGCGCG GCGCTGCGAGCCGTG CGCCGTGTGCGCGGA

CCGCCGGTGGCGCGG CGCTGCGAGCCGTGC GCCGTGTGCGCGGAG

CGCCGGTGGCGCGGG GCTGCGAGCCGTGCG CCGTGTGCGCGGAGC

GCCGGTGGCGCGGGC CTGCGAGCCGTGCGA CGTGTGCGCGGAGCT

CGGTGGCGCGGGCTG GCGAGCCGTGCGACG TGTGCGCGGAGCTGG

GTGCGCGGAGCTGGT ACTGAGCGAGGGCCA CCTTCGCTGCCAGCC

TGCGCGGAGCTGGTG CTGAGCGAGGGCCAG CTTCGCTGCCAGCCG

GCGCGGAGCTGGTGC TGAGCGAGGGCCAGC TTCGCTGCCAGCCGT

CGCGGAGCTGGTGCG GAGCGAGGGCCAGCC TCGCTGCCAGCCGTC

GCGGAGCTGGTGCGC AGCGAGGGCCAGCCG CGCTGCCAGCCGTCG

CGGAGCTGGTGCGCG GCGAGGGCCAGCCGT GCTGCCAGCCGTCGC

GGAGCTGGTGCGCGA CGAGGGCCAGCCGTG CTGCCAGCCGTCGCC

GAGCTGGTGCGCGAG GAGGGCCAGCCGTGC TGCCAGCCGTCGCCC

AGCTGGTGCGCGAGC AGGGCCAGCCGTGCG GCCAGCCGTCGCCCG

CTGGTGCGCGAGCCG GGCCAGCCGTGCGGC CAGCCGTCGCCCGAC

TGGTGCGCGAGCCGG GCCAGCCGTGCGGCA AGCCGTCGCCCGACG

GGTGCGCGAGCCGGG CCAGCCGTGCGGCAT GCCGTCGCCCGACGA

GTGCGCGAGCCGGGC CAGCCGTGCGGCATC CCGTCGCCCGACGAG

GCGCGAGCCGGGCTG GCCGTGCGGCATCTA GTCGCCCGACGAGGC

CGCGAGCCGGGCTGC CCGTGCGGCATCTAC TCGCCCGACGAGGCG

GCGAGCCGGGCTGCG ' CGTGCGGCATCTACA CGCCCGACGAGGCGC

CGAGCCGGGCTGCGG GTGCGGCATCTACAC. GCCCGACGAGGCGCG

AGCCGGGCTGCGGCT GCGGCATCTACACCG CCGACGAGGCGCGAC

GCCGGGCTGCGGCTG CGGCATCTACACCGA CGACGAGGCGCGACC

CCGGGCTGCGGCTGC GGCATCTACACCGAG GACGAGGCGCGACCG

CGGGCTGCGGCTGCT GCATCTACACCGAGC ACGAGGCGCGACCGC

GGCTGCGGCTGCTGC ATCTACACCGAGCGC GAGGCGCGACCGCTG

GCTGCGGCTGCTGCC TCTACACCGAGCGCT AGGCGCGACCGCTGC

CTGCGGCTGCTGCCT CTACACCGAGCGCTG GGCGCGACCGCTGCA

TGCGGCTGCTGCCTG TACACCGAGCGCTGT GCGCGACCGCTGCAG

CGGCTGCTGCCTGAC CACCGAGCGCTGTGG GCGACCGCTGCAGGC

GGCTGCTGCCTGACG ACCGAGCGCTGTGGC CGACCGCTGCAGGCG

GCTGCTGCCTGACGT CCGAGCGCTGTGGCT GACCGCTGCAGGCGC

CTGCTGCCTGACGTG CGAGCGCTGTGGCTC ACCGCTGCAGGCGCT

GCTGCCTGACGTGCG AGCGCTGTGGCTCCG CGCTGCAGGCGCTGC

CTGCCTGACGTGCGC GCGCTGTGGCTCCGG GCTGCAGGCGCTGCT

TGCCTGACGTGCGCA CGCTGTGGCTCCGGC CTGCAGGCGCTGCTG

GCCTGACGTGCGCAC GCTGTGGCTCCGGCC TGCAGGCGCTGCTGG

CTGACGTGCGCACTG TGTGGCTCCGGCCTT CAGGCGCTGCTGGAC

TGACGTGCGCACTGA GTGGCTCCGGCCTTC AGGCGCTGCTGGACG

GACGTGCGCACTGAG TGGCTCCGGCCTTCG GGCGCTGCTGGACGG

ACGTGCGCACTGAGC GGCTCCGGCCTTCGC GCGCTGCTGGACGGC

GTGCGCACTGAGCGA CTCCGGCCTTCGCTG GCTGCTGGACGGCCG

TGCGCACTGAGCGAG TCCGGCCTTCGCTGC CTGCTGGACGGCCGC

GCGCACTGAGCGAGG CCGGCCTTCGCTGCC TGCTGGACGGCCGCG

CGCACTGAGCGAGGG CGGCCTTCGCTGCCA GCTGGACGGCCGCGG

SOGCACTGAGCGAGGGC GGCCTTCGCTGCCAG CTGGACGGCCGCGGG

CACTGAGCGAGGGCC GCCTTCGCTGCCAGC TGGACGGCCGCGGGC

GGACGGCCGCGGGCT CTACCTGCTGCCAGC AGACCGCAGCGCCGG

GACGGCCGCGGGCTC TACCTGCTGCCAGCG GACCGCAGCGCCGGC

ACGGCCGCGGGCTCT ACCTGCTGCCAGCGC ACCGCAGCGCCGGCA

CGGCCGCGGGCTCTG CCTGCTGCCAGCGCC CCGCAGCGCCGGCAG

GGCCGCGGGCTCTGC CTGCTGCCAGCGCCG CGCAGCGCCGGCAGT

GCCGCGGGCTCTGCG TGCTGCCAGCGCCGC GCAGCGCCGGCAGTG

CCGCGGGCTCTGCGT GCTGCCAGCGCCGCC CAGCGCCGGCAGTGT

CGCGGGCTCTGCGTC CTGCCAGCGCCGCCA AGCGCCGGCAGTGTG

GCGGGCTCTGCGTCA TGCCAGCGCCGCCAG GCGCCGGCAGTGTGG

GGGCTCTGCGTCAAC CCAGCGCCGCCAGCT GCCGGCAGTGTGGAG

GGCTCTGCGTCAACG CAGCGCCGCCAGCTC CCGGCAGTGTGGAGA

GCTCTGCGTCAACGC AGCGCCGCCAGCTCC CGGCAGTGTGGAGAG

CTCTGCGTCAACGCT GCGCCGCCAGCTCCA GGCAGTGTGGAGAGC

CTGCGTCAACGCTAG GCCGCCAGCTCCAGG CAGTGTGGAGAGCCC

TGCGTCAACGCTAGT CCGCCAGCTCCAGGA AGTGTGGAGAGCCCG

GCGTCAACGCTAGTG CGCCAGCTCCAGGAA GTGTGGAGAGCCCGT

CGTCAACGCTAGTGC GCCAGCTCCAGGAAA TGTGGAGAGCCCGTC

TCAACGCTAGTGCCG CAGCTCCAGGAAATG TGGAGAGCCCGTCCG

CAACGCTAGTGCCGT AGCTCCAGGAAATGC GGAGAGCCCGTCCGT

AACGCTAGTGCCGTC GCTCCAGGAAATGCT GAGAGCCCGTCCGTC

ACGCTAGTGCCGTCA CTCCAGGAAATGCTA AGAGCCCGTCCGTCT

GCTAGTGCCGTCAGC CCAGGAAATGCTAGT AGCCCGTCCGTCTCC

CTAGTGCCGTCAGCC CAGGAAATGCTAGTG GCCCGTCCGTCTCCA

TAGTGCCGTCAGCCG AGGAAATGCTAGTGA CCCGTCCGTCTCCAG

AGTGCCGTCAGCCGC GGAAATGCTAGTGAG CCGTCCGTCTCCAGC

TGCCGTCAGCCGCCT AAATGCTAGTGAGTC GTCCGTCTCCAGCAC

GCCGTCAGCCGCCTG AATGCTAGTGAGTCG TCCGTCTCCAGCACG

CCGTCAGCCGCCTGC ATGCTAGTGAGTCGG CCGTCTCCAGCACGC

CGTCAGCCGCCTGCG TGCTAGTGAGTCGGA CGTCTCCAGCACGCA

TCAGCCGCCTGCGCG CTAGTGAGTCGGAGG TCTCCAGCACGCACC

CAGCCGCCTGCGCGC TAGTGAGTCGGAGGA CTCCAGCACGCACCG

AGCCGCCTGCGCGCC AGTGAGTCGGAGGAA TCCAGCACGCACCGG

GCCGCCTGCGCGCCT GTGAGTCGGAGGAAG CCAGCACGCACCGGG

CGCCTGCGCGCCTAC GAGTCGGAGGAAGAC AGCACGCACCGGGTG

GCCTGCGCGCCTACC AGTCGGAGGAAGACC GCACGCACCGGGTGT

CCTGCGCGCCTACCT GTCGGAGGAAGACCG CACGCACCGGGTGTC

CTGCGCGCCTACCTG TCGGAGGAAGACCGC ACGCACCGGGTGTCT

GCGCGCCTACCTGCT GGAGGAAGACCGCAG GCACCGGGTGTCTGA

CGCGCCTACCTGCTG GAGGAAGACCGCAGC CACCGGGTGTCTGAT

GCGCCTACCTGCTGC AGGAAGACCGCAGCG ACCGGGTGTCTGATC

CGCCTACCTGCTGCC GGAAGACCGCAGCGC CCGGGTGTCTGATCC

CCTACCTGCTGCCAG AAGACCGCAGCGCCG GGGTGTCTGATCCCA

GGTGTCTGATCCCAA GAAAGGGCATGCTAA GAGCACAGATACCCA

GTGTCTGATCCCAAG AAAGGGCATGCTAAA AGCACAGATACCCAG

TGTCTGATCCCAAGT AAGGGCATGCTAAAG GCACAGATACCCAGA

GTCTGATCCCAAGTT AGGGCATGCTAAAGA CACAGATACCCAGAA

TCTGATCCCAAGTTC GGGCATGCTAAAGAC ACAGATACCCAGAAC

CTGATCCCAAGTTCC GGCATGCTAAAGACA CAGATACCCAGAACT

TGATCCCAAGTTCCA GCATGCTAAAGACAG AGATACCCAGAACTT

GATCCCAAGTTCCAC CATGCTAAAGACAGC GATACCCAGAACTTC

ATCCCAAGTTCCACC ATGCTAAAGACAGCC ATACCCAGAACTTCT

CCCAAGTTCCACCCC GCTAAAGACAGCCAG ACCCAGAACTTCTCC

CCAAGTTCCACCCCC CTAAAGACAGCCAGC CCCAGAACTTCTCCT

CAAGTTCCACCCCCT TAAAGACAGCCAGCG CCAGAACTTCTCCTC

AAGTTCCACCCCCTC AAAGACAGCCAGCGC CAGAACTTCTCCTCC

GTTCCACCCCCTCCA AGACAGCCAGCGCTA GAACTTCTCCTCCGA

TTCCACCCCCTCCAT GACAGCCAGCGCTAC AACTTCTCCTCCGAG

TCCACCCCCTCCATT ACAGCCAGCGCTACA ACTTCTCCTCCGAGT

CCACCCCCTCCATTC CAGCCAGCGCTACAA CTTCTCCTCCGAGTC

ACCCCCTCCATTCAA GCCAGCGCTACAAAG TCTCCTCCGAGTCCA

CCCCCTCCATTCAAA CCAGCGCTACAAAGT CTCCTCCGAGTCCAA

CCCCTCCATTCAAAG CAGCGCTACAAAGTT TCCTCCGAGTCCAAG

CCCTCCATTCAAAGA AGCGCTACAAAGTTG CCTCCGAGTCCAAGC

CTCCATTCAAAGATA CGCTACAAAGTTGAC TCCGAGTCCAAGCGG

TCCATTCAAAGATAA GCTACAAAGTTGACT CCGAGTCCAAGCGGG

CCATTCAAAGATAAT CTACAAAGTTGACTA CGAGTCCAAGCGGGA

CATTCAAAGATAATC TACAAAGTTGACTAC GAGTCCAAGCGGGAG

TTCAAAGATAATCAT CAAAGTTGACTACGA GTCCAAGCGGGAGAC

TCAAAGATAATCATC AAAGTTGACTACGAG TCCAAGCGGGAGACA

CAAAGATAATCATCA AAGTTGACTACGAGT CCAAGCGGGAGACAG

AAAGATAATCATCAT AGTTGACTACGAGTC CAAGCGGGAGACAGA

AGATAATCATCATCA TTGACTACGAGTCTC AGCGGGAGACAGAAT

GATAATCATCATCAA TGACTACGAGTCTCA GCGGGAGACAGAATA

ATAATCATCATCAAG GACTACGAGTCTCAG CGGGAGACAGAATAT

TAATCATCATCAAGA ACTACGAGTCTCAGA GGGAGACAGAATATG

ATCATCATCAAGAAA TACGAGTCTCAGAGC GAGACAGAATATGGT

TCATCATCAAGAAAG ACGAGTCTCAGAGCA AGACAGAATATGGTC

CATCATCAAGAAAGG CGAGTCTCAGAGCAC GACAGAATATGGTCC

ATCATCAAGAAAGGG GAGTCTCAGAGCACA ACAGAATATGGTCCC

CATCAAGAAAGGGCA GTCTCAGAGCACAGA AGAATATGGTCCCTG

ATCAAGAAAGGGCAT TCTCAGAGCACAGAT GAATATGGTCCCTGC

TCAAGAAAGGGCATG CTCAGAGCACAGATA AATATGGTCCCTGCC

CAAGAAAGGGCATGC TCAGAGCACAGATAC ATATGGTCCCTGCCG

AGAAAGGGCATGCTA AGAGCACAGATACCC ATGGTCCCTGCCGTA

TGGTCCCTGCCGTAG CAATGTGCTGAGTCC ATTTTATAAGAA.AAA

GGTCCCTGCCGTAGA AATGTGCTGAGTCCC TTTTATAAGAAAAAG

GTCCCTGCCGTAGAG ATGTGCTGAGTCCCA TTTATAAGAAAAAGC

TCCCTGCCGTAGAGA TGTGCTGAGTCCCAG TTATAAGAAAAAGCA

CCCTGCCGTAGAGAA GTGCTGAGTCCCAGG TATAAGAAAAAGCAG

CCTGCCGTAGAGAAA TGCTGAGTCCCAGGG ATAAGAAAAAGCAGT

CTGCCGTAGAGAAAT GCTGAGTCCCAGGGG TAAGAA.AAAGCAGTG

TGCCGTAGAGAAATG CTGAGTCCCAGGGGT AAGAAAAAGCAGTGT

GCCGTAGAGAAATGG TGAGTCCCAGGGGTG AGAAAAAGCAGTGTC

CGTAGAGAAATGGAA AGTCCCAGGGGTGTA AAAAAGCAGTGTCGC

GTAGAGAAATGGAAG GTCCCAGGGGTGTAC AAAAGCAGTGTCGCC

TAGAGAAATGGAAGA TCCCAGGGGTGTACA AAAGCAGTGTCGCCC

AGAGAAATGGAAGAC CCCAGGGGTGTACAC AAGCAGTGTCGCCCT

AGAAATGGAAGACAC CAGGGGTGTACACAT GCAGTGTCGCCCTTC

GAAATGGAAGACACA AGGGGTGTACACATT CAGTGTCGCCCTTCC

AAATGGAAGACACAC GGGGTGTACACATTC AGTGTCGCCCTTCCA

AATGGAAGACACACT GGGTGTACACATTCC GTGTCGCCCTTCCAA

TGGAAGACACACTGA GTGTACACATTCCCA GTCGCCCTTCCAAAG

GGAAGACACACTGAA TGTACACATTCCCAA TCGCCCTTCCAAAGG

GAAGACACACTGAAT GTACACATTCCCAAC CGCCCTTCCAAAGGC

AAGACACACTGAATC TACACATTCCCAACT GCCCTTCCAAAGGCA

GACACACTGAATCAC CACATTCCCAACTGT CCTTCCAAAGGCAGG

ACACACTGAATCACC ACATTCCCAACTGTG CTTCCAAAGGCAGGA

CACACTGAATCACCT CATTCCCAACTGTGA TTCCAAAGGCAGGAA

ACACTGAATCACCTG ATTCCCAACTGTGAC TCCAAAGGCAGGAAG

ACTGAATCACCTGAA TCCCAACTGTGACAA CAAAGGCAGGAAGCG

CTGAATCACCTGAAG CCCAACTGTGACAAG AAAGGCAGGAAGCGG

TGAATCACCTGAAGT CCAACTGTGACAAGA AAGGCAGGAAGCGGG

GAATCACCTGAAGTT CAACTGTGACAAGAA AGGCAGGAAGCGGGG

ATCACCTGAAGTTCC ACTGTGACAAGAAGG GCAGGAAGCGGGGCT

TCACCTGAAGTTCCT CTGTGACAAGAAGGG CAGGAAGCGGGGCTT

CACCTGAAGTTCCTC TGTGACAAGAAGGGA AGGAAGCGGGGCTTC

ACCTGAAGTTCCTCA GTGACAAGAAGGGAT GGAAGCGGGGCTTCT

CTGAAGTTCCTCAAT GACAAGAAGGGATTT AAGCGGGGCTTCTGC

TGAAGTTCCTCAATG ACAAGAAGGGATTTT AGCGGGGCTTCTGCT

GAAGTTCCTCAATGT CAAGAAGGGATTTTA GCGGGGCTTCTGCTG

AAGTTCCTCAATGTG AAGAAGGGATTTTAT CGGGGCTTCTGCTGG

GTTCCTCAATGTGCT GAAGGGATTTTATAA GGGCTTCTGCTGGTG

TTCCTCAATGTGCTG AAGGGATTTTATAAG GGCTTCTGCTGGTGT

TCCTCAATGTGCTGA AGGGATTTTATAAGA GCTTCTGCTGGTGTG

CCTCAATGTGCTGAG GGGATTTTATAAGAA CTTCTGCTGGTGTGT

TCAATGTGCTGAGTC GATTTTATAAGAAAA TCTGCTGGTGTGTGG

CTGCTGGTGTGTGGA GGGGAAGGAGGACGT CGCAAGTTAATGTGG

TGCTGGTGTGTGGAT GGGAAGGAGGACGTG GCAAGTTAATGTGGA

GCTGGTGTGTGGATA GGAAGGAGGACGTGC CAAGTTAATGTGGAG

CTGGTGTGTGGATAA GAAGGAGGACGTGCA AAGTTAATGTGGAGC

S TGGTGTGTGGATAAG AAGGAGGACGTGCAC AGTTAATGTGGAGCT

GGTGTGTGGATAAGT AGGAGGACGTGCACT GTTAATGTGGAGCTC

GTGTGTGGATAAGTA GGAGGACGTGCACTG TTAATGTGGAGCTCA

TGTGTGGATAAGTAT GAGGACGTGCACTGC TAATGTGGAGCTCAA

GTGTGGATAAGTATG AGGACGTGCACTGCT AATGTGGAGCTCAAA

GTGGATAAGTATGGG GACGTGCACTGCTAC TGTGGAGCTCAAATA

TGGATAAGTATGGGC ACGTGCACTGCTACA GTGGAGCTCAAATAT

GGATAAGTATGGGCA CGTGCACTGCTACAG TGGAGCTCAAATATG

GATAAGTATGGGCAG GTGCACTGCTACAGC GGAGCTCAAATATGC

TAAGTATGGGCAGCC GCACTGCTACAGCAT AGCTCAAATATGCCT

AAGTATGGGCAGCCT CACTGCTACAGCATG GCTCAAATATGCCTT

AGTATGGGCAGCCTC ACTGCTACAGCATGC CTCAAATATGCCTTA

GTATGGGCAGCCTCT CTGCTACAGCATGCA TCAAATATGCCTTAT

ATGGGCAGCCTCTCC GCTACAGCATGCAGA AAATATGCCTTATTT

TGGGCAGCCTCTCCC CTACAGCATGCAGAG AATATGCCTTATTTT

GGGCAGCCTCTCCCA TACAGCATGCAGAGC ATATGCCTTATTTTG

GGCAGCCTCTCCCAG ACAGCATGCAGAGCA TATGCCTTATTTTGC

CAGCCTCTCCCAGGC AGCATGCAGAGCAAG TGCCTTATTTTGCAC

AGCCTCTCCCAGGCT GCATGCAGAGCAAGT GCCTTATTTTGCACA

GCCTCTCCCAGGCTA CATGCAGAGCAAGTA CCTTATTTTGCACAA

CCTCTCCCAGGCTAC ATGCAGAGCAAGTAG CTTATTTTGCACAAA

TCTCCCAGGCTACAC GCAGAGCAAGTAGAC TATTTTGCACAAAAG

CTCCCAGGCTACACC CAGAGCAAGTAGACG ATTTTGCACAAAAGA

TCCCAGGCTACACCA AGAGCAAGTAGACGC TTTTGCACAAAAGAC

CCCAGGCTACACCAC GAGCAAGTAGACGCC TTTGCACAAAAGACT

CAGGCTACACCACCA GCAAGTAGACGCCTG TGCACAAAAGACTGC

AGGCTACACCACCAA CAAGTAGACGCCTGC GCACAAAAGACTGCC

GGCTACACCACCAAG AAGTAGACGCCTGCC CACAAAAGACTGCCA

GCTACACCACCAAGG AGTAGACGCCTGCCG ACAAAAGACTGCCAA

TACACCACCAAGGGG TAGACGCCTGCCGCA AAAAGACTGCCAAGG

ACACCACCAAGGGGA AGACGCCTGCCGCAA AAAGACTGCCAAGGA

CACCACCAAGGGGAA GACGCCTGCCGCAAG AAGACTGCCAAGGAC

ACCACCAAGGGGAAG ACGCCTGCCGCAAGT AGACTGCCAAGGACA

CACCAAGGGGAAGGA GCCTGCCGCAAGTTA ACTGCCAAGGACATG

ACCAAGGGGAAGGAG CCTGCCGCAAGTTAA CTGCCAAGGACATGA

CCAAGGGGAAGGAGG CTGCCGCAAGTTAAT TGCCAAGGACATGAC

CAAGGGGAAGGAGGA TGCCGCAAGTTAATG GCCAAGGACATGACC

SOAAGGGGAAGGAGGAC GCCGCAAGTTAATGT CCAAGGACATGACCA

AGGGGAAGGAGGACG CCGCAAGTTAATGTG CAAGGACATGACCAG

AAGGACATGACCAGC GTGAACTGATTTTTT TATGGTTTCTTTGAA

AGGACATGACCAGCA TGAACTGATTTTTTT ATGGTTTCTTTGAAT

GGACATGACCAGCAG GAACTGATTTTTTTT TGGTTTCTTTGAATG

GACATGACCAGCAGC AACTGATTTTTTTTA GGTTTCTTTGAATGG

ACATGACCAGCAGCT ACTGATTTTTTTTAA GTTTCTTTGAATGGT

CATGACCAGCAGCTG CTGATTTTTTTTAAA TTTCTTTGAATGGTA

ATGACCAGCAGCTGG TGATTTTTTTTAAAC TTCTTTGAATGGTAA

TGACCAGCAGCTGGC GATTTTTTTTAAACC TCTTTGAATGGTAAA

GACCAGCAGCTGGCT ATTTTTTTTAAACCA CTTTGAATGGTAAAC

CCAGCAGCTGGCTAC TTTTTTTAAACCAAA TTGAATGGTAAACTT

CAGCAGCTGGCTACA TTTTTTAAACCAAAG TGAATGGTAAACTTG

AGCAGCTGGCTACAG TTTTTAAACCAAAGT GAATGGTAAACTTGA

GCAGCTGGCTACAGC TTTTAAACCAAAGTT AATGGTAAACTTGAG

AGCTGGCTACAGCCT TTAAACCAAAGTTTA TGGTAAACTTGAGCA

GCTGGCTACAGCCTC TAAACCAAAGTTTAG GGTAAACTTGAGCAT

CTGGCTACAGCCTCG AAACCAAAGTTTAGA GTAAACTTGAGCATC

TGGCTACAGCCTCGA AACCAAAGTTTAGAA TAAACTTGAGCATCT

GCTACAGCCTCGATT CCAAAGTTTAGAAAG AACTTGAGCATCTTT

CTACAGCCTCGATTT CAAAGTTTAGAAAGA ACTTGAGCATCTTTT

TACAGCCTCGATTTA AAAGTTTAGAAAGAG CTTGAGCATCTTTTC

ACAGCCTCGATTTAT AAGTTTAGAAAGAGG TTGAGCATCTTTTCA

AGCCTCGATTTATAT GTTTAGAAAGAGGTT GAGCATCTTTTCACT

GCCTCGATTTATATT TTTAGAAAGAGGTTT AGCATCTTTTCACTT

CCTCGATTTATATTT TTAGAAAGAGGTTTT GCATCTTTTCACTTT

CTCGATTTATATTTC TAGAAAGAGGTTTTT CATCTTTTCACTTTC

CGATTTATATTTCTG GAAAGAGGTTTTTGA TCTTTTCACTTTCCA

GATTTATATTTCTGT AAAGAGGTTTTTGAA CTTTTCACTTTCCAG

ATTTATATTTCTGTT AAGAGGTTTTTGAAA TTTTCACTTTCCAGT

TTTATATTTCTGTTT AGAGGTTTTTGAAAT TTTCACTTTCCAGTA

TATATTTCTGTTTGT AGGTTTTTGAAATGC TCACTTTCCAGTAGT

ATATTTCTGTTTGTG GGTTTTTGAAATGCC CACTTTCCAGTAGTC

TATTTCTGTTTGTGG GTTTTTGAAATGCCT ACTTTCCAGTAGTCA

ATTTCTGTTTGTGGT TTTTTGAAATGCCTA CTTTCCAGTAGTCAG

TTCTGTTTGTGGTGA TTTGAAATGCCTATG TTCCAGTAGTCAGCA

TCTGTTTGTGGTGAA TTGAAATGCCTATGG TCCAGTAGTCAGCAA

CTGTTTGTGGTGAAC TGAAATGCCTATGGT CCAGTAGTCAGCAAA

TGTTTGTGGTGAACT GAAATGCCTATGGTT CAGTAGTCAGCAAAG

TTTGTGGTGAACTGA AATGCCTATGGTTTC GTAGTCAGCAAAGAG

TTGTGGTGAACTGAT ATGCCTATGGTTTCT TAGTCAGCAAAGAGC

TGTGGTGAACTGATT TGCCTATGGTTTCTT AGTCAGCAAAGAGCA

GTGGTGAACTGATTT GCCTATGGTTTCTTT GTCAGCAAAGAGCAG

GGTGAACTGATTTTT CTATGGTTTCTTTGA CAGCAAAGAGCAGTT

AGCAAAGAGCAGTTT ACTCGAGCACAGCAC TTGGTCGAAGCGGCC

GCAAAGAGCAGTTTG CTCGAGCACAGCACC TGGTCGAAGCGGCCG

CAAAGAGCAGTTTGA TCGAGCACAGCACCC GGTCGAAGCGGCCGA

AAAGAGCAGTTTGAA CGAGCACAGCACCCA GTCGAAGCGGCCGAC

AAGAGCAGTTTGAAT GAGCACAGCACCCAG TCGAAGCGGCCGACC

AGAGCAGTTTGAATT AGCACAGCACCCAGA CGAAGCGGCCGACCA

GAGCAGTTTGAATTT GCACAGCACCCAGAC GAAGCGGCCGACCAC

AGCAGTTTGAATTTT CACAGCACCCAGACT AAGCGGCCGACCACT

GCAGTTTGAATTTTC ACAGCACCCAGACTT AGCGGCCGACCACTG

AGTTTGAATTTTCTT AGCACCCAGACTTCA CGGCCGACCACTGAC

GTTTGAATTTTCTTG GCACCCAGACTTCAT GGCCGACCACTGACT

TTTGAATTTTCTTGT CACCCAGACTTCATG GCCGACCACTGACTT

TTGAATTTTCTTGTC ACCCAGACTTCATGC CCGACCACTGACTTT

GAATTTTCTTGTCGC CCAGACTTCATGCGC GACCACTGACTTTGT

AATTTTCTTGTCGCT CAGACTTCATGCGCC ACCACTGACTTTGTG

ATTTTCTTGTCGCTT AGACTTCATGCGCCC CCACTGACTTTGTGA

TTTTCTTGTCGCTTC GACTTCATGCGCCCG CACTGACTTTGTGAC

TTCTTGTCGCTTCCT CTTCATGCGCCCGTG CTGACTTTGTGACTT

TCTTGTCGCTTCCTA TTCATGCGCCCGTGG TGACTTTGTGACTTA

CTTGTCGCTTCCTAT TCATGCGCCCGTGGA GACTTTGTGACTTAG

TTGTCGCTTCCTATC CATGCGCCCGTGGAA ACTTTGTGACTTAGG

GTCGCTTCCTATCAA TGCGCCCGTGGAATG TTTGTGACTTAGGCG

TCGCTTCCTATCAAA GCGCCCGTGGAATGC TTGTGACTTAGGCGG

CGCTTCCTATCAAAA CGCCCGTGGAATGCT TGTGACTTAGGCGGC

GCTTCCTATCAAAAT GCCCGTGGAATGCTC GTGACTTAGGCGGCT

TTCCTATCAAAATAT CCGTGGAATGCTCAC GACTTAGGCGGCTGT

TCCTATCAAAATATT CGTGGAATGCTCACC ACTTAGGCGGCTGTG

CCTATCAAAATATTC GTGGAATGCTCACCA CTTAGGCGGCTGTGT

CTATCAAAATATTCA TGGAATGCTCACCAC TTAGGCGGCTGTGTT

ATCAAAATATTCAGA GAATGCTCACCACAT AGGCGGCTGTGTTGC

TCAAAATATTCAGAG AATGCTCACCACATG GGCGGCTGTGTTGCC

CAAAATATTCAGAGA ATGCTCACCACATGT GCGGCTGTGTTGCCT

AAAATATTCAGAGAC TGCTCACCACATGTT CGGCTGTGTTGCCTA

AATATTCAGAGACTC CTCACCACATGTTGG GCTGTGTTGCCTATG

ATATTCAGAGACTCG TCACCACATGTTGGT CTGTGTTGCCTATGT

TATTCAGAGACTCGA CACCACATGTTGGTC TGTGTTGCCTATGTA

ATTCAGAGACTCGAG ACCACATGTTGGTCG GTGTTGCCTATGTAG

TCAGAGACTCGAGCA CACATGTTGGTCGAA GTTGCCTATGTAGAG

CAGAGACTCGAGCAC ACATGTTGGTCGAAG TTGCCTATGTAGAGA

AGAGACTCGAGCACA CATGTTGGTCGAAGC TGCCTATGTAGAGAA

GAGACTCGAGCACAG ATGTTGGTCGAAGCG GCCTATGTAGAGAAC

GACTCGAGCACAGCA GTTGGTCGAAGCGGC CTATGTAGAGAACAC

TATGTAGAGAACACG TATCGAGAATAGGAA ATGCTCCTGGAGCTC

ATGTAGAGAACACGC ATCGAGAATAGGAAA TGCTCCTGGAGCTCA

TGTAGAGAACACGCT TCGAGAATAGGAAAA GCTCCTGGAGCTCAC

GTAGAGAACACGCTT CGAGAATAGGAAAAC CTCCTGGAGCTCACA

TAGAGAACACGCTTC GAGAATAGGAAAACC TCCTGGAGCTCACAG

AGAGAACACGCTTCA AGAATAGGAAAACCT CCTGGAGCTCACAGC

GAGAACACGCTTCAC GAATAGGAAAACCTT CTGGAGCTCACAGCC

AGAACACGCTTCACC AATAGGAAAACCTTT TGGAGCTCACAGCCT

GAACACGCTTCACCC ATAGGAAAACCTTTA GGAGCTCACAGCCTT

ACACGCTTCACCCCC AGGAAAACCTTTAAA AGCTCACAGCCTTCT

CACGCTTCACCCCCA GGAAAACCTTTAAAC GCTCACAGCCTTCTG

ACGCTTCACCCCCAC GAAAACCTTTAAACC CTCACAGCCTTCTGT

CGCTTCACCCCCACT AAAACCTTTAAACCC TCACAGCCTTCTGTG

CTTCACCCCCACTCC AACCTTTAAACCCCG ACAGCCTTCTGTGGT

TTCACCCCCACTCCC ACCTTTAAACCCCGG CAGCCTTCTGTGGTG

TCACCCCCACTCCCC CCTTTAAACCCCGGT AGCCTTCTGTGGTGT

CACCCCCACTCCCCG CTTTAAACCCCGGTC GCCTTCTGTGGTGTC

CCCCCACTCCCCGTA TTAAACCCCGGTCAT CTTCTGTGGTGTCAT

CCCCACTCCCCGTAC TAAACCCCGGTCATC TTCTGTGGTGTCATT

CCCACTCCCCGTACA AAACCCCGGTCATCC TCTGTGGTGTCATTT

CCACTCCCCGTACAG AACCCCGGTCATCCG CTGTGGTGTCATTTC

ACTCCCCGTACAGTG CCCCGGTCATCCGGA GTGGTGTCATTTCTG

CTCCCCGTACAGTGC CCCGGTCATCCGGAC TGGTGTCATTTCTGA

TCCCCGTACAGTGCG CCGGTCATCCGGACA GGTGTCATTTCTGAA

CCCCGTACAGTGCGC CGGTCATCCGGACAT GTGTCATTTCTGAAA

CCGTACAGTGCGCAC GTCATCCGGACATCC GTCATTTCTGAAACA

CGTACAGTGCGCACA TCATCCGGACATCCC TCATTTCTGAAACAA

GTACAGTGCGCACAG CATCCGGACATCCCA CATTTCTGAAACAAG

TACAGTGCGCACAGG ATCCGGACATCCCAA ATTTCTGAAACAAGG

CAGTGCGCACAGGCT CCGGACATCCCAACG TTCTGAAACAAGGGC

AGTGCGCACAGGCTT CGGACATCCCAACGC TCTGAAACAAGGGCG

GTGCGCACAGGCTTT GGACATCCCAACGCA CTGAAACAAGGGCGT

TGCGCACAGGCTTTA GACATCCCAACGCAT TGAAACAAGGGCGTG

CGCACAGGCTTTATC CATCCCAACGCATGC AAACAAGGGCGTGGA

GCACAGGCTTTATCG ATCCCAACGCATGCT AACAAGGGCGTGGAT

CACAGGCTTTATCGA TCCCAACGCATGCTC ACAAGGGCGTGGATC

ACAGGCTTTATCGAG CCCAACGCATGCTCC CAAGGGCGTGGATCC

AGGCTTTATCGAGAA CAACGCATGCTCCTG AGGGCGTGGATCCCT

GGCTTTATCGAGAAT AACGCATGCTCCTGG GGGCGTGGATCCCTC

GCTTTATCGAGAATA ACGCATGCTCCTGGA GGCGTGGATCCCTCA

CTTTATCGAGAATAG CGCATGCTCCTGGAG GCGTGGATCCCTCAA

TTATCGAGAATAGGA CATGCTCCTGGAGCT GTGGATCCCTCAACC

TGGATCCCTCAACCA TTGGGGACTATTGGA GTATCTAAGAATGTT

GGATCCCTCAACCAA TGGGGACTATTGGAG TATCTAAGAATGTTC

GATCCCTCAACCAAG GGGGACTATTGGAGA ATCTAAGAATGTTCT

ATCCCTCAACCAAGA GGGACTATTGGAGAA TCTAAGAATGTTCTA

S TCCCTCAACCAAGAA GGACTATTGGAGAAA CTAAGAATGTTCTAG

CCCTCAACCAAGAAG GACTATTGGAGAAAA TAAGAATGTTCTAGG

CCTCAACCAAGAAGA ACTATTGGAGAAAAT AAGAATGTTCTAGGG

CTCAACCAAGAAGAA CTATTGGAGAAAATA AGAATGTTCTAGGGC

TCAACCAAGAAGAAT TATTGGAGAAAATAA GAATGTTCTAGGGCA

AACCAAGAAGAATGT TTGGAGAAAATAAGG ATGTTCTAGGGCACT

ACCAAGAAGAATGTT TGGAGAAAATAAGGT TGTTCTAGGGCACTC

CCAAGAAGAATGTTT GGAGAAAATAAGGTG GTTCTAGGGCACTCT

CAAGAAGAATGTTTA GAGAAAATAAGGTGG TTCTAGGGCACTCTG

AGAAGAATGTTTATG GAAAATAAGGTGGAG CTAGGGCACTCTGGG

GAAGAATGTTTATGT AAAATAAGGTGGAGT TAGGGCACTCTGGGA

AAGAATGTTTATGTC AAATAAGGTGGAGTC AGGGCACTCTGGGAA

AGAATGTTTATGTCT AATAAGGTGGAGTCC GGGCACTCTGGGAAC

AATGTTTATGTCTTC TAAGGTGGAGTCCTA GCACTCTGGGAACCT

ATGTTTATGTCTTCA AAGGTGGAGTCCTAC CACTCTGGGAACCTA

TGTTTATGTCTTCAA AGGTGGAGTCCTACT ACTCTGGGAACCTAT

GTTTATGTCTTCAAG GGTGGAGTCCTACTT CTCTGGGAACCTATA

TTATGTCTTCAAGTG TGGAGTCCTACTTGT CTGGGAACCTATAAA

TATGTCTTCAAGTGA GGAGTCCTACTTGTT TGGGAACCTATAAAG

ATGTCTTCAAGTGAC GAGTCCTACTTGTTT GGGAACCTATAAAGG

TGTCTTCAAGTGACC AGTCCTACTTGTTTA GGAACCTATAAAGGC

TCTTCAAGTGACCTG TCCTACTTGTTTAAA AACCTATAAAGGCAG

CTTCAAGTGACCTGT CCTACTTGTTTAAAA ACCTATAAAGGCAGG

TTCAAGTGACCTGTA CTACTTGTTTAAAAA CCTATAAAGGCAGGT

TCAAGTGACCTGTAC TACTTGTTTAAAAAA CTATAAAGGCAGGTA

AAGTGACCTGTACTG CTTGTTTAAAAAATA ATAAAGGCAGGTATT

AGTGACCTGTACTGC TTGTTTAAAAAATAT TAAAGGCAGGTATTT

GTGACCTGTACTGCT TGTTTAAAAAATATG AAAGGCAGGTATTTC

TGACCTGTACTGCTT GTTTAAAAAATATGT AAGGCAGGTATTTCG

40GACCTGTACTGCTTG TTTAA.AA.A.ATATGTA AGGCAGGTATTTCGG

ACCTGTACTGCTTGG TTAAAAAATATGTAT GGCAGGTATTTCGGG

CCTGTACTGCTTGGG TAAAAAATATGTATC GCAGGTATTTCGGGC

CTGTACTGCTTGGGG AAAAAATATGTATCT CAGGTATTTCGGGCC

TGTACTGCTTGGGGA AAAAATATGTATCTA AGGTATTTCGGGCCC

TACTGCTTGGGGACT AAATATGTATCTAAG GTATTTCGGGCCCTC

ACTGCTTGGGGACTA AATATGTATCTAAGA TATTTCGGGCCCTCC

CTGCTTGGGGACTAT ATATGT'ATCTAAGAA ATTTCGGGCCCTCCT

TGCTTGGGGACTATT TATGTATCTAAGAAT TTTCGGGCCCTCCTC

SOGCTTGGGGACTATTG ATGTATCTAAGAATG TTCGGGCCCTCCTCT

CTTGGGGACTATTGG TGTATCTAAGAATGT TCGGGCCCTCCTCTT

CGGGCCCTCCTCTTC CAGGATGGCTTTTGC AGAGTCAGCCTCCAC

GGGCCCTCCTCTTCA AGGATGGCTTTTGCT GAGTCAGCCTCCACA

GGCCCTCCTCTTCAG GGATGGCTTTTGCTG AGTCAGCCTCCACAT

GCCCTCCTCTTCAGG GATGGCTTTTGCTGC GTCAGCCTCCACATT

CCCTCCTCTTCAGGA ATGGCTTTTGCTGCG TCAGCCTCCACATTC

CCTCCTCTTCAGGAA TGGCTTTTGCTGCGG CAGCCTCCACATTCA

CTCCTCTTCAGGAAT GGCTTTTGCTGCGGC AGCCTCCACATTCAG

TCCTCTTCAGGAATC GCTTTTGCTGCGGCC GCCTCCACATTCAGA

CCTCTTCAGGAATCT CTTTTGCTGCGGCCC CCTCCACATTCAGAG

TCTTCAGGAATCTTC TTTGCTGCGGCCCCG TCCACATTCAGAGGC

CTTCAGGAATCTTCC TTGCTGCGGCCCCGT CCACATTCAGAGGCA

TTCAGGAATCTTCCT TGCTGCGGCCCCGTG CACATTCAGAGGCAT

TCAGGAATCTTCCTG GCTGCGGCCCCGTGG ACATTCAGAGGCATC

AGGAATCTTCCTGAA TGCGGCCCCGTGGGG ATTCAGAGGCATCAC

GGAATCTTCCTGAAG GCGGCCCCGTGGGGT TTCAGAGGCATCACA

GAATCTTCCTGAAGA CGGCCCCGTGGGGTA TCAGAGGCATCACAA

AATCTTCCTGAAGAC GGCCCCGTGGGGTAG CAGAGGCATCACAAG

TCTTCCTGAAGACAT CCCCGTGGGGTAGGA GAGGCATCACAAGTA

CTTCCTGAAGACATG CCCGTGGGGTAGGAG AGGCATCACAAGTAA

TTCCTGAAGACATGG CCGTGGGGTAGGAGG GGCATCACAAGTAAT

TCCTGAAGACATGGC CGTGGGGTAGGAGGG GCATCACAAGTAATG

CTGAAGACATGGCCC TGGGGTAGGAGGGAC ATCACAAGTAATGGC

TGAAGACATGGCCCA GGGGTAGGAGGGACA TCACAAGTAATGGCA

GAAGACATGGCCCAG GGGTAGGAGGGACAG CACAAGTAATGGCAC

AAGACATGGCCCAGT GGTAGGAGGGACAGA ACAAGTAATGGCACA

GACATGGCCCAGTCG TAGGAGGGACAGAGA AAGTAATGGCACAAT

ACATGGCCCAGTCGA AGGAGGGACAGAGAG AGTAATGGCACAATT

CATGGCCCAGTCGAA GGAGGGACAGAGAGA GTAATGGCACAATTC

ATGGCCCAGTCGAAG GAGGGACAGAGAGAC TAATGGCACAATTCT

GGCCCAGTCGAAGGC GGGACAGAGAGACGG ATGGCACAATTCTTC

GCCCAGTCGAAGGCC GGACAGAGAGACGGG TGGCACAATTCTTCG

CCCAGTCGAAGGCCC GACAGAGAGACGGGA GGCACAATTCTTCGG

CCAGTCGAAGGCCCA ACAGAGAGACGGGAG GCACAATTCTTCGGA

AGTCGAAGGCCCAGG AGAGAGACGGGAGAG ACAATTCTTCGGATG

GTCGAAGGCCCAGGA GAGAGACGGGAGAGT CAATTCTTCGGATGA

TCGAAGGCCCAGGAT AGAGACGGGAGAGTC AATTCTTCGGATGAC

CGAAGGCCCAGGATG GAGACGGGAGAGTCA ATTCTTCGGATGACT

AAGGCCCAGGATGGC GACGGGAGAGTCAGC TCTTCGGATGACTGC

AGGCCCAGGATGGCT ACGGGAGAGTCAGCC CTTCGGATGACTGCA

GGCCCAGGATGGCTT CGGGAGAGTCAGCCT TTCGGATGACTGCAG

GCCCAGGATGGCTTT GGGAGAGTCAGCCTC TCGGATGACTGCAGA

CCAGGATGGCTTTTG GAGAGTCAGCCTCCA GGATGACTGCAGAAA

GATGACTGCAGAAAA ATTTCTGAGGATAAG TTTTGTCCTCCTTAG

ATGACTGCAGAAAAT TTTCTGAGGATAAGC TTTGTCCTCCTTAGC

TGACTGCAGAAAATA TTCTGAGGATAAGCT TTGTCCTCCTTAGCA

GACTGCAGAAAATAG TCTGAGGATAAGCTC TGTCCTCCTTAGCAC

ACTGCAGAAAATAGT CTGAGGATAAGCTCT GTCCTCCTTAGCACA

CTGCAGAAAATAGTG TGAGGATAAGCTCTT TCCTCCTTAGCACAA

TGCAGAAAATAGTGT GAGGATAAGCTCTTT CCTCCTTAGCACAAT

GCAGAAAATAGTGTT AGGATAAGCTCTTTA CTCCTTAGCACAATG

CAGAAAATAGTGTTT GGATAAGCTCTTTAA TCCTTAGCACAATGT

GAAAATAGTGTTTTG ATAAGCTCTTTAAAG CTTAGCACAATGTAA

AAAATAGTGTTTTGT TAAGCTCTTTAAAGG TTAGCACAATGTAAA

AAATAGTGTTTTGTA AAGCTCTTTAAAGGC TAGCACAATGTAAAA

AATAGTGTTTTGTAG AGCTCTTTAAAGGCA AGCACAATGTAAAAA

TAGTGTTTTGTAGTT CTCTTTAAAGGCAAA CACAATGTAAAAAAG

AGTGTTTTGTAGTTC TCTTTAAAGGCAAAG ACAATGTAAAAAAGA

GTGTTTTGTAGTTCA CTTTAAAGGCAAAGC CAATGTAAAAAAGAA

TGTTTTGTAGTTCAA TTTAAAGGCAAAGCT AATGTAAAAAAGAAT

TTTTGTAGTTCAACA TAAAGGCAAAGCTTT TGTAAAAAAGAATAG

TTTGTAGTTCAACAA AAAGGCAAAGCTTTA GTAAAA.AAGAATAGT

TTGTAGTTCAACAAC AAGGCAAAGCTTTAT TAAAAAAGAATAGTA

TGTAGTTCAACAACT AGGCAAAGCTTTATT AAAAAAGAATAGTAA

TAGTTCAACAACTCA GCAAAGCTTTATTTT AAAAGAATAGTAATA

AGTTCAACAACTCAA CAAAGCTTTATTTTC AAAGAATAGTAATAT

GTTCAACAACTCAAG AAAGCTTTATTTTCA AAGAATAGTAATATC

TTCAACAACTCAAGA AAGCTTTATTTTCAT AGAATAGTAATATCA

CAACAACTCAAGACG GCTTTATTTTCATCT AATAGTAATATCAGA

AACAACTCAAGACGA CTTTATTTTCATCTC ATAGTAATATCAGAA

ACAACTCAAGACGAA TTTATTTTCATCTCT TAGTAATATCAGAAC

CAACTCAAGACGAAG TTATTTTCATCTCTC AGTAATATCAGAACA

ACTCAAGACGAAGCT ATTTTCATCTCTCAT TAATATCAGAACAGG

CTCAAGACGAAGCTT TTTTCATCTCTCATC AATATCAGAACAGGA

TCAAGACGAAGCTTA TTTCATCTCTCATCT ATATCAGAACAGGAA

CAAGACGAAGCTTAT TTCATCTCTCATCTT TATCAGAACAGGAAG

AGACGAAGCTTATTT CATCTCTCATCTTTT TCAGAACAGGAAGGA

GACGAAGCTTATTTC ATCTCTCATCTTTTG CAGAACAGGAAGGAG

ACGAAGCTTATTTCT TCTCTCATCTTTTGT AGAACAGGAAGGAGG

CGAAGCTTATTTCTG CTCTCATCTTTTGTC GAACAGGAAGGAGGA

AAGCTTATTTCTGAG CTCATCTTTTGTCCT ACAGGAAGGAGGAAT

AGCTTATTTCTGAGG TCATCTTTTGTCCTC CAGGAAGGAGGAATG

GCTTATTTCTGAGGA CATCTTTTGTCCTCC AGGAAGGAGGAATGG

CTTATTTCTGAGGAT ATCTTTTGTCCTCCT GGAAGGAGGAATGGC

TATTTCTGAGGATAA CTTTTGTCCTCCTTA AAGGAGGAATGGCTT

AGGAGGAATGGCTTG GATTCACCCATGTTT ATTCACACATATATG

GGAGGAATGGCTTGC ATTCACCCATGTTTG TTCACACATATATGC

GAGGAATGGCTTGCT TTCACCCATGTTTGT TCACACATATATGCA

AGGAATGGCTTGCTG TCACCCATGTTTGTT CACACATATATGCAG

GGAATGGCTTGCTGG CACCCATGTTTGTTG ACACATATATGCAGA

GAATGGCTTGCTGGG ACCCATGTTTGTTGA CACATATATGCAGAG

AATGGCTTGCTGGGG CCCATGTTTGTTGAA ACATATATGCAGAGA

ATGGCTTGCTGGGGA CCATGTTTGTTGAAC CATATATGCAGAGAA

TGGCTTGCTGGGGAG CATGTTTGTTGAACT ATATATGCAGAGAAG

GCTTGCTGGGGAGCC TGTTTGTTGAACTTA ATATGCAGAGAAGAT

CTTGCTGGGGAGCCC GTTTGTTGAACTTAG TATGCAGAGAAGATA

TTGCTGGGGAGCCCA TTTGTTGAACTTAGA ATGCAGAGAAGATAT

TGCTGGGGAGCCCAT TTGTTGAACTTAGAG TGCAGAGAAGATATG

CTGGGGAGCCCATCC GTTGAACTTAGAGTC CAGAGAAGATATGTT

TGGGGAGCCCATCCA TTGAACTTAGAGTCA AGAGAAGATATGTTC

GGGGAGCCCATCCAG TGAACTTAGAGTCAT GAGAAGATATGTTCT

GGGAGCCCATCCAGG GAACTTAGAGTCATT AGAAGATATGTTCTT

GAGCCCATCCAGGAC ACTTAGAGTCATTCT AAGATATGTTCTTGT

AGCCCATCCAGGACA CTTAGAGTCATTCTC AGATATGTTCTTGTT

GCCCATCCAGGACAC TTAGAGTCATTCTCA GATATGTTCTTGTTA

CCCATCCAGGACACT TAGAGTCATTCTCAT ATATGTTCTTGTTAA

CATCCAGGACACTGG GAGTCATTCTCATGC ATGTTCTTGTTAACA

ATCCAGGACACTGGG AGTCATTCTCATGCT TGTTCTTGTTAACAT

TCCAGGACACTGGGA GTCATTCTCATGCTT GTTCTTGTTAACATT

CCAGGACACTGGGAG TCATTCTCATGCTTT TTCTTGTTAACATTG

AGGACACTGGGAGCA ATTCTCATGCTTTTC CTTGTTAACATTGTA

GGACACTGGGAGCAC TTCTCATGCTTTTCT TTGTTAACATTGTAT

GACACTGGGAGCACA TCTCATGCTTTTCTT TGTTAACATTGTATA

ACACTGGGAGCACAT CTCATGCTTTTCTTT GTTAACATTGTATAC

ACTGGGAGCACATAG CATGCTTTTCTTTAT TAACATTGTATACAA

CTGGGAGCACATAGA ATGCTTTTCTTTATA AACATTGTATACAAC

TGGGAGCACATAGAG TGCTTTTCTTTATAA ACATTGTATACAACA

GGGAGCACATAGAGA GCTTTTCTTTATAAT CATTGTATACAACAT

GAGCACATAGAGATT TTTTCTTTATAATTC TTGTATACAACATAG

AGCACATAGAGATTC TTTCTTTATAATTCA TGTATACAACATAGC

GCACATAGAGATTCA TTCTTTATAATTCAC GTATACAACATAGCC

CACATAGAGATTCAC TCTTTATAATTCACA TATACAACATAGCCC

CATAGAGATTCACCC TTTATAATTCACACA TACAACATAGCCCCA

ATAGAGATTCACCCA TTATAATTCACACAT ACAACATAGCCCCAA

TAGAGATTCACCCAT TATAATTCACACATA CAACATAGCCCCAAA

AGAGATTCACCCATG ATAATTCACACATAT AACATAGCCCCAAAT

AGATTCACCCATGTT AATTCACACATATAT CATAGCCCCAAATAT

ATAGCCCCAAATATA AGAGATGCTATATGA CCCAGAGACTGGGCT

TAGCCCCAAATATAG GAGATGCTATATGAT CCAGAGACTGGGCTG

AGCCCCAAATATAGT AGATGCTATATGATA CAGAGACTGGGCTGC

GCCCCAAATATAGTA GATGCTATATGATAC AGAGACTGGGCTGCT

CCCCAAATATAGTAA ATGCTATATGATACA GAGACTGGGCTGCTC

CCCAAATATAGTAAG TGCTATATGATACAA AGACTGGGCTGCTCT

CCAAATATAGTAAGA GCTATATGATACAAC GACTGGGCTGCTCTC

CAAATATAGTAAGAT CTATATGATACAACT ACTGGGCTGCTCTCC

AAATATAGTAAGATC TATATGATACAACTG CTGGGCTGCTCTCCC

ATATAGTAAGATCTA TATGATACAACTGTG GGGCTGCTCTCCCGG

TATAGTAAGATCTAT ATGATACAACTGTGG GGCTGCTCTCCCGGA

ATAGTAAGATCTATA TGATACAACTGTGGC GCTGCTCTCCCGGAG

TAGTAAGATCTATAC GATACAACTGTGGCC CTGCTCTCCCGGAGG

GTAAGATCTATACTA TACAACTGTGGCCAT GCTCTCCCGGAGGCC

TAAGATCTATACTAG ACAACTGTGGCCATG CTCTCCCGGAGGCCA

AAGATCTATACTAGA CAACTGTGGCCATGA TCTCCCGGAGGCCAA

AGATCTATACTAGAT AACTGTGGCCATGAC CTCCCGGAGGCCAAA

ATCTATACTAGATAA CTGTGGCCATGACTG CCCGGAGGCCAAACC

TCTATACTAGATAAT TGTGGCCATGACTGA CCGGAGGCCAAACCC

CTATACTAGATAATC GTGGCCATGACTGAG CGGAGGCCAAACCCA

TATACTAGATAATCC TGGCCATGACTGAGG GGAGGCCAAACCCAA

TACTAGATAATCCTA GCCATGACTGAGGAA AGGCCAAACCCAAGA

ACTAGATAATCCTAG CCATGACTGAGGAAA GGCCAAACCCAAGAA

CTAGATAATCCTAGA CATGACTGAGGAAAG GCCAAACCCAAGAAG

TAGATAATCCTAGAT ATGACTGAGGAAAGG CCAAACCCAAGAAGG

GATAATCCTAGATGA GACTGAGGAAAGGAG AAACCCAAGAAGGTC

ATAATCCTAGATGAA ACTGAGGAAAGGAGC AACCCAAGAAGGTCT

TAATCCTAGATGAAA CTGAGGAAAGGAGCT ACCCAAGAAGGTCTG

AATCCTAGATGAAAT TGAGGAAAGGAGCTC CCCAAGAAGGTCTGG

TCCTAGATGAAATGT AGGAAAGGAGCTCAC CAAGAAGGTCTGGCA

CCTAGATGAAATGTT GGAAAGGAGCTCACG AAGAAGGTCTGGCAA

CTAGATGAAATGTTA GAAAGGAGCTCACGC AGAAGGTCTGGCAAA

TAGATGAAATGTTAG AAAGGAGCTCACGCC GAAGGTCTGGCAAAG

GATGAAATGTTAGAG AGGAGCTCACGCCCA AGGTCTGGCAAAGTC

ATGAAATGTTAGAGA GGAGCTCACGCCCAG GGTCTGGCAAAGTCA

TGAAATGTTAGAGAT GAGCTCACGCCCAGA GTCTGGCAAAGTCAG

GAAATGTTAGAGATG AGCTCACGCCCAGAG TCTGGCAAAGTCAGG

AATGTTAGAGATGCT CTCACGCCCAGAGAC TGGCAAAGTCAGGCT

ATGTTAGAGATGCTA TCACGCCCAGAGACT GGCAAAGTCAGGCTC

TGTTAGAGATGCTAT CACGCCCAGAGACTG GCAAAGTCAGGCTCA

GTTAGAGATGCTATA ACGCCCAGAGACTGG CAAAGTCAGGCTCAG

TAGAGATGCTATATG GCCCAGAGACTGGGC AAGTCAGGCTCAGGG

AGTCAGGCTCAGGGA GCTGCATAGAGCTCT CCTATTAGCTTTTCT

GTCAGGCTCAGGGAG CTGCATAGAGCTCTC CTATTAGCTTTTCTT

TCAGGCTCAGGGAGA TGCATAGAGCTCTCC TATTAGCTTTTCTTT

CAGGCTCAGGGAGAC GCATAGAGCTCTCCT ATTAGCTTTTCTTTA

AGGCTCAGGGAGACT CATAGAGCTCTCCTT TTAGCTTTTCTTTAT

GGCTCAGGGAGACTC ATAGAGCTCTCCTTG TAGCTTTTCTTTATT

GCTCAGGGAGACTCT TAGAGCTCTCCTTGA AGCTTTTCTTTATTT

CTCAGGGAGACTCTG AGAGCTCTCCTTGAA GCTTTTCTTTATTTT

TCAGGGAGACTCTGC GAGCTCTCCTTGAAA CTTTTCTTTATTTTT

AGGGAGACTCTGCCC GCTCTCCTTGAAAAC TTTCTTTATTTTTTT

GGGAGACTCTGCCCT CTCTCCTTGAAAACA TTCTTTATTTTTTTA

GGAGACTCTGCCCTG TCTCCTTGAAAACAG TCTTTATTTTTTTAA

GAGACTCTGCCCTGC CTCCTTGAAAACAGA CTTTATTTTTTTAAC

GACTCTGCCCTGCTG CCTTGAAAACAGAGG TTATTTTTTTAACTT

ACTCTGCCCTGCTGC CTTGAAAACAGAGGG TATTTTTTTAACTTT

CTCTGCCCTGCTGCA TTGAAAACAGAGGGG ATTTTTTTAACTTTT

TCTGCCCTGCTGCAG TGAAAACAGAGGGGT TTTTTTTAACTTTTT

TGCCCTGCTGCAGAC AAAACAGAGGGGTCT TTTTTAACTTTTTGG

GCCCTGCTGCAGACC AAACAGAGGGGTCTC TTTTAACTTTTTGGG

CCCTGCTGCAGACCT AACAGAGGGGTCTCA TTTAACTTTTTGGGG

CCTGCTGCAGACCTC ACAGAGGGGTCTCAA TTAACTTTTTGGGGG

TGCTGCAGACCTCGG AGAGGGGTCTCAAGA AACTTTTTGGGGGGA

GCTGCAGACCTCGGT GAGGGGTCTCAAGAC ACTTTTTGGGGGGAA

CTGCAGACCTCGGTG AGGGGTCTCAAGACA CTTTTTGGGGGGAAA

TGCAGACCTCGGTGT GGGGTCTCAAGACAT TTTTTGGGGGGAAAA

CAGACCTCGGTGTGG GGTCTCAAGACATTC TTTGGGGGGAAAAGT

AGACCTCGGTGTGGA GTCTCAAGACATTCT TTGGGGGGAAAAGTA

GACCTCGGTGTGGAC TCTCAAGACATTCTG TGGGGGGAAAAGTAT

ACCTCGGTGTGGACA CTCAAGACATTCTGC GGGGGGAAAAGTATT

CTCGGTGTGGACACA CAAGACATTCTGCCT GGGGAAAAGTATTTT

TCGGTGTGGACACAC AAGACATTCTGCCTA GGGAAAAGTATTTTT

CGGTGTGGACACACG AGACATTCTGCCTAC GGAAAAGTATTTTTG

GGTGTGGACACACGC GACATTCTGCCTACC GAAAAGTATTTTTGA

TGTGGACACACGCTG CATTCTGCCTACCTA AAAGTATTTTTGAGA

GTGGACACACGCTGC ATTCTGCCTACCTAT AAGTATTTTTGAGAA

TGGACACACGCTGCA TTCTGCCTACCTATT AGTATTTTTGAGAAG

GGACACACGCTGCAT TCTGCCTACCTATTA GTATTTTTGAGAAGT

ACACACGCTGCATAG TGCCTACCTATTAGC ATTTTTGAGAAGTTT

CACACGCTGCATAGA GCCTACCTATTAGCT TTTTTGAGAAGTTTG

ACACGCTGCATAGAG CCTACCTATTAGCTT TTTTGAGAAGTTTGT

CACGCTGCATAGAGC CTACCTATTAGCTTT TTTGAGAAGTTTGTC

CGCTGCATAGAGCTC ACCTATTAGCTTTTC TGAGAAGTTTGTCTT

GAGAAGTTTGTCTTG
AGAAGTTTGTCTTGC
GAAGTTTGTCTTGCA
AAGTTTGTCTTGCAA
AGTTTGTCTTGCAAT
GTTTGTCTTGCAATG
TTTGTCTTGCAATGT
TTGTCTTGCAATGTA
TGTCTTGCAATGTAT
GTCTTGCAATGTATT
TCTTGCAATGTATTT
CTTGCAATGTATTTA
TTGCAATGTATTTAT
TGCAATGTATTTATA
GCAATGTATTTATAA
CAATGTATTTATAAA
AATGTATTTATAAAT
ATGTATTTATAAATA
TGTATTTATAAATAG
GTATTTATAAATAGT
TATTTATAAATAGTA
ATTTATAAATAGTAA
TTTATAAATAGTAAA
TTATAAATAGTAAAT
TATAAATAGTAAATA
ATAAATAGTAAATAA
TAAATAGTAAATAAA
AAATAGTAAATAAAG
AATAGTAAATAAAGT
ATAGTAAATAAAGTT
TAGTAAATAAAGTTT
AGTAAATAAAGTTTT
GTAAATAAAGTTTTT
TAAATAAAGTTTTTA
AAATAAAGTTTTTAC
AATAAAGTTTTTACC
ATAAAGTTTTTACCA
TAAAGTTTTTACCAT
AAAGTTTTTACCATT

Antisense oligonucleotides to IGF-I may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:
TTTTTTTTTTTTTTG TTTTTTTTTTTGAGA TTTTTTTTGAGAAAG
TTTTTTTTTTTTTGA TTTTTTTTTTGAGAA TTTTTTTGAGAAAGG
TTTTTTTTTTTTGAG TTTTTTTTTGAGAAA TTTTTTGAGAAAGGG

TTTTTGAGAAAGGGA GGAGGAGGGTCCCCG CTCTCGCTCTGGCCG

TTTTGAGAAAGGGAA GAGGAGGGTCCCCGA TCTCGCTCTGGCCGA

TTTGAGAAAGGGAAT AGGAGGGTCCCCGAC CTCGCTCTGGCCGAC

TTGAGAAAGGGAATT GGAGGGTCCCCGACC TCGCTCTGGCCGACG

S TGAGAAAGGGAATTT GAGGGTCCCCGACCT CGCTCTGGCCGACGA

GAGAAAGGGAATTTC AGGGTCCCCGACCTC GCTCTGGCCGACGAG

AGAAAGGGAATTTCA GGGTCCCCGACCTCG CTCTGGCCGACGAGT

GAAAGGGAATTTCAT GGTCCCCGACCTCGC TCTGGCCGACGAGTG

AAAGGGAATTTCATC GTCCCCGACCTCGCT CTGGCCGACGAGTGG

AGGGAATTTCATCCC CCCCGACCTCGCTGT GGCCGACGAGTGGAG

GGGAATTTCATCCCA CCCGACCTCGCTGTG GCCGACGAGTGGAGA

GGAATTTCATCCCAA CCGACCTCGCTGTGG CCGACGAGTGGAGAA

GAATTTCATCCCAAA CGACCTCGCTGTGGG CGACGAGTGGAGAAA

ATTTCATCCCAAATA ACCTCGCTGTGGGGG ACGAGTGGAGAAATC

TTTCATCCCAAATAA CCTCGCTGTGGGGGC CGAGTGGAGAAATCT

TTCATCCCAAATAAA CTCGCTGTGGGGGCT GAGTGGAGAAATCTG

TCATCCCAAATAAAA TCGCTGTGGGGGCTC AGTGGAGAAATCTGC

ATCCCAAATAAAAGG GCTGTGGGGGCTCCT TGGAGAAATCTGCGG

TCCCAAATAAAAGGA CTGTGGGGGCTCCTG GGAGAAATCTGCGGG

CCCAAATAAAAGGAA TGTGGGGGCTCCTGT GAGAAATCTGCGGGC

CCAAATAAAAGGAAT GTGGGGGCTCCTGTT AGAAATCTGCGGGCC

25CAAATAAAAGGAAT'G TGGGGGCTCCTGTTT GAAATCTGCGGGCCA

AAATAAAAGGAATGA GGGGGCTCCTGTTTC AAATCTGCGGGCCAG

AATAAAAGGAATGAA GGGGCTCCTGTTTCT AATCTGCGGGCCAGG

ATAAAAGGAATGAAG GGGCTCCTGTTTCTC ATCTGCGGGCCAGGC

TAAAAGGAATGAAGT GGCTCCTGTTTCTCT TCTGCGGGCCAGGCA

AAAGGAATGAAGTCT CTCCTGTTTCTCTCC TGCGGGCCAGGCATC

AAGGAATGAAGTCTG TCCTGTTTCTCTCCG GCGGGCCAGGCATCG

AGGAATGAAGTCTGG CCTGTTTCTCTCCGC CGGGCCAGGCATCGA

GGAATGAAGTCTGGC CTGTTTCTCTCCGCC GGGCCAGGCATCGAC

AATGAAGTCTGGCTC GTTTCTCTCCGCCGC GCCAGGCATCGACAT

ATGAAGTCTGGCTCC TTTCTCTCCGCCGCG CCAGGCATCGACATC

TGAAGTCTGGCTCCG TTCTCTCCGCCGCGC CAGGCATCGACATCC

GAAGTCTGGCTCCGG TCTCTCCGCCGCGCT AGGCATCGACATCCG

AGTCTGGCTCCGGAG TCTCCGCCGCGCTCT GCATCGACATCCGCA

GTCTGGCTCCGGAGG CTCCGCCGCGCTCTC CATCGACATCCGCAA

TCTGGCTCCGGAGGA TCCGCCGCGCTCTCG ATCGACATCCGCAAC

CTGGCTCCGGAGGAG CCGCCGCGCTCTCGC TCGACATCCGCAACG

GGCTCCGGAGGAGGG GCCGCGCTCTCGCTC GACATCCGCAACGAC

GCTCCGGAGGAGGGT CCGCGCTCTCGCTCT ACATCCGCAACGACT

CTCCGGAGGAGGGTC CGCGCTCTCGCTCTG CATCCGCAACGACTA

TCCGGAGGAGGGTCC GCGCTCTCGCTCTGG ATCCGCAACGACTAT

CGGAGGAGGGTCCCC GCTCTCGCTCTGGCC CCGCAACGACTATCA

CGCAACGACTATCAG GGCTACCTCCACATC CGCTTCCCCAAGCTC

GCAACGACTATCAGC GCTACCTCCACATCC GCTTCCCCAAGCTCA

CAACGACTATCAGCA CTACCTCCACATCCT CTTCCCCAAGCTCAC

AACGACTATCAGCAG TACCTCCACATCCTG TTCCCCAAGCTCACG

ACGACTATCAGCAGC ACCTCCACATCCTGC TCCCCAAGCTCACGG

CGACTATCAGCAGCT CCTCCACATCCTGCT CCCCAAGCTCACGGT

GACTATCAGCAGCTG CTCCACATCCTGCTC CCCAAGCTCACGGTC

ACTATCAGCAGCTGA TCCACATCCTGCTCA CCAAGCTCACGGTCA

CTATCAGCAGCTGAA CCACATCCTGCTCAT CAAGCTCACGGTCAT

ATCAGCAGCTGAAGC ACATCCTGCTCATCT AGCTCACGGTCATTA

TCAGCAGCTGAAGCG CATCCTGCTCATCTC GCTCACGGTCATTAC

CAGCAGCTGAAGCGC ATCCTGCTCATCTCC CTCACGGTCATTACC

AGCAGCTGAAGCGCC TCCTGCTCATCTCCA TCACGGTCATTACCG

CAGCTGAAGCGCCTG CTGCTCATCTCCAAG ACGGTCATTACCGAG

AGCTGAAGCGCCTGG TGCTCATCTCCAAGG CGGTCATTACCGAGT

GCTGAAGCGCCTGGA GCTCATCTCCAAGGC . GGTCATTACCGAGTA

CTGAAGCGCCTGGAG CTCATCTCCAAGGCC GTCATTACCGAGTAC

GAAGCGCCTGGAGAA CATCTCCAAGGCCGA CATTACCGAGTACTT

AAGCGCCTGGAGAAC ATCTCCAAGGCCGAG ATTACCGAGTACTTG

AGCGCCTGGAGAACT TCTCCAAGGCCGAGG TTACCGAGTACTTGC

GCGCCTGGAGAACTG CTCCAAGGCCGAGGA TACCGAGTACTTGCT

GCCTGGAGAACTGCA CCAAGGCCGAGGACT CCGAGTACTTGCTGC

CCTGGAGAACTGCAC CAAGGCCGAGGACTA CGAGTACTTGCTGCT

CTGGAGAACTGCACG AAGGCCGAGGACTAC GAGTACTTGCTGCTG

TGGAGAACTGCACGG AGGCCGAGGACTACC AGTACTTGCTGCTGT

GAGAACTGCACGGTG GCCGAGGACTACCGC TACTTGCTGCTGTTC

AGAACTGCACGGTGA CCGAGGACTACCGCA ACTTGCTGCTGTTCC

GAACTGCACGGTGAT CGAGGACTACCGCAG CTTGCTGCTGTTCCG

AACTGCACGGTGATC GAGGACTACCGCAGC TTGCTGCTGTTCCGA

CTGCACGGTGATCGA GGACTACCGCAGCTA GCTGCTGTTCCGAGT

TGCACGGTGATCGAG GACTACCGCAGCTAC CTGCTGTTCCGAGTG

GCACGGTGATCGAGG ACTACCGCAGCTACC TGCTGTTCCGAGTGG

CACGGTGATCGAGGG CTACCGCAGCTACCG GCTGTTCCGAGTGGC

CGGTGATCGAGGGCT ACCGCAGCTACCGCT TGTTCCGAGTGGCTG

GGTGATCGAGGGCTA CCGCAGCTACCGCTT GTTCCGAGTGGCTGG

GTGATCGAGGGCTAC CGCAGCTACCGCTTC TTCCGAGTGGCTGGC

TGATCGAGGGCTACC GCAGCTACCGCTTCC TCCGAGTGGCTGGCC

ATCGAGGGCTACCTC AGCTACCGCTTCCCC CGAGTGGCTGGCCTC

TCGAGGGCTACCTCC GCTACCGCTTCCCCA GAGTGGCTGGCCTCG

CGAGGGCTACCTCCA CTACCGCTTCCCCAA AGTGGCTGGCCTCGA

GAGGGCTACCTCCAC TACCGCTTCCCCAAG GTGGCTGGCCTCGAG

GGGCTACCTCCACAT CCGCTTCCCCAAGCT GGCTGGCCTCGAGAG

GCTGGCCTCGAGAGC GGCTGGAAACTCTTC CTCAAGGATATTGGG

CTGGCCTCGAGAGCC GCTGGAAACTCTTCT TCAAGGATATTGGGC

TGGCCTCGAGAGCCT CTGGAAACTCTTCTA CAAGGATATTGGGCT

GGCCTCGAGAGCCTC TGGAAACTCTTCTAC AAGGATATTGGGCTT

GCCTCGAGAGCCTCG GGAAACTCTTCTACA AGGATATTGGGCTTT

CCTCGAGAGCCTCGG GAAACTCTTCTACAA GGATATTGGGCTTTA

CTCGAGAGCCTCGGA AAACTCTTCTACAAC GATATTGGGCTTTAC

TCGAGAGCCTCGGAG AACTCTTCTACAACT ATATTGGGCTTTACA

CGAGAGCCTCGGAGA ACTCTTCTACAACTA TATTGGGCTTTACAA

AGAGCCTCGGAGACC TCTTCTACAACTACG TTGGGCTTTACAACC

GAGCCTCGGAGACCT CTTCTACAACTACGC TGGGCTTTACAACCT

AGCCTCGGAGACCTC TTCTACAACTACGCC GGGCTTTACAACCTG

GCCTCGGAGACCTCT TCTACAACTACGCCC GGCTTTACAACCTGA

CTCGGAGACCTCTTC TACAACTACGCCCTG CTTTACAACCTGAGG

TCGGAGACCTCTTCC ACAACTACGCCCTGG TTTACAACCTGAGGA

CGGAGACCTCTTCCC CAACTACGCCCTGGT TTACAACCTGAGGAA

GGAGACCTCTTCCCC AACTACGCCCTGGTC TACAACCTGAGGAAC

AGACCTCTTCCCCAA CTACGCCCTGGTCAT CAACCTGAGGAACAT

GACCTCTTCCCCAAC TACGCCCTGGTCATC AACCTGAGGAACATT

ACCTCTTCCCCAACC ACGCCCTGGTCATCT ACCTGAGGAACATTA

CCTCTTCCCCAACCT CGCCCTGGTCATCTT CCTGAGGAACATTAC

TCTTCCCCAACCTCA CCCTGGTCATCTTCG TGAGGAACATTACTC

CTTCCCCAACCTCAC CCTGGTCATCTTCGA GAGGAACATTACTCG

TTCCCCAACCTCACG CTGGTCATCTTCGAG AGGAACATTACTCGG

TCCCCAACCTCACGG TGGTCATCTTCGAGA GGAACATTACTCGGG

CCCAACCTCACGGTC GTCATCTTCGAGATG AACATTACTCGGGGG

CCAACCTCACGGTCA TCATCTTCGAGATGA ACATTACTCGGGGGG

CAACCTCACGGTCAT CATCTTCGAGATGAC CATTACTCGGGGGGC

AACCTCACGGTCATC ATCTTCGAGATGACC ATTACTCGGGGGGCC

CCTCACGGTCATCCG CTTCGAGATGACCAA TACTCGGGGGGCCAT

CTCACGGTCATCCGC TTCGAGATGACCAAT ACTCGGGGGGCCATC

TCACGGTCATCCGCG TCGAGATGACCAATC CTCGGGGGGCCATCA

CACGGTCATCCGCGG CGAGATGACCAATCT TCGGGGGGCCATCAG

CGGTCATCCGCGGCT AGATGACCAATCTCA GGGGGGCCATCAGGA

GGTCATCCGCGGCTG GATGACCAATCTCAA GGGGGCCATCAGGAT

GTCATCCGCGGCTGG ATGACCAATCTCAAG GGGGCCATCAGGATT

TCATCCGCGGCTGGA TGACCAATCTCAAGG GGGCCATCAGGATTG

ATCCGCGGCTGGAAA ACCAATCTCAAGGAT GCCATCAGGATTGAG

TCCGCGGCTGGAAAC CCAATCTCAAGGATA CCATCAGGATTGAGA

CCGCGGCTGGAAACT CAATCTCAAGGATAT CATCAGGATTGAGAA

CGCGGCTGGAAACTC AATCTCAAGGATATT ATCAGGATTGAGAAA

CGGCTGGAAACTCTT TCTCAAGGATATTGG CAGGATTGAGAAAAA

AGGATTGAGAAP~AAT CTGATCCTGGATGCG AAGGAATGTGGGGAC

GGATTGAGAA.P.AATG TGATCCTGGATGCGG AGGAATGTGGGGACC

GATTGAGAAAAATGC GATCCTGGATGCGGT GGAATGTGGGGACCT

ATTGAGAAAAATGCT ATCCTGGATGCGGTG GAATGTGGGGACCTG

S TTGAGAAAAATGCTG TCCTGGATGCGGTGT AATGTGGGGACCTGT

TGAGAAAAATGCTGA CCTGGATGCGGTGTC ATGTGGGGACCTGTG

GAGAAAAATGCTGAC CTGGATGCGGTGTCC TGTGGGGACCTGTGT

AGAAAAATGCTGACC TGGATGCGGTGTCCA GTGGGGACCTGTGTC

GAAAAATGCTGACCT GGATGCGGTGTCCAA TGGGGACCTGTGTCC

10AAAA.ATGCTGACCTC GATGCGGTGTCCAAT GGGGACCTGTGTCCA

AAAATGCTGACCTCT ATGCGGTGTCCAATA GGGACCTGTGTCCAG

AAATGCTGACCTCTG TGCGGTGTCCAATAA GGACCTGTGTCCAGG

AATGCTGACCTCTGT GCGGTGTCCAATAAC GACCTGTGTCCAGGG

ATGCTGACCTCTGTT CGGTGTCCAATAACT ACCTGTGTCCAGGGA

GCTGACCTCTGTTAC GTGTCCAATAACTAC CTGTGTCCAGGGACC

CTGACCTCTGTTACC TGTCCAATAACTACA TGTGTCCAGGGACCA

TGACCTCTGTTACCT GTCCAATAACTACAT GTGTCCAGGGACCAT

GACCTCTGTTACCTC TCCAATAACTACATT TGTCCAGGGACCATG

CCTCTGTTACCTCTC CAATAACTACATTGT TCCAGGGACCATGGA

CTCTGTTACCTCTCC AATAACTACATTGTG CCAGGGACCATGGAG

TCTGTTACCTCTCCA ATAACTACATTGTGG CAGGGACCATGGAGG

CTGTTACCTCTCCAC TAACTACATTGTGGG AGGGACCATGGAGGA

GTTACCTCTCCACTG ACTACATTGTGGGGA GGACCATGGAGGAGA

TTACCTCTCCACTGT CTACATTGTGGGGAA GACCATGGAGGAGAA

TACCTCTCCACTGTG TACATTGTGGGGAAT ACCATGGAGGAGAAG

ACCTCTCCACTGTGG ACATTGTGGGGAATA CCATGGAGGAGAAGC

CTCTCCACTGTGGAC ATTGTGGGGAATAAG ATGGAGGAGAAGCCG

TCTCCACTGTGGACT TTGTGGGGAATAAGC TGGAGGAGAAGCCGA

CTCCACTGTGGACTG TGTGGGGAATAAGCC GGAGGAGAAGCCGAT

TCCACTGTGGACTGG GTGGGGAATAAGCCC GAGGAGAAGCCGATG

CACTGTGGACTGGTC GGGGAATAAGCCCCC GGAGAAGCCGATGTG

ACTGTGGACTGGTCC GGGAATAAGCCCCCA GAGAAGCCGATGTGT

CTGTGGACTGGTCCC GGAATAAGCCCCCAA AGAAGCCGATGTGTG

TGTGGACTGGTCCCT GAATAAGCCCCCAAA GAAGCCGATGTGTGA

TGGACTGGTCCCTGA ATAAGCCCCCAAAGG AGCCGATGTGTGAGA

GGACTGGTCCCTGAT TAAGCCCCCAAAGGA GCCGATGTGTGAGAA

GACTGGTCCCTGATC AAGCCCCCAAAGGAA CCGATGTGTGAGAAG

ACTGGTCCCTGATCC AGCCCCCAAAGGAAT CGATGTGTGAGAAGA

TGGTCCCTGATCCTG CCCCCAAAGGAATGT ATGTGTGAGAAGACC

GGTCCCTGATCCTGG CCCCAAAGGAATGTG TGTGTGAGAAGACCA

GTCCCTGATCCTGGA CCCAAAGGAATGTGG GTGTGAGAAGACCAC

TCCCTGATCCTGGAT CCAAAGGAATGTGGG TGTGAGAAGACCACC

CCTGATCCTGGATGC AAAGGAATGTGGGGA TGAGAAGACCACCAT

GAGAAGACCACCATC CGCTGCCAGAAAATG AACAATGAGTGCTGC

AGAAGACCACCATCA GCTGCCAGAAAATGT ACAATGAGTGCTGCC

GAAGACCACCATCAA CTGCCAGAAAATGTG CAATGAGTGCTGCCA

AAGACCACCATCAAC TGCCAGAAAATGTGC AATGAGTGCTGCCAC

AGACCACCATCAACA GCCAGAAAATGTGCC ATGAGTGCTGCCACC

GACCACCATCAACAA CCAGAAAATGTGCCC TGAGTGCTGCCACCC

ACCACCATCAACAAT CAGAAAATGTGCCCA GAGTGCTGCCACCCC

CCACCATCAACAATG AGAAAATGTGCCCAA AGTGCTGCCACCCCG

CACCATCAACAATGA GAAAATGTGCCCAAG GTGCTGCCACCCCGA

CCATCAACAATGAGT AAATGTGCCCAAGCA GCTGCCACCCCGAGT

CATCAACAATGAGTA AATGTGCCCAAGCAC CTGCCACCCCGAGTG

ATCAACAATGAGTAC ATGTGCCCAAGCACG TGCCACCCCGAGTGC

TCAACAATGAGTACA TGTGCCCAAGCACGT GCCACCCCGAGTGCC

AACAATGAGTACAAC TGCCCAAGCACGTGT CACCCCGAGTGCCTG

ACAATGAGTACAACT GCCCAAGCACGTGTG ACCCCGAGTGCCTGG

CAATGAGTACAACTA CCCAAGCACGTGTGG CCCCGAGTGCCTGGG

AATGAGTACAACTAC CCAAGCACGTGTGGG CCCGAGTGCCTGGGC

TGAGTACAACTACCG AAGCACGTGTGGGAA CGAGTGCCTGGGCAG

GAGTACAACTACCGC AGCACGTGTGGGAAG GAGTGCCTGGGCAGC

AGTACAACTACCGCT GCACGTGTGGGAAGC AGTGCCTGGGCAGCT

GTACAACTACCGCTG CACGTGTGGGAAGCG GTGCCTGGGCAGCTG

ACAACTACCGCTGCT CGTGTGGGAAGCGGG GCCTGGGCAGCTGCA

CAACTACCGCTGCTG GTGTGGGAAGCGGGC CCTGGGCAGCTGCAG

AACTACCGCTGCTGG TGTGGGAAGCGGGCG CTGGGCAGCTGCAGC

ACTACCGCTGCTGGA GTGGGAAGCGGGCGT TGGGCAGCTGCAGCG

TACCGCTGCTGGACC GGGAAGCGGGCGTGC GGCAGCTGCAGCGCG

ACCGCTGCTGGACCA GGAAGCGGGCGTGCA GCAGCTGCAGCGCGC

CCGCTGCTGGACCAC GAAGCGGGCGTGCAC CAGCTGCAGCGCGCC

CGCTGCTGGACCACA AAGCGGGCGTGCACC AGCTGCAGCGCGCCT

CTGCTGGACCACAAA GCGGGCGTGCACCGA CTGCAGCGCGCCTGA

TGCTGGACCACAAAC CGGGCGTGCACCGAG TGCAGCGCGCCTGAC

GCTGGACCACAAACC GGGCGTGCACCGAGA GCAGCGCGCCTGACA

CTGGACCACAAACCG GGCGTGCACCGAGAA CAGCGCGCCTGACAA

GGACCACAAACCGCT CGTGCACCGAGAACA GCGCGCCTGACAACG

GACCACAAACCGCTG GTGCACCGAGAACAA CGCGCCTGACAACGA

ACCACAAACCGCTGC TGCACCGAGAACAAT GCGCCTGACAACGAC

CCACAAACCGCTGCC GCACCGAGAACAATG CGCCTGACAACGACA

ACAAACCGCTGCCAG ACCGAGAACAATGAG CCTGACAACGACACG

CAAACCGCTGCCAGA CCGAGAACAATGAGT CTGACAACGACACGG

AAACCGCTGCCAGAA CGAGAACAATGAGTG TGACAACGACACGGC

AACCGCTGCCAGAAA GAGAACAATGAGTGC GACAACGACACGGCC

CCGCTGCCAGAAAAT GAACAATGAGTGCTG CAACGACACGGCCTG

AACGACACGGCCTGT GTGCCTGCCTGCCCG GACCGTGACTTCTGC

ACGACACGGCCTGTG TGCCTGCCTGCCCGC ACCGTGACTTCTGCG

CGACACGGCCTGTGT GCCTGCCTGCCCGCC CCGTGACTTCTGCGC

GACACGGCCTGTGTA CCTGCCTGCCCGCCC CGTGACTTCTGCGCC

ACACGGCCTGTGTAG CTGCCTGCCCGCCCA GTGACTTCTGCGCCA

CACGGCCTGTGTAGC TGCCTGCCCGCCCAA TGACTTCTGCGCCAA

ACGGCCTGTGTAGCT GCCTGCCCGCCCAAC GACTTCTGCGCCAAC

CGGCCTGTGTAGCTT CCTGCCCGCCCAACA ACTTCTGCGCCAACA

GGCCTGTGTAGCTTG CTGCCCGCCCAACAC CTTCTGCGCCAACAT

CCTGTGTAGCTTGCC GCCCGCCCAACACCT TCTGCGCCAACATCC

CTGTGTAGCTTGCCG CCCGCCCAACACCTA CTGCGCCAACATCCT

TGTGTAGCTTGCCGC CCGCCCAACACCTAC TGCGCCAACATCCTC

GTGTAGCTTGCCGCC CGCCCAACACCTACA GCGCCAACATCCTCA

GTAGCTTGCCGCCAC CCCAACACCTACAGG GCCAACATCCTCAGC

TAGCTTGCCGCCACT CCAACACCTACAGGT CCAACATCCTCAGCG

AGCTTGCCGCCACTA CAACACCTACAGGTT CAACATCCTCAGCGC

GCTTGCCGCCACTAC AACACCTACAGGTTT AACATCCTCAGCGCC

TTGCCGCCACTACTA CACCTACAGGTTTGA CATCCTCAGCGCCGA

TGCCGCCACTACTAC ACCTACAGGTTTGAG ATCCTCAGCGCCGAG

GCCGCCACTACTACT CCTACAGGTTTGAGG TCCTCAGCGCCGAGA

CCGCCACTACTACTA CTACAGGTTTGAGGG CCTCAGCGCCGAGAG

GCCACTACTACTATG ACAGGTTTGAGGGCT TCAGCGCCGAGAGCA

CCACTACTACTATGC CAGGTTTGAGGGCTG CAGCGCCGAGAGCAG

CACTACTACTATGCC AGGTTTGAGGGCTGG AGCGCCGAGAGCAGC

ACTACTACTATGCCG GGTTTGAGGGCTGGC GCGCCGAGAGCAGCG

TACTACTATGCCGGT TTTGAGGGCTGGCGC GCCGAGAGCAGCGAC

ACTACTATGCCGGTG TTGAGGGCTGGCGCT CCGAGAGCAGCGACT

CTACTATGCCGGTGT TGAGGGCTGGCGCTG CGAGAGCAGCGACTC

TACTATGCCGGTGTC GAGGGCTGGCGCTGT GAGAGCAGCGACTCC

CTATGCCGGTGTCTG GGGCTGGCGCTGTGT GAGCAGCGACTCCGA

TATGCCGGTGTCTGT GGCTGGCGCTGTGTG AGCAGCGACTCCGAG

ATGCCGGTGTCTGTG GCTGGCGCTGTGTGG GCAGCGACTCCGAGG

TGCCGGTGTCTGTGT CTGGCGCTGTGTGGA CAGCGACTCCGAGGG

CCGGTGTCTGTGTGC GGCGCTGTGTGGACC GCGACTCCGAGGGGT

CGGTGTCTGTGTGCC GCGCTGTGTGGACCG CGACTCCGAGGGGTT

GGTGTCTGTGTGCCT CGCTGTGTGGACCGT GACTCCGAGGGGTTT

GTGTCTGTGTGCCTG GCTGTGTGGACCGTG ACTCCGAGGGGTTTG

GTCTGTGTGCCTGCC TGTGTGGACCGTGAC TCCGAGGGGTTTGTG

TCTGTGTGCCTGCCT GTGTGGACCGTGACT CCGAGGGGTTTGTGA

CTGTGTGCCTGCCTG TGTGGACCGTGACTT CGAGGGGTTTGTGAT

TGTGTGCCTGCCTGC GTGGACCGTGACTTC GAGGGGTTTGTGATC

TGTGCCTGCCTGCCC GGACCGTGACTTCTG GGGGTTTGTGATCCA

GGGTTTGTGATCCAC ATCCGCAACGGCAGC CCGAAGGTCTGTGAG

GGTTTGTGATCCACG TCCGCAACGGCAGCC CGAAGGTCTGTGAGG

GTTTGTGATCCACGA CCGCAACGGCAGCCA GAAGGTCTGTGAGGA

TTTGTGATCCACGAC CGCAACGGCAGCCAG AAGGTCTGTGAGGAA

TTGTGATCCACGACG GCAACGGCAGCCAGA AGGTCTGTGAGGAAG

TGTGATCCACGACGG CAACGGCAGCCAGAG GGTCTGTGAGGAAGA

GTGATCCACGACGGC AACGGCAGCCAGAGC GTCTGTGAGGAAGAA

TGATCCACGACGGCG ACGGCAGCCAGAGCA TCTGTGAGGAAGAAA

GATCCACGACGGCGA CGGCAGCCAGAGCAT CTGTGAGGAAGAAAA

TCCACGACGGCGAGT GCAGCCAGAGCATGT GTGAGGAAGAAAAGA

CCACGACGGCGAGTG CAGCCAGAGCATGTA TGAGGAAGAAAAGAA

CACGACGGCGAGTGC AGCCAGAGCATGTAC GAGGAAGAAAAGAAA

ACGACGGCGAGTGCA GCCAGAGCATGTACT AGGAAGAAAAGAAAA

GACGGCGAGTGCATG CAGAGCATGTACTGC GAAGAAAAGAAAACA

ACGGCGAGTGCATGC AGAGCATGTACTGCA AAGAAAAGAAAACAA

CGGCGAGTGCATGCA GAGCATGTACTGCAT AGAAAAGAAAACAAA

GGCGAGTGCATGCAG AGCATGTACTGCATC GAAAAGAAAACAAAG

CGAGTGCATGCAGGA CATGTACTGCATCCC AAAGAAAACAAAGAC

GAGTGCATGCAGGAG ATGTACTGCATCCCT AAGAAAACAAAGACC

AGTGCATGCAGGAGT TGTACTGCATCCCTT AGAAAACAAAGACCA

GTGCATGCAGGAGTG GTACTGCATCCCTTG GAAAACAAAGACCAT

GCATGCAGGAGTGCC ACTGCATCCCTTGTG AAACAAAGACCATTG

CATGCAGGAGTGCCC CTGCATCCCTTGTGA AACAAAGACCATTGA

ATGCAGGAGTGCCCC TGCATCCCTTGTGAA ACAAAGACCATTGAT

TGCAGGAGTGCCCCT GCATCCCTTGTGAAG CAAAGACCATTGATT

CAGGAGTGCCCCTCG ATCCCTTGTGAAGGT AAGACCATTGATTCT

AGGAGTGCCCCTCGG TCCCTTGTGAAGGTC AGACCATTGATTCTG

GGAGTGCCCCTCGGG CCCTTGTGAAGGTCC GACCATTGATTCTGT

GAGTGCCCCTCGGGC CCTTGTGAAGGTCCT ACCATTGATTCTGTT

GTGCCCCTCGGGCTT TTGTGAAGGTCCTTG CATTGATTCTGTTAC

TGCCCCTCGGGCTTC TGTGAAGGTCCTTGC ATTGATTCTGTTACT

GCCCCTCGGGCTTCA GTGAAGGTCCTTGCC TTGATTCTGTTACTT

CCCCTCGGGCTTCAT TGAAGGTCCTTGCCC TGATTCTGTTACTTC

CCTCGGGCTTCATCC AAGGTCCTTGCCCGA ATTCTGTTACTTCTG

CTCGGGCTTCATCCG AGGTCCTTGCCCGAA TTCTGTTACTTCTGC

TCGGGCTTCATCCGC GGTCCTTGCCCGAAG TCTGTTACTTCTGCT

CGGGCTTCATCCGCA GTCCTTGCCCGAAGG CTGTTACTTCTGCTC

GGCTTCATCCGCAAC CCTTGCCCGAAGGTC GTTACTTCTGCTCAG

GCTTCATCCGCAACG CTTGCCCGAAGGTCT TTACTTCTGCTCAGA

CTTCATCCGCAACGG TTGCCCGAAGGTCTG TACTTCTGCTCAGAT

TTCATCCGCAACGGC TGCCCGAAGGTCTGT ACTTCTGCTCAGATG

CATCCGCAACGGCAG CCCGAAGGTCTGTGA TTCTGCTCAGATGCT

TCTGCTCAGATGCTC AACATCCGACGGGGG CTCATCGAGGTGGTG

CTGCTCAGATGCTCC ACATCCGACGGGGGA TCATCGAGGTGGTGA

TGCTCAGATGCTCCA CATCCGACGGGGGAA CATCGAGGTGGTGAC

GCTCAGATGCTCCAA ATCCGACGGGGGAAT ATCGAGGTGGTGACG

CTCAGATGCTCCAAG TCCGACGGGGGAATA TCGAGGTGGTGACGG

TCAGATGCTCCAAGG CCGACGGGGGAATAA CGAGGTGGTGACGGG

CAGATGCTCCAAGGA CGACGGGGGAATAAC GAGGTGGTGACGGGC

AGATGCTCCAAGGAT GACGGGGGAATAACA AGGTGGTGACGGGCT

GATGCTCCAAGGATG ACGGGGGAATAACAT GGTGGTGACGGGCTA

TGCTCCAAGGATGCA GGGGGAATAACATTG TGGTGACGGGCTACG

GCTCCAAGGATGCAC GGGGAATAACATTGC GGTGACGGGCTACGT

CTCCAAGGATGCACC GGGAATAACATTGCT GTGACGGGCTACGTG

TCCAAGGATGCACCA GGAATAACATTGCTT TGACGGGCTACGTGA

CAAGGATGCACCATC AATAACATTGCTTCA ACGGGCTACGTGAAG

AAGGATGCACCATCT ATAACATTGCTTCAG CGGGCTACGTGAAGA

AGGATGCACCATCTT TAACATTGCTTCAGA GGGCTACGTGAAGAT

GGATGCACCATCTTC AACATTGCTTCAGAG GGCTACGTGAAGATC

ATGCACCATCTTCAA CATTGCTTCAGAGCT CTACGTGAAGATCCG

TGCACCATCTTCAAG ATTGCTTCAGAGCTG TACGTGAAGATCCGC

GCACCATCTTCAAGG TTGCTTCAGAGCTGG ACGTGAAGATCCGCC

CACCATCTTCAAGGG TGCTTCAGAGCTGGA CGTGAAGATCCGCCA

CCATCTTCAAGGGCA CTTCAGAGCTGGAGA TGAAGATCCGCCATT

CATCTTCAAGGGCAA TTCAGAGCTGGAGAA GAAGATCCGCCATTC

ATCTTCAAGGGCAAT TCAGAGCTGGAGAAC AAGATCCGCCATTCT

TCTTCAAGGGCAATT CAGAGCTGGAGAACT AGATCCGCCATTCTC

TTCAAGGGCAATTTG GAGCTGGAGAACTTC ATCCGCCATTCTCAT

TCAAGGGCAATTTGC AGCTGGAGAACTTCA TCCGCCATTCTCATG

CAAGGGCAATTTGCT GCTGGAGAACTTCAT CCGCCATTCTCATGC

AAGGGCAATTTGCTC CTGGAGAACTTCATG CGCCATTCTCATGCC

GGGCAATTTGCTCAT GGAGAACTTCATGGG CCATTCTCATGCCTT

GGCAATTTGCTCATT GAGAACTTCATGGGG CATTCTCATGCCTTG

GCAATTTGCTCATTA AGAACTTCATGGGGC ATTCTCATGCCTTGG

CAATTTGCTCATTAA GAACTTCATGGGGCT TTCTCATGCCTTGGT

ATTTGCTCATTAACA ACTTCATGGGGCTCA CTCATGCCTTGGTCT

TTTGCTCATTAACAT CTTCATGGGGCTCAT TCATGCCTTGGTCTC

TTGCTCATTAACATC TTCATGGGGCTCATC CATGCCTTGGTCTCC

TGCTCATTAACATCC TCATGGGGCTCATCG ATGCCTTGGTCTCCT

CTCATTAACATCCGA ATGGGGCTCATCGAG GCCTTGGTCTCCTTG

TCATTAACATCCGAC TGGGGCTCATCGAGG CCTTGGTCTCCTTGT

CATTAACATCCGACG GGGGCTCATCGAGGT CTTGGTCTCCTTGTC

ATTAACATCCGACGG GGGCTCATCGAGGTG TTGGTCTCCTTGTCC

TAACATCCGACGGGG GCTCATCGAGGTGGT GGTCTCCTTGTCCTT

GTCTCCTTGTCCTTC CTAGAAGGGAATTAC CTGTGGGACTGGGAC

TCTCCTTGTCCTTCC TAGAAGGGAATTACT TGTGGGACTGGGACC

CTCCTTGTCCTTCCT AGAAGGGAATTACTC GTGGGACTGGGACCA

TCCTTGTCCTTCCTA GAAGGGAATTACTCC TGGGACTGGGACCAC

CCTTGTCCTTCCTAA AAGGGAATTACTCCT GGGACTGGGACCACC

CTTGTCCTTCCTAAA AGGGAATTACTCCTT GGACTGGGACCACCG

TTGTCCTTCCTAAAA GGGAATTACTCCTTC GACTGGGACCACCGC

TGTCCTTCCTAAAAA GGAATTACTCCTTCT ACTGGGACCACCGCA

GTCCTTCCTAAAAAA GAATTACTCCTTCTA CTGGGACCACCGCAA

10TCCTTCCTAAAP~AAC AATTACTCCTTCTAC TGGGACCACCGCAAC

CCTTCCTAAAAAACC ATTACTCCTTCTACG GGGACCACCGCAACC

CTTCCTAAAAAACCT TTACTCCTTCTACGT GGACCACCGCAACCT

TTCCTAAAAAACCTT TACTCCTTCTACGTC GACCACCGCAACCTG

TCCTAAAAAACCTTC ACTCCTTCTACGTCC ACCACCGCAACCTGA

15CCTAAP.A.A.ACCTTCG CTCCTTCTACGTCCT CCACCGCAACCTGAC

CTP.AAP.AACCTTCGC TCCTTCTACGTCCTC CACCGCAACCTGACC

TAA.A.A.A.ACCTTCGCCCCTTCTACGTCCTCG ACCGCAACCTGACCA

AAAAAACCTTCGCCT CTTCTACGTCCTCGA CCGCAACCTGACCAT

P.AAAACCTTCGCCTC TTCTACGTCCTCGAC CGCAACCTGACCATC

AAACCTTCGCCTCAT CTACGTCCTCGACAA CAACCTGACCATCAA

AACCTTCGCCTCATC TACGTCCTCGACAAC AACCTGACCATCAAA

ACCTTCGCCTCATCC ACGTCCTCGACAACC ACCTGACCATCAAAG

CCTTCGCCTCATCCT CGTCCTCGACAACCA CCTGACCATCAAAGC

TTCGCCTCATCCTAG TCCTCGACAACCAGA TGACCATCAAAGCAG

TCGCCTCATCCTAGG CCTCGACAACCAGAA GACCATCAAAGCAGG

CGCCTCATCCTAGGA CTCGACAACCAGAAC ACCATCAAAGCAGGG

GCCTCATCCTAGGAG TCGACAACCAGAACT CCATCAAAGCAGGGA

CTCATCCTAGGAGAG GACAACCAGAACTTG ATCAAAGCAGGGAAA

TCATCCTAGGAGAGG ACAACCAGAACTTGC TCAAAGCAGGGAAAA

CATCCTAGGAGAGGA CAACCAGAACTTGCA CAAAGCAGGGAAAAT

ATCCTAGGAGAGGAG AACCAGAACTTGCAG AAAGCAGGGAAAATG

CCTAGGAGAGGAGCA CCAGAACTTGCAGCA AGCAGGGAAAATGTA

CTAGGAGAGGAGCAG CAGAACTTGCAGCAA GCAGGGAAAATGTAC

TAGGAGAGGAGCAGC AGAACTTGCAGCAAC CAGGGAAAATGTACT

AGGAGAGGAGCAGCT GAACTTGCAGCAACT AGGGAAAATGTACTT

GAGAGGAGCAGCTAG ACTTGCAGCAACTGT GGAAAATGTACTTTG

AGAGGAGCAGCTAGA CTTGCAGCAACTGTG GAAAATGTACTTTGC

GAGGAGCAGCTAGAA TTGCAGCAACTGTGG AAAATGTACTTTGCT

AGGAGCAGCTAGAAG TGCAGCAACTGTGGG AAATGTACTTTGCTT

GAGCAGCTAGAAGGG CAGCAACTGTGGGAC ATGTACTTTGCTTTC

AGCAGCTAGAAGGGA AGCAACTGTGGGACT TGTACTTTGCTTTCA

GCAGCTAGAAGGGAA GCAACTGTGGGACTG GTACTTTGCTTTCAA

CAGCTAGAAGGGAAT CAACTGTGGGACTGG TACTTTGCTTTCAAT

GCTAGAAGGGAATTA ACTGTGGGACTGGGA CTTTGCTTTCAATCC

TTTGCTTTCAATCCC GTGACGGGGACTAAA AACGGGGAGAGAGCC

TTGCTTTCAATCCCA TGACGGGGACTAAAG ACGGGGAGAGAGCCT

TGCTTTCAATCCCAA GACGGGGACTAAAGG CGGGGAGAGAGCCTC

GCTTTCAATCCCAAA ACGGGGACTAAAGGG GGGGAGAGAGCCTCC

CTTTCAATCCCAAAT CGGGGACTAAAGGGC GGGAGAGAGCCTCCT

TTTCAATCCCAAATT GGGGACTAAAGGGCG GGAGAGAGCCTCCTG

TTCAATCCCAAATTA GGGACTAAAGGGCGC GAGAGAGCCTCCTGT

TCAATCCCAAATTAT GGACTAAAGGGCGCC AGAGAGCCTCCTGTG

CAATCCCAAATTATG GACTAAAGGGCGCCA GAGAGCCTCCTGTGA

ATCCCAAATTATGTG CTAAAGGGCGCCAAA GAGCCTCCTGTGAAA

TCCCAAATTATGTGT TAAAGGGCGCCAAAG AGCCTCCTGTGAAAG

CCCAAATTATGTGTT AAAGGGCGCCAAAGC GCCTCCTGTGAAAGT

CCAAATTATGTGTTT AAGGGCGCCAAAGCA CCTCCTGTGAAAGTG

AAATTATGTGTTTCC GGGCGCCAAAGCAAA TCCTGTGAAAGTGAC

AATTATGTGTTTCCG GGCGCCAAAGCAAAG CCTGTGAAAGTGACG

ATTATGTGTTTCCGA GCGCCAAAGCAAAGG CTGTGAAAGTGACGT

TTATGTGTTTCCGAA CGCCAAAGCAAAGGG TGTGAAAGTGACGTC

ATGTGTTTCCGAAAT CCAAAGCAAAGGGGA TGAAAGTGACGTCCT

TGTGTTTCCGAAATT CAAAGCAAAGGGGAC GAAAGTGACGTCCTG

GTGTTTCCGAAATTT AAAGCAAAGGGGACA AAAGTGACGTCCTGC

TGTTTCCGAAATTTA AAGCAAAGGGGACAT AAGTGACGTCCTGCA

TTTCCGAAATTTACC GCAAAGGGGACATAA GTGACGTCCTGCATT

TTCCGAAATTTACCG CAAAGGGGACATAAA TGACGTCCTGCATTT

TCCGAAATTTACCGC AAAGGGGACATAAAC GACGTCCTGCATTTC

CCGAAATTTACCGCA AAGGGGACATAAACA ACGTCCTGCATTTCA

GAAATTTACCGCATG GGGGACATAAACACC GTCCTGCATTTCACC

AAATTTACCGCATGG GGGACATAAACACCA TCCTGCATTTCACCT

AATTTACCGCATGGA GGACATAAACACCAG CCTGCATTTCACCTC

ATTTACCGCATGGAG GACATAAACACCAGG CTGCATTTCACCTCC

TTACCGCATGGAGGA CATAAACACCAGGAA GCATTTCACCTCCAC

TACCGCATGGAGGAA ATAAACACCAGGAAC CATTTCACCTCCACC

ACCGCATGGAGGAAG TAAACACCAGGAACA ATTTCACCTCCACCA

CCGCATGGAGGAAGT AAACACCAGGAACAA TTTCACCTCCACCAC

GCATGGAGGAAGTGA ACACCAGGAACAACG TCACCTCCACCACCA

CATGGAGGAAGTGAC CACCAGGAACAACGG CACCTCCACCACCAC

ATGGAGGAAGTGACG ACCAGGAACAACGGG ACCTCCACCACCACG

TGGAGGAAGTGACGG CCAGGAACAACGGGG CCTCCACCACCACGT

GAGGAAGTGACGGGG AGGAACAACGGGGAG TCCACCACCACGTCG

AGGAAGTGACGGGGA GGAACAACGGGGAGA CCACCACCACGTCGA

GGAAGTGACGGGGAC GAACAACGGGGAGAG CACCACCACGTCGAA

GAAGTGACGGGGACT AACAACGGGGAGAGA ACCACCACGTCGAAG

AGTGACGGGGACTAA CAACGGGGAGAGAGC CACCACGTCGAAGAA

ACCACGTCGAAGAAT GACTACAGGGATCTC AAGAATGTCACAGAG

CCACGTCGAAGAATC ACTACAGGGATCTCA AGAATGTCACAGAGT

CACGTCGAAGAATCG CTACAGGGATCTCAT GAATGTCACAGAGTA

ACGTCGAAGAATCGC TACAGGGATCTCATC AATGTCACAGAGTAT

CGTCGAAGAATCGCA ACAGGGATCTCATCA ATGTCACAGAGTATG

GTCGAAGAATCGCAT CAGGGATCTCATCAG TGTCACAGAGTATGA

TCGAAGAATCGCATC AGGGATCTCATCAGC GTCACAGAGTATGAT

CGAAGAATCGCATCA GGGATCTCATCAGCT TCACAGAGTATGATG

GAAGAATCGCATCAT GGATCTCATCAGCTT CACAGAGTATGATGG

AGAATCGCATCATCA ATCTCATCAGCTTCA CAGAGTATGATGGGC

GAATCGCATCATCAT TCTCATCAGCTTCAC AGAGTATGATGGGCA

AATCGCATCATCATA CTCATCAGCTTCACC GAGTATGATGGGCAG

ATCGCATCATCATAA TCATCAGCTTCACCG AGTATGATGGGCAGG

CGCATCATCATAACC ATCAGCTTCACCGTT TATGATGGGCAGGAT

GCATCATCATAACCT TCAGCTTCACCGTTT ATGATGGGCAGGATG

CATCATCATAACCTG CAGCTTCACCGTTTA TGATGGGCAGGATGC

ATCATCATAACCTGG AGCTTCACCGTTTAC GATGGGCAGGATGCC

CATCATAACCTGGCA CTTCACCGTTTACTA TGGGCAGGATGCCTG

ATCATAACCTGGCAC TTCACCGTTTACTAC GGGCAGGATGCCTGC

TCATAACCTGGCACC TCACCGTTTACTACA GGCAGGATGCCTGCG

CATAACCTGGCACCG CACCGTTTACTACAA GCAGGATGCCTGCGG

TAACCTGGCACCGGT CCGTTTACTACAAGG AGGATGCCTGCGGCT

AACCTGGCACCGGTA CGTTTACTACAAGGA GGATGCCTGCGGCTC

ACCTGGCACCGGTAC GTTTACTACAAGGAA GATGCCTGCGGCTCC

CCTGGCACCGGTACC TTTACTACAAGGAAG ATGCCTGCGGCTCCA

TGGCACCGGTACCGG TACTACAAGGAAGCA GCCTGCGGCTCCAAC

GGCACCGGTACCGGC ACTACAAGGAAGCAC CCTGCGGCTCCAACA

GCACCGGTACCGGCC CTACAAGGAAGCACC CTGCGGCTCCAACAG

CACCGGTACCGGCCC TACAAGGAAGCACCC TGCGGCTCCAACAGC

CCGGTACCGGCCCCC CAAGGAAGCACCCTT CGGCTCCAACAGCTG

CGGTACCGGCCCCCT AAGGAAGCACCCTTT GGCTCCAACAGCTGG

GGTACCGGCCCCCTG AGGAAGCACCCTTTA GCTCCAACAGCTGGA

GTACCGGCCCCCTGA GGAAGCACCCTTTAA CTCCAACAGCTGGAA

ACCGGCCCCCTGACT AAGCACCCTTTAAGA CCAACAGCTGGAACA

CCGGCCCCCTGACTA AGCACCCTTTAAGAA CAACAGCTGGAACAT

CGGCCCCCTGACTAC GCACCCTTTAAGAAT AACAGCTGGAACATG

GGCCCCCTGACTACA CACCCTTTAAGAATG ACAGCTGGAACATGG

CCCCCTGACTACAGG CCCTTTAAGAATGTC AGCTGGAACATGGTG

CCCCTGACTACAGGG CCTTTAAGAATGTCA GCTGGAACATGGTGG

CCCTGACTACAGGGA CTTTAAGAATGTCAC CTGGAACATGGTGGA

CCTGACTACAGGGAT TTTAAGAATGTCACA TGGAACATGGTGGAC

TGACTACAGGGATCT TAAGAATGTCACAGA GAACATGGTGGACGT

AACATGGTGGACGTG TTACTACATGGGCTG GTGACCCTCACCATG

ACATGGTGGACGTGG TACTACATGGGCTGA TGACCCTCACCATGG

CATGGTGGACGTGGA ACTACATGGGCTGAA GACCCTCACCATGGT

ATGGTGGACGTGGAC CTACATGGGCTGAAG ACCCTCACCATGGTG

TGGTGGACGTGGACC TACATGGGCTGAAGC CCCTCACCATGGTGG

GGTGGACGTGGACCT ACATGGGCTGAAGCC CCTCACCATGGTGGA

GTGGACGTGGACCTC CATGGGCTGAAGCCC CTCACCATGGTGGAG

TGGACGTGGACCTCC ATGGGCTGAAGCCCT TCACCATGGTGGAGA

GGACGTGGACCTCCC TGGGCTGAAGCCCTG CACCATGGTGGAGAA

ACGTGGACCTCCCGC GGCTGAAGCCCTGGA CCATGGTGGAGAACG

CGTGGACCTCCCGCC GCTGAAGCCCTGGAC CATGGTGGAGAACGA

GTGGACCTCCCGCCC CTGAAGCCCTGGACT ATGGTGGAGAACGAC

TGGACCTCCCGCCCA TGAAGCCCTGGACTC TGGTGGAGAACGACC

GACCTCCCGCCCAAC AAGCCCTGGACTCAG GTGGAGAACGACCAT

ACCTCCCGCCCAACA AGCCCTGGACTCAGT TGGAGAACGACCATA

CCTCCCGCCCAACAA GCCCTGGACTCAGTA GGAGAACGACCATAT

CTCCCGCCCAACAAG CCCTGGACTCAGTAC GAGAACGACCATATC

CCCGCCCAACAAGGA CTGGACTCAGTACGC GAACGACCATATCCG

CCGCCCAACAAGGAC TGGACTCAGTACGCC AACGACCATATCCGT

CGCCCAACAAGGACG GGACTCAGTACGCCG ACGACCATATCCGTG

GCCCAACAAGGACGT GACTCAGTACGCCGT CGACCATATCCGTGG

CCAACAAGGACGTGG CTCAGTACGCCGTTT ACCATATCCGTGGGG

CAACAAGGACGTGGA TCAGTACGCCGTTTA CCATATCCGTGGGGC

AACAAGGACGTGGAG CAGTACGCCGTTTAC CATATCCGTGGGGCC

ACAAGGACGTGGAGC AGTACGCCGTTTACG ATATCCGTGGGGCCA

AAGGACGTGGAGCCC TACGCCGTTTACGTC ATCCGTGGGGCCAAG

AGGACGTGGAGCCCG ACGCCGTTTACGTCA TCCGTGGGGCCAAGA

GGACGTGGAGCCCGG CGCCGTTTACGTCAA CCGTGGGGCCAAGAG

GACGTGGAGCCCGGC GCCGTTTACGTCAAG CGTGGGGCCAAGAGT

CGTGGAGCCCGGCAT CGTTTACGTCAAGGC TGGGGCCAAGAGTGA

GTGGAGCCCGGCATC GTTTACGTCAAGGCT GGGGCCAAGAGTGAG

TGGAGCCCGGCATCT TTTACGTCAAGGCTG GGGCCAAGAGTGAGA

GGAGCCCGGCATCTT TTACGTCAAGGCTGT GGCCAAGAGTGAGAT

AGCCCGGCATCTTAC ACGTCAAGGCTGTGA CCAAGAGTGAGATCT

GCCCGGCATCTTACT CGTCAAGGCTGTGAC CAAGAGTGAGATCTT

CCCGGCATCTTACTA GTCAAGGCTGTGACC AAGAGTGAGATCTTG

CCGGCATCTTACTAC TCAAGGCTGTGACCC AGAGTGAGATCTTGT

GGCATCTTACTACAT AAGGCTGTGACCCTC AGTGAGATCTTGTAC

GCATCTTACTACATG AGGCTGTGACCCTCA GTGAGATCTTGTACA

CATCTTACTACATGG GGCTGTGACCCTCAC TGAGATCTTGTACAT

ATCTTACTACATGGG GCTGTGACCCTCACC GAGATCTTGTACATT

CTTACTACATGGGCT TGTGACCCTCACCAT GATCTTGTACATTCG

ATCTTGTACATTCGC CTTTCAGCATCGAAC TCTCTGCCCAACGGC

TCTTGTACATTCGCA TTTCAGCATCGAACT CTCTGCCCAACGGCA

CTTGTACATTCGCAC TTCAGCATCGAACTC TCTGCCCAACGGCAA

TTGTACATTCGCACC TCAGCATCGAACTCC CTGCCCAACGGCAAC

S TGTACATTCGCACCA CAGCATCGAACTCCT TGCCCAACGGCAACC

GTACATTCGCACCAA AGCATCGAACTCCTC GCCCAACGGCAACCT

TACATTCGCACCAAT GCATCGAACTCCTCT CCCAACGGCAACCTG

ACATTCGCACCAATG CATCGAACTCCTCTT CCAACGGCAACCTGA

CATTCGCACCAATGC ATCGAACTCCTCTTC CAACGGCAACCTGAG

TTCGCACCAATGCTT CGAACTCCTCTTCTC ACGGCAACCTGAGTT

TCGCACCAATGCTTC GAACTCCTCTTCTCA CGGCAACCTGAGTTA

CGCACCAATGCTTCA AACTCCTCTTCTCAG GGCAACCTGAGTTAC

GCACCAATGCTTCAG ACTCCTCTTCTCAGT GCAACCTGAGTTACT

ACCAATGCTTCAGTT TCCTCTTCTCAGTTA AACCTGAGTTACTAC

CCAATGCTTCAGTTC CCTCTTCTCAGTTAA ACCTGAGTTACTACA

CAATGCTTCAGTTCC CTCTTCTCAGTTAAT CCTGAGTTACTACAT

AATGCTTCAGTTCCT TCTTCTCAGTTAATC CTGAGTTACTACATT

TGCTTCAGTTCCTTC TTCTCAGTTAATCGT GAGTTACTACATTGT

GCTTCAGTTCCTTCC TCTCAGTTAATCGTG AGTTACTACATTGTG

CTTCAGTTCCTTCCA CTCAGTTAATCGTGA GTTACTACATTGTGC

TTCAGTTCCTTCCAT TCAGTTAATCGTGAA TTACTACATTGTGCG

CAGTTCCTTCCATTC AGTTAATCGTGAAGT ACTACATTGTGCGCT

AGTTCCTTCCATTCC GTTAATCGTGAAGTG CTACATTGTGCGCTG

GTTCCTTCCATTCCC TTAATCGTGAAGTGG TACATTGTGCGCTGG

TTCCTTCCATTCCCT TAATCGTGAAGTGGA ACATTGTGCGCTGGC

CCTTCCATTCCCTTG ATCGTGAAGTGGAAC ATTGTGCGCTGGCAG

CTTCCATTCCCTTGG TCGTGAAGTGGAACC TTGTGCGCTGGCAGC

TTCCATTCCCTTGGA CGTGAAGTGGAACCC TGTGCGCTGGCAGCG

TCCATTCCCTTGGAC GTGAAGTGGAACCCT GTGCGCTGGCAGCGG

CATTCCCTTGGACGT GAAGTGGAACCCTCC GCGCTGGCAGCGGCA

ATTCCCTTGGACGTT AAGTGGAACCCTCCC CGCTGGCAGCGGCAG

TTCCCTTGGACGTTC AGTGGAACCCTCCCT GCTGGCAGCGGCAGC

TCCCTTGGACGTTCT GTGGAACCCTCCCTC CTGGCAGCGGCAGCC

CCTTGGACGTTCTTT GGAACCCTCCCTCTC GGCAGCGGCAGCCTC

CTTGGACGTTCTTTC GAACCCTCCCTCTCT GCAGCGGCAGCCTCA

TTGGACGTTCTTTCA AACCCTCCCTCTCTG CAGCGGCAGCCTCAG

TGGACGTTCTTTCAG ACCCTCCCTCTCTGC AGCGGCAGCCTCAGG

GACGTTCTTTCAGCA CCTCCCTCTCTGCCC CGGCAGCCTCAGGAC

ACGTTCTTTCAGCAT CTCCCTCTCTGCCCA GGCAGCCTCAGGACG

CGTTCTTTCAGCATC TCCCTCTCTGCCCAA GCAGCCTCAGGACGG

GTTCTTTCAGCATCG CCCTCTCTGCCCAAC CAGCCTCAGGACGGC

TCTTTCAGCATCGAA CTCTCTGCCCAACGG GCCTCAGGACGGCTA

CCTCAGGACGGCTAC CCCATCAGGAAGTAT AACCCCAAGACTGAG

CTCAGGACGGCTACC CCATCAGGAAGTATG ACCCCAAGACTGAGG

TCAGGACGGCTACCT CATCAGGAAGTATGC CCCCAAGACTGAGGT

CAGGACGGCTACCTT ATCAGGAAGTATGCC CCCAAGACTGAGGTG

AGGACGGCTACCTTT TCAGGAAGTATGCCG CCAAGACTGAGGTGT

GGACGGCTACCTTTA CAGGAAGTATGCCGA CAAGACTGAGGTGTG

GACGGCTACCTTTAC AGGAAGTATGCCGAC AAGACTGAGGTGTGT

ACGGCTACCTTTACC GGAAGTATGCCGACG AGACTGAGGTGTGTG

CGGCTACCTTTACCG GAAGTATGCCGACGG GACTGAGGTGTGTGG

GCTACCTTTACCGGC AGTATGCCGACGGCA CTGAGGTGTGTGGTG

CTACCTTTACCGGCA GTATGCCGACGGCAC TGAGGTGTGTGGTGG

TACCTTTACCGGCAC TATGCCGACGGCACC GAGGTGTGTGGTGGG

ACCTTTACCGGCACA ATGCCGACGGCACCA AGGTGTGTGGTGGGG

CTTTACCGGCACAAT GCCGACGGCACCATC GTGTGTGGTGGGGAG

TTTACCGGCACAATT CCGACGGCACCATCG TGTGTGGTGGGGAGA

TTACCGGCACAATTA CGACGGCACCATCGA GTGTGGTGGGGAGAA

TACCGGCACAATTAC GACGGCACCATCGAC TGTGGTGGGGAGAAA

CCGGCACAATTACTG CGGCACCATCGACAT TGGTGGGGAGAAAGG

CGGCACAATTACTGC GGCACCATCGACATT GGTGGGGAGAAAGGG

GGCACAATTACTGCT GCACCATCGACATTG GTGGGGAGAAAGGGC

GCACAATTACTGCTC CACCATCGACATTGA TGGGGAGAAAGGGCC

ACAATTACTGCTCCA CCATCGACATTGAGG GGGAGAAAGGGCCTT

CAATTACTGCTCCAA CATCGACATTGAGGA GGAGAAAGGGCCTTG

AATTACTGCTCCAAA ATCGACATTGAGGAG GAGAAAGGGCCTTGC

ATTACTGCTCCAAAG TCGACATTGAGGAGG AGAAAGGGCCTTGCT

TACTGCTCCAAAGAC GACATTGAGGAGGTC AAAGGGCCTTGCTGC

ACTGCTCCAAAGACA ACATTGAGGAGGTCA AAGGGCCTTGCTGCG

CTGCTCCAAAGACAA CATTGAGGAGGTCAC AGGGCCTTGCTGCGC

TGCTCCAAAGACAAA ATTGAGGAGGTCACA GGGCCTTGCTGCGCC

CTCCAAAGACAAAAT TGAGGAGGTCACAGA GCCTTGCTGCGCCTG

TCCAAAGACAAAATC GAGGAGGTCACAGAG CCTTGCTGCGCCTGC

CCAAAGACAAAATCC AGGAGGTCACAGAGA CTTGCTGCGCCTGCC

CAAAGACAAAATCCC GGAGGTCACAGAGAA TTGCTGCGCCTGCCC

AAGACAAAATCCCCA AGGTCACAGAGAACC GCTGCGCCTGCCCCA

AGACAAAATCCCCAT GGTCACAGAGAACCC CTGCGCCTGCCCCAA

GACAAAATCCCCATC GTCACAGAGAACCCC TGCGCCTGCCCCAAA

ACAAAATCCCCATCA TCACAGAGAACCCCA GCGCCTGCCCCAAAA

AAAATCCCCATCAGG ACAGAGAACCCCAAG GCCTGCCCCAAAACT

AAATCCCCATCAGGA CAGAGAACCCCAAGA CCTGCCCCAAAACTG

AATCCCCATCAGGAA AGAGAACCCCAAGAC CTGCCCCAAAACTGA

ATCCCCATCAGGAAG GAGAACCCCAAGACT TGCCCCAAAACTGAA

CCCCATCAGGAAGTA GAACCCCAAGACTGA CCCCAAAACTGAAGC

CCCAAAACTGAAGCC AAAGTCTTTGAGAAT AGGAAGCGGAGAGAT

CCAAAACTGAAGCCG AAGTCTTTGAGAATT GGAAGCGGAGAGATG

CAAAACTGAAGCCGA AGTCTTTGAGAATTT GAAGCGGAGAGATGT

AAAACTGAAGCCGAG GTCTTTGAGAATTTC AAGCGGAGAGATGTC

AAACTGAAGCCGAGA TCTTTGAGAATTTCC AGCGGAGAGATGTCA

AACTGAAGCCGAGAA CTTTGAGAATTTCCT GCGGAGAGATGTCAT

ACTGAAGCCGAGAAG TTTGAGAATTTCCTG CGGAGAGATGTCATG

CTGAAGCCGAGAAGC TTGAGAATTTCCTGC GGAGAGATGTCATGC

TGAAGCCGAGAAGCA TGAGAATTTCCTGCA GAGAGATGTCATGCA

AAGCCGAGAAGCAGG AGAATTTCCTGCACA GAGATGTCATGCAAG

AGCCGAGAAGCAGGC GAATTTCCTGCACAA AGATGTCATGCAAGT

GCCGAGAAGCAGGCC AATTTCCTGCACAAC GATGTCATGCAAGTG

CCGAGAAGCAGGCCG ATTTCCTGCACAACT ATGTCATGCAAGTGG

GAGAAGCAGGCCGAG TTCCTGCACAACTCC GTCATGCAAGTGGCC

AGAAGCAGGCCGAGA TCCTGCACAACTCCA TCATGCAAGTGGCCA

GAAGCAGGCCGAGAA CCTGCACAACTCCAT CATGCAAGTGGCCAA

AAGCAGGCCGAGAAG CTGCACAACTCCATC ATGCAAGTGGCCAAC

GCAGGCCGAGAAGGA GCACAACTCCATCTT GCAAGTGGCCAACAC

CAGGCCGAGAAGGAG CACAACTCCATCTTC CAAGTGGCCAACACC

AGGCCGAGAAGGAGG ACAACTCCATCTTCG AAGTGGCCAACACCA

GGCCGAGAAGGAGGA CAACTCCATCTTCGT AGTGGCCAACACCAC

CCGAGAAGGAGGAGG ACTCCATCTTCGTGC TGGCCAACACCACCA

CGAGAAGGAGGAGGC CTCCATCTTCGTGCC GGCCAACACCACCAT

GAGAAGGAGGAGGCT TCCATCTTCGTGCCC GCCAACACCACCATG

AGAAGGAGGAGGCTG CCATCTTCGTGCCCA CCAACACCACCATGT

AAGGAGGAGGCTGAA ATCTTCGTGCCCAGA AACACCACCATGTCC

AGGAGGAGGCTGAAT TCTTCGTGCCCAGAC ACACCACCATGTCCA

GGAGGAGGCTGAATA CTTCGTGCCCAGACC CACCACCATGTCCAG

GAGGAGGCTGAATAC TTCGTGCCCAGACCT ACCACCATGTCCAGC

GGAGGCTGAATACCG CGTGCCCAGACCTGA CACCATGTCCAGCCG

GAGGCTGAATACCGC GTGCCCAGACCTGAA ACCATGTCCAGCCGA

AGGCTGAATACCGCA TGCCCAGACCTGAAA CCATGTCCAGCCGAA

GGCTGAATACCGCAA GCCCAGACCTGAAAG CATGTCCAGCCGAAG

CTGAATACCGCAAAG CCAGACCTGAAAGGA TGTCCAGCCGAAGCA

TGAATACCGCAAAGT CAGACCTGAAAGGAA GTCCAGCCGAAGCAG

GAATACCGCAAAGTC AGACCTGAAAGGAAG TCCAGCCGAAGCAGG

AATACCGCAAAGTCT GACCTGAAAGGAAGC CCAGCCGAAGCAGGA

TACCGCAAAGTCTTT CCTGAAAGGAAGCGG AGCCGAAGCAGGAAC

ACCGCAAAGTCTTTG CTGAAAGGAAGCGGA GCCGAAGCAGGAACA

CCGCAAAGTCTTTGA TGAAAGGAAGCGGAG CCGAAGCAGGAACAC

CGCAAAGTCTTTGAG GAAAGGAAGCGGAGA CGAAGCAGGAACACC

CAAAGTCTTTGAGAA AAGGAAGCGGAGAGA AAGCAGGAACACCAC

AGCAGGAACACCACG CTGGAGACAGAGTAC ACTGTCATTTCTAAC

GCAGGAACACCACGG TGGAGACAGAGTACC CTGTCATTTCTAACC

CAGGAACACCACGGC GGAGACAGAGTACCC TGTCATTTCTAACCT

AGGAACACCACGGCC GAGACAGAGTACCCT GTCATTTCTAACCTT

GGAACACCACGGCCG AGACAGAGTACCCTT TCATTTCTAACCTTC

GAACACCACGGCCGC GACAGAGTACCCTTT CATTTCTAACCTTCG

AACACCACGGCCGCA ACAGAGTACCCTTTC ATTTCTAACCTTCGG

ACACCACGGCCGCAG CAGAGTACCCTTTCT TTTCTAACCTTCGGC

CACCACGGCCGCAGA AGAGTACCCTTTCTT TTCTAACCTTCGGCC

CCACGGCCGCAGACA AGTACCCTTTCTTTG CTAACCTTCGGCCTT

CACGGCCGCAGACAC GTACCCTTTCTTTGA TAACCTTCGGCCTTT

ACGGCCGCAGACACC TACCCTTTCTTTGAG AACCTTCGGCCTTTC

CGGCCGCAGACACCT ACCCTTTCTTTGAGA ACCTTCGGCCTTTCA

GCCGCAGACACCTAC CCTTTCTTTGAGAGC CTTCGGCCTTTCACA

CCGCAGACACCTACA CTTTCTTTGAGAGCA TTCGGCCTTTCACAT

CGCAGACACCTACAA TTTCTTTGAGAGCAG TCGGCCTTTCACATT

GCAGACACCTACAAC TTCTTTGAGAGCAGA CGGCCTTTCACATTG

AGACACCTACAACAT CTTTGAGAGCAGAGT GCCTTTCACATTGTA

GACACCTACAACATC TTTGAGAGCAGAGTG CCTTTCACATTGTAC

ACACCTACAACATCA TTGAGAGCAGAGTGG CTTTCACATTGTACC

CACCTACAACATCAC TGAGAGCAGAGTGGA TTTCACATTGTACCG

CCTACAACATCACCG AGAGCAGAGTGGATA TCACATTGTACCGCA

CTACAACATCACCGA GAGCAGAGTGGATAA CACATTGTACCGCAT

TACAACATCACCGAC AGCAGAGTGGATAAC ACATTGTACCGCATC

ACAACATCACCGACC GCAGAGTGGATAACA CATTGTACCGCATCG

AACATCACCGACCCG AGAGTGGATAACAAG TTGTACCGCATCGAT

ACATCACCGACCCGG GAGTGGATAACAAGG TGTACCGCATCGATA

CATCACCGACCCGGA AGTGGATAACAAGGA GTACCGCATCGATAT

ATCACCGACCCGGAA GTGGATAACAAGGAG TACCGCATCGATATC

CACCGACCCGGAAGA GGATAACAAGGAGAG CCGCATCGATATCCA

ACCGACCCGGAAGAG GATAACAAGGAGAGA CGCATCGATATCCAC

CCGACCCGGAAGAGC ATAACAAGGAGAGAA GCATCGATATCCACA

CGACCCGGAAGAGCT TAACAAGGAGAGAAC CATCGATATCCACAG

ACCCGGAAGAGCTGG ACAAGGAGAGAACTG TCGATATCCACAGCT

CCCGGAAGAGCTGGA CAAGGAGAGAACTGT CGATATCCACAGCTG

CCGGAAGAGCTGGAG AAGGAGAGAACTGTC GATATCCACAGCTGC

CGGAAGAGCTGGAGA AGGAGAGAACTGTCA ATATCCACAGCTGCA

GAAGAGCTGGAGACA GAGAGAACTGTCATT ATCCACAGCTGCAAC

AAGAGCTGGAGACAG AGAGAACTGTCATTT TCCACAGCTGCAACC

AGAGCTGGAGACAGA GAGAACTGTCATTTC CCACAGCTGCAACCA

GAGCTGGAGACAGAG AGAACTGTCATTTCT CACAGCTGCAACCAC

GCTGGAGACAGAGTA AACTGTCATTTCTAA CAGCTGCAACCACGA

_77_ AGCTGCAACCACGAG TTTGCAAGGACTATG ACCTGGGAGCCAAGG

GCTGCAACCACGAGG TTGCAAGGACTATGC CCTGGGAGCCAAGGC

CTGCAACCACGAGGC TGCAAGGACTATGCC CTGGGAGCCAAGGCC

TGCAACCACGAGGCT GCAAGGACTATGCCC TGGGAGCCAAGGCCT

GCAACCACGAGGCTG CAAGGACTATGCCCG GGGAGCCAAGGCCTG

CAACCACGAGGCTGA AAGGACTATGCCCGC GGAGCCAAGGCCTGA

AACCACGAGGCTGAG AGGACTATGCCCGCA GAGCCAAGGCCTGAA

ACCACGAGGCTGAGA GGACTATGCCCGCAG AGCCAAGGCCTGAAA

CCACGAGGCTGAGAA GACTATGCCCGCAGA GCCAAGGCCTGAAAA

ACGAGGCTGAGAAGC CTATGCCCGCAGAAG CAAGGCCTGAAAACT

CGAGGCTGAGAAGCT TATGCCCGCAGAAGG AAGGCCTGAAAACTC

GAGGCTGAGAAGCTG ATGCCCGCAGAAGGA AGGCCTGAAAACTCC

AGGCTGAGAAGCTGG TGCCCGCAGAAGGAG GGCCTGAAAACTCCA

GCTGAGAAGCTGGGC CCCGCAGAAGGAGCA CCTGAAAACTCCATC

CTGAGAAGCTGGGCT CCGCAGAAGGAGCAG CTGAAAACTCCATCT

TGAGAAGCTGGGCTG CGCAGAAGGAGCAGA TGAAAACTCCATCTT

GAGAAGCTGGGCTGC GCAGAAGGAGCAGAT GAAAACTCCATCTTT

GAAGCTGGGCTGCAG AGAAGGAGCAGATGA AAACTCCATCTTTTT

AAGCTGGGCTGCAGC GAAGGAGCAGATGAC AACTCCATCTTTTTA

AGCTGGGCTGCAGCG AAGGAGCAGATGACA ACTCCATCTTTTTAA

GCTGGGCTGCAGCGC AGGAGCAGATGACAT CTCCATCTTTTTAAA

TGGGCTGCAGCGCCT GAGCAGATGACATTC CCATCTTTTTAAAGT

GGGCTGCAGCGCCTC AGCAGATGACATTCC CATCTTTTTAAAGTG

GGCTGCAGCGCCTCC GCAGATGACATTCCT ATCTTTTTAAAGTGG

GCTGCAGCGCCTCCA CAGATGACATTCCTG TCTTTTTAAAGTGGC

TGCAGCGCCTCCAAC GATGACATTCCTGGG TTTTTAAAGTGGCCG

GCAGCGCCTCCAACT ATGACATTCCTGGGC TTTTAAAGTGGCCGG

CAGCGCCTCCAACTT TGACATTCCTGGGCC TTTAAAGTGGCCGGA

AGCGCCTCCAACTTC GACATTCCTGGGCCA TTAAAGTGGCCGGA.A

CGCCTCCAACTTCGT CATTCCTGGGCCAGT AAAGTGGCCGGAACC

GCCTCCAACTTCGTC ATTCCTGGGCCAGTG AAGTGGCCGGAACCT

CCTCCAACTTCGTCT TTCCTGGGCCAGTGA AGTGGCCGGAACCTG

CTCCAACTTCGTCTT TCCTGGGCCAGTGAC GTGGCCGGAACCTGA

CCAACTTCGTCTTTG CTGGGCCAGTGACCT GGCCGGAACCTGAGA

CAACTTCGTCTTTGC TGGGCCAGTGACCTG GCCGGAACCTGAGAA

AACTTCGTCTTTGCA GGGCCAGTGACCTGG CCGGAACCTGAGAAT

ACTTCGTCTTTGCAA GGCCAGTGACCTGGG CGGAACCTGAGAATC

TTCGTCTTTGCAAGG CCAGTGACCTGGGAG GAACCTGAGAATCCC

TCGTCTTTGCAAGGA CAGTGACCTGGGAGC AACCTGAGAATCCCA

CGTCTTTGCAAGGAC AGTGACCTGGGAGCC ACCTGAGAATCCCAA

GTCTTTGCAAGGACT GTGACCTGGGAGCCA CCTGAGAATCCCAAT

CTTTGCAAGGACTAT GACCTGGGAGCCAAG TGAGAATCCCAATGG

_7g_ GAGAATCCCAATGGA GTTGAGGATCAGCGA GGGGCCAAGCTAAAC

AGAATCCCAATGGAT TTGAGGATCAGCGAG GGGCCAAGCTAAACC

GAATCCCAATGGATT TGAGGATCAGCGAGA GGCCAAGCTAA.P.CCG

AATCCCAATGGATTG GAGGATCAGCGAGAA GCCAAGCTAAACCGG

ATCCCAATGGATTGA AGGATCAGCGAGAAT CCAAGCTAAACCGGC

TCCCAATGGATTGAT GGATCAGCGAGAATG CAAGCTAAACCGGCT

CCCAATGGATTGATT GATCAGCGAGAATGT AAGCTAAACCGGCTA

CCAATGGATTGATTC ATCAGCGAGAATGTG AGCTAAACCGGCTAA

CAATGGATTGATTCT TCAGCGAGAATGTGT GCTAAACCGGCTAAA

ATGGATTGATTCTAA AGCGAGAATGTGTGT TAAACCGGCTAAACC

TGGATTGATTCTAAT GCGAGAATGTGTGTC AAACCGGCTAAACCC

GGATTGATTCTAATG CGAGAATGTGTGTCC AACCGGCTAAACCCG

GATTGATTCTAATGT GAGAATGTGTGTCCA ACCGGCTAAACCCGG

TTGATTCTAATGTAT GAATGTGTGTCCAGA CGGCTAA.ACCCGGGG

TGATTCTAATGTATG AATGTGTGTCCAGAC GGCTAAACCCGGGGA

GATTCTAATGTATGA ATGTGTGTCCAGACA GCTAAACCCGGGGAA

ATTCTAATGTATGAA TGTGTGTCCAGACAG CTAAACCCGGGGAAC

TCTAATGTATGAAAT TGTGTCCAGACAGGA AAACCCGGGGAACTA

CTAATGTATGAAATA GTGTCCAGACAGGAA AACCCGGGGAACTAC

TAATGTATGAAATAA TGTCCAGACAGGAAT ACCCGGGGAACTACA

AATGTATGAAATAAA GTCCAGACAGGAATA CCCGGGGAACTACAC

TGTATGAAATAAAAT CCAGACAGGAATACA CGGGGAACTACACAG

GTATGAAATAAAATA CAGACAGGAATACAG GGGGAACTACACAGC

TATGAA.ATAAAATAC AGACAGGAATACAGG GGGAACTACACAGCC

ATGAAATAAAATACG GACAGGAATACAGGA GGAACTACACAGCCC

GAAATAAAATACGGA CAGGAATACAGGAAG AACTACACAGCCCGG

AAATAAAATACGGAT AGGAATACAGGAAGT ACTACACAGCCCGGA

AATAAAATACGGATC GGAATACAGGAAGTA CTACACAGCCCGGAT

ATAAAATACGGATCA GAATACAGGAAGTAT TACACAGCCCGGATT

AAAATACGGATCACA ATACAGGAAGTATGG CACAGCCCGGATTCA

AAATACGGATCACAA TACAGGAAGTATGGA ACAGCCCGGATTCAG

AATACGGATCACAAG ACAGGAAGTATGGAG CAGCCCGGATTCAGG

ATACGGATCACAAGT CAGGAAGTATGGAGG AGCCCGGATTCAGGC

ACGGATCACAAGTTG GGAAGTATGGAGGGG CCCGGATTCAGGCCA

CGGATCACAAGTTGA GAAGTATGGAGGGGC CCGGATTCAGGCCAC

GGATCACAAGTTGAG AAGTATGGAGGGGCC CGGATTCAGGCCACA

GATCACAAGTTGAGG AGTATGGAGGGGCCA GGATTCAGGCCACAT

TCACAAGTTGAGGAT TATGGAGGGGCCAAG ATTCAGGCCACATCT

CACAAGTTGAGGATC ATGGAGGGGCCAAGC TTCAGGCCACATCTC

ACAAGTTGAGGATCA TGGAGGGGCCAAGCT TCAGGCCACATCTCT

CAAGTTGAGGATCAG GGAGGGGCCAAGCTA CAGGCCACATCTCTC

AGTTGAGGATCAGCG AGGGGCCAAGCTAAA GGCCACATCTCTCTC

GCCACATCTCTCTCT GTCCAGGCCAAAACA CCCGTCGCTGTCCTG

CCACATCTCTCTCTG TCCAGGCCAAAACAG CCGTCGCTGTCCTGT

CACATCTCTCTCTGG CCAGGCCAAAACAGG CGTCGCTGTCCTGTT

ACATCTCTCTCTGGG CAGGCCAAAACAGGA GTCGCTGTCCTGTTG

CATCTCTCTCTGGGA AGGCCAAAACAGGAT TCGCTGTCCTGTTGA

ATCTCTCTCTGGGAA GGCCAAAACAGGATA CGCTGTCCTGTTGAT

TCTCTCTCTGGGAAT GCCAAAACAGGATAT GCTGTCCTGTTGATC

CTCTCTCTGGGAATG CCAAAACAGGATATG CTGTCCTGTTGATCG

TCTCTCTGGGAATGG CAAAACAGGATATGA TGTCCTGTTGATCGT

TCTCTGGGAATGGGT AAACAGGATATGAAA TCCTGTTGATCGTGG

CTCTGGGAATGGGTC AACAGGATATGAAAA CCTGTTGATCGTGGG

TCTGGGAATGGGTCG ACAGGATATGAAAAC CTGTTGATCGTGGGA

CTGGGAATGGGTCGT CAGGATATGAAAACT TGTTGATCGTGGGAG

GGGAATGGGTCGTGG GGATATGAAAACTTC TTGATCGTGGGAGGG

GGAATGGGTCGTGGA GATATGAAAACTTCA TGATCGTGGGAGGGT

GAATGGGTCGTGGAC ATATGAAAACTTCAT GATCGTGGGAGGGTT

AATGGGTCGTGGACA TATGAAAACTTCATC ATCGTGGGAGGGTTG

TGGGTCGTGGACAGA TGAAAACTTCATCCA CGTGGGAGGGTTGGT

GGGTCGTGGACAGAT GAAAACTTCATCCAT GTGGGAGGGTTGGTG

GGTCGTGGACAGATC AAAACTTCATCCATC TGGGAGGGTTGGTGA

GTCGTGGACAGATCC AAACTTCATCCATCT GGGAGGGTTGGTGAT

CGTGGACAGATCCTG ACTTCATCCATCTGA GAGGGTTGGTGATTA

GTGGACAGATCCTGT CTTCATCCATCTGAT AGGGTTGGTGATTAT

TGGACAGATCCTGTG TTCATCCATCTGATC GGGTTGGTGATTATG

GGACAGATCCTGTGT TCATCCATCTGATCA GGTTGGTGATTATGC

ACAGATCCTGTGTTC ATCCATCTGATCATC TTGGTGATTATGCTG

CAGATCCTGTGTTCT TCCATCTGATCATCG TGGTGATTATGCTGT

AGATCCTGTGTTCTT CCATCTGATCATCGC GGTGATTATGCTGTA

GATCCTGTGTTCTTC CATCTGATCATCGCT GTGATTATGCTGTAC

TCCTGTGTTCTTCTA TCTGATCATCGCTCT GATTATGCTGTACGT

CCTGTGTTCTTCTAT CTGATCATCGCTCTG ATTATGCTGTACGTC

CTGTGTTCTTCTATG TGATCATCGCTCTGC TTATGCTGTACGTCT

TGTGTTCTTCTATGT GATCATCGCTCTGCC TATGCTGTACGTCTT

TGTTCTTCTATGTCC TCATCGCTCTGCCCG TGCTGTACGTCTTCC

GTTCTTCTATGTCCA CATCGCTCTGCCCGT GCTGTACGTCTTCCA

TTCTTCTATGTCCAG ATCGCTCTGCCCGTC CTGTACGTCTTCCAT

TCTTCTATGTCCAGG TCGCTCTGCCCGTCG TGTACGTCTTCCATA

TTCTATGTCCAGGCC GCTCTGCCCGTCGCT TACGTCTTCCATAGA

TCTATGTCCAGGCCA CTCTGCCCGTCGCTG ACGTCTTCCATAGAA

CTATGTCCAGGCCAA TCTGCCCGTCGCTGT CGTCTTCCATAGAAA

TATGTCCAGGCCAAA CTGCCCGTCGCTGTC GTCTTCCATAGAAAG

TGTCCAGGCCAAAAC GCCCGTCGCTGTCCT CTTCCATAGAAAGAG

TTCCATAGAAAGAGA TCTGTGAACCCGGAG TGGGAGGTGGCTCGG

TCCATAGAAAGAGAA CTGTGAACCCGGAGT GGGAGGTGGCTCGGG

CCATAGAAAGAGAAA TGTGAACCCGGAGTA GGAGGTGGCTCGGGA

CATAGAAAGAGAAAT GTGAACCCGGAGTAC GAGGTGGCTCGGGAG

ATAGAAAGAGAAATA TGAACCCGGAGTACT AGGTGGCTCGGGAGA

TAGAAAGAGAAATAA GAACCCGGAGTACTT GGTGGCTCGGGAGAA

AGAAAGAGAAATAAC AACCCGGAGTACTTC GTGGCTCGGGAGAAG

GAAAGAGAAATAACA ACCCGGAGTACTTCA TGGCTCGGGAGAAGA

AAAGAGAAATAACAG CCCGGAGTACTTCAG GGCTCGGGAGAAGAT

AGAGAAATAACAGCA CGGAGTACTTCAGCG CTCGGGAGAAGATCA

GAGAAATAACAGCAG GGAGTACTTCAGCGC TCGGGAGAAGATCAC

AGAAATAACAGCAGG GAGTACTTCAGCGCT CGGGAGAAGATCACC

GAAATAACAGCAGGC AGTACTTCAGCGCTG GGGAGAAGATCACCA

AATAACAGCAGGCTG TACTTCAGCGCTGCT GAGAAGATCACCATG

ATAACAGCAGGCTGG ACTTCAGCGCTGCTG AGAAGATCACCATGA

TAACAGCAGGCTGGG CTTCAGCGCTGCTGA GAAGATCACCATGAG

AACAGCAGGCTGGGG TTCAGCGCTGCTGAT AAGATCACCATGAGC

CAGCAGGCTGGGGAA CAGCGCTGCTGATGT GATCACCATGAGCCG

AGCAGGCTGGGGAAT AGCGCTGCTGATGTG ATCACCATGAGCCGG

GCAGGCTGGGGAATG GCGCTGCTGATGTGT TCACCATGAGCCGGG

CAGGCTGGGGAATGG CGCTGCTGATGTGTA CACCATGAGCCGGGA

GGCTGGGGAATGGAG CTGCTGATGTGTACG CCATGAGCCGGGAAC

GCTGGGGAATGGAGT TGCTGATGTGTACGT CATGAGCCGGGAACT

CTGGGGAATGGAGTG GCTGATGTGTACGTT ATGAGCCGGGAACTT

TGGGGAATGGAGTGC CTGATGTGTACGTTC TGAGCCGGGAACTTG

GGGAATGGAGTGCTG GATGTGTACGTTCCT AGCCGGGAACTTGGG

GGAATGGAGTGCTGT ATGTGTACGTTCCTG GCCGGGAACTTGGGC

GAATGGAGTGCTGTA TGTGTACGTTCCTGA CCGGGAACTTGGGCA

AATGGAGTGCTGTAT GTGTACGTTCCTGAT CGGGAACTTGGGCAG

TGGAGTGCTGTATGC GTACGTTCCTGATGA GGAACTTGGGCAGGG

GGAGTGCTGTATGCC TACGTTCCTGATGAG GAACTTGGGCAGGGG

GAGTGCTGTATGCCT ACGTTCCTGATGAGT AACTTGGGCAGGGGT

AGTGCTGTATGCCTC CGTTCCTGATGAGTG ACTTGGGCAGGGGTC

TGCTGTATGCCTCTG TTCCTGATGAGTGGG TTGGGCAGGGGTCGT

GCTGTATGCCTCTGT TCCTGATGAGTGGGA TGGGCAGGGGTCGTT

CTGTATGCCTCTGTG CCTGATGAGTGGGAG GGGCAGGGGTCGTTT

TGTATGCCTCTGTGA CTGATGAGTGGGAGG GGCAGGGGTCGTTTG

TATGCCTCTGTGAAC GATGAGTGGGAGGTG CAGGGGTCGTTTGGG

ATGCCTCTGTGAACC ATGAGTGGGAGGTGG AGGGGTCGTTTGGGA

TGCCTCTGTGAACCC TGAGTGGGAGGTGGC GGGGTCGTTTGGGAT

GCCTCTGTGAACCCG GAGTGGGAGGTGGCT GGGTCGTTTGGGATG

SOCCTCTGTGAACCCGG AGTGGGAGGTGGCTC GGTCGTTTGGGATGG

CTCTGTGAACCCGGA GTGGGAGGTGGCTCG GTCGTTTGGGATGGT

TCGTTTGGGATGGTC CCTGAAACCAGAGTG GAGAGGATTGAGTTT

CGTTTGGGATGGTCT CTGAAACCAGAGTGG AGAGGATTGAGTTTC

GTTTGGGATGGTCTA TGAAACCAGAGTGGC GAGGATTGAGTTTCT

TTTGGGATGGTCTAT GAAACCAGAGTGGCC AGGATTGAGTTTCTC

TTGGGATGGTCTATG AAACCAGAGTGGCCA GGATTGAGTTTCTCA

TGGGATGGTCTATGA AACCAGAGTGGCCAT GATTGAGTTTCTCAA

GGGATGGTCTATGAA ACCAGAGTGGCCATT ATTGAGTTTCTCAAC

GGATGGTCTATGAAG CCAGAGTGGCCATTA TTGAGTTTCTCAACG

GATGGTCTATGAAGG CAGAGTGGCCATTAA TGAGTTTCTCAACGA

TGGTCTATGAAGGAG GAGTGGCCATTAAAA AGTTTCTCAACGAAG

GGTCTATGAAGGAGT AGTGGCCATTAAAAC GTTTCTCAACGAAGC

GTCTATGAAGGAGTT GTGGCCATTAAAACA TTTCTCAACGAAGCT

TCTATGAAGGAGTTG TGGCCATTAAAACAG TTCTCAACGAAGCTT

TATGAAGGAGTTGCC GCCATTAAAACAGTG CTCAACGAAGCTTCT

ATGAAGGAGTTGCCA CCATTAAAACAGTGA TCAACGAAGCTTCTG

TGAAGGAGTTGCCAA CATTAAAACAGTGAA CAACGAAGCTTCTGT

GAAGGAGTTGCCAAG ATTAAAACAGTGAAC AACGAAGCTTCTGTG

AGGAGTTGCCAAGGG TAAAACAGTGAACGA CGAAGCTTCTGTGAT

GGAGTTGCCAAGGGT AAAACAGTGAACGAG GAAGCTTCTGTGATG

GAGTTGCCAAGGGTG AAACAGTGAACGAGG AAGCTTCTGTGATGA

AGTTGCCAAGGGTGT AACAGTGAACGAGGC AGCTTCTGTGATGAA

TTGCCAAGGGTGTGG CAGTGAACGAGGCCG CTTCTGTGATGAAGG

TGCCAAGGGTGTGGT AGTGAACGAGGCCGC TTCTGTGATGAAGGA

GCCAAGGGTGTGGTG GTGAACGAGGCCGCA TCTGTGATGAAGGAG

CCAAGGGTGTGGTGA TGAACGAGGCCGCAA CTGTGATGAAGGAGT

AAGGGTGTGGTGAAA AACGAGGCCGCAAGC GTGATGAAGGAGTTC

AGGGTGTGGTGAAAG ACGAGGCCGCAAGCA TGATGAAGGAGTTCA

GGGTGTGGTGAAAGA CGAGGCCGCAAGCAT GATGAAGGAGTTCAA

GGTGTGGTGAAAGAT GAGGCCGCAAGCATG ATGAAGGAGTTCAAT

TGTGGTGAAAGATGA GGCCGCAAGCATGCG GAAGGAGTTCAATTG

GTGGTGAAAGATGAA GCCGCAAGCATGCGT AAGGAGTTCAATTGT

TGGTGAAAGATGAAC CCGCAAGCATGCGTG AGGAGTTCAATTGTC

GGTGAAAGATGAACC CGCAAGCATGCGTGA GGAGTTCAATTGTCA

TGAAAGATGAACCTG CAAGCATGCGTGAGA AGTTCAATTGTCACC

GAAAGATGAACCTGA AAGCATGCGTGAGAG GTTCAATTGTCACCA

AAAGATGAACCTGAA AGCATGCGTGAGAGG TTCAATTGTCACCAT

AAGATGAACCTGAAA GCATGCGTGAGAGGA TCAATTGTCACCATG

GATGAACCTGAAACC ATGCGTGAGAGGATT AATTGTCACCATGTG

ATGAACCTGAAACCA TGCGTGAGAGGATTG ATTGTCACCATGTGG

TGAACCTGAAACCAG GCGTGAGAGGATTGA TTGTCACCATGTGGT

GAACCTGAAACCAGA CGTGAGAGGATTGAG TGTCACCATGTGGTG

ACCTGAAACCAGAGT TGAGAGGATTGAGTT TCACCATGTGGTGCG

CACCATGTGGTGCGA GTCATCATGGAACTG CTGAGGCCAGAAATG

ACCATGTGGTGCGAT TCATCATGGAACTGA TGAGGCCAGAAATGG

CCATGTGGTGCGATT CATCATGGAACTGAT GAGGCCAGAAATGGA

CATGTGGTGCGATTG ATCATGGAACTGATG AGGCCAGAAATGGAG

ATGTGGTGCGATTGC TCATGGAACTGATGA GGCCAGAAATGGAGA

TGTGGTGCGATTGCT CATGGAACTGATGAC GCCAGAAATGGAGAA

GTGGTGCGATTGCTG ATGGAACTGATGACA CCAGAAATGGAGAAT

TGGTGCGATTGCTGG TGGAACTGATGACAC CAGAAATGGAGAATA

GGTGCGATTGCTGGG GGAACTGATGACACG AGAAATGGAGAATAA

TGCGATTGCTGGGTG AACTGATGACACGGG AAATGGAGAATAATC

GCGATTGCTGGGTGT ACTGATGACACGGGG AATGGAGAATAATCC

CGATTGCTGGGTGTG CTGATGACACGGGGC ATGGAGAATAATCCA

GATTGCTGGGTGTGG TGATGACACGGGGCG TGGAGAATAATCCAG

TTGCTGGGTGTGGTG ATGACACGGGGCGAT GAGAATAATCCAGTC

TGCTGGGTGTGGTGT TGACACGGGGCGATC AGAATAATCCAGTCC

GCTGGGTGTGGTGTC GACACGGGGCGATCT GAATAATCCAGTCCT

CTGGGTGTGGTGTCC ACACGGGGCGATCTC AATAATCCAGTCCTA

GGGTGTGGTGTCCCA ACGGGGCGATCTCAA TAATCCAGTCCTAGC

GGTGTGGTGTCCCAA CGGGGCGATCTCAAA AATCCAGTCCTAGCA

GTGTGGTGTCCCAAG GGGGCGATCTCAAAA ATCCAGTCCTAGCAC

TGTGGTGTCCCAAGG GGGCGATCTCAAAAG TCCAGTCCTAGCACC

TGGTGTCCCAAGGCC GCGATCTCAAAAGTT CAGTCCTAGCACCTC

GGTGTCCCAAGGCCA CGATCTCAAAAGTTA AGTCCTAGCACCTCC

GTGTCCCAAGGCCAG GATCTCAAAAGTTAT GTCCTAGCACCTCCA

TGTCCCAAGGCCAGC ATCTCAAAAGTTATC TCCTAGCACCTCCAA

TCCCAAGGCCAGCCA CTCAAAAGTTATCTC CTAGCACCTCCAAGC

CCCAAGGCCAGCCAA TCAAAAGTTATCTCC TAGCACCTCCAAGCC

CCAAGGCCAGCCAAC CAAAAGTTATCTCCG AGCACCTCCAAGCCT

CAAGGCCAGCCAACA AAAAGTTATCTCCGG GCACCTCCAAGCCTG

AGGCCAGCCAACACT AAGTTATCTCCGGTC ACCTCCAAGCCTGAG

GGCCAGCCAACACTG AGTTATCTCCGGTCT CCTCCAAGCCTGAGC

GCCAGCCAACACTGG GTTATCTCCGGTCTC CTCCAAGCCTGAGCA

CCAGCCAACACTGGT TTATCTCCGGTCTCT TCCAAGCCTGAGCAA

AGCCAACACTGGTCA ATCTCCGGTCTCTGA CAAGCCTGAGCAAGA

GCCAACACTGGTCAT TCTCCGGTCTCTGAG AAGCCTGAGCAAGAT

CCAACACTGGTCATC CTCCGGTCTCTGAGG AGCCTGAGCAAGATG

CAACACTGGTCATCA TCCGGTCTCTGAGGC GCCTGAGCAAGATGA

ACACTGGTCATCATG CGGTCTCTGAGGCCA CTGAGCAAGATGATT

CACTGGTCATCATGG GGTCTCTGAGGCCAG TGAGCAAGATGATTC

ACTGGTCATCATGGA GTCTCTGAGGCCAGA GAGCAAGATGATTCA

CTGGTCATCATGGAA TCTCTGAGGCCAGAA AGCAAGATGATTCAG

SOTGGTCATCATGGAAC CTCTGAGGCCAGAAA GCAAGATGATTCAGA

GGTCATCATGGAACT TCTGAGGCCAGAAAT CAAGATGATTCAGAT

AAGATGATTCAGATG GCCAATAAGTTCGTC GAAGATTTCACAGTC

AGATGATTCAGATGG CCAATAAGTTCGTCC AAGATTTCACAGTCA

GATGATTCAGATGGC CAATAAGTTCGTCCA AGATTTCACAGTCAA

ATGATTCAGATGGCC AATAAGTTCGTCCAC GATTTCACAGTCAAA

TGATTCAGATGGCCG ATAAGTTCGTCCACA ATTTCACAGTCAAAA

GATTCAGATGGCCGG TAAGTTCGTCCACAG TTTCACAGTCAAAAT

ATTCAGATGGCCGGA AAGTTCGTCCACAGA TTCACAGTCAAAATC

TTCAGATGGCCGGAG AGTTCGTCCACAGAG TCACAGTCAAAATCG

TCAGATGGCCGGAGA GTTCGTCCACAGAGA CACAGTCAAAATCGG

AGATGGCCGGAGAGA TCGTCCACAGAGACC CAGTCAAAATCGGAG

GATGGCCGGAGAGAT CGTCCACAGAGACCT AGTCAAAATCGGAGA

ATGGCCGGAGAGATT GTCCACAGAGACCTT GTCAAAATCGGAGAT

TGGCCGGAGAGATTG TCCACAGAGACCTTG TCAAAATCGGAGATT

GCCGGAGAGATTGCA CACAGAGACCTTGCT AAAATCGGAGATTTT

CCGGAGAGATTGCAG ACAGAGACCTTGCTG AAATCGGAGATTTTG

CGGAGAGATTGCAGA CAGAGACCTTGCTGC AATCGGAGATTTTGG

GGAGAGATTGCAGAC AGAGACCTTGCTGCC ATCGGAGATTTTGGT

AGAGATTGCAGACGG AGACCTTGCTGCCCG CGGAGATTTTGGTAT

GAGATTGCAGACGGC GACCTTGCTGCCCGG GGAGATTTTGGTATG

AGATTGCAGACGGCA ACCTTGCTGCCCGGA GAGATTTTGGTATGA

GATTGCAGACGGCAT CCTTGCTGCCCGGAA AGATTTTGGTATGAC

TTGCAGACGGCATGG TTGCTGCCCGGAATT ATTTTGGTATGACGC

TGCAGACGGCATGGC TGCTGCCCGGAATTG TTTTGGTATGACGCG

GCAGACGGCATGGCA GCTGCCCGGAATTGC TTTGGTATGACGCGA

CAGACGGCATGGCAT CTGCCCGGAATTGCA TTGGTATGACGCGAG

GACGGCATGGCATAC GCCCGGAATTGCATG GGTATGACGCGAGAT

ACGGCATGGCATACC CCCGGAATTGCATGG GTATGACGCGAGATA

CGGCATGGCATACCT CCGGAATTGCATGGT TATGACGCGAGATAT

GGCATGGCATACCTC CGGAATTGCATGGTA ATGACGCGAGATATC

CATGGCATACCTCAA GAATTGCATGGTAGC GACGCGAGATATCTA

ATGGCATACCTCAAC AATTGCATGGTAGCC ACGCGAGATATCTAT

TGGCATACCTCAACG ATTGCATGGTAGCCG CGCGAGATATCTATG

GGCATACCTCAACGC TTGCATGGTAGCCGA GCGAGATATCTATGA

CATACCTCAACGCCA GCATGGTAGCCGAAG GAGATATCTATGAGA

ATACCTCAACGCCAA CATGGTAGCCGAAGA AGATATCTATGAGAC

TACCTCAACGCCAAT ATGGTAGCCGAAGAT GATATCTATGAGACA

ACCTCAACGCCAATA TGGTAGCCGAAGATT ATATCTATGAGACAG

CTCAACGCCAATAAG GTAGCCGAAGATTTC ATCTATGAGACAGAC

TCAACGCCAATAAGT TAGCCGAAGATTTCA TCTATGAGACAGACT

CAACGCCAATAAGTT AGCCGAAGATTTCAC CTATGAGACAGACTA

AACGCCAATAAGTTC GCCGAAGATTTCACA TATGAGACAGACTAT

CGCCAATAAGTTCGT CGAAGATTTCACAGT TGAGACAGACTATTA

GAGACAGACTATTAC ATGTCTCCTGAGTCC TGGTCCTTCGGGGTC

AGACAGACTATTACC TGTCTCCTGAGTCCC GGTCCTTCGGGGTCG

GACAGACTATTACCG GTCTCCTGAGTCCCT GTCCTTCGGGGTCGT

ACAGACTATTACCGG TCTCCTGAGTCCCTC TCCTTCGGGGTCGTC

CAGACTATTACCGGA CTCCTGAGTCCCTCA CCTTCGGGGTCGTCC

AGACTATTACCGGAA TCCTGAGTCCCTCAA CTTCGGGGTCGTCCT

GACTATTACCGGAAA CCTGAGTCCCTCAAG TTCGGGGTCGTCCTC

ACTATTACCGGAAAG CTGAGTCCCTCAAGG TCGGGGTCGTCCTCT

CTATTACCGGAAAGG TGAGTCCCTCAAGGA CGGGGTCGTCCTCTG

ATTACCGGAAAGGAG AGTCCCTCAAGGATG GGGTCGTCCTCTGGG

TTACCGGAAAGGAGG GTCCCTCAAGGATGG GGTCGTCCTCTGGGA

TACCGGAAAGGAGGC TCCCTCAAGGATGGA GTCGTCCTCTGGGAG

ACCGGAAAGGAGGCA CCCTCAAGGATGGAG TCGTCCTCTGGGAGA

CGGAAAGGAGGCAAA CTCAAGGATGGAGTC GTCCTCTGGGAGATC

GGAAAGGAGGCAAAG TCAAGGATGGAGTCT TCCTCTGGGAGATCG

GAAAGGAGGCAAAGG CAAGGATGGAGTCTT CCTCTGGGAGATCGC

AAAGGAGGCAAAGGG AAGGATGGAGTCTTC CTCTGGGAGATCGCC

AGGAGGCAAAGGGCT GGATGGAGTCTTCAC CTGGGAGATCGCCAC

GGAGGCAAAGGGCTG GATGGAGTCTTCACC TGGGAGATCGCCACA

GAGGCAAAGGGCTGC ATGGAGTCTTCACCA GGGAGATCGCCACAC

AGGCAAAGGGCTGCT TGGAGTCTTCACCAC GGAGATCGCCACACT

GCAAAGGGCTGCTGC GAGTCTTCACCACTT AGATCGCCACACTGG

CAAAGGGCTGCTGCC AGTCTTCACCACTTA GATCGCCACACTGGC

AAAGGGCTGCTGCCC GTCTTCACCACTTAC ATCGCCACACTGGCC

AAGGGCTGCTGCCCG TCTTCACCACTTACT TCGCCACACTGGCCG

GGGCTGCTGCCCGTG TTCACCACTTACTCG GCCACACTGGCCGAG

GGCTGCTGCCCGTGC TCACCACTTACTCGG CCACACTGGCCGAGC

GCTGCTGCCCGTGCG CACCACTTACTCGGA CACACTGGCCGAGCA

CTGCTGCCCGTGCGC ACCACTTACTCGGAC ACACTGGCCGAGCAG

GCTGCCCGTGCGCTG CACTTACTCGGACGT ACTGGCCGAGCAGCC

CTGCCCGTGCGCTGG ACTTACTCGGACGTC CTGGCCGAGCAGCCC

TGCCCGTGCGCTGGA CTTACTCGGACGTCT TGGCCGAGCAGCCCT

GCCCGTGCGCTGGAT TTACTCGGACGTCTG GGCCGAGCAGCCCTA

CCGTGCGCTGGATGT ACTCGGACGTCTGGT CCGAGCAGCCCTACC

CGTGCGCTGGATGTC CTCGGACGTCTGGTC CGAGCAGCCCTACCA

GTGCGCTGGATGTCT TCGGACGTCTGGTCC GAGCAGCCCTACCAG

TGCGCTGGATGTCTC CGGACGTCTGGTCCT AGCAGCCCTACCAGG

CGCTGGATGTCTCCT GACGTCTGGTCCTTC CAGCCCTACCAGGGC

GCTGGATGTCTCCTG ACGTCTGGTCCTTCG AGCCCTACCAGGGCT

CTGGATGTCTCCTGA CGTCTGGTCCTTCGG GCCCTACCAGGGCTT

TGGATGTCTCCTGAG GTCTGGTCCTTCGGG CCCTACCAGGGCTTG

GATGTCTCCTGAGTC CTGGTCCTTCGGGGT CTACCAGGGCTTGTC

TACCAGGGCTTGTCC CTTCTGGACAAGCCA ATGTGCTGGCAGTAT

ACCAGGGCTTGTCCA TTCTGGACAAGCCAG TGTGCTGGCAGTATA

CCAGGGCTTGTCCAA TCTGGACAAGCCAGA GTGCTGGCAGTATAA

CAGGGCTTGTCCAAC CTGGACAAGCCAGAC TGCTGGCAGTATAAC

AGGGCTTGTCCAACG TGGACAAGCCAGACA GCTGGCAGTATAACC

GGGCTTGTCCAACGA GGACAAGCCAGACAA CTGGCAGTATAACCC

GGCTTGTCCAACGAG GACAAGCCAGACAAC TGGCAGTATAACCCC

GCTTGTCCAACGAGC ACAAGCCAGACAACT GGCAGTATAACCCCA

CTTGTCCAACGAGCA CAAGCCAGACAACTG GCAGTATAACCCCAA

TGTCCAACGAGCAAG AGCCAGACAACTGTC AGTATAACCCCAAGA

GTCCAACGAGCAAGT GCCAGACAACTGTCC GTATAACCCCAAGAT

TCCAACGAGCAAGTC CCAGACAACTGTCCT TATAACCCCAAGATG

CCAACGAGCAAGTCC CAGACAACTGTCCTG ATAACCCCAAGATGA

AACGAGCAAGTCCTT GACAACTGTCCTGAC AACCCCAAGATGAGG

ACGAGCAAGTCCTTC ACAACTGTCCTGACA ACCCCAAGATGAGGC

CGAGCAAGTCCTTCG CAACTGTCCTGACAT CCCCAAGATGAGGCC

GAGCAAGTCCTTCGC AACTGTCCTGACATG CCCAAGATGAGGCCT

GCAAGTCCTTCGCTT CTGTCCTGACATGCT CAAGATGAGGCCTTC

CAAGTCCTTCGCTTC TGTCCTGACATGCTG AAGATGAGGCCTTCC

AAGTCCTTCGCTTCG GTCCTGACATGCTGT AGATGAGGCCTTCCT

AGTCCTTCGCTTCGT TCCTGACATGCTGTT GATGAGGCCTTCCTT

TCCTTCGCTTCGTCA CTGACATGCTGTTTG TGAGGCCTTCCTTCC

CCTTCGCTTCGTCAT TGACATGCTGTTTGA GAGGCCTTCCTTCCT

CTTCGCTTCGTCATG GACATGCTGTTTGAA AGGCCTTCCTTCCTG

TTCGCTTCGTCATGG ACATGCTGTTTGAAC GGCCTTCCTTCCTGG

CGCTTCGTCATGGAG ATGCTGTTTGAACTG CCTTCCTTCCTGGAG

GCTTCGTCATGGAGG TGCTGTTTGAACTGA CTTCCTTCCTGGAGA

CTTCGTCATGGAGGG GCTGTTTGAACTGAT TTCCTTCCTGGAGAT

TTCGTCATGGAGGGC CTGTTTGAACTGATG TCCTTCCTGGAGATC

CGTCATGGAGGGCGG GTTTGAACTGATGCG CTTCCTGGAGATCAT

GTCATGGAGGGCGGC TTTGAACTGATGCGC TTCCTGGAGATCATC

TCATGGAGGGCGGCC TTGAACTGATGCGCA TCCTGGAGATCATCA

CATGGAGGGCGGCCT TGAACTGATGCGCAT CCTGGAGATCATCAG

TGGAGGGCGGCCTTC AACTGATGCGCATGT TGGAGATCATCAGCA

GGAGGGCGGCCTTCT ACTGATGCGCATGTG GGAGATCATCAGCAG

GAGGGCGGCCTTCTG CTGATGCGCATGTGC GAGATCATCAGCAGC

AGGGCGGCCTTCTGG TGATGCGCATGTGCT AGATCATCAGCAGCA

GGCGGCCTTCTGGAC ATGCGCATGTGCTGG ATCATCAGCAGCATC

GCGGCCTTCTGGACA TGCGCATGTGCTGGC TCATCAGCAGCATCA

CGGCCTTCTGGACAA GCGCATGTGCTGGCA CATCAGCAGCATCAA

GGCCTTCTGGACAAG CGCATGTGCTGGCAG ATCAGCAGCATCAAA

CCTTCTGGACAAGCC CATGTGCTGGCAGTA CAGCAGCATCAAAGA

AGCAGCATCAAAGAG TACAGCGAGGAGAAC GAGAACATGGAGAGC

GCAGCATCAAAGAGG ACAGCGAGGAGAACA AGAACATGGAGAGCG

CAGCATCAAAGAGGA CAGCGAGGAGAACAA GAACATGGAGAGCGT

AGCATCAAAGAGGAG AGCGAGGAGAACAAG AACATGGAGAGCGTC

GCATCAAAGAGGAGA GCGAGGAGAACAAGC ACATGGAGAGCGTCC

CATCAAAGAGGAGAT CGAGGAGAACAAGCT CATGGAGAGCGTCCC

ATCAAAGAGGAGATG GAGGAGAACAAGCTG ATGGAGAGCGTCCCC

TCAAAGAGGAGATGG AGGAGAACAAGCTGC TGGAGAGCGTCCCCC

CAAAGAGGAGATGGA GGAGAACAAGCTGCC GGAGAGCGTCCCCCT

AAGAGGAGATGGAGC AGAACAAGCTGCCCG AGAGCGTCCCCCTGG

AGAGGAGATGGAGCC GAACAAGCTGCCCGA GAGCGTCCCCCTGGA

GAGGAGATGGAGCCT AACAAGCTGCCCGAG AGCGTCCCCCTGGAC

AGGAGATGGAGCCTG ACAAGCTGCCCGAGC GCGTCCCCCTGGACC

GAGATGGAGCCTGGC AAGCTGCCCGAGCCG GTCCCCCTGGACCCC

AGATGGAGCCTGGCT AGCTGCCCGAGCCGG TCCCCCTGGACCCCT

GATGGAGCCTGGCTT GCTGCCCGAGCCGGA CCCCCTGGACCCCTC

ATGGAGCCTGGCTTC CTGCCCGAGCCGGAG CCCCTGGACCCCTCG

GGAGCCTGGCTTCCG GCCCGAGCCGGAGGA CCTGGACCCCTCGGC

GAGCCTGGCTTCCGG CCCGAGCCGGAGGAG CTGGACCCCTCGGCC

AGCCTGGCTTCCGGG CCGAGCCGGAGGAGC TGGACCCCTCGGCCT

GCCTGGCTTCCGGGA CGAGCCGGAGGAGCT GGACCCCTCGGCCTC

CTGGCTTCCGGGAGG AGCCGGAGGAGCTGG ACCCCTCGGCCTCCT

TGGCTTCCGGGAGGT GCCGGAGGAGCTGGA CCCCTCGGCCTCCTC

GGCTTCCGGGAGGTC CCGGAGGAGCTGGAC CCCTCGGCCTCCTCG

GCTTCCGGGAGGTCT CGGAGGAGCTGGACC CCTCGGCCTCCTCGT

TTCCGGGAGGTCTCC GAGGAGCTGGACCTG TCGGCCTCCTCGTCC

TCCGGGAGGTCTCCT AGGAGCTGGACCTGG CGGCCTCCTCGTCCT

CCGGGAGGTCTCCTT GGAGCTGGACCTGGA GGCCTCCTCGTCCTC

CGGGAGGTCTCCTTC GAGCTGGACCTGGAG GCCTCCTCGTCCTCC

GGAGGTCTCCTTCTA GCTGGACCTGGAGCC CTCCTCGTCCTCCCT

GAGGTCTCCTTCTAC CTGGACCTGGAGCCA TCCTCGTCCTCCCTG

AGGTCTCCTTCTACT TGGACCTGGAGCCAG CCTCGTCCTCCCTGC

GGTCTCCTTCTACTA GGACCTGGAGCCAGA CTCGTCCTCCCTGCC

TCTCCTTCTACTACA ACCTGGAGCCAGAGA CGTCCTCCCTGCCAC

CTCCTTCTACTACAG CCTGGAGCCAGAGAA GTCCTCCCTGCCACT

TCCTTCTACTACAGC CTGGAGCCAGAGAAC TCCTCCCTGCCACTG

CCTTCTACTACAGCG TGGAGCCAGAGAACA CCTCCCTGCCACTGC

TTCTACTACAGCGAG GAGCCAGAGAACATG TCCCTGCCACTGCCC

TCTACTACAGCGAGG AGCCAGAGAACATGG CCCTGCCACTGCCCG

CTACTACAGCGAGGA GCCAGAGAACATGGA CCTGCCACTGCCCGA

TACTACAGCGAGGAG CCAGAGAACATGGAG CTGCCACTGCCCGAC

SOACTACAGCGAGGAGA CAGAGAACATGGAGA TGCCACTGCCCGACA

CTACAGCGAGGAGAA AGAGAACATGGAGAG GCCACTGCCCGACAG

_g7_ CCACTGCCCGACAGA GGGGTGCTGGTCCTC ATGAACGGGGGCCGC

CACTGCCCGACAGAC GGGTGCTGGTCCTCC TGAACGGGGGCCGCA

ACTGCCCGACAGACA GGTGCTGGTCCTCCG GAACGGGGGCCGCAA

CTGCCCGACAGACAC GTGCTGGTCCTCCGC AACGGGGGCCGCAAG

TGCCCGACAGACACT TGCTGGTCCTCCGCG ACGGGGGCCGCAAGA

GCCCGACAGACACTC GCTGGTCCTCCGCGC CGGGGGCCGCAAGAA

CCCGACAGACACTCA CTGGTCCTCCGCGCC GGGGGCCGCAAGAAC

CCGACAGACACTCAG TGGTCCTCCGCGCCA GGGGCCGCAAGAACG

CGACAGACACTCAGG GGTCCTCCGCGCCAG GGGCCGCAAGAACGA

ACAGACACTCAGGAC TCCTCCGCGCCAGCT GCCGCAAGAACGAGC

CAGACACTCAGGACA CCTCCGCGCCAGCTT CCGCAAGAACGAGCG

AGACACTCAGGACAC CTCCGCGCCAGCTTC CGCAAGAACGAGCGG

GACACTCAGGACACA TCCGCGCCAGCTTCG GCAAGAACGAGCGGG

CACTCAGGACACAAG CGCGCCAGCTTCGAC AAGAACGAGCGGGCC

ACTCAGGACACAAGG GCGCCAGCTTCGACG AGAACGAGCGGGCCT

CTCAGGACACAAGGC CGCCAGCTTCGACGA GAACGAGCGGGCCTT

TCAGGACACAAGGCC GCCAGCTTCGACGAG AACGAGCGGGCCTTG

AGGACACAAGGCCGA CAGCTTCGACGAGAG CGAGCGGGCCTTGCC

GGACACAAGGCCGAG AGCTTCGACGAGAGA GAGCGGGCCTTGCCG

GACACAAGGCCGAGA GCTTCGACGAGAGAC AGCGGGCCTTGCCGC

ACACAAGGCCGAGAA CTTCGACGAGAGACA GCGGGCCTTGCCGCT

ACAAGGCCGAGAACG TCGACGAGAGACAGC GGGCCTTGCCGCTGC

CAAGGCCGAGAACGG CGACGAGAGACAGCC GGCCTTGCCGCTGCC

AAGGCCGAGAACGGC GACGAGAGACAGCCT GCCTTGCCGCTGCCC

AGGCCGAGAACGGCC ACGAGAGACAGCCTT CCTTGCCGCTGCCCC

GCCGAGAACGGCCCC GAGAGACAGCCTTAC TTGCCGCTGCCCCAG

CCGAGAACGGCCCCG AGAGACAGCCTTACG TGCCGCTGCCCCAGT

CGAGAACGGCCCCGG GAGACAGCCTTACGC GCCGCTGCCCCAGTC

GAGAACGGCCCCGGC AGACAGCCTTACGCC CCGCTGCCCCAGTCT

GAACGGCCCCGGCCC ACAGCCTTACGCCCA GCTGCCCCAGTCTTC

AACGGCCCCGGCCCT CAGCCTTACGCCCAC CTGCCCCAGTCTTCG

ACGGCCCCGGCCCTG AGCCTTACGCCCACA TGCCCCAGTCTTCGA

CGGCCCCGGCCCTGG GCCTTACGCCCACAT GCCCCAGTCTTCGAC

GCCCCGGCCCTGGGG CTTACGCCCACATGA CCCAGTCTTCGACCT

CCCCGGCCCTGGGGT TTACGCCCACATGAA CCAGTCTTCGACCTG

CCCGGCCCTGGGGTG TACGCCCACATGAAC CAGTCTTCGACCTGC

CCGGCCCTGGGGTGC ACGCCCACATGAACG AGTCTTCGACCTGCT

GGCCCTGGGGTGCTG GCCCACATGAACGGG TCTTCGACCTGCTGA

GCCCTGGGGTGCTGG CCCACATGAACGGGG CTTCGACCTGCTGAT

CCCTGGGGTGCTGGT CCACATGAACGGGGG TTCGACCTGCTGATC

CCTGGGGTGCTGGTC CACATGAACGGGGGC TCGACCTGCTGATCC

TGGGGTGCTGGTCCT CATGAACGGGGGCCG GACCTGCTGATCCTT

_$g_ ACCTGCTGATCCTTG GCGCAGCGGGGTGGG TCCTGTACCTCAGTG

CCTGCTGATCCTTGG CGCAGCGGGGTGGGG CCTGTACCTCAGTGG

CTGCTGATCCTTGGA GCAGCGGGGTGGGGG CTGTACCTCAGTGGA

TGCTGATCCTTGGAT CAGCGGGGTGGGGGG TGTACCTCAGTGGAT

GCTGATCCTTGGATC AGCGGGGTGGGGGGG GTACCTCAGTGGATC

CTGATCCTTGGATCC GCGGGGTGGGGGGGG TACCTCAGTGGATCT

TGATCCTTGGATCCT CGGGGTGGGGGGGGA ACCTCAGTGGATCTT

GATCCTTGGATCCTG GGGGTGGGGGGGGAG CCTCAGTGGATCTTC

ATCCTTGGATCCTGA GGGTGGGGGGGGAGA CTCAGTGGATCTTCA

CCTTGGATCCTGAAT GTGGGGGGGGAGAGA CAGTGGATCTTCAGT

CTTGGATCCTGAATC TGGGGGGGGAGAGAG AGTGGATCTTCAGTT

TTGGATCCTGAATCT GGGGGGGGAGAGAGA GTGGATCTTCAGTTC

TGGATCCTGAATCTG GGGGGGGAGAGAGAG TGGATCTTCAGTTCT

GATCCTGAATCTGTG GGGGGAGAGAGAGTT GATCTTCAGTTCTGC

ATCCTGAATCTGTGC GGGGAGAGAGAGTTT ATCTTCAGTTCTGCC

TCCTGAATCTGTGCA GGGAGAGAGAGTTTT TCTTCAGTTCTGCCC

CCTGAATCTGTGCAA GGAGAGAGAGTTTTA CTTCAGTTCTGCCCT

TGAATCTGTGCAAAC AGAGAGAGTTTTAAC TCAGTTCTGCCCTTG

GAATCTGTGCAAACA GAGAGAGTTTTAACA CAGTTCTGCCCTTGC

AATCTGTGCAAACAG AGAGAGTTTTAACAA AGTTCTGCCCTTGCT

ATCTGTGCAAACAGT GAGAGTTTTAACAAT GTTCTGCCCTTGCTG
~

CTGTGCAAACAGTAA GAGTTTTAACAATCC TCTGCCCTTGCTGCC

TGTGCAAACAGTAAC AGTTTTAACAATCCA CTGCCCTTGCTGCCC

GTGCAAACAGTAACG GTTTTAACAATCCAT TGCCCTTGCTGCCCG

TGCAAACAGTAACGT TTTTAACAATCCATT GCCCTTGCTGCCCGC

CAAACAGTAACGTGT TTAACAATCCATTCA CCTTGCTGCCCGCGG

AAACAGTAACGTGTG TAACAATCCATTCAC CTTGCTGCCCGCGGG

AACAGTAACGTGTGC AACAATCCATTCACA TTGCTGCCCGCGGGA

ACAGTAACGTGTGCG ACAATCCATTCACAA TGCTGCCCGCGGGAG

AGTAACGTGTGCGCA AATCCATTCACAAGC CTGCCCGCGGGAGAC

GTAACGTGTGCGCAC ATCCATTCACAAGCC TGCCCGCGGGAGACA

TAACGTGTGCGCACG TCCATTCACAAGCCT GCCCGCGGGAGACAG

AACGTGTGCGCACGC CCATTCACAAGCCTC . CCCGCGGGAGACAGC

CGTGTGCGCACGCGC ATTCACAAGCCTCCT CGCGGGAGACAGCTT

GTGTGCGCACGCGCA TTCACAAGCCTCCTG GCGGGAGACAGCTTC

TGTGCGCACGCGCAG TCACAAGCCTCCTGT CGGGAGACAGCTTCT

GTGCGCACGCGCAGC CACAAGCCTCCTGTA GGGAGACAGCTTCTC

GCGCACGCGCAGCGG CAAGCCTCCTGTACC GAGACAGCTTCTCTG

CGCACGCGCAGCGGG AAGCCTCCTGTACCT AGACAGCTTCTCTGC

GCACGCGCAGCGGGG AGCCTCCTGTACCTC GACAGCTTCTCTGCA

CACGCGCAGCGGGGT GCCTCCTGTACCTCA ACAGCTTCTCTGCAG

CGCGCAGCGGGGTGG CTCCTGTACCTCAGT AGCTTCTCTGCAGTA

GCTTCTCTGCAGTAA CAGCTTTTTATTCCC CTTAATGACAACACT

CTTCTCTGCAGTAAA AGCTTTTTATTCCCT TTAATGACAACACTT

TTCTCTGCAGTAAAA GCTTTTTATTCCCTG TAATGACAACACTTA

TCTCTGCAGTAAAAC CTTTTTATTCCCTGC AATGACAACACTTAA

CTCTGCAGTAAAACA TTTTTATTCCCTGCC ATGACAACACTTAAT

TCTGCAGTAAAACAC TTTTATTCCCTGCCC TGACAACACTTAATA

CTGCAGTAAAACACA TTTATTCCCTGCCCA GACAACACTTAATAG

TGCAGTAAAACACAT TTATTCCCTGCCCAA ACAACACTTAATAGC

GCAGTAAAACACATT TATTCCCTGCCCAAA CAACACTTAATAGCA

AGTAAAACACATTTG TTCCCTGCCCAAACC ACACTTAATAGCAAC

GTAAAACACATTTGG TCCCTGCCCAAACCC CACTTAATAGCAACA

TAAAACACATTTGGG CCCTGCCCAAACCCT ACTTAATAGCAACAG

AAAACACATTTGGGA CCTGCCCAAACCCTT CTTAATAGCAACAGA

AACACATTTGGGATG TGCCCAAACCCTTAA TAATAGCAACAGAGC

ACACATTTGGGATGT GCCCAAACCCTTAAC AATAGCAACAGAGCA

CACATTTGGGATGTT CCCAAACCCTTAACT ATAGCAACAGAGCAC

ACATTTGGGATGTTC CCAAACCCTTAACTG TAGCAACAGAGCACT

ATTTGGGATGTTCCT AAACCCTTAACTGAC GCAACAGAGCACTTG

TTTGGGATGTTCCTT AACCCTTAACTGACA CAACAGAGCACTTGA

TTGGGATGTTCCTTT ACCCTTAACTGACAT AACAGAGCACTTGAG

TGGGATGTTCCTTTT CCCTTAACTGACATG ACAGAGCACTTGAGA

GGATGTTCCTTTTTT CTTAACTGACATGGG AGAGCACTTGAGAAC

GATGTTCCTTTTTTC TTAACTGACATGGGC GAGCACTTGAGAACC

ATGTTCCTTTTTTCA TAACTGACATGGGCC AGCACTTGAGAACCA

TGTTCCTTTTTTCAA AACTGACATGGGCCT GCACTTGAGAACCAG

TTCCTTTTTTCAATA CTGACATGGGCCTTT ACTTGAGAACCAGTC

TCCTTTTTTCAATAT TGACATGGGCCTTTA CTTGAGAACCAGTCT

CCTTTTTTCAATATG GACATGGGCCTTTAA TTGAGAACCAGTCTC

CTTTTTTCAATATGC ACATGGGCCTTTAAG TGAGAACCAGTCTCC

TTTTTCAATATGCAA ATGGGCCTTTAAGAA AGAACCAGTCTCCTC

TTTTCAATATGCAAG TGGGCCTTTAAGAAC GAACCAGTCTCCTCA

TTTCAATATGCAAGC GGGCCTTTAAGAACC AACCAGTCTCCTCAC

TTCAATATGCAAGCA GGCCTTTAAGAACCT ACCAGTCTCCTCACT

CAATATGCAAGCAGC CCTTTAAGAACCTTA CAGTCTCCTCACTCT

AATATGCAAGCAGCT CTTTAAGAACCTTAA AGTCTCCTCACTCTG

ATATGCAAGCAGCTT TTTAAGAACCTTAAT GTCTCCTCACTCTGT

TATGCAAGCAGCTTT TTAAGAACCTTAATG TCTCCTCACTCTGTC

TGCAAGCAGCTTTTT AAGAACCTTAATGAC TCCTCACTCTGTCCC

GCAAGCAGCTTTTTA AGAACCTTAATGACA CCTCACTCTGTCCCT

CAAGCAGCTTTTTAT GAACCTTAATGACAA CTCACTCTGTCCCTG

AAGCAGCTTTTTATT AACCTTAATGACAAC TCACTCTGTCCCTGT

GCAGCTTTTTATTCC CCTTAATGACAACAC ACTCTGTCCCTGTCC

CTCTGTCCCTGTCCT AACGGAAAAATAATT TGAGGAAGTGGCTGT

TCTGTCCCTGTCCTT ACGGAAA.AATAATTG GAGGAAGTGGCTGTC

CTGTCCCTGTCCTTC CGGAAAA.ATAATTGC AGGAAGTGGCTGTCC

TGTCCCTGTCCTTCC GGAAAAATAATTGCC GGAAGTGGCTGTCCC

S GTCCCTGTCCTTCCC GAAAAATAATTGCCA GAAGTGGCTGTCCCT

TCCCTGTCCTTCCCT AAAAATAATTGCCAC AAGTGGCTGTCCCTG

CCCTGTCCTTCCCTG AAAATAATTGCCACA AGTGGCTGTCCCTGT

CCTGTCCTTCCCTGT AAATAATTGCCACAA GTGGCTGTCCCTGTG

CTGTCCTTCCCTGTT AATAATTGCCACAAG TGGCTGTCCCTGTGG

GTCCTTCCCTGTTCT TAATTGCCACAAGTC GCTGTCCCTGTGGCC

TCCTTCCCTGTTCTC AATTGCCACAAGTCC CTGTCCCTGTGGCCC

CCTTCCCTGTTCTCC ATTGCCACAAGTCCA TGTCCCTGTGGCCCC

CTTCCCTGTTCTCCC TTGCCACAAGTCCAG GTCCCTGTGGCCCCA

TCCCTGTTCTCCCTT GCCACAAGTCCAGCT CCCTGTGGCCCCATC

CCCTGTTCTCCCTTT CCACAAGTCCAGCTG CCTGTGGCCCCATCC

CCTGTTCTCCCTTTC CACAAGTCCAGCTGG CTGTGGCCCCATCCA

CTGTTCTCCCTTTCT ACAAGTCCAGCTGGG TGTGGCCCCATCCAA

GTTCTCCCTTTCTCT AAGTCCAGCTGGGAA TGGCCCCATCCAACC

TTCTCCCTTTCTCTC AGTCCAGCTGGGAAG GGCCCCATCCAACCA

TCTCCCTTTCTCTCT GTCCAGCTGGGAAGC GCCCCATCCAACCAC

CTCCCTTTCTCTCTC TCCAGCTGGGAAGCC CCCCATCCAACCACT

CCCTTTCTCTCTCCT CAGCTGGGAAGCCCT CCATCCAACCACTGT

CCTTTCTCTCTCCTC AGCTGGGAAGCCCTT CATCCAACCACTGTA

CTTTCTCTCTCCTCT GCTGGGAAGCCCTTT ATCCAACCACTGTAC

TTTCTCTCTCCTCTC CTGGGAAGCCCTTTT TCCAACCACTGTACA

TCTCTCTCCTCTCTG GGGAAGCCCTTTTTA CAACCACTGTACACA

CTCTCTCCTCTCTGC GGAAGCCCTTTTTAT AACCACTGTACACAC

TCTCTCCTCTCTGCT GAAGCCCTTTTTATC ACCACTGTACACACC

CTCTCCTCTCTGCTT AAGCCCTTTTTATCA CCACTGTACACACCC

CTCCTCTCTGCTTCA GCCCTTTTTATCAGT ACTGTACACACCCGC

TCCTCTCTGCTTCAT CCCTTTTTATCAGTT CTGTACACACCCGCC

CCTCTCTGCTTCATA CCTTTTTATCAGTTT TGTACACACCCGCCT

CTCTCTGCTTCATAA CTTTTTATCAGTTTG GTACACACCCGCCTG

CTCTGCTTCATAACG TTTTATCAGTTTGAG ACACACCCGCCTGAC

TCTGCTTCATAACGG TTTATCAGTTTGAGG CACACCCGCCTGACA

CTGCTTCATAACGGA TTATCAGTTTGAGGA ACACCCGCCTGACAC

TGCTTCATAACGGAA TATCAGTTTGAGGAA CACCCGCCTGACACC

CTTCATAACGGAAAA TCAGTTTGAGGAAGT CCCGCCTGACACCGT

TTCATAACGGAAAAA CAGTTTGAGGAAGTG CCGCCTGACACCGTG

TCATAACGGAAAA.AT AGTTTGAGGAAGTGG CGCCTGACACCGTGG

CATAACGGAAAAATA GTTTGAGGAAGTGGC GCCTGACACCGTGGG

TAACGGAAAAATAAT TTGAGGAAGTGGCTG CTGACACCGTGGGTC

TGACACCGTGGGTCA TTATCTTTCACCTTT CCAAGGCTGTTACCA

GACACCGTGGGTCAT TATCTTTCACCTTTC CAAGGCTGTTACCAT

ACACCGTGGGTCATT ATCTTTCACCTTTCT AAGGCTGTTACCATT

CACCGTGGGTCATTA TCTTTCACCTTTCTA AGGCTGTTACCATTT

ACCGTGGGTCATTAC CTTTCACCTTTCTAG GGCTGTTACCATTTT

CCGTGGGTCATTACA TTTCACCTTTCTAGG GCTGTTACCATTTTA

CGTGGGTCATTACAA TTCACCTTTCTAGGG CTGTTACCATTTTAA

GTGGGTCATTACAAA TCACCTTTCTAGGGA TGTTACCATTTTAAC

TGGGTCATTACAAAA CACCTTTCTAGGGAC GTTACCATTTTAACG

GGTCATTACAAAAAA CCTTTCTAGGGACAT TACCATTTTAACGCT

GTCATTACAAAAAAA CTTTCTAGGGACATG ACCATTTTAACGCTG

TCATTACAAAAAAAC TTTCTAGGGACATGA CCATTTTAACGCTGC

CATTACAAAAAAACA TTCTAGGGACATGAA CATTTTAACGCTGCC

TTACAA.AA.AA.ACACG CTAGGGACATGAAAT TTTTAACGCTGCCTA

TACAAAAAAACACGT TAGGGACATGAAATT TTTAACGCTGCCTAA

ACAA.AAAA.ACACGTG AGGGACATGAAATTT TTAACGCTGCCTAAT

CAAAAAAACACGTGG GGGACATGAAATTTA TAACGCTGCCTAATT

AAAAAACACGTGGAG GACATGAAATTTACA ACGCTGCCTAATTTT

AAAAACACGTGGAGA ACATGAAATTTACAA CGCTGCCTAATTTTG

AAAACACGTGGAGAT CATGAAATTTACAAA GCTGCCTAATTTTGC

AAACACGTGGAGATG ATGAAATTTACAAAG CTGCCTAATTTTGCC

ACACGTGGAGATGGA GAAATTTACAAAGGG GCCTAATTTTGCCAA

CACGTGGAGATGGAA AAATTTACAAAGGGC CCTAATTTTGCCAAA

ACGTGGAGATGGAAA AATTTACAAAGGGCC CTAATTTTGCCAAAA

CGTGGAGATGGAAAT ATTTACAAAGGGCCA TAATTTTGCCAAAAT

TGGAGATGGAAATTT TTACAAAGGGCCATC ATTTTGCCAAAATCC

GGAGATGGAAATTTT TACAAAGGGCCATCG TTTTGCCAAAATCCT

GAGATGGAAATTTTT ACAAAGGGCCATCGT TTTGCCAAAATCCTG

AGATGGAAATTTTTA CAAAGGGCCATCGTT TTGCCAAAATCCTGA

ATGGAAATTTTTACC AAGGGCCATCGTTCA GCCAAAATCCTGAAC

TGGAAATTTTTACCT AGGGCCATCGTTCAT CCAAAATCCTGAACT

GGAAATTTTTACCTT GGGCCATCGTTCATC CAAAATCCTGAACTT

GAAATTTTTACCTTT GGCCATCGTTCATCC AAAATCCTGAACTTT

AATTTTTACCTTTAT CCATCGTTCATCCAA AATCCTGAACTTTCT

ATTTTTACCTTTATC CATCGTTCATCCAAG ATCCTGAACTTTCTC

TTTTTACCTTTATCT ATCGTTCATCCAAGG TCCTGAACTTTCTCC

TTTTACCTTTATCTT TCGTTCATCCAAGGC CCTGAACTTTCTCCC

TTACCTTTATCTTTC GTTCATCCAAGGCTG TGAACTTTCTCCCTC

TACCTTTATCTTTCA TTCATCCAAGGCTGT GAACTTTCTCCCTCA

ACCTTTATCTTTCAC TCATCCAAGGCTGTT AACTTTCTCCCTCAT

CCTTTATCTTTCACC CATCCAAGGCTGTTA ACTTTCTCCCTCATC

TTTATCTTTCACCTT TCCAAGGCTGTTACC TTTCTCCCTCATCGG

TTCTCCCTCATCGGC GCATGGCAGCTGGTT CCATCCGACTGCCCC

TCTCCCTCATCGGCC CATGGCAGCTGGTTG CATCCGACTGCCCCT

CTCCCTCATCGGCCC ATGGCAGCTGGTTGC ATCCGACTGCCCCTG

TCCCTCATCGGCCCG TGGCAGCTGGTTGCT TCCGACTGCCCCTGC

CCCTCATCGGCCCGG GGCAGCTGGTTGCTC CCGACTGCCCCTGCT

CCTCATCGGCCCGGC GCAGCTGGTTGCTCC CGACTGCCCCTGCTG

CTCATCGGCCCGGCG CAGCTGGTTGCTCCA GACTGCCCCTGCTGT

TCATCGGCCCGGCGC AGCTGGTTGCTCCAT ACTGCCCCTGCTGTG

CATCGGCCCGGCGCT GCTGGTTGCTCCATT CTGCCCCTGCTGTGC

TCGGCCCGGCGCTGA TGGTTGCTCCATTTG GCCCCTGCTGTGCTG

CGGCCCGGCGCTGAT GGTTGCTCCATTTGA CCCCTGCTGTGCTGC

GGCCCGGCGCTGATT GTTGCTCCATTTGAG CCCTGCTGTGCTGCT

GCCCGGCGCTGATTC TTGCTCCATTTGAGA CCTGCTGTGCTGCTC

CCGGCGCTGATTCCT GCTCCATTTGAGAGA TGCTGTGCTGCTCAA

CGGCGCTGATTCCTC CTCCATTTGAGAGAC GCTGTGCTGCTCAAG

GGCGCTGATTCCTCG TCCATTTGAGAGACA CTGTGCTGCTCAAGG

GCGCTGATTCCTCGT CCATTTGAGAGACAC TGTGCTGCTCAAGGC

GCTGATTCCTCGTGT ATTTGAGAGACACGC TGCTGCTCAAGGCCA

CTGATTCCTCGTGTC TTTGAGAGACACGCT GCTGCTCAAGGCCAC

TGATTCCTCGTGTCC TTGAGAGACACGCTG CTGCTCAAGGCCACA

GATTCCTCGTGTCCG TGAGAGACACGCTGG TGCTCAAGGCCACAG

TTCCTCGTGTCCGGA AGAGACACGCTGGCG CTCAAGGCCACAGGC

TCCTCGTGTCCGGAG GAGACACGCTGGCGA TCAAGGCCACAGGCA

CCTCGTGTCCGGAGG AGACACGCTGGCGAC CAAGGCCACAGGCAC

CTCGTGTCCGGAGGC GACACGCTGGCGACA AAGGCCACAGGCACA

CGTGTCCGGAGGCAT CACGCTGGCGACACA GGCCACAGGCACACA

GTGTCCGGAGGCATG ACGCTGGCGACACAC GCCACAGGCACACAG

TGTCCGGAGGCATGG CGCTGGCGACACACT CCACAGGCACACAGG

GTCCGGAGGCATGGG GCTGGCGACACACTC CACAGGCACACAGGT

CCGGAGGCATGGGTG TGGCGACACACTCCG CAGGCACACAGGTCT

CGGAGGCATGGGTGA GGCGACACACTCCGT AGGCACACAGGTCTC

GGAGGCATGGGTGAG GCGACACACTCCGTC GGCACACAGGTCTCA

GAGGCATGGGTGAGC CGACACACTCCGTCC GCACACAGGTCTCAT

GGCATGGGTGAGCAT ACACACTCCGTCCAT ACACAGGTCTCATTG

GCATGGGTGAGCATG CACACTCCGTCCATC CACAGGTCTCATTGC

CATGGGTGAGCATGG ACACTCCGTCCATCC ACAGGTCTCATTGCT

ATGGGTGAGCATGGC CACTCCGTCCATCCG CAGGTCTCATTGCTT

GGGTGAGCATGGCAG CTCCGTCCATCCGAC GGTCTCATTGCTTCT

GGTGAGCATGGCAGC TCCGTCCATCCGACT GTCTCATTGCTTCTG

GTGAGCATGGCAGCT CCGTCCATCCGACTG TCTCATTGCTTCTGA

TGAGCATGGCAGCTG CGTCCATCCGACTGC CTCATTGCTTCTGAC

AGCATGGCAGCTGGT TCCATCCGACTGCCC CATTGCTTCTGACTA

ATTGCTTCTGACTAG CTCTCAGTGAAGGTG

TTGCTTCTGACTAGA TCTCAGTGAAGGTGG

TGCTTCTGACTAGAT CTCAGTGAAGGTGGG

GCTTCTGACTAGATT TCAGTGAAGGTGGGG

CTTCTGACTAGATTA CAGTGAAGGTGGGGA

TTCTGACTAGATTAT AGTGAAGGTGGGGAG

TCTGACTAGATTATT GTGAAGGTGGGGAGA

CTGACTAGATTATTA TGAAGGTGGGGAGAA

TGACTAGATTATTAT GAAGGTGGGGAGAAG

ACTAGATTATTATTT AGGTGGGGAGAAGCT

CTAGATTATTATTTG GGTGGGGAGAAGCTG

TAGATTATTATTTGG GTGGGGAGAAGCTGA

AGATTATTATTTGGG TGGGGAGAAGCTGAA

ATTATTATTTGGGGG GGGAGAAGCTGAACC

TTATTATTTGGGGGA GGAGAAGCTGAACCG

TATTATTTGGGGGAA GAGAAGCTGAACCGG

ATTATTTGGGGGAAC AGAAGCTGAACCGGC

TATTTGGGGGAACTG

ATTTGGGGGAACTGG

TTTGGGGGAACTGGA

TTGGGGGAACTGGAC

GGGGGAACTGGACAC

GGGGAACTGGACACA

GGGAACTGGACACAA .

GGAACTGGACACAAT

AACTGGACACAATAG

ACTGGACACAATAGG

CTGGACACAATAGGT

TGGACACAATAGGTC

GACACAATAGGTCTT

ACACAATAGGTCTTT

CACAATAGGTCTTTC

ACAATAGGTCTTTCT

AATAGGTCTTTCTCT

ATAGGTCTTTCTCTC

TAGGTCTTTCTCTCA

AGGTCTTTCTCTCAG

GTCTTTCTCTCAGTG

TCTTTCTCTCAGTGA

CTTTCTCTCAGTGAA

TTTCTCTCAGTGAAG

TCTCTCAGTGAAGGT

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

The results of this experiment are shown in Figures 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 O.SmI
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 100.1 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 'zsI-IGF-I-binding, autoradiography and computerised imaging densitometry. Triplicate wells (except in Figure 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 'ZSI-IGF-I
(30,OOOcpm/well) at 4°C.

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).

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.

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.

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.

Twenty-one antisense oligonucleotides targeted to mRNA sequences enducing the receptor, and four random oligonucleotides were synthesized. The antisense oligonucleotides are CS-propynyl-dU, dC l5mer 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 Figure 9.

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, 30nM) and cytofectin GSV
(2,ug/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. Figure 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 8451 (30nM or 100 nM) plus cytofectin GSV (2,ug/ml or S,ug/ml) over 120 hours, viewed by fluorescence microscopy, tryptan blue stained, and counted. The graphs in Figure 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,ug/ml GSV provided optimal uptake and minimal toxicity.

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 (30nM) were completed with cytofectin GSV (2,ug/ml) and added tot he 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 RNAzoIB
protocol (Biotecx Laboratories, Inc. 6023 South Loop East, Houston, TX 77033) 96 hours following the first S 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, TX
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.
Figure 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 Figure 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 Figure 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 Figure 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

Another experiment was performed demonstrating that antisense oligonucleotides targeted to genetic sequences encoding the IGFOI 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 30nM random sequence or antisense oligonucleotide and 2,um/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 lml cold PBS. Serum-free DMEM
containing 10-'°M'ZSI-IGF-I was added with or without the IGF-I analogue, des (1-3) IGF-I, at 10-"M to 10-'M. Cells were incubated at 4°C for 17 hours with gentle shaking, then washed three times with lml cold PBS and lysed in 250~c1 O.SM 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 Figure 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, 8766. As shown in Figure 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 8451. 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.

Further experiments demonstrated the efficacy of antisense oligonucleotides targeted tot he 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 Figure 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, SO,uI, lO,uM
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. Figure 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:

Graft Number Treatment Volume ODN Duration of Concentrationof Injection Treatment 1-3 Vehicle (PBS) SO,uI - 20 days 4-6 RandomODN#R451 SO,uI lO,uM 20 days S 7-9 ODN#27 SO,uI 10~M 20 days 10-12 ODN#74 501 lO,uM 20 days 13-15 ODN#50 SO,uI 10~M 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 #5O (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 Figures 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. Figures 18(a)-(d) are shown at 100x magnification; figures 19(a)-(d) are shown at 400x 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 Figure 20.
As shown in Figures 18(a)-(d) and 19(a)-(d), the vehicle-treated (control) grafts were marginally thinner than thepregraft 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 Figure 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.

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 84541, 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 aKi67 antibody (DAKO, Glostrup, Denmark) recognizes the Ki67 antigen transiently expressed in nuclei of proliferating cells during late G,, S, M and GZ phases of the cycle and thsu provides a marker for proliferation. Pregraft and graft sections were immunohistochemically processed by standard methods using aKi67 (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 Figure 21 as immunohistochemical sections at 100x magnification. The top panel of Figure 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 Figure 21 also exhibits evidence of proliferation, including parakeratosis and Ki67-positive cells appearing as brown-staining nuclei. The center panel of Figure 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.

Topical formulations of complexes of oligonucleotides with cytofectin GSV in aqueous or methylcellulose gel formulations were prepared and assessed foruptake 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 8451 to nuclei and cytoplasm of keratinocytes in normal human skin grafts on nuce mice was observed. Figure 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 (lO~cM 8451) complexed with cytofectin GSV (l0,ug/ml). Figure 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.

Thirteen antisense oligonucleotides targeted to IGFBP-3 were synthesized. The antisense oligonucleotides are CS-propynyl-dU, DclS mer phosphorothioate oligodeoxyribonucleotides. Figure 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 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 (30nM or 100nM) were complexed with GSV cytofectin (2,ug/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, 8451, 8766 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 (l5,ug) 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.
Figures 25(a)-(d) provide graphs which depict results in this screening process. In these graphs, R1 and R12 refer to 8121; R4, R4(0) and R45 rfer to 8451; R7, R7(0) and R76 refer to 8766; and R9 and R96 refer to 8961. 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 Figure 26. As demonstrated, at a concentration of 30nM, 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 100nM, 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.

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.

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 ,ug/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I receptor specific oligonucleotides (#26 to #86) or random sequence oligonucleotides (R121, 8451 and R76c~. Figure 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. Figure 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).

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 ,ug/ml GSV lipid alone (GSV) or complexed with 30 nM IGF-I
receptor specific AONS (#27, #50 and #64) or the random sequence oligonucleotide, 8451.
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. Figure 28(a) shows duplicate treated cellular extracts following the IGF-I receptor at the predicted size of 110 kD. Figure 28(b) is a densitometric quantification of IGF-I receptor protein.

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 'ZSI-IGF-I and the receptor-specific analogue, des(1-3)IGF-I were performed.
Results are shown in Figure 29.

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 8451 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 Figure 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 Figure 30.

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 Figure 31. In Figure 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 Figure 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.

Figure 32 shows the reversal of epidermal hyperplasia correlating with reduced IGF-I
receptor mRNA in grafted psoriasis lesions treated with antisense oligonucleotides. Figure 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 1 S are indicated by a dark brown nucleus (arrows). Figure 32(b) shows the same lesion prior to grafting and after oligonucleotide treatment as in Figure 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.

Figure 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 ,ug/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.

Figure 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 ,ug/ml GSV lipid alone (GSV) or complexed with 30 nM oligonucleotide.
Cells were lysed in a buffer containing 50 mM HEPES, 150 mM NaCI, 10 % v/v glycerol, 1 v/v Trison X-100 and 100 ,ug/ml aprotinin on ice for 30 minutes, then 30 ,ug 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, California) for 1 hour at room temperature and developed using the Vistra ECF western blotting kit (Amersham). The results shown in Figure 34 confirm that IGF-I receptor protein is reduced in HaCaT keratinocytes following treatment with oligonucleotides.

This example shows a reduction in HaCaT keratinocyte cell number following treatment with oligonucleotides. The results are shown in Figure 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 ~g/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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SEQUENCE LISTING
<110> MURDOCH CHILDREN'S RESEARCH INSTITUTE
<120> A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF
MEDICAL DISORDERS
<130> 2288267/EJH
<140> INTERNATIONAL
<141> 2000-06-21 <150> 60/140345 <151> 1999-06-21 <160> 24 <170> PatentIn Ver. 2.1 <210> 1 <211> 1433 <212> DNA
<213> synthetic construct <400> 1 attcggggcg agggaggagg aagaagcgga ggaggcggct cccgctcgca gggccgtgca 60 cctgcccgcc cgcccgctcg ctcgctcgcc cgccgcgccg cgctgccgac cgccagcatg 120 ctgccgagag tgggctgccc cgcgctgccg ctgccgccgc cgccgctgct gccgctgctg 180 ccgctgctgc tgctgctact gggcgcgagt ggcggcggcg gcggggcgcg cgcggaggtg 240 ctgttccgct gcccgccctg cacacccgag cgcctggccg cctgcgggcc cccgccggtt 300 gcgccgcccg ccgcggtggc cgcagtggcc ggaggcgccc gcatgccatg cgcggagctc 360 gtccgggagc cgggctgcgg ctgctgctcg gtgtgcgccc ggctggaggg cgaggcgtgc 420 ggcgtctaca ccccgcgctg cggccagggg ctgcgctgct atccccaccc gggctccgag 480 ctgcccctgc aggcgctggt catgggcgag ggcacttgtg agaagcgccg ggacgccgag 540 tatggcgcca gcccggagca ggttgcagac aatggcgatg accactcaga aggaggcctg 600 gtggagaacc acgtggacag caccatgaac atgttgggcg ggggaggcag tgctggccgg 660 aagcccctca agtcgggtat gaaggagctg gccgtgttcc gggagaaggt cactgagcag 720 caccggcaga tgggcaaggg tggcaagcat caccttggcc tggaggagcc caagaagctg 780 cgaccacccc ctgccaggac tccctgccaa caggaactgg accaggtcct ggagcggatc 840 tccaccatgc gccttccgga tgagcggggc cctctggagc acctctactc cctgcacatc 900 cccaactgtg acaagcatgg cctgtacaac ctcaaacagt gcaagatgtc tctgaacggg 960 cagcgtgggg agtgctggtg tgtgaacccc aacaccggga agctgatcca gggagccccc 1020 accatccggg gggaccccga gtgtcatctc ttctacaatg agcagcagga ggcttgcggg 1080 gtgcacaccc agcggatgca gtagaccgca gccagccggt gcctggcgcc cctgcccccc 1140 gcccctctcc aaacaccggc agaaaacgga gagtgcttgg gtggtgggtg ctggaggatt 1200 ttccagttct gacacacgta tttatatttg gaaagagacc agcaccgagc tcggcacctc 1260 cccggcctct ctcttcccag ctgcagatgc cacacctgct ccttcttgct ttccccgggg 1320 gaggaagggg gttgtggtcg gggagctggg gtacaggttt ggggaggggg aagagaaatt 1380 tttatttttg aacccctgtg tcccttttgc ataagattaa aggaaggaaa agt 1433 <210> 2 <211> 2474 <212> DNA
<213> synthetic construct <400> 2 ctcagcgccc agccgcttcc tgcctggatt ccacagcttc gcgccgtgta ctgtcgcccc 60 atccctgcgc gcccagcctg ccaagcagcg tgccccggtt gcaggcgtca tgcagcgggc 120 gcgacccacg ctctgggccg ctgcgctgac tctgctggtg ctgctccgcg ggccgccggt 180 ggcgcgggct ggcgcgagct cggggggctt gggtcccgtg gtgcgctgcg agccgtgcga 240 cgcgcgtgca ctggcccagt gcgcgcctcc gcccgccgtg tgcgcggagc tggtgcgcga 300 gccgggctgc ggctgctgcc tgacgtgcgc actgagcgag ggccagccgt gcggcatcta 360 caccgagcgc tgtggctccg gccttcgctg ccagccgtcg cccgacgagg cgcgaccgct 420 gcaggcgctg ctggacggcc gcgggctctg cgtcaacgct agtgccgtca gccgcctgcg 480 cgcctacctg ctgccagcgc cgccagctcc aggaaatgct agtgagtcgg aggaagaccg 540 cagcgccggc agtgtggaga gcccgtccgt ctccagcacg caccgggtgt ctgatcccaa 600 gttccacccc ctccattcaa agataatcat catcaagaaa gggcatgcta aagacagcca 660 gcgctacaaa gttgactacg agtctcagag cacagatacc cagaacttct cctccgagtc 720 caagcgggag acagaatatg gtccctgccg tagagaaatg gaagacacac tgaatcacct 780 gaagttcctc aatgtgctga gtcccagggg tgtacacatt cccaactgtg acaagaaggg 840 attttataag aaaaagcagt gtcgcccttc caaaggcagg aagcggggct tctgctggtg 900 tgtggataag tatgggcagc ctctcccagg ctacaccacc aaggggaagg aggacgtgca 960 ctgctacagc atgcagagca agtagacgcc tgccgcaagt taatgtggag ctcaaatatg 1020 ccttattttg cacaaaagac tgccaaggac atgaccagca gctggctaca gcctcgattt 1080 atatttctgt ttgtggtgaa ctgatttttt ttaaaccaaa gtttagaaag aggtttttga 1140 aatgcctatg gtttctttga atggtaaact tgagcatctt ttcactttcc agtagtcagc 1200 aaagagcagt ttgaattttc ttgtcgcttc ctatcaaaat attcagagac tcgagcacag 1260 cacccagact tcatgcgccc gtggaatgct caccacatgt tggtcgaagc ggccgaccac 1320 tgactttgtg acttaggcgg ctgtgttgcc tatgtagaga acacgcttca cccccactcc 1380 ccgtacagtg cgcacaggct ttatcgagaa taggaaaacc tttaaacccc ggtcatccgg 1440 acatcccaac gcatgctcct ggagctcaca gccttctgtg gtgtcatttc tgaaacaagg 1500 gcgtggatcc ctcaaccaag aagaatgttt atgtcttcaa gtgacctgta ctgcttgggg 1560 actattggag aaaataaggt ggagtcctac ttgtttaaaa aatatgtatc taagaatgtt 1620 ctagggcact ctgggaacct ataaaggcag gtatttcggg ccctcctctt caggaatctt 1680 cctgaagaca tggcccagtc gaaggcccag gatggctttt gctgcggccc cgtggggtag 1740 gagggacaga gagacgggag agtcagcctc cacattcaga ggcatcacaa gtaatggcac 1800 aattcttcgg atgactgcag aaaatagtgt tttgtagttc aacaactcaa gacgaagctt 1860 atttctgagg ataagctctt taaaggcaaa gctttatttt catctctcat cttttgtcct 1920 ccttagcaca atgtaaaaaa gaatagtaat atcagaacag gaaggaggaa tggcttgctg 1980 gggagcccat ccaggacact gggagcacat agagattcac ccatgtttgt tgaacttaga 2040 gtcattctca tgcttttctt tataattcac acatatatgc agagaagata tgttcttgtt 2100 aacattgtat acaacatagc cccaaatata gtaagatcta tactagataa tcctagatga 2160 aatgttagag atgctatatg atacaactgt ggccatgact gaggaaagga gctcacgccc 2220 agagactggg ctgctctccc ggaggccaaa cccaagaagg tctggcaaag tcaggctcag 2280 ggagactctg ccctgctgca gacctcggtg tggacacacg ctgcatagag ctctccttga 2340 aaacagaggg gtctcaagac attctgccta cctattagct tttctttatt tttttaactt 2400 tttgggggga aaagtatttt tgagaagttt gtcttgcaat gtatttataa atagtaaata 2460 aagtttttac catt 2474 <210> 3 <211> 4989 <212> DNA
<213> synthetic construct <400> 3 tttttttttt ttttgagaaa gggaatttca tcccaaataa aaggaatgaa gtctggctcc 60 ggaggagggt ccccgacctc gctgtggggg ctcctgtttc tctccgccgc gctctcgctc 120 tggccgacga gtggagaaat ctgcgggcca ggcatcgaca tccgcaacga ctatcagcag 180 ctgaagcgcc tggagaactg cacggtgatc gagggctacc tccacatcct gctcatctcc 240 aaggccgagg actaccgcag ctaccgcttc cccaagctca cggtcattac cgagtacttg 300 ctgctgttcc gagtggctgg cctcgagagc ctcggagacc tcttccccaa cctcacggtc 360 atccgcggct ggaaactctt ctacaactac gccctggtca tcttcgagat gaccaatctc 420 aaggatattg ggctttacaa cctgaggaac attactcggg gggccatcag gattgagaaa 480 aatgctgacc tctgttacct ctccactgtg gactggtccc tgatcctgga tgcggtgtcc 540 aataactaca ttgtggggaa taagccccca aaggaatgtg gggacctgtg tccagggacc 600 atggaggaga agccgatgtg tgagaagacc accatcaaca atgagtacaa ctaccgctgc 660 tggaccacaa accgctgcca gaaaatgtgc ccaagcacgt gtgggaagcg ggcgtgcacc 720 gagaacaatg agtgctgcca ccccgagtgc ctgggcagct gcagcgcgcc tgacaacgac 780 acggcctgtg tagcttgccg ccactactac tatgccggtg tctgtgtgcc tgcctgcccg 840 cccaacacct acaggtttga gggctggcgc tgtgtggacc gtgacttctg cgccaacatc 900 ctcagcgccg agagcagcga ctccgagggg tttgtgatcc acgacggcga gtgcatgcag 960 gagtgcccct cgggcttcat ccgcaacggc agccagagca tgtactgcat cccttgtgaa 1020 ggtccttgcc cgaaggtctg tgaggaagaa aagaaaacaa agaccattga ttctgttact 1080 tctgctcaga tgctccaagg atgcaccatc ttcaagggca atttgctcat taacatccga 1140 cgggggaata acattgcttc agagctggag aacttcatgg ggctcatcga ggtggtgacg 1200 ggctacgtga agatccgcca ttctcatgcc ttggtctcct tgtccttcct aaaaaacctt 1260 cgcctcatcc taggagagga gcagctagaa gggaattact ccttctacgt cctcgacaac 1320 cagaacttgc agcaactgtg ggactgggac caccgcaacc tgaccatcaa agcagggaaa 1380 atgtactttg ctttcaatcc caaattatgt gtttccgaaa tttaccgcat ggaggaagtg 1440 acggggacta aagggcgcca aagcaaaggg gacataaaca ccaggaacaa cggggagaga 1500 gcctcctgtg aaagtgacgt cctgcatttc acctccacca ccacgtcgaa gaatcgcatc 1560 atcataacct ggcaccggta ccggccccct gactacaggg atctcatcag cttcaccgtt 1620 tactacaagg aagcaccctt taagaatgtc acagagtatg atgggcagga tgcctgcggc 1680 tccaacagct ggaacatggt ggacgtggac ctcccgccca acaaggacgt ggagcccggc 1740 atcttactac atgggctgaa gccctggact cagtacgccg tttacgtcaa ggctgtgacc 1800 ctcaccatgg tggagaacga ccatatccgt ggggccaaga gtgagatctt gtacattcgc 1860 accaatgctt cagttccttc cattcccttg gacgttcttt cagcatcgaa ctcctcttct 1920 cagttaatcg tgaagtggaa ccctccctct ctgcccaacg gcaacctgag ttactacatt 1980 gtgcgctggc agcggcagcc tcaggacggc tacctttacc ggcacaatta ctgctccaaa 2040 gacaaaatcc ccatcaggaa gtatgccgac ggcaccatcg acattgagga ggtcacagag 2100 aaccccaaga ctgaggtgtg tggtggggag aaagggcctt gctgcgcctg ccccaaaact 2160 gaagccgaga agcaggccga gaaggaggag gctgaatacc gcaaagtctt tgagaatttc 2220 ctgcacaact ccatcttcgt gcccagacct gaaaggaagc ggagagatgt catgcaagtg 2280 gccaacacca ccatgtccag ccgaagcagg aacaccacgg ccgcagacac ctacaacatc 2340 accgacccgg aagagctgga gacagagtac cctttctttg agagcagagt ggataacaag 2400 gagagaactg tcatttctaa ccttcggcct ttcacattgt accgcatcga tatccacagc 2460 tgcaaccacg aggctgagaa gctgggctgc agcgcctcca acttcgtctt tgcaaggact 2520 atgcccgcag aaggagcaga tgacattcct gggccagtga cctgggagcc aaggcctgaa 2580 aactccatct ttttaaagtg gccggaacct gagaatccca atggattgat tctaatgtat 2640 gaaataaaat acggatcaca agttgaggat cagcgagaat gtgtgtccag acaggaatac 2700 aggaagtatg gaggggccaa gctaaaccgg ctaaacccgg ggaactacac agcccggatt 2760 caggccacat ctctctctgg gaatgggtcg tggacagatc ctgtgttctt ctatgtccag 2820 gccaaaacag gatatgaaaa cttcatccat ctgatcatcg ctctgcccgt cgctgtcctg 2880 ttgatcgtgg gagggttggt gattatgctg tacgtcttcc atagaaagag aaataacagc 2940 aggctgggga atggagtgct gtatgcctct gtgaacccgg agtacttcag cgctgctgat 3000 gtgtacgttc ctgatgagtg ggaggtggct cgggagaaga tcaccatgag ccgggaactt 3060 gggcaggggt cgtttgggat ggtctatgaa ggagttgcca agggtgtggt gaaagatgaa 3120 cctgaaacca gagtggccat taaaacagtg aacgaggccg caagcatgcg tgagaggatt 3180 gagtttctca acgaagcttc tgtgatgaag gagttcaatt gtcaccatgt ggtgcgattg 3240 ctgggtgtgg tgtcccaagg ccagccaaca ctggtcatca tggaactgat gacacggggc 3300 gatctcaaaa gttatctccg gtctctgagg ccagaaatgg agaataatcc agtcctagca 3360 cctccaagcc tgagcaagat gattcagatg gccggagaga ttgcagacgg catggcatac 3420 ctcaacgcca ataagttcgt ccacagagac cttgctgccc ggaattgcat ggtagccgaa 3480 gatttcacag tcaaaatcgg agattttggt atgacgcgag atatctatga gacagactat 3540 taccggaaag gaggcaaagg gctgctgccc gtgcgctgga tgtctcctga gtccctcaag 3600 gatggagtct tcaccactta ctcggacgtc tggtccttcg gggtcgtcct ctgggagatc 3660 gccacactgg ccgagcagcc ctaccagggc ttgtccaacg agcaagtcct tcgcttcgtc 3720 atggagggcg gccttctgga caagccagac aactgtcctg acatgctgtt tgaactgatg 3780 cgcatgtgct ggcagtataa ccccaagatg aggccttcct tcctggagat catcagcagc 3840 atcaaagagg agatggagcc tggcttccgg gaggtctcct tctactacag cgaggagaac 3900 aagctgcccg agccggagga gctggacctg gagccagaga acatggagag cgtccccctg 3960 gacccctcgg cctcctcgtc ctccctgcca ctgcccgaca gacactcagg acacaaggcc 4020 gagaacggcc ccggccctgg ggtgctggtc ctccgcgcca gcttcgacga gagacagcct 4080 tacgcccaca tgaacggggg ccgcaagaac gagcgggcct tgccgctgcc ccagtcttcg 4140 acctgctgat ccttggatcc tgaatctgtg caaacagtaa cgtgtgcgca cgcgcagcgg 4200 ggtggggggg gagagagagt tttaacaatc cattcacaag cctcctgtac ctcagtggat 4260 cttcagttct gcccttgctg cccgcgggag acagcttctc tgcagtaaaa cacatttggg 4320 atgttccttt tttcaatatg caagcagctt tttattccct gcccaaaccc ttaactgaca 4380 tgggccttta agaaccttaa tgacaacact taatagcaac agagcacttg agaaccagtc 4440 tcctcactct gtccctgtcc ttccctgttc tccctttctc tctcctctct gcttcataac 4500 ggaaaaataa ttgccacaag tccagctggg aagccctttt tatcagtttg aggaagtggc 4560 tgtccctgtg gccccatcca accactgtac acacccgcct gacaccgtgg gtcattacaa 4620 aaaaacacgt ggagatggaa atttttacct ttatctttca cctttctagg gacatgaaat 4680 ttacaaaggg ccatcgttca tccaaggctg ttaccatttt aacgctgcct aattttgcca 4740 aaatcctgaa ctttctccct catcggcccg gcgctgattc ctcgtgtccg gaggcatggg 4800 tgagcatggc agctggttgc tccatttgag agacacgctg gcgacacact ccgtccatcc 4860 gactgcccct gctgtgctgc tcaaggccac aggcacacag gtctcattgc ttctgactag 4920 attattattt gggggaactg gacacaatag gtctttctct cagtgaaggt ggggagaagc 4980 tgaaccggc 4989 <210> 4 <211> 25 <212> DNA
<213> synthetic construct <400> 4 gcgcccgctg catgacgcct gcaac 25 <210> 5 <211> 24 <212> DNA
<213> synthetic construct <400> 5 cgggcggctc acctggagct ggcg 24 <210> 6 <211> 18 <212> DNA
<213> synthetic construct <400> 6 aggcggctga cggcacta 18 <210> 7 <211> 19 <212> DNA
<213> synthetic construct <400> 7 caggcgtcat gcagcgggc 19 <210> 8 <211> 25 <212> DNA
<213> synthetic construct <400> 8 cggagatgcc gcatgccagc gcagg 25 <210> 9 <211> 18 <212> DNA
<213> synthetic construct <400> 9 gacagcgtcg gagcgatc 18 <210> 10 <211> 18 <212> DNA
<213> synthetic construct <400> 10 atctctccgc ttcctttc 18 <210> 11 <211> 18 <212> DNA
<213> synthetic construct <400> 11 gaaaggaagc ggagagat 18 <210> 12 <211> 12 <212> DNA
<213> synthetic construct <400> 12 ccggagccag ac 12 <210> 13 <211> 12 <212> DNA
<213> synthetic construct <400> 13 cacaggcgca ag 12 <210> 14 <211> 8 <212> DNA
<213> synthetic construct _g_ <400> 14 cccgcccc 8 <210> 15 <211> 15 <212> DNA
<213> synthetic construct <400> 15 agcccccaca gcgag 15 <210> 16 <211> 12 <212> DNA
<213> synthetic construct <400> 16 gccggagaga gc 12 <210> 17 <211> 13 <212> DNA
<213> synthetic construct <400> 17 aacagaggca gca 13 <210> 18 <211> 13 <212> DNA
<213> synthetic construct <400> 18 ggacagggac cag 13 <210> 19 <211> 14 <212> DNA
<213> synthetic construct <400> 19 cggcaagcac acag 14 <210> 20 <211> 15 <212> DNA
<213> synthetic construct <400> 20 ggcaggcagg cacac 15 <210> 21 <211> 328 <212> PRT
<213> human <400> 21 Met Leu Pro Arg Val Gly Cys Pro Ala Leu Pro Leu Pro Pro Pro Pro Leu Leu Pro Leu Leu Pro Leu Leu Leu Leu Leu Leu Gly Ala Ser Gly Gly Gly Gly Gly Ala Arg Ala Glu Val Leu Phe Arg Cys Pro Pro Cys Thr Pro Glu Arg Leu Ala Ala Cys Gly Pro Pro Pro Val Ala Pro Pro Ala Ala Val Ala Ala Val Ala Gly Gly Ala Arg Met Pro Cys Ala Glu Leu Val Arg Glu Pro Gly Cys Gly Cys Cys Ser Val Cys Ala Arg Leu Glu Gly Glu Ala Cys Gly Val Tyr Thr Pro Arg Cys Gly Gln Gly Leu Arg Cys Tyr Pro His Pro Gly Ser Glu Leu Pro Leu Gln Ala Leu Val Met Gly Glu Gly Thr Cys Glu Lys Arg Arg Asp Ala Glu Tyr Gly Ala Ser Pro Glu Gln Val Ala Asp Asn Gly Asp Asp His Ser Glu Gly Gly Leu Val Glu Asn His Val Asp Ser Thr Met Asn Met Leu Gly Gly Gly Gly Ser Ala Gly Arg Lys Pro Leu Lys Ser Gly Met Lys Glu Leu Ala Val Phe Arg Glu Lys Val Thr Glu Gln His Arg Gln Met Gly Lys Gly Gly Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg Pro Pro Pro Ala Arg Thr Pro Cys Gln Gln Glu Leu Asp Gln Val Leu Glu Arg Ile Ser Thr Met Arg Leu Pro Asp Glu Arg Gly Pro Leu Glu His Leu Tyr Ser Leu His Ile Pro Asn Cys Asp Lys His Gly Leu Tyr Asn Leu Lys Gln Cys Lys Met Ser Leu Asn Gly Gln Arg Gly Glu Cys Trp Cys Val Asn Pro Asn Thr Gly Lys Leu Ile Gln Gly Ala Pro Thr Ile Arg Gly Asp Pro Glu Cys His Leu Phe Tyr Asn Glu Gln Gln Glu Ala Cys Gly Val His Thr Gln Arg Met Gln <210> 22 <211> 39 <212> PRT
<213> human <400> 22 Met Leu Pro Arg Val Gly Cys Pro Ala Leu Pro Leu Pro Pro Pro Pro Leu Leu Pro Leu Leu Pro Leu Leu Leu Leu Leu Leu Gly Ala Ser Gly Gly Gly Gly Gly Ala Arg Ala <210> 23 <211> 289 <212> PRT
<213> human <400> 23 Glu Val Leu Phe Arg Cys Pro Pro Cys Thr Pro Glu Arg Leu Ala Ala Cys Gly Pro Pro Pro Val Ala Pro Pro Ala Ala Val Ala Ala Val Ala Gly Gly Ala Arg Met Pro Cys Ala Glu Leu Val Arg Glu Pro Gly Cys Gly Cys Cys Ser Val Cys Ala Arg Leu Glu Gly Glu Ala Cys Gly Val Tyr Thr Pro Arg Cys Gly Gln Gly Leu Arg Cys Tyr Pro His Pro Gly Ser Glu Leu Pro Leu Gln Ala Leu Val Met Gly Glu Gly Thr Cys Glu Lys Arg Arg Asp Ala Glu Tyr Gly Ala Ser Pro Glu Gln Val Ala Asp Asn Gly Asp Asp His Ser Glu Gly Gly Leu Val Glu Asn His Val Asp Ser Thr Met Asn Met Leu Gly Gly Gly Gly Ser Ala Gly Arg Lys Pro Leu Lys Ser Gly Met Lys Glu Leu Ala Val Phe Arg Glu Lys Val Thr Glu Gln His Arg Gln Met Gly Lys Gly Gly Lys His His Leu Gly Leu Glu Glu Pro Lys Lys Leu Arg Pro Pro Pro Ala Arg Thr Pro Cys Gln Gln Glu Leu Asp Gln Val Leu Glu Arg Ile Ser Thr Met Arg Leu Pro Asp Glu Arg Gly Pro Leu Glu His Leu Tyr Ser Leu His Ile Pro Asn Cys Asp Lys His Gly Leu Tyr Asn Leu Lys Gln Cys Lys Met Ser Leu Asn Gly Gln Arg Gly Glu Cys Trp Cys Val Asn Pro Asn Thr Gly Lys Leu Ile Gln Gly Ala Pro Thr Ile Arg Gly Asp Pro Glu Cys His Leu Phe Tyr Asn Glu Gln Gln Glu Ala Cys Gly Val His Thr Gln Arg Met Gln <210> 24 <211> 291 <212> PRT
<213> human <400> 24 Met Gln Arg Ala Arg Pro Thr Leu Trp Ala Ala Ala Leu Thr Leu Leu Val Leu Leu Arg Gly Pro Pro Val Ala Arg Ala Gly Ala Ser Ser Gly Gly Leu Gly Pro Val Val Arg Cys Glu Pro Cys Asp Ala Arg Ala Leu Ala Gln Cys Ala Pro Pro Pro Ala Val Cys Ala Glu Leu Val Arg Glu Pro Gly Cys Gly Cys Cys Leu Thr Cys Ala Leu Ser Glu Gly Gln Pro Cys Gly Ile Tyr Thr Glu Arg Cys Gly Ser Gly Leu Arg Cys Gln Pro Ser Pro Asp Glu Ala Arg Pro Leu Gln Ala Leu Leu Asp Gly Arg Gly Leu Cys Val Asn Ala Ser Ala Val Ser Arg Leu Arg Ala Tyr Leu Leu Pro Ala Pro Pro Ala Pro Gly Asn Ala Ser Glu Ser Glu Glu Asp Arg Ser Ala Gly Ser Val Glu Ser Pro Ser Val Ser Ser Thr His Arg Val Ser Asp Pro Lys Phe His Pro Leu His Ser Lys Ile Ile Ile Ile Lys Lys Gly His Ala Lys Asp Ser Gln Arg Tyr Lys Val Asp Tyr Glu Ser Gln Ser Thr Asp Thr Gln Asn Phe Ser Ser Glu Ser Lys Arg Glu Thr Glu Tyr Gly Pro Cys Arg Arg Glu Met Glu Asp Thr Leu Asn His Leu Lys Phe Leu Asn Val Leu Ser Pro Arg Gly Val His Ile Pro Asn Cys Asp Lys Lys Gly Phe Tyr Lys Lys Lys Gln Cys Arg Pro Ser Lys Gly Arg Lys Arg Gly Phe Cys Trp Cys Val Asp Lys Tyr Gly Gln Pro Leu Pro Gly Tyr Thr Thr Lys Gly Lys Glu Asp Val His Cys Tyr Ser Met Gln Ser Lys

Claims (40)

CLAIMS:
1. A method for ameliorating the effects of 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 with an effective amount of a nucleic acid molecule selected from the group consisting of 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID
NO:13); 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID
NO:18); 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19); 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue of any one of said nucleic acid molecules wherein said nucleic acid molecule or its chemical analogue is capable of inhibiting or otherwise reducing growth factor mediated cell proliferation and/or inflammation and/or other medical disorders.
2. A method according to Claim 1 wherein the mammal is a human.
3. A method according to Claim 1 or 2 wherein cell proliferation and/or inflammation is mediated by at least one of insulin-like growth factor I (IGF-I), keratinocyte growth factor (KGF), transforming growth factor-.alpha.
(TGF.alpha.), tumour necrosis factor-.alpha. (TNF.alpha.), interleukin (IL) -1 (IL-1), IL-4, IL-6, IL-8 and/or basic fibroblast growth factor (bFGF).
4. A method according to Claim 3 wherein cell proliferation and/or inflammation is mediated by IGF-I.
5. A method according to Claim 1 or 2 wherein the proliferative or inflammatory skin disorder is psoriasis, eczema, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths or cancers of the skin.
6. A method according to Claim 5 wherein the skin condition is psoriasis.
7. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12) or chemical analogue thereof.
8. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13) or chemical analogue thereof.
9. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14) or chemical analogue thereof.
10. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15) or chemical analogue thereof.
11. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16) or chemical analogue thereof.
12. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ 1D NO:17) or chemical analogue thereof.
13. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ 1D NO:18) or chemical analogue thereof.
14. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19) or chemical analogue thereof.
15. A method according to Claim 1 or 4 or 6 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof.
16. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQID ID NO:12 to SEQ ID NO:20 inclusive.
17. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQ ID NO:12 to SEQ ID NO:20 inclusive.
18. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridizing to or forming a heteroduplex or otherwise interacting with a complementary form of SEQ ID NO:12 to SEQ ID NO:14 or SEQ ID NO:20 inclusive.
19. A method of ameliorating the effects of psoriasis in a mammal, said method comprising contacting proliferating skin or skin capable of proliferation 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 wherein said one or more molecules comprises a polynucleotide selected from the group consisting of 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID
NO:13); 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID
NO:18); 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19); 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue of any one of said nucleic acid molecules which is capable of interacting with mRNA directed from an IGF-I gene, an IGF-I
receptor gene or a gene encoding an IGFBP.
20. A method according to Claim 19 wherein the mammal is a human.
21. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12) or chemical analogue thereof.
22. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13) or chemical analogue thereof.
23. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14) or chemical analogue thereof.
24. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15) or chemical analogue thereof.
25. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16) or chemical analogue thereof.
26. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17) or chemical analogue thereof.
27. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18) or chemical analogue thereof.
28. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19) or chemical analogue thereof.
29. A method according to Claim 19 or 20 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof.
30. A composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation, said composition comprising a nucleic acid molecule selected from the group consisting of 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12); 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13); 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14); 5'-AGCCCCCACAGCGAG-3' (SEQ ID
NO:15); 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16); 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17); 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18); 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19); 5'-GGCAGGCAGGCACAC-3' (SEQ ID
NO:20) or chemical analogue of any one of said nucleic acid molecules, said composition further comprising one or more pharmaceutically acceptable carriers and/or diluents.
31. A method according to Claim 30 wherein the mammal is a human.
32. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UCCGGAGCCAGACUU-3' (SEQ ID NO:12) or chemical analogue thereof.
33. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-CACAGUUGCUGCAAG-3' (SEQ ID NO:13) or chemical analogue thereof.
34. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UCUCCGCUUCCUUUC-3' (SEQ ID NO:14) or chemical analogue thereof.
35. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-AGCCCCCACAGCGAG-3' (SEQ ID NO:15) or chemical analogue thereof.
36. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GCCUUGGAGAUGAGC-3' (SEQ ID NO:16) or chemical analogue thereof.
37. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-UAACAGAGGUCAGCA-3' (SEQ ID NO:17) or chemical analogue thereof.
38. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GGAUCAGGGACCAGU-3' (SEQ ID NO:18) or chemical analogue thereof.
39. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-CGGCAAGCUACACAG-5' (SEQ ID NO:19) or chemical analogue thereof.
40. A method according to Claim 30 or 31 wherein the nucleic acid molecule is 5'-GGCAGGCAGGCACAC-3' (SEQ ID NO:20) or chemical analogue thereof.
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