AU692278B2 - A method for the prophylaxis and/or treatment of proliferative and/or inflammatory skin disorders - Google Patents

Description

SI WO 96101636 PCr]U95/00410 k-- A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF PROLIFERATIVE AND/OR INFLAMMATORY SKIN DISORDERS 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.

Bibliographic details of the publications numerically referred to in this specification are collected at the end of the descrip.ion. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide sequences referred to in the specification are defined following the bibliography.

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.

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.

WO 96/01636 PCT/AU95/00410 -2- 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 Particular proteins, referred to as IGF binding proteins (IGFBPs), appear to be involved in autocrine/paracrine regulation of tissue IGF availability 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 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 fiboblasts Fibroblasts synthesize IGF-I as well as IGFBPs-3, -5 and -6 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 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 abberations in the normal functioning of these molecules or abberations in their interaction with their receptors is an important factor in 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 abberant activity during or leading to skin disease conditions.

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WO 96/01636 PCT/AU95/00410 -3- Accordingly, one aspect of the present invention contemplates 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 or chemical analogue thereof capable of inhibiting or otherwise reducing a growth factor mediated cell proliferation and/or inflammation.

Growth factor mediated cell proliferation and inflammation are also referred to as epidermal hyperplasias and 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-ct (TNFa), interleukin-1, -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 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 or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

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 seborrhoea, keloids, keratoses, I WO 96/01636 PCT/AU95/00410 -4neoplasias and scleroderma, warts, benign growths and cancers of the skin.

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

The present invention extends to any mammal such as but not limited to humans, livestock animals horses, sheep, cows, goats, pigs, donkeys), laboratory test animals rabbits, mice, guinea pigs), companion animals 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.

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, -4, and The most preferred molecules are IGFBP-2 and IGFBP-3.

The nucleotide sequences of IGFBP-2 and IGFBP-3 are set forth irn Figures 1 (SEQ ID NO. 1) and 2 (SEQ ID NO. 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 heterodouplex or otherwise interacting with an mRNA molecule directed from a gene corresponding to

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0 WO 96/0636 PCT/AU95/00410 a genomic form of SEQ ID NO. 1 and/or SEQ ID NO. 2 and which thereby reduces or inhibits translation of said mRNA mol.cule. 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 SEQ ID NO. 1 or SEQ ID NO. 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.

Examples of suitable oligonucleotide analogues are conveniently described in Ts'O et al 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-Ireceptor. Examples of suitable antisense molecules capable of targetting the IGF-I receptor are those capable of interacting with sequences selected from the list in WO 96/01636 PCT/AU95100410 -6- Example 8. One particularly useful antisense molecule is ATCTCTCCGCTTCCTTTC (SEQ ID NO. 10). A particularly preferred embodiment of the present invention contemplates a method of ameliorating the effects of psoriasis, 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 capable of interacting with mRNA directed from two or more of an IGF-I gene, an IGF-I receptor gene or a gene encoding an IGFBP such as IGFBP-2 and/or IGFBP-3.

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 Ribozymes are synthetic nucleic acid molecules which possess highly specific endoribonuclease activity. In particular, they comprise a hybidising region which is complementary in nucleotide sequence to at least part of a target RNA. Ribozymes are well described by Haseloff and Gerlach 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.

WO 96/01636 PCT/AU95/00410 -7- 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 SEQ ID NO. 1 or SEQ ID NO. 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.

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 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 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.

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WO 96/01636 PCT/AU95/00410 -8- Another aspect of the present invention contemplates a pharmaceutical composition for topical administration which comprises a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation such as psoriasis and one or more pharmaceutically acceptable carriers and/or diluents. Preferably, the nucleic acid molecule is an antisense molecule to IGF-I, the IGF-I receptor or an IGFBP such as IGFBP-2 and/or IGFBP-3 or comprises a ribozyme to one or more of these targets or is a molecule suitable for co-suppression of one or more of these targets. The composition may comprise a single species of a nuleic acid molecule capable of targeting one of IGF-I, its receptor or an IGFBP, such as IGFBP-2 or IGFBP-3 or may be a multi-valent molecule capable of targeting two or more of IGF-I, its receptor or an IGFBP, such as IGFBP-2 and/or IGFBP-3.

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

The pharmaceutical forms suitable for topical use include sterile aqueous solutions (where water soluble) or dispersions and powders for the extemporaneous preparation of topical solutions or dispersion. 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, thirmerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugais or sodium chloride.

WO 96/01636 PCT/AU9S/00410 -9- 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.

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 incompatable with the active ingredient, use thereof in the pharmaceutical compositions is contemplated. Supplementary active ingredients can also be incorporated into the c3mpositions. 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 mediated by a growth factor. The proliferative and/or inflammatory skin disorder is generally psoriasis 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.

The present invention is further described by the following non-limiting Figures and/or Examples.

I I Wo 96101636 W096/1636PCT/A1J95/00410 In the Figures: Figure 1 is a representation of the nucleotide sequence of IGFBP-2.

LOCUS

DEFINITION

ACCESS ION

KEYWORDS

SOUR~CE

ORGANISM

REFERENCE

AUTHORS

TITLE

JOURNAL

STANDARD

COMMENT

FEATURES

source HSIGFBP2 1433 bp RNA PRI 31-JAN-1990 Human mRNA for insulin-like growth factor binding protei.n ',±GFBP-2) X16302 insulin-like growth factor binding protein.

human Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; Vertebrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidk..

1 (bases 1 to 1433) Binkert,C.. Landwehr,J., Mary,J.L., Schwander,J. and Heinrich,G.

Cloning, sequence analysis and expression of a cDNA encoding a novel insulin-like growth factor binding protein (IGFBP-2) EMBO J. 8, 2497-2502 (1989) full automatic NCBI gi: 33009 Location/Qualifiers 1. .1433 /organism= "Homo sapiens" /iLcr stage-"fetal" /tissue type="liver" misc-featu polyA,_site

CDS

re 1416. .1420 /note=1"pot. polyadenylation signal" 1433 /note-"polyadenylation site" 118. .1104 /note-",precursor polypeptide; (AA -39 to 289); NCBI gi: 33010."1 /codon -start=1 transla tion= "MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGCARAXVLFR

CPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGEACG

VYTPRCGQGLRCYPHPGSELPLAJVGEGTCEKGRRlAEYGASPEQVADNGDDHSEGG

LVENVDSTMRLGGGGSAGRKPLSGMKELAVFRKVTEQHQMGKGGKHHLGLEEP

KKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHLYSLHIPNDGiGLYNLKQCK MSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEACGVHTQR4Q" 118. .234 /note="signal peptide; (AA -39 to NCBI gi: 33011." /codon-start=1 translation= "MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARAI 235. .1101 /note="1mature IGFBP-2; (AA 1 to 289); NCBI gi: 33012."1 /codon -start=1 /trans lat ion=" EVLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARNPCAELVR

EPGCGCCSVCARLEGE-ACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAE

YGASPEQVAflNGDDHSEGGLVEHVDSM~nMLGGGSAGRKPLKSGMKELAVFREKVT

EQHRQMGKGGKHHILEEPICIU.RPPPARTPCQQELDQVLERISTMRIPDERGPLEHLY

SLHI PNCDKHGLYNLKQCKa4SLNGQRGECWCVNPNTGKLIQ GAP TIRGDPECHLFYNE QQEACGVHTQRMQ"1 239 a 466 c 501 g 227 t BASE COUNT

ORIGIN

HSIGFBP2 Length: 1433 May 11, 1994 10:06 Type: N Check: 6232

I

W096/163 6 PCTAU9SIOO4 Figure 2 is a representation of the nucleotide sequence of IGFBP-3.

LOCUS HUMGFIBPA 2474 bp ss-mRNA PRI 15-JUN-15'90 DEFINITION Human growth hormone-dependent insulin-like growth factor-binding protein mRNA, complete cds.

ACCESSION M31159 KEYWORDS insulin-like growth factor oinding protein.

SOURCE Hunan plasma, cDNA to mRNA, clone BP-53.

ORGANISM Homo sapiens Eukaryota; AnimaJlia; Chordata; Vertebrate; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae, REFERENCE 1 (bases 1 to 2474) AUTHORS Wood,W.I., Cachianes,G., Henzel,W.J., Winslow,G.A,, Spencer,S.A., Hellniss,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

COMMENT

FEATURES

MRNA

CDS

full autenmatic NC13I gli tr3115 A .cation/Qualifiers .2474 /note="GFIBP mRNA1 110. .985 /gene="IGFBP1" /note="1insulir ike growth factor-binding protein; NCBI gi: 183116."1 /codon start=1 t ranslat ion= "IMQRARPTLWAAALTLLVLLRGPPVARAGASSGGLGPVVRCEPCD

ARALAQCAPPPAVCAELVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPSPDEAR

PLQALLDGRGLCVNASAVSRLsRAYLLPAPPAPGNASESEEDRSAGSVESPSVSSTHRV SDPKFHPLHSKII IIKKGHAKDSQRYKVDYESQSTDTQNFSSES1K.ETEYGPCRREME DTLNWiLKFLNVLSPRGVHIPNCDKKGFYKKKQCRPSKGRKGFCWCVDKYGQPLPGYT

TKGKEDVHCYSMQSK"

1. .2474 organism= "Homo sapiens" 597 a 646 c 651 g 580 t source BASE COUNT

ORIGIN

HUMGFIBPA Length: 2474 May 11, 1994 10:00 Type: N Check: 9946 Figure 3 is a representation of the nucleotide sequence of IGF-1 -receptor.

LOCUS

DEFINITION

ACCESSION

KEYWORDS

HSIGFIRR 4989 bp RNA PRI 28-MAR-1991 Human mRNA for insulin-like growth factor I receptor X04434 M24599 glycoprotein; insulin receptor; insulin-like growth factor I receptor; membrane glycoprotein; receptor; tyrosine kinase.

SOURCE human ORGANISM Homo sapiens Eukaryota; Animalia; Metazoa; Chordata; VerLnrata; Mammalia; Theria; Eutheria; Primates; Haplorhini; Catarrhini; Hominidae.

REFERENCE 1 (bases 1 to 4989) AUTHORS Ullrich,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, Ramachandran,J. and Fuj ita-Yamaguchi, Y.

TITLE Insulin-like growth factor I receptor primary structure: comparison WO 96/01636PC/19040 PCTIAU95100410 12 with insulin receptor suggests structural dererminants that c2efine functional specificity JOURNAL EMBO J. 5, 2S03-2512 (1986) STANDARD full automatic CoMMENT NCBI gi% 33058

FEATURES

source sigpeptide matpeptide misc-feature misc feature misc-feature misc-feature misc-feature misc-feature misc-feature misc feature misc feature misc-feature misc-feature misc feature m feature misc-feature misc feature misc-feature misc-feature mi~c-feature misc-feature misc-feature misc-feature mis cf eature misc feature misc-feature Location/Qualifiers 1. .4989 /organism="IHomo sapiens" /tissuetype= "placenta'l /clone-lib="I(lamda)gtlO"I /clone=" (lambda)IGF-1-R.85, (lambda)IGF-1-R.76"1 32. .121.

122. .4132 /note=" IGF-I receptor" 122. .2251 /note="alpha-subunit (AA 1 710)" 182. .190 /note.."pot.N-linked glycosylation site 335, .343 /note="pot .N-linked glycostlation site 434, .442 /note="pot.N-.linked glycostlation site 761. .769 /note. "pot. N- linked glycostlation site 971. .979 /note="pot.N-linked glycostlation site 1280. .1288 /note="pot.N-linked glycostlation site 1343. .1351 /note-"pot.N-linked glycosylation site 1631. .1639 /note="pot.N-linked glycostlation site 1850. .1858 /note="pot.N-linked glycosylation site 1895. .1903 fnote="pot .N-linked glycosylation site 1949, .1957 /note= "pot. N-linked glycosylation site 2240. .2251 /note="putative proreceptor processing 710)" 2252. .4132 /note="lbeta-subunit (AA 711 1337)"t 2270. .2278 /noteol"pot.N-linked glycosylatiom site 2297. .2305 /note="pot.N-linked glycosylation site 2321. .2329 /note="pot .N-linked glycosylation site 2729. .2737 /note="potN-linked glycosylation site 2768. .2776 (AA 21 23)" (AA 72 74)" (AA 105 107)" (AA 214 216)" (AA 284 286)" (AA 387 389)" (AA 408 410)" (AA 504 -506)" (AA 577 -579)" (AA 592 -594)" (AA 610 -612)11 site (AA 707 719)1 728)" 736)" 872)" /note="pot .N-linked 2837. .2908 glycosylation site (AA 883 885)"I /note="transmembrane region (AA 906 929)" 2918. .2926 /note="1potN-linked glycosylation site (AA 933 935)" 3047. .3049 /note="potATP binding site (AA 976)" 3053. .3055 /note="pot.ATP binding site (AA 978)" 3062. .3064 /note="pot.ATP binding site (AA 981)" WO 96101636 PCT/AU95/00410 13 miscfeature 3128. .3130 /note="pot.ATP binding site (AA 1003)" "S 32. .4132 /product="IGF-I receptor" /note="50 stops when translation attempted, frame 1, code 0" BASE COUNT 1216 a 1371 c 1320 g 1082 t

ORIGIN

HSIGFIRR Length: 4989 May 11, 1994 12:10 Type: N Check: 133 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 0.5p1M and 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 0.5uM compared with several control oligonucleotides at 0.5pM. oligonucleotide BP3AS2NS; oligonucleotide BP3AS4; oligonucleotide BP3AS4NS; and (untreated), no oligonucleotide added.

Figure 5B is a graphical representation of a scanning imaging densitometry of Western ligand blot (Figure 5A), showing relative band intensities of IGFBP-3 after treatment with phosphorothioate oligonucleotides as in Figure 5A, 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.

WO 96101636 PCT/AU95/00410 14- 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.

EXAMPLE 1 IN VITRO ASSAY: CELLS The differentiated human keratinocyte cell line, HaCaT was used in the in vitro assay. Cells at passage numbers 33 to 36 were maintained as monolayer cultures in v/v CO, at 37 0 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 EXAMPLE 2 IN VITRO ASSAY: THYMIDINE INCORPORATION ASSAY Cells were grown to 4 days post confluence in 2cm 2 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 Chemial Co, USA), 50IU/ml penicillin and streptomycin (Flow Laboratories). After 24 hours, IGF-I or tIGF-I was added to triplicate wells, at the concentrations indicated, in 0.5ml fresh DMEM containing 0.02% v/v bovine serum albumin (Sigma molecular biology grade) and incubated for a further 21 hours. 3 H]-Thymidine (O.1pCi/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 WO 96/01636 PCT/AU95/00410 15 then solubilized with 0.25M NaOH (200pl/well), transferred to scintillation vials and radioactivity determined by liquid scintillation counting (Pharmacia Wallac 1410 liquid scintillation counter).

EXAMPLE 3 WESTERN LIGAND BLOTTING HaCaT conditioned medium (250pl) was concentrated by adding 7501l cold ethanol, incubating at -20 0 C for 2 hours and centrifuging at 16,000g for 20 min at 4 0 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 using [1251]- IGF-I, followed by autoradiography. Autoradiographs were scanned in a BioRad Model GS-670 Imaging Densitometer and band densities were determined using the Molecular Analyst program.

EXAMPLE 4 ANTISENSE OLIGONUCLEOTIDES Phosphorothioate oligodeoxynucleotides were synthesised by Bresatec, Adelaide, South Australia, Australia. The following antisense sequences were used: BP3AS2, GCG CCC GCT GCA TGA CGC CTG CAA C (SEQ ID NO. a 25mer complementary to the start codon region of the human IGFBP-3 mRNA; BP3AS3, CGG GCG GCT CAC CTG GAG CTG GCG (SEQ ID NO. 24mer complementary to the exon 1/intron 1 splice site; BP3AS4, AGG CGG CTG ACG GCA CTA (SEQ ID NO.

an 18mer complementary to a region of the coding sequence lacking RNA secondary structure and oligouucleotide-dimer formation (using the computer software "OLIGO for 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, CAG GCG TCA TGC AGC GGG C (SEQ ID NO. an 18mer sense control sequence equivalent to the start codon region; BP3AS2NS, CGG AGA II I WO 96/01636 PCT/AU95/00410 16- TGC CGC ATG CCA GCG CAG G (SEQ ID NO. a 25mer randomised sequence with the same GC content as BP3AS2; BP3AS4NS, GAC AGC GTC GGA GCG ATC (SEQ ID NO. an 18mer 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 2cm 2 wells with daily medium changes of 0.5ml Keratinocyte-SFM, then subjected to daily medium changes of Keratinocyte- SFM for a further 4 days. Daily additions of 0.5ml fresh Keratinocyte-SFM were then continued for a further 7 days, except that at the time of medium addition, 5[1l 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 EXAMPLE ANTISENSE OLIGONUCLEOTIDES INHIBIT IGFBP-3 SYNTHESIS HaCaT cells secrete mainly IGFBP-3 with the only other IGFBP detectable in HaCaT conditioned medium being IGFBP-4 The effect on IGFBP-3 and IGFBP- 4 synthesis of antisense oligonucleotides at two concentrations, 5uM and 0.5.M, was tested. Two oligonucleotides were used, BP3AS2 and BP3AS3, directed against the start site and the intron 1/exon 1 splice site, respectively of the IGFBP-3 mRNA. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in Figures 4A and 4B, all oligonucleotides at 5uM caused a significant reduction of IGFBP-3 synthesis compared with untreated cells, however, the two antisense oligonucleotides inhibited IGFBP-3 synthesis of approximately 50% compared to the sense control (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 0.5pM. 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 I WO096101636 PTA25041 PCT/AU95/00410 17 significant observation that IGFBP-4 levels were unaffected by oligonucleotide addition to the cells, suggesting that the observed inhibitory effects on IGFBP-3 are specific.

To further investigate the inhibitory effects of the more effective of the two antisense oligonucleotides, BP3AS2, inhibition by this oligonucleotide at 0.5 jLM was compared with a number of control oligonucleotides, including one antisense oligonucleotide to IGFBP-3 that had proved to be ineffective at 0.5[iM. As shown in Figures 5A and BP3AS2 was again inhibitory, resulting in levels of IGFBP-3 of approximately 50% of the most non-specifically inhibitory control oligonucleotide, the randomised equivalent of MPASI. The other control oligonucleotides caused no reduction in IGFBP-3 levels at 0.54iM, 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 pairinig with non-target mRNAs. However, the lack of inibition of IGFBP-4 secretion by BP3AS2 suggests that this oligonucleotide is selective even compared with the most closely related protein likely to be present in this cell line.

EXAMPLE 6 ANTISENSE OLIGONUCLEOTIDES OF IGFBP2 Antisense oligonucleotides to IGFBP2 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:

ATTCGGGGCGAGGGA

TTCGGGGCGAGGGAG

TCGGGGCGAGGGAGG

CGGGGCGAGGGAGGA

GGGGCGAGGGAGGAG

GGGCGAGGGAGGAGG

GGCGAGGGAGGAGGA

GCGAGGGAGGAGGAA

CGAGGGAGGAGGAAG

GAGGGAGGAGGAAGA

AGGGAGGAGGAAGAA

GGGAGGAGGAAGAAG

GGAGGAGGAAGAAGC

GAGGAGGAAGAAGCG

AGGAGGAAGAAGCGG

GGAGGAAGAAGCGGA

GAGGAAGAAGCGGAG

AGGAAGAAGCGGAGG

GGAAGAAGCGGAGGA

GAAGAAGCGGAGGAG

AAGAAGCGGAGGAGG

AGAAGCGGAGGAGGC

GAAGCGGAGGAGGCG

AAGCGGAGGAGGCGG

AGCGGAGGAGGCGGC

GCGGAGGAGGCGGCT

CGGAGGAGGCGGCTC

GGAGGAGGCGGCTCC

GAGGAGGCGGCTCCC

AGGAGGCGGCTCCCG

GGAGGCGGCTCCCGC

GAGGCGGCTCCCGCT

AGG CGGCT CCCG CT C

GGCGGCTCCCGCTCG

GCGGCTCCCGCTCGC

CGGCTCCCGCTCGCA

GGCTCCCGCTCGCAG

GCTCCCGCTCGCAGG

CTCCCGCTCGCAGGG

TCCCGCTCGCAGGGC

CCCGCTCGCAGGGCC

CCGCTCGCAGGGCCG

CGCTCGCAGGGCCGT

GCTCGCAGGGCCGTG

CTCGCAGGGCCGTGC

TCGCAGGGCCGTGCA

CGCAGGGCCGTGCAC

GCAGGGCCGTGCACC

CAGGGCCGTGCACCT

AGGGCCGTGCACCTG

GGGCCGTGCACCTGC

GGCCGTGCACCTGCC

GCCGTGCACCTGCCC

CCGTGCACCTGCCCG

CGTGCACCTGCCCGC

GTGCACCTGCCCGCC

TGCACCTGCCCGCCC

GCACCTGCCCGCCCG

CACCTGCCCGCCCGC

ACCTGCCCGCCCGCC

WO 9610 1636 PTA9/01 PCT/AU95/00410 18

CCTGCCCGCCCGCCC

CTGCCCGCCCGCCCG

TGCCCGCCCGCCCGC

GCCCGCCCGCCCGCT

CCCGCCCGCCCGCTC

CCGCCCGCCCGCTCG

CGCCCGCCCGCTCGC

GCCCGCCCGCTCGCT

CCCGCCCGCTCGCTC

CCGCCCGCTCGCTCG

CGCCCGCTCGCTCGC

GCCCGCTCGCTCGCT

CCCGCTCGCTCGCTC

CCGCTCGCTCGCTCG

CGCTCGCTCGCTCGC

GCTCGCTCGCTCGCC

CTCGCTCGCTCGCCC

TCGCTCGCTCGCCCG

CGCTCGCTCGCCCGC

GCTCGCTCGCCCGCC

CTCGCTCGCCCGCCG

TCGCTCGCCCGCCGC

CGCTCGCCCGCCGCG

GCTCGCCCGCCGCGC

CTCGCCCGCCGCGCC

TCGCCCGCCGCGCCG

CGCCCGCCGCGCCGC

GCCCGCCGCGCCGCG

CCCGCCGCGCCGCGC

CCGCCGCGCCGCGCT

CGCCGCGCCGCGCTG

GCCGCGCCGCGCTGC

CCGCGCCGCGCTGCC

CGCGCCGCGCTGCCG

GCGCCGCGCTGCCGA

CGCCGCGCTGCCGAC

GCCGCGCTGCCGACC

CCGCGCTGCCGACCG

CGCGCTGCCGACCGC

GCGCTGCCGACCGCC

CGCTGCCGACCGCCA

GCTGCCGACCGCCAG

CTGCCGACCGCCAGC

TGCC2GACCGCCAGCA

GCCGACCGCCAGC-AT

CCGACCGCCAGCATG

CGACCGCCAGCATGC

GACCGCCAGCATGCT

ACCGCCAGCATGCTG

CCGCC2AGCATGCTGC

CGCCAGCATGCTGCC

GCCAGCATGCTGCCG

CCAGCATGCTGCCGA

CAGCATGCTGCCGAG

AGCATGCTGCCGAGA

(CATGCTGCCGAGAG

CATGCTGCCGAGAGT

ATGCTGCCGAGAGTG

TGCTGCCGAGAGTGG

GCTGCCGAGAGTGGG

CTGCCGAGAGTGGGC

TGCCGAGAGTGGGCT

GCCGAGAGTGGGCTG

CCGAGAGTGGGCTGC

CGAGAGTGGGCTGCC

GAGAGTGGGCTGCCC

AGAGTGGG CTG C CCC

GAGTGGGCTGCCCCG

AGTGGGCTGCCCCGC

GTGGGCTGCCCCGCG

TGGGCTGCCCCGCGC

GGGCTGCCCCGCGCT

GGCTGCCCCGCGCTG

GCTGCCCCGCGCTGC

CTGCCCCGCGCTGCC

TGCCCCGCGCTGCCG

GCCCCGCGCTGCCGC

CCCCGCGCTGCCGCT

CCCGCGCTGCCGCTG

CCGCGCTGCCGCTGC

CGCGCTGCCGCTGCC

GCGCTGCCGCTGCCG

CGCTGCCGCTGCCGC

GCTGCCGCTGCCGCC

CTGCCGCTGCCGCCG

TGCCGCTGCCGCCGC

GCCGCTGCCGCCGCC

CCGCTGCCGCCGCCG

CGCTGCCGCCGCCGC

GCTGCCGCCGCCGCC

CTGCCGCCGCCGCCG

TGCCGCCGCCGCCGC

GCCGCCGCCGCCGCT

CCGCCGCCGCCGCTG

CGCCGCCGCCGCTGC

GCCGCCGCCGCTGCT

CCGCCGCCGCTGCTG

CGCCGCCGCTGCTGC

GCCGCC-GCTGCTGCC

CCGCCGCTGCTGCCG

CGCCGCTGCTGCCGC

GCCGCTGCTGCCGCT

CCGCTGCTGCCGCTG

CGCTGCTGCCGCTGC

GCTGCTGCCGCTGCT

CTGCTGCCGCTGCTG

TGCTGCCGCTGCTGC

GCTGCCGCTGCTGCC

CTGCCGCTGCTGCCG

TGCCGCTGCTGCCGC

GCCGCTGCTGCCGCT

CCGCTGCTGCCGCTG

CGCTGCTGCCGCTGC

GCTGCTGCCGCTGCT

CTGCTGCCGCTGCTG

TGCTGCCGCTGCTGC

GCTGCCGCTGCTGCT

CTGCCGCTGCTGCTG

TGCCGCTGCTGCTGC

GCCGCTGCTGCTGCT

CCGCTGCTGCTGCTG

CGCTGCTGCTGCTGC

GCTGCTGCTGCTGCT

CTGCTGCTGCTGCTA

TGCTGCTGCTGCTAC

GCTGCTGCTGCTACT

CTGCTGCTGCTACTG

TGCTGCTGCTACTGG

GCTGCTGCTACTGGG

CTGCTGCTACTGGGC

TGCTGCTACTGGGCG

GCTGCTACTGGGCGC

CTGCTACTGGGCGCG

TGCTACTGGGCGCGA

GCTACTGGGCGCGAG

CTACTGGGCGCGAGT

TACTGGGCGCGAGTG

ACTGGGCGCGAGTGG

CTGGGCGCGAGTGGC

TGGGCGCGAGTGGCG

GGGCGCGAGTGGCGG

GGCGCGAGTGGCGGC

GCGCGAGTGGCGGCG

CGCGAGTGGCGGCGG

GCGAGTGGCGGCGGC

CGAGTGGCGGCGGCG

GAGTGGCGGCGGCGG

AGTGGCGGCGGCGGC

GTCGCGGCGGCGGCG

TGGCGGCGGCGGCGG

GGCGGCGGCGGCGGG

GCGGCGGCGGCGGGG

CGGCGGCGGCGGGGC

GGCGGCGGCGGGGCG

GCGGCGGCGGGGCGC

CGGCGGCGGGGCGCG

GGCGGCGGGGCGCGC

GCGGCGGGGCGCGCG

CGGCGGGGCGCGCGC

GGCGGGGCGCGCGCG

GCGGGGCGCGCGCGG

CGGGGCGCGCGCGGA

GGGGCGCGCGCGGAG

GGGCGCGCGCGGAGG

GGCGCGCGCGGAGGT

GCGCGCGCGGAGGTG

CGCGCGCGGAGGTGC

GCGCGCGGAGGTGCT

I WO 96101636 W096/1636PCT/AU9S/0041 0 19

CGCGCGGAGGTGCTG

GCGCGGAGGTGCTGT

CGCGGAGGTCICTGTT

GCGGAGGTGCTGTTC

CGGAGGTGCTGTTCC

GGAGGTGCTGTTCCG

GAGGTGCTGTTCCGC

AGGTGCTGTTCCGCT

GGTGCTGTTCCGCTG

GTGCTGTTCCGCTGC

TGCTGTTCCGCTGCC

GCTGTTCCGCTGCCC

CTGTTCCGCTGCCCG

TGTTCCGCTGCCCGC

GTTCCGCTGCCCGCC

TTCCGCTGCCCGCCC

TCCGCTGCCCGCCCT

CCGCTGCCCGCCCTG

CGCTGCCCGCCCTGC

GCTGCCCGCCCTGCA

CTGCCCGCCCTGCAC

TGCCCGCCCTGCACA

GCCCGCCCTGCACAC

CCCGCCCTGCACACC

CCGCCCTGCACACCC

CGCCCTGCACACCCG

GCCCTGCACACCCGA

CCCTGCACACCCGAG

CCTGCACACCCGAGC

CTGCACACCCGAGCG

TGCACACCCGAGCGC

GCACACCCGAGCGCC

CACACCCGAGCGCCT

ACACCCGAGCGCCTG

CACCCGAGCGCCTGG

ACCCGAGCGCCTGGC

CCCGAGCGCCTGGCC

CCGAGCGCCTGGCCG

CGAGCGCCTGGCCGC

GAGCGCCTGGCCGCC

AGCGCCTGGCCGCCT

GCGCCTGGCCGCCTG

CGCCTGGCCGCCTGC

GCCTGGCCGCCTGCG

CCTGGCCGCCTGCGG

CTGGCCGCCTGCGGG

TGGCCGCCTGCGGGC

GGCCGCCTGCGGGCC

GCCGCCTGCGGGCCC

CCGCCTGCGGGCCCC

CGCCTGCGGGCCCCC

GCCTGCGGGCCCCCG

CCTGCGGGCCCCCGC

CTGCGGGCCCCCGCC

TGCGGGCCCCCGCCG

GCGGGCCCCCGCCGG

CGGGCCCCCGCCGGT

GGGCCCCCGCCGGTT

GGCCCCCGCCGGTTG

GCCCCCGCCGGTTGC

CCCCCGCCGGTTGCG

CCCCGCCGGTTGCGC

CCCGCCGGTTGCGCC

CCGCCGGTTGCGCCG

fCGCCGGTTGCGCCGC

GCCGGTTGCGCCGCC

CCGGTTGCGCCGCCC

CGGTTGCGCCGCCCG

GGTTGCGCCGCCCGC

GTTGCGCCGCCCGCC

TTGCGCCGCCCGCCG

TGCGCCGCCCGCCGC

GCGCCGCCCGCCGCG

CGCCGCCCGCCGCGG

GCCGCCCGCCGCGGT

CCGCCCGCCGCGGTG

CGCCCGCCGCGGTGG

GCCCGCCGCGGTGGC

CCCGCCGCGGTGGCC

CCGCCGCGGTGGCCG

CGCCGCGGTGGCCGC

GCCGCGGTGGCCGCA

CCGCGGTGGCCGCAG

CGCGGTGGCCGCAGT

GCGGTGGCCGCAGTG

CGGTGGCCGCAGTGG

GGTGGCCGCAGTGGC

GTGGCCGCAGTGGCC

TGGCCGCAGTGGCCG

GGCCGCAGTGGCCGG

GCCGCAGTGGCCGGA

CCGCAGTGGCCGGAG

CGCAGTGGCCGGAGG

GCAGTGGCCGGAGGC

CAGTGGCCGGAGGCG

AGTGGCCGGAGGCGC

GTGGCCGGAGGCGCC

TGGCCGGAGGCGCCC

GGCCGGAGGCGCCCG

GCCGGAGGCGCCCGC

CCGGAGGCGCCCGCA

CGGAGGCGCCCGCAT

GGAGGCGCCCGCATG

GAGGCGCCCGCATGC

AGGCGCCCGCATGCC

GGCGCCCGCATGCCA

GCGCCCGCATGCCAT

CGCCCGCATGCCATG

GCCCGCATGCCATGC

CCCGCATGCCATGCG

CCGCATGCCATGCGC

CGCATGCCATGCGCG

GCATGCCATGCGCGG

CATGCCATGCGCGGA

ATGCCATGCGCGGAG

TGCCATGCGCGGAGC

GCCATGCGCGGAGCT

CCATGCGCGGAGCTC

CATGCGCGCGAGCTCG

ATGCGCGGAGCTCGT

TGCGCGGAGCTCGTC

GCGCGGAGCTCGTCC

CGCGGAGCTCGTCCG

GCGGAGCTCGTCCGG

CGGAGCTCGTCCGGG

GGAGCTCGTCCGGGA

GAGCTCGTCCGGGAG

AGCTCGTCCGGGAGC

GCTCGTCCGGGAGCC

CTCGTCCGGGAGCCG

TCGTCCGGGAGCCGG

CGTCCGGGAGCCGGG

GTCCGGGAGCCGGGC

TCCGGGAGCCGGGCT

CCGGGAGCCGGGCTG

CGGGAGCCGGGCTGC

GGGAGCCGGGCTGCG

GGAGCCGGGCTGCGG

GAGCCGGGCTGCGGC

AGCCGGGCTGCGGCT

GCCGGGCTGCGGCTG

CCGGGCTGCGGCTGC

CGGGCTGCGGCTGCT

GGGCTGCGGCTGCTG

GGCTGCGGCTGCTGC

GCTGCGGCTGCTGCT

CTGCGGCTGCTGCTC

TGCGGCTGCTGCTCG

GCGGCTGCTGCTCGG

CGGCTGCTGCTCGGT

GGCTGCTGCTCGGTG

GCTGCTGCTCGGTGT

CTGCTGCTCGGTGTG

TGCTGCTCGGTGTGC

GCTGCTCGGTGTGCG

CTGCTCGGTGTGCGC

TGCTCGGTGTGCGCC

GCTCGGTGTGCGCCC

CTCGGTGTGCGCCCG

TCGGTGTGCGCCCGG

CGGTGTGCGCCCGGC

GGTGTGCGCCCGGCT

GTGTGCGCCCGGCTG

TGTGCGCCCGGCTGG

GTGCGCCCGGCTGGA

TGCGCCCGGCTGGAG

GCGCCCGGCTGGAGG

CGCCCGGCTGGAGGG

YWO 96101636 PTA9/01 PCT/A'U95/00410 20

GCCCGGCTGGAGGGC

CCCGGCTGGAGGGCG

CCGGCTGGAGGGCGA

CGGCTGGAGGGCGAG

GGCTGGAGGGCGAGG

GCTGGAGGGCGAGGC

CTGGAGGGCGAGGCG

TGGAGGGCGAGGCGT

GGAGGGCGAGGCGTG

GAGGGCGAGGCGTGC

AGGGCGAGGCGTGCG

GGGCGAGGCGTGCGG

GGCGAGGCGTGCGGC

GCGAGGCGTGCGGCG

CGAGGCGTGCGGCGT

GAGGCGTGCGGCGTC

AGGCGTGCGGCGTCT

GGCGTGCGGCGTCTA

GCGTGCGGCGTCTAC

CGTGCGGCGTCTACA

GTGCGGCGTCTACAC

TGCGGCGTCTACACC

GCGGCGTCTACACCC

CGGCGTCTACACCCC

GGCGTCTACACCCCG

GCGTCTACACCCCGC

CGTCTACACCCCGCG

GTCTACACCCCGCGC

TCTACACCCCGCGCT

CTACACCCCGCGCTG

TACACCCCGCGCTGC

ACACCCCGCGCTGCG

CACCCCGCGCTGCGG

ACCCCGCGCTGCGGC

CCCCGCGCTGCGGCC

CCCGCGCTGCGGCCA

CCGCGCTGCGGCCAG

CGCGCTGCGGCCAGG

GCGCTGCGGCCAGGG

CGCTGCGGCCAGGGG

GCTGCGGCCAGGGGC

CTGCGGCCAGGGGCT

TGCGGCCAGGGGCTG

GCGGCCAGGGGCTGC

CGGCCAGGGGCTGCG

GGCCAGGGGCTGCGC

GCCAGGGGCTGCGCT

CCAGGGGCTGCGCTG

CAGGGGCTGCGCTGC

AGGGGCTGCGCTGCT

GGGGCTGCGCTGCTA

GGGCTGCGCTGCTAT

GGCTGCGCTGCTATC

GCTGCGCTGCTATCC

CTGCGCTGCTATCCC

TGCGCTGCTATCCCC

GCGCTGCTATCCCCA

CGCTGCTATCCCC

GCTGCTATCCCCACC

CTGCTATCCCCACCC

TGCTATCCCCACCCG

GCTATCCCCACCCGG

C TAT CCC CAC CCGGG

TATCCCCACCCGGGC

ATCCCCACCCGGGCT

TCCCCACCCGGGCTC

CCCCACCCGGGCTCC

CCCACCCGGGCTCCG

CCACCCGGGCTCCGA

CACCCGGGCTCCGAG

ACC CGGG CT CCGAG C

CCCGGGCTCCGAGCT

CCGGGCTCCGAGCTG

CGGGCTCCGAGCTGC

GGGCTCCGAGCTGCC

GGCTC CGAGCTG CC C G CT CCGAGCTG CCC C

CTCCGAGCTGCCCCT

TC CGAG CTGC C CCTG

CCGAGCTGCCCCTGC

CGAGCTGCCCCTGCA

GAGCTGCCCCTGCAG

AGCTGCCCCTGCAGG

G CTGC C CCTGCAGGC

CTGCCCCTGCALGGCG

TGCCCCTGCAGGCGC

GCCCCTGCAGGCGCT

CCCCTGCAGGCGCTG

CCCTGCAGGCGCTGG

CCTGCAGGCGCTGGT

CTGCAGGCGCTGGTC

TGCAGGCGCTGGTCA

GCAGGCG CTGGT CAT

CAGGCGCTGGTCATG

AGGCGCTGGTCATGG

GGCGCTGGTCATGGG

GCGCTGGTCATGGGC

CGCTGGTCATGGGCG

GCTGGTCATGGGCGA

CTGGTCATGGGCGAG

TGGTCATGGGCGAGG

GGTCATGGGCGAGGG

GTCATGGGCGAGGGC

TCATGGGCGAGGGCA

CATGGGCGAGGGCAC

ATGGGCGAGGGCACT

TGGGCGAGGGCACTT

GGGCGAGGGCACTTG

GGCGAGGGCACTTGT

GCGAGGGCACTTGTG

CGAGGGCACTTGTGA

GAGGGCACTTGTGAG

AGGGCACTTGTGAGA

GGGCACTTGTGAGAA

GGCACTTGTGAGAAG

GCACTTGTGAGAAGC

CACTTGTGAGAAGCG

ACTTGTGAGAAGCGC

CTTGTGAGAAGCGCC

TTGTGAGAAGCGCCG

TGTGAGAAGCGCCGG

GTGAGAAGCGCCGGG

TGAC-AAGCGCCGGGA

GAGAAGCGCCGGGAC

AGAAGCGCCGGGACG

GAAGCGCCGGGACGC

AAGCGCCGGGACGCC

AGCGCCGGGACGCCG

GCGCCGGGACGCCGA

CGCCGGGACGCCGAG

GCCGGGACGCCGAGT

CCGGGACGCCGAG'fA

CGGGACGCCGAGTAT

GGGACGCCGAGTATG

GGACGCCGAGTATGG

GACGCCGAGTATGGC

ACGCCGAGTATGGCG

CGCCGAG'TATGGCGC

GCCGAGTATGGCGCC

CCGAGTATGGCGCCA

CGAGTATGGCGCCAG

GAGTATGGCGCCAGC

AGTATGGCGCCAGCC

GTATGGCGCCAGCCC

TATGGCGCCAGCCCG

ATGGCGCCAGCCCGG

TGGCGCCAGCCCGGA

GGCGCCAGCCCGGAG

GCGCCAGCCCGGAGC

CGCCAGCCCGGAGCA

GCCAGCCCGGAGCAG

CCAGCCCGGAGCAGG

CAGCCCGGAGCAGGT

AGCCCGGAGCAGGTT

GCCCGGAGCAGGTTG

CCCGGAGCAGGTTGC

CCGGAGCAGGTTGCA

CGGAGCAGGTTGCAG

GGAGCAGGTTGCAGA

GAGCAGGTTGCAGAC

AGCAGGTTGCAGACA

GCAGGTTGCAGACAA

CAGGTTGCAGACAAT

AGGTTGCAGACAATG

GGTTGCAGACAATGG

GTTGCAGACAATGGC

TTGCAGACAATGGCG

TGCAGACAATGGCGA

WO 96101636 WO 9601636PCTAU95OO41O 21

GCAGACAATGGCGAT

CAGACAATGGCGATG

AGACAATGGCGATGA

GACAATGGCGATGAC

ACAATGGCGATGACC

CAATGGCGATGACCA

AATGGCGATGACCAC

ATGGCGATGACCACT

TGGCGATGACCACTC

GGCGATGACCACTCA

GCGATGACCACTCAG

CGATGACCACTCAGA

GATGACCACTCAGAA

ATGACCACTCAGAAG

TGACCACTCAGAAGG

GACCACTCAGAAGGA

ACCACTCAGAAGGAG

CCACTCAGAAGGAGG

CACTCAGAAGGAGGC

ACTCAGAAGGXGGCC

CTCAGAAGGAGGCCT

TCAGAAGGAGGCCTG

CAGAAGGAGGCCTGG

AGAAGGAGGCCTGGT

GAAGGAGGCCTGGTG

AAGGAGGCCTGGTGG

AGGAGGCCTGGTGGA

GGAGGCCTGGTGGAG

GAGGCCTGGTGGAGA

AGGCCTGGTGGAGAA

GGCCTGGTGGAGAAC

GCCTGGTGGAGAACC

CCTGGTGGAGAACCA

CTGGTGGAGAACCAC

TGGTGGAGAACCACG

GGTGGAGAACCACGT

GTGGAGAACCACGTG

TGGAGAACCACGTGG

GGAGAACCACGTGGA

GAGAACCACGTGGAC

AGAACCACGTGGACA

GAACCACGTGGACAG

AACCACGTGGACAGC

ACCACGTGGACAGCA

CC,-ACGTGGACAGCAC

CACGTGGACAGCACC

ACGTGGACAGCACCA

CGTGGACAGCACCAT

GTGGACAGCACCATG

TGGACAGCACCATGA

GGACAGCACCATGAA

GACAGCACCATGAAC

ACAGCACCATGAACA

CAGCACCATGAACAT

AGCACCATGAACATG

GCACCATGAACATGT

CACCATGAACATGTT

ACCATGAACATGTTG

CCATGAACATGTTGG

CATGAACATGTTGGG

ATGAACATGTTGGGC

TGAACATGTTGGGCG

GAACATGTTGGGCGG

AACATGTTGGGCGGG

ACATGTTGGGCGGGG

CATGTTGGGCGGGGG

ATGTTGGGCGGGGGA

TGTTGGGCGGGGGAG

GTTGGGCGGGGGAGG

TTGGGCGGGGGAGGC

TGGGCGGGGGAGGCA

GGGCGGGGGAGGCAG

GGCGGGGGAGGCAGT

GCGGGGGAGGCAGTG

CGGGGGAGGCAGTGC

GGGGGAGGCAGTGCT

GGGGAGGCAGTGCTG

GGGAGGCAGTGCTGG

GGAGGCAGTGCTGGC

GAGGCAGTGCTGGCC

AGGCAGTGCTGGCCG

GGCAGTGCTGGCCGG

GCAGTGCTGGCCS'-GA

CAGTGCTGGCCGGAA

AGTGCTGGCCGGAAG

GTGCTGGCCGGAAGC

TGCTGGCCGGAAGCC

GCTGGCCGGAAGCCC

CTGGCCGGAAGCCCC

TGGCCGGAAGCCCCT

GGCCGGAAGCCCCTC

GCC"3GAAGCCCCTCA

CCGGAAGCCCCTCAA

CGGAAGCCCCTCAAG

GGAAGCCCCTCAAGT

GAAGCCCCTCAAGTC

AAGCCCCTCAAGTCG

AGCCCCTCAAGTCGG

GCCCCTCAAGTCGGG

CCCCTCAAGTCGGGT

CCCTCAAGTCGGGTA

CCTCAAGTCGGGTAT

CTCAAGTCGGGTATG

TCAAGTCGGGTATGA

CAAGTCGGGTATGAA

AAGTCGGGTATGAAG

AGTCGGGTATGAAGG

GTCGGGTATGAAGGA

TCGGGTATGAAGGAG

CGGGTATGAAGGAGC

GGGTATGAAGGAGCT

GGTATGAAGGAGCTG

GTATGAAGGAGCTGG

TATGAAGGAGCTC'GC

ATGAAGGAGCTGGCC

TGAAGGAGCTGGCCG

GAAGGAGCTGGCCGT

AAGGA 2CTGGCCGTG ACG7AGCTGGCCGTGT

GGAGCTGGCCGTGTT

GAGCTGGCCGTGTTC

AGCTGGCCGTGTTCC

GCTGGCCGTGTTCCG

CTGGCCGTGTTCCGG

TGGCCGTGTTCCGGG

GGCCGTGTTCCGGGA

GCCGTGTTCCGGGAG

CCGTGTTCCGGGAGA

CGTGTTCCGGGAGAA

GTGTTCCGGGAGAAG

TGTTCCGGGAGAAGG

GTTCCGGGAGAAGGT

TTCCGGGAGAAGGTC

TCCGGGAGAAGGTCA

CCGGGAGAAGGTCAC

CGGGAGAAGGTCACT

GGGAGAAGGTCACTG

GGAGAAGGTCACTGA

GAGAAGGr7TCACTGAG

AGAAGGTCACTGAGC

GAAGGTCACTGAGCA

AAGGTCACTGAGCAG

AGGTCACTGAGCAGC

GGTCACTGAGCAGCA

GTCACTGAGCAGCAC

TCACTGAGCAGCACC

CACTGAGCAGCACCG

ACTGAGCAGCACCGG

CTGAGCAGCACCGGC

TGAGCAGCACCGGCA

GAGCAGCACCGGCAG

AGCAGCACCGGCAGA

GCAGCACCGGCAGAT

CAGCACCGGCAGATG

AGCACCGGCAGATGG

GCACCGGCAGATGGG

CACCGGCAGATGGGC

ACCGGCAGATGGGCA

CCGGCAGATGGGCAA

CGGCAGATGGGCAAG

GGCAGATGGGCAAGG

GCAGATGGGCAAGGG

CAGATGGGCAAGGGT

AGATGGGCAAGGGTG

GATGGGCAAGGGTGG

ATGGGCAAGGGTGGC

TGGGCAAGGGTGGCA

GGGCAAGGGTGGCAA

WO 96/01636 WO 9601636PCT/AU95/00410 22

GGCAAGGGTGGCAAC-

GCAAGGGTGGCAAG.

CAAGGGTGGCAAGCA

AAGGGTGGCAAGCAT

AGGGTGGCAAGCATC

GGGTGGCAAGCATCA

GGTGGCAAGCATCAC

GTGGCAAGCATCACC

TGGCAAGCATCACCT

GGCAAGCATCACCTT

GCAAGCATCACCTTG

CAAGCATCACCTTGG

AAGCATCACCTTGGC

AGCATCACCTTGGCC

GCATCACCTTGGCCT

CATCACCTTGGCCTG

ATCACCTTGGCCTGG

TCACCTTGGCCTGGA

CACCTTGGCCTGGAG

ACCTTGGCCTGGAGG

CCTTGGCCTGGAGGA

CTTGGCCTGGAGGAG

TTGGCCTGGAGGAGC

TGGCCTGGAGGAGCC

GGCCTGGAGGAGCCC

GCCTGGAGGAGCCCA

CCTGGAGGAGCCCAA

CTGGAGGAGCCCAAG

TGGAGGAGCCCAAGA

GGAGGAGCCCAAGAM

GAGGAGCCCAAGAA.

AGGAGCCCAAGAAC-

GGAGCCCAAGAAGCT

GAGCCCAAGAAGCTG

AGCCCAAGAAGCTGC

GCCCAAGAAGCTGCG

CCCAAGAAGCTGCGA

CCAAGAAGCTGCGAC

CAAGAAGCTGCGACC

AAGAAGCTGCGACCA

AGAAGCTGCGACCAC

GAAGCTGC.GACCACC

AAGCTGCGA.CCACCC

AGCT'GCGACCACCCC

GCTGCGACCACCCCC

CTGCGACCACCCCCT

TGCGACCACCCCCTG

GCGACCACCCCCTGC

CGACCACCCCCTGCC

GACCACCCCCTGCCA

ACCACCCCCTGCCAG

CCACCCCCTGCCAGG

CACCCCCTGCCAGGA

ACCCCCTGCCAGGAC

CCCCCTGCrAGGACT

CCCCTGCCAGGACTC

CCCTGCCAGGACTCC

CCTGCCAGGACTCCC

CTGCCAGGACTCCCT

TGCCAGGACTCCCTG

GCCAGGACTCCCTGC

CCAGGACTCCCTGCC

CAGGACTCCCTGCCA

AGGACTCCCTGCCAA

GGACTCCCTGCCAAC

GACTCCCTGCCAACA

ACTCCCTGCCAACAG

CTCCCTGCCAACAGG

TCCCTGCCAACAGGA

CCCTGCCAACAGGAA

CCTGCCAACAGGAAC

CTGCCAACAGGAACT

TGCCAACAGGAACTG

GCCAACAGGAACTGG

CCAACAGGAACTGGA

CAACAGGAACTGGAC

AACAGGAACTGGACC

ACAGGAACTGGACCA

CAGGAACTGGACCAG

AGGAACTGGACCAGG

GGAACTGGACCAGGT

GAACTGGACCAGGTC

AACTGGACCAGCOTCC

ACTGGACCAG7GTCCT

CTGGACCAGGTCCTG

TGGACCAGGTCCTGG

GGACCAGGTCCTGGA

GACCAGGTCCTGGAG

ACCAGGTCCTGGAGC

CCAGGTCCTGGAGCG

CAGGTCCTGGAGCGG

AGGTCCTGGAGCGGA

GGTCCTGGAGCGGAT

GTCCTGGAGCGGATC

TCCTGGAGCGGATCT

CCTGGAGCGGATCTC

CTGGAG CGGAT CTC C

TGGAGCGGATCTCCA

GGAGCGGATCTCCAC

GAGCGGATCTCCACC

AGCGGATCTCCACCA

GCGGATCTCCACCAT

CGGATCTCCACCATG

GGATCTCCACCATGC

GATCTCCACCATGCG

ATCTCCACCATGCGC

TCTCCACCATGCGCC

CTCCACCATGCGCCT

TCCACCATGCGCCTT

CCACCATGCGCCTTC

CACCATGCGCCTTCC

ACCATGCGCCTTCCG

CCATGCGCCTTCCGG

CATGCGCCTTCCGGA

ATG CG CCT TC CGGAT

TGCGCCTTCCGGATG

GCGCCTTCCGGATGA

CGCCTTCCGGATGAG

GCCTTCI-GGATGAGC

CCTTCCGGATGAGCG

CTTCCGGATGAGCGG

TTCCGGATGAGCGGG

TCCGGATGAGCGGGG

CCGGATGAGCGGGGC

CGGATGAGCGGGGCC

GGATGAGCGGGGCCC

GATGAGCGGGGCCCT

ATGAGCGGGGCCCTC

TGAGCGGGGCCCTCT

GAGCGGGGCCCTCTG

AGCGGGGCCCTCTGG

GCGGGGCCCTCTGGA

CGGGGCCCTCTGGAG

GGGGCCCTCTGGAGC

GGGCCCTCTGGAGCA

GGCCCTCTGGAGCAC

GCCCTCTGGAGCACC

CCCTCTGGAGCACCT

CCTCTGGAGCACCTC

CTCTGGAGCACCTCT

TCTGGAGCACCTCTA

CTGGAGCACCTCTAC

TGGAGCACCTCTACT

GGAGCACCTCTACTC

GAGCACCTCTACTCC

AGCACCTCTACTCCC

GCACCTCTACTCCCT

CACCTCTACTCCCTG

ACCTCTACTCCCTGC

CCTCTACTCCCTGCA

CTCTACTCCCTGCAC

TCTACTCCCTGCACA

CTACTCCCTGCACAT

TACTCCCTGCACATC

ACTCCCTGCACATCC

CT CCCTG CACAT C CC

TCCCTGCACATCCCC

CCCTGCACATCCCCA

CCTGCACATCCCCAA

CTGCACATCCCCAAC

TGCACATCCCCAACT

GCACATrCCCCAACTG

CACATCCCCAACTGT

ACATCCCCAACTGTG

CAT CCCCAACTGTGA

ATCCCCAACTGTGAC

TCCCCAACTGTGACA

CCCCAACTGTGACAA

WO 96101636 PTA9/01 PCT/AU95/00410 23

CCCAACTGTGACAAG

CCAACTGTGACAAGC

CAACTGTGACAAGCA

AACTGTGACAAGCAT

ACTGTGACAAGCATG

CTGTGACAAGCATGG

TGTGACAAGCATGGC

GTGACAAGCATGGCC

TGACAAGCATGGCCT

GACAAGCATGGCCTG

ACAAGC.ATGGCCTGT

CAAGCATGGCCTGTA

AAGCATGGCCTGTAC

AG CAT GG CCT ~ACA

GCATGG",CCTGTACAA

CATGGC.CTGTACAAC

ATGGCCTGTACAACC

TGGCCTGTACAACCT

GGCCTGTACAACCTC

GCCTGTACAACCTCA

CCTGTACAACCTCAA

CTGTACAACCTCAAA

TGTACAACCTCAAAC

GTACAACCTCAAACA

TACAACCTCAAACAG

ACAACCTCAAACAGT

CAACCTCAAACAGTG

AACCTCAAACAGTGC

ACCTCA1AACAGTGCA

CCTCAAACAGTGCAA

CTCA1AACAGTGCAAG

TCAAACAGTGCAAGA

CAAACAGTGCAAGAT

AAACAGTGCAAGATG

AACAGTGCAAGATGT

ACAGTGCAAGATGTC

CAGTGCAAGATGTCT

AGTGCAAGATGTCTC

GTGCAAGATGTCTC',

TGCAAGATGTCTCTG

GCAAGATGTCTCTGA

CAAGATOTCTCTGAA

AT!AGATGTCTCTGAAC

AGATGTCTCTGAACG

GATGTCTCTGAACGG

ATGTCTCTGAACGGG

TGTCTCTGAACGGGC

GTCTCTGAACGGGCA

TCTCTGAACGGGCAG

CTCTGAACGGGCAGC

TCTGAACGGGCAGCG

CTGAACGGGCAGCGT

TGAACGGGCAGCGTG

GAACGGGCAGCGTGG

AACGGGCAGCGTGGG

ACGGGCAGCGTGGGG

CGGGCAGCGTGGGGA

GGGCAGCGTGGGGAG

GGCAGCGTGGGGAGT

GCAGCGTGGGGAGTG

CAGCGTGGGGAGTGC

AGCGTGGGGAGTGCT

GCGTGGGGAGTGCTG

CGTGGGGAGTGCTGG

GTGGGGAGTGCTGGT

TGGGGAGTGCTGGTG

GGGGAGTGCTGGTGT

GGGAG7TGCTGGTGTG

GGAGTGCTGGTGTGT

GAGTGCTGGTGTGTG

AGTGCTGGTGTGTGA

GTGCTGGTGTGTGAA

TGCTGGTGTGTGAAC

GCTGGTGTGTGAACC

CTGGTGTGTGAACCC

TGGTGTGTGAACCCC

GGTGTGTGAACCCCA

GTGTGTGAACCCCAA

TGTGTGAACCCCAAC

GTGTGAACCCCAACA

TGTGAACCCCAACAC

GTGAACCCCAACACC

TGAACCCCAACACCG

GAACCCCAACACCGG

AACCCCAACACCGGG

ACCCCAACACCGGGA

CCCCAACACCGGGAA

CCCAACACCGGGAAG

CCAACACCGGGAAG

CAACACCGGGAAGCT

AACACCGGGAAGCTG

ACACCGGGAAGCTGA

CACCGGGAAGCTGAT

ACCGGGAAGCTGATC

CCGGGAAGCTGATCC

CGGGAACGCTGATCCA

GGGAAGCTGATCCAG

GGAAGCTGATCCAGG

GAAGCTGATCC-AGGG

AAGCTGATCCAGGGA

AGCTGATCCAGGGAG

GCTGATCCAGGGAGC

CTGATCCAGGGAGCC

TGATCCAGGGAG CC C

GATCCAGGGAGCCCC

ATCCAGGGAGCCCCC

TCCAGGGAGCCCCCA

CCAGGGAGCCCCCAC

CAGGGAGCCCCCACC

AGGGAGCCCCCACCA

GGGAGCCCCCACCAT

GGAGCCCCCACCATC

GAG CC C CCACCATC C AG CC C CCAC CAT CCG

GCCCCCACCATCCGG

CCCCCACCATCCGGG

CCCCACCATCCGGGG

CCCACCATCCGGGGG

CCACCATCCGGGGGG

CACCATCCGGGGGGA

ACCATCCGGGGGGAC

CCATCCGGGGGGACC

CATCCGGGGGGACCC

ATCCGGGGGGACCCC

TCCGGGGGGACCCCG

CCGGGGGGACCCCGA

CGGGGGGACCCCGAG

GGGGGGACCCCGAGT

GGGGGACCCCGAGTG

GGGGACCCCGAGTGT

GGGACCCCGAGTGTC

GGACCCCGAGTGTCA

GACCCCGAGTGTCAT

ACCCCGAGTGTCATC

CCCCGAGTGTCATCT

CCCGAGTGTC.ATCTC

CCGAGTGTCATCTCT

CGAGTGTCATCTCTT

GAGTGTCATCTCTTC

AGTGTCATCTCTTCT

GTGTCATCTCTTCTA

TGTCATCTCTTCTAC

GTCATCTCTTCTACA

TCATCTCTTCTACAA

CliTCTCTTCTACAAT

ATCTCTTCTACAATG

TCTCTTCTACAATGA

CTCTTCTACAATGAG

TCTTCTACAATGAGC

CTTCTACAATGAGCA

TTCTACAATGAGCAG

TCTACAATG-"AGCAGC

CTACAATGAGCAGCA

TACAATGAGCAGCAG

ACAATrGAGCAGCAGG

CAATGAGCAGCAGGA

AATGAGCAGCAGGAG

ATGAGCAGCAGGAGG

TGAGCAGCAGGAGGC

GAGCAGCAGGAGGCT

AGCAGCAGGAGGCTT

GCAGCAGGAGGCTTG

CAGCAGGAGGCTTGC

AGCAGGAGGCTTGCG

GCAGGAGGCTTGCGG

CAGGAGGCTTGCGGG

A'GGAGGCTTGCGGGG

GGAGGCTTGCGGGGT

WO 96101636 WO 9601636PCT/AU95/004 24

GAGGCTTGCGGGGTG

AGGCTTGCGGGGTGC

GGCTTGCGGGGTGCA

GCTTGCGGGGTGCAC

CTTGCGGGGTGCACA

TTGCGGGGTGCACAC

TGCGGGGTC4CACACC

GCGGGGTGCACACCC

CGGGGTGCACACCCA

GGGGTGCACACCCAG

GGGTGCACACCCAGC

GGTGCACACCCAGCG

GTGCACACCCAGCGG

TGCACACCCAGCGGA

GCACACCCAGCGGAT

CACACCCAGCGGATG

ACACCCAGCGGATGC

CACCCAGCGGATGCA

ACCCAGCGGATGCAG

CCCAGCGGATGCAGT

CCAGCGGATGCAGTA

CAGCGGATGCAGTAG

AGCGGATGCAGTAGA

GCGGATGCAGTAGAC

CGGATGCAGTAGACC

GGATGCAGTAGACCG

GATGCAGTAGACCGC

ATGCAGTAGACCGCA

TGCAGTAGACCGCAG

GCAGTAGACCGCAGC

CAGTAGACCGCAGCC

AGTAGACCGCAGCCA

GTAGACCGCAGCCAG

TAGACCGCAGCCAGC

AGACCGCAGCCAGCC

GACCGCAGCCAGCCG

ACCGCAGCCAGCCGG

CCGCAGCCAGCCGGT

CGCAGCCAGCCGGTG

GCAGCCAGCCGGTGC

CAGCCAGCCGGTGCC

AGCCAGCCGGTGCCT

GCCAGCCGGTGCCTG

CCAGCCGGTGCCTGG

CAGCCGGTGCCTGGC

AGCCGGTGCCTGGCG

GCCGGTGCCTGGCGC

CCGGTGCCTGGCGCC

CGGTGCCTGGCGCCC

GGTGCCTGGCGCCCC

GTGCCTGGCGCCCCT

TGCCTGGCGCCCCTG

GCCTGGCGCCCCTGC

CCTGGCGCCCCTGCC

CTGGCGCCCCTGCCC

TGGCGCCCCTGCCCC

GGCGCCCCTGCCCCC

GCGCCCCTGCCCCCC

CGCCCCTGCCCCCCG

GCCCCTGCCCCCCGC

CCCCTGCCCCCCGCC

CCCTGCCCCCCGCCC

CCTGCCCCCCGCCCC

CTGCCCCCCGCCCCT

TGCCCCCCGCCCCTC

GCr-CCCCCGCCCCTCT

CCCCCCGCCCCTCTC

CCCCCGCCCCTCTCC

CCC CGC C CCTCTC CA

CCCGCCCCTCTCCAA

C CGC C CCT CT CCAAA

CGCCCCTCTCCAAAC

GCCCCTCTCCAAACA

CCCCTCTCCAAACAC

CCCT CT CCAAACACC

CCTCTCCAAACACCG

CTCTCCAAACACCGG

TCTCCAAACACCGGC

CTCCAAACACCGGCA

TCCAAACACCGGCAG

CCAAACACCGGCAGA

CAAACACCGGCAGAA

AAACACCGGCAGAAA

AACACCGGCAGAAAA

ACACCGGCAGAAAAC

CACCGGCAGAAAACG

ACCGGCAGAAAACGG

CCGGCAGAAAACGGA

CGGCAGAAAACGGAG

GGCAGAAAACGGAGA

GCAGAAAACGGAGAG

CAGAAAACGGAGAGT

AGAAAACGGAGAGTG

GAAAACGGAGAGTGC

AAAACGGAGAGTGCT

AAACGGAGAGTGCTT

AACGGAGAGTG.CTTG

ACGGAGAGTGCTTGG

CGGAGAGTGCTTGGG

GGAGAGTGCTTGGGT

GAGAGTGCTTGGGTG

AGAGTGCTTGGGTGG

GAGTGCTTGGJ3TGGT

AGTGCTTGGGTGGTG

GTGCTTGGGTGGTGG

TGCTTGGGTGGTGGG

GCTTGGGTGGTGGGT

CTTGGGTGGTGGGTG

TTGGGTGGTGGGTGC

TGGGTGGTGGGTGCT

GGGTGGTGGGTGCTG

GGTGGTGGGTGCTGG

GTGGTGGGTGCTGGA

TGGTGGGTGCTGGAG

GGTGGGTGCTGGA.GG

GTGGGTGCTGGAGGA

TGGGTGCTGGAGGAT

GGGTGCTGGAGGATT

GGTGCTGGAGGATTT

GTGCTGGAGGATTTT

TGCTGGAGGATTTTC

GCTGGAGGATTTTCC

CTGGAGGATTTTCCA

TGGAGGATTTTCCAG

GGAGGATTTTCCAGT

GAGGATTTTCCAGTT

AGGATTTTCCAGTTC

GGATTTTCCAGTTCT

GATTTTCCAGTTCTG

ATTTTCCAGTTCTGA

TTTTCCAGTTCTGAC

TTTCCAGTTCTGACA

TTCCAGTTCTGACAC

TCCAGTLTCTGACACA

CCAGTTCTGACACAC

CAGTTCTGACACACG

AGTTCTGACACACGT

GTTCTGACACACGTA

TTCTGACACACGTAT

TCTGACACACGTATT

CTGACACACGTATTT

TGACACACGTATTTA

GACACACGTATTTAT

ACACACGTATTTATA

CACACGTATTTATAT

ACACGTP rTTATATT CACGTA"77PATATTT

ACGTATTTATATTTG

CGTATTTATATTTGG

GTATTTATATTTGGA

TATTTATATTTGGAA

ATTTATATTTGGAAA

TTTATATTTGGAAAG

TTATATTTGGA~kAGA

TATATTTGGAAAGAG

ATATTTGGAAAGAGA

TATTTGGAAAGAGAC

ATTTGGAAAGAGACC

TTTGGAAAGAGACCA

TTGGAAAGAGACCAG

TGGAAAGAGACCAGC

GGAAAGAGACCAGCA

GAAAGAGACCAGCAC

AAAGAGACCAGCACC

AAGAGACCAGCACCG

AGAGACCAGCACCGA

GAGACCAGCACCGAG

AGACCAGCACCGAGC

I

WO 96101636 WO 9/0166 CT/A'U95/00410 25

GACCAGCACCGAGCT

ACCAGCACCGAGCTC

CCAGCACCGAGCTCG

CAGCACCGAGCTCGG

AGCACCGAGCTCGGC

GCACCGAGCTCGGCA

C~fCCGAGCTCGGCAC

ACCGAGCTCGGCACC

CCGAGCTCGGCACCT

CGAGCTCGGCACCTC

GAGCTCGGCACCTCC

AGCTCGGCACCTCCC

GCTCGGCACCTCCCC

CTCGGCACCTCCCCG

TCGGCACCTCCCCGG

CGGCACCTCCCCGGC

GGCACCTCCCCGGCC

GCACCTCCCCGGCCT

CACCTCCCCGGCCTC

ACCTCCCCGGCCTCT

CCTCCCCGGCCTCTC

CTCCCCGGCCTCTCT

TCCCCGGCCTCTCTC

CCCCGGCCTCTCTCT

CCCGGCCTCTCTCTT

CCGGCCTCTCTCTTC

CGGCCTCTCTCTTCC

GGCCTCTCTCTTCCC

GCCTCTCTCTTCCCA

CCTCTCTCTTCCCAG

CTCTCTCTTCCCAGC

TCTCTCTTCCCAGCT

CT CT CTT CC CAG CTG

TCTCTTC'CCAGCTGC

CTCTTCCCAGCTGCA

TCTTCCCAGCTGCAG

CTTCCCAGCTGCAGA

TTCCCAGCTGCAGAT

TCCCAGCTGCAGATGu

CCCAGCTGCAG-ATGC

CCAGCTGCAGATGCC

CAGCTGCAGATGCCA

"%GCTGCAGATGCCAC

GCTGCAGATGCCACA

CTGCAGATGCCACAC

TGCAGATGCCACACC

GCAGATGCCACACCT

CAGATGCCACACCTG

AGATGCCACACCTGC

GATGCCACACCTGCT

ATGCCACACCTGCTC

TGCCACACCTGCTCC

GCCACACCTGCTCCT

CCACACCTGCTCCTT

CACACCTGCTCCTTC

ACACCTGCTCCTTCT

CACCTGCTCCTTCTT

AC CTG CT CCTT CTTG

CCTGCTCCTTCTTGC

CTGCTCCTTC2 TGCT TGCTCCTTCTTtCT

GCTCCTTCTTGCTTT

CTCCTTCTTGCTTTC

TCCTTCTTGCTTTCC

CCTTCTTGCTTTCCC

CTTCTTGCTTTCCCC

TTCTTGCTTTCCCCG

TCTTGCTTTCCCCGC

CTTGCTTTCCCCGGG

TTGCTTTCCCCGGGG

TGCTTTCCCCGGGGG

GCTTTCCCCGGGGGA

CTTTCCCCGGGGG;IG

TTTCCCCGGGGGAGG

TTCCCCGGGGGAGGA

TCCCCGGGGGAGGAA

CCCCGGGGGAGGAAG

CCCGGGGGAGGAAGG

CCGGGGGAGGAAGGG

CGGGGGAGGAAGGGG

GGGGGAGGAAGGGG

GGGGAGGAAGGGGGT

GGGAGGAAGGGGGTT

GGAGGAAGGGG37TTG

GAGGAAGGGGGTTGT

AGGAAGGGGGT'GTG

GGAAGGGGGTTGTGG

GAAGGGGGTTGTGGT

AA.GGGGGTTGTGGTC

AGGGGGTTGTGGTCG

GGGGGTTGTGGTCGG

GGGGTTGTGGTCGGG

GGGTTGTGGTCGGGG

GGTTGTGGTCGGGGA

GTTGTGGTCGGGG.AG

TTGTGGTCGGGGAGC

TGTGGTCGGGGAGCT

GTGGTCGGGGAGCTG

TGGTCGGGGAGCTGG

GGTCGGGGAGCTGGG

GTCGGGGAGCTGGGG

TCGGGGAGCTGGGGT

CGGGGAGCTGGGGTA

GGGGAGCTGGGGTAC

GGGAGCTGGGGTACA

GGAGCTGGGGTACAG

GAGCTGGGGTACAGG

AGCTGGGGTACAGGT

GCTGGGGTACAGGTT

CTGGGGTACAGGTTT

TGGGGTACAGGTT"rG

GGGGTACAGGTTTU~G

GGGTACAGGTTTGG

GGTACAGGTTTGGGG

GTACAGGTTTG3IGGA

TACAGGTTTGGGGAG

ACAGGTTTGGGGAGG

CAGGTTTGGGGAGGG

AGGTTTGGGGAGGGG

GGTTTGGGGAGGGGG

GTTTGGGGAGGGGGA

TTTGGGGAGGGGGAA

TTGGGGAGGGGGAAG

TGGGGAGGGGGAAGA

GGGGAGGGGGAAGAG

GGGAGGGGGAAGAGA

GGAGGGGGAAGAGAA

GAGGGGGAAGAGAAA

AGGGGGAAGAGAAAT

GGGGGAAGAGAAATT

GGGGAAGAGAAATTT

GGGAAGAGAAATTTT

GG2AGAGAAATTTTT

GAAGAGAAATTTTTA

AAGAGAAATTTTTAT

AGAGAAATrT.J2TATT

GAGAAATTTTTATTT

AGAAATTTTTATTTT

GAAATTTTTATTTTT

AAATTTTTATTTTTG

AATTTTTATTTTTGA

ATTTTTATTTTTGAA

TTTTTATTTTTGAAC

TI.TTATTTTTGAACC

TTTATTrTTTGAACCC

TTATTTTTGA'ACCCC

TATTTTTGAACCCCT

ATTTTTGAACCCCTG

TTTTTGAACCCCTGT

TTTTGAACCCCTGTG

TTTGAACCCCTGTGT

TTGAACCCCTGTGTC

TGAAC CC CTGTGTC C

GAACCCCTGTGTCCC

AACCCCTGTGTCCCT

ACCCCTGTGTCCCTT

CCCCTGTGTCCCTTT

CCCTGTGTCCCTTTT

CCTGTGTCCCTTTTG

CTGTGTCCCTTTTGC

TGTGTCCCTTTTGCA

GTGTCCCTTTTGCAT

TGTCCCTTTTGCATA

GTCCCTTTTGCATAA

TCCCTTTTGCATP kG

CCCTTTTGCATAAGA

CCTTTTGCATAAGAT

CTTTTGCATAAGATT

WO 96101636 PTA9/01 PCT/AU95/00410 26

TTTTGCATAAGATTA

TTTGCATAAGATTAA

TTGCATAAGATTAAA

TGCATAAGATTAAAG

GCATAAGATTAAAGG

CATAAGATTAAAGGA

ATAAGATTAAAGGAA

TAAGATTAAAGGAAG

AAGATTAAAGGAAGG

AGATTAAAGGAAGGA

GATTAAAGGAAGGAA

ATTAAAGGAAGGAAA

TTAAAGGAAGGAAAA

TAAAGGAAGGAAAAG

AAAGGAAGGAAAAGT

EXAMPLE 7 ANTISENSE OLIGONTJCLEOTIDES OF IGFBP3 Antisense oligonucleotides to IGFBP3 may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides:

CTCAGCGCCCAGCCG

TCAGCGCCCAGCCGC

CAGCGCCCAGCCGCT

AG CG CC CAG CCGCTT

GCGCCCAGCCGCTTC

CGCCCAGCCGCTTCC

GCCCAGCCGCTTCCT

CCCAGCCGCTTCCTG

CCAGCCGCTTCCTGC

CAGCCGCTTCCTGCC

AGCCGCTTCCTGCCT

GCCGCTTCCTGCCTG

CCGCTTCCTGCCTGG

CGCTTCCTGCCTGGA

GCTTCCTGCCTGGAT

CTTCCTGCCTGGATT

TTCCTGCCTGGATTC

TCCTGCCTGGATTCC

CCTGCCTGGATTCCA

CTGCCTGGATTCCAC

TGCCTGGATTCCACA

GCCTGGATTCCACAG

CCTGGATTCC-ACAGC

CTGGATTCCACAGCT

TGGATTCCACAGCTT

GGATTCCACAGCTTC

GATTCCACAGCTTCG

ATTCCACAGCTTCGC

TTCCACAGCTTCGCG

TCCACAGCTTCGCGC

CCACAGCTTCGCGCC

CACAGCTTCGCGCCG

ACAGCTTCGCGCCGT

CAGCTTCGCGCCGTG

AGCTTCGCGCCGTGT

GCTTCGCGCCGTGTA

CTTCGCGCCGTGTAC

TTCGCGCCGTGTACT

TCGCGCCGTGTACTG

CGCGCCGTGTACTGT

GCGCCGTGTACTGTC

CGCCGTGTACTGTCG

GCCGTGTACTGTCGC

CCGTGTACTGTCGCC

CGTGTACTGTCGCCC

GTGTACTGTCGCCCC

TGTACTGTCGCCCCA

GTACTGTCGCCCCAT

TACTGTCGCCCCATC

ACTGTCGCCCCATCC

CTGT CGC C CCATCA2

TGTCGCCCCATCCCT

GTCGCCCCATCCCTG

TCGCCCCATCCCTGC

CGCCCCATCCCTGCG

GCCCCATCCCTGCGC

CCCCATCCC rGCGCG

C%-CCATCCCTGCGCGC

CCATCCCTGCGCGCC

CATCCCTGCGCGCCC

AT CC CTGCG CGC CCA

TCCCTGCGCGCCCAG

CCCTGCGCGCCCAGC

CCTGCGCGCCCAGCC

CTGCGCGCCCAGCCT

TGCGCGCCCAGCCTG

GCGCGCCCAGCCTGC

CGCGCCCAGCCTGCC

G CG CC CAG CCTG CCA

CGCCCAGCCTGCCAA

GCCCAGCCTGCCAAG

CCCAGCCTGCCAAGC

CCAGCCTGCCAAGCA

CAGCCTGCCAAGCAG

AGCCTGCCAAGCAGC

GCCTGCCAAGCAGCG

CCTGCCAAGCAGCGT

CTGCCAAGCAGCGTG

TGCCAAGCAGCGTGC

GCCAAGCAGCGTGCC

CCAAGCAGCGTGCCC

CAAGCAG CGTG C CCC

AAGCAGCGTGCCCCG

AGCAGCGTGCCCCGG

GCAGCGTGCCCCGGT

CAGCGTGCCCCGGTT

AGCGTGCCCCGGTTG

GCGTGCCCCGGTTGC

CGTGCCCCGGTTGCA

GTGCCCCGGTTGCAG

WO 96101636 PTA9IOI PCT/AU95/00410 27

TGCCCCGGTTGCAGG

GCCCCGGTTGCAGGC

CCCCGGTTGCAGGCG

CCCGGTTGCAGGCGT

CCGGTTGCAGGCGTC

CGGTTGCAGGCGTCA

GGTTGCAGGCGTCAT

GTTGCAGGCGTCATG

TTGCAGGCGTCATGC

TGCAGGCGTCATGCA

GCAGGC'2TCATGCAG

CAGGCGTCATGCAGC

AGGCGTCATGCAGCG

GGCGTCATGCAGCGG

GCGTCATGCAGCGGG

CGTCATGCAGCGGGC

GTCATGCAGCGGGCG

TCATGCAGCGGGCGC

CATGCAGCGGGCGCG

ATGCAGCGGGCGCGA

TGCAGCGGGCGCGAC

GCAGCGGGCGCGACC

CAGCGGGCGCGACCC

AGCGGGCGCGACCCA

GCGGGCGCGACCCAC

CGGGCGCGACCCACG

GGGCGCGACCCACGC

GGCGCGACCCACGCT

GCGCGACCCACGC%"TC

CGCGACCCACGCTCT

GCGACCCACGCTCTG

CGACCCACGCTCTGG

GACCCACGCTCTGGG

ACCCACGCTCTGGGC

CCCACGCTCTGGGCC

CCACGCTCTGGGCCG

CACGCTCTGGGCCGC

ACGCTCTGGGCCGCT

CGCTCTGGGCCGCTG

GCTCTGGGCCGCTGC

CTCTGGGCCGCTGCG

TCTGGGCCGCTGCGC

CTGGGCCGCTGCGCT

TGGGCCGCTGCGCTG

GGGCCGCTGCGCTGA

GGCCGCTGCGCTGAC

GCCGCTGCGCTGACT

CCGCTGCGCTGACTC

CGCTGCGCTGACTCT

GCTGCGCTGACTCTG

CTGCGCTGACTCTGC

TGCGCTGACTCTGCT

GCGCTGACTCTGCTG

CGCTGACTCTGCTGG

GCTGACTCTGCTGGT

CTGACTCTGCTGGTG

TGACTCTGCTGGTGC

GACTCTGCTGGTGCT

ACTCTGCTGGTGCTG

CTCTGCTGGTGCTGC

TCTGCTGGTGCTGCT

CTGCTGGTGCTGCTC

TGCTGGTGCTGCTCC

GCTGGTGCTGCTCCG

CTGGTGCTGCTCCGC

TGGTGCTGCTCCGCG

GGTGCTGCTCCGCGG

GTGCTGCTCCGCGGG

TGCTGCTCCGCGGGC

GCTGCTCCGCGGGCC

CTGCTCCGCGGGCCG

TGCTCCGCGGGCCGC

GCTCCGCGGGCCGCC

CTCCGCGGGCCGCCG

TCCGCGGGCCGCC"G

CCGCGGGCCGCCGGT

CGCGGGCCGCCGGTG

GCGGGCCGCCGGTGG

CGGGCCGCCGGTGGC

GGGCCGCCGGTGGCG

GGCCGCCGGTGGCGC

GCCGCCGGTGGCGCG

CCGCCGGTGGCGCGG

CGCCGGTGGCGCGGG

GCCGGTGGCGCGGGC

CCGGTGGCGCGGGCT

CGGTGGCGCGGGCTG

GGTGGCGCGGGCTGG

GTGGCGCGGGCTGGC

TGGCGCGGGCTGGCG

GGCGCGGGCTGGCGC

GCGCGGGCTGGCGCG

CGCGGGCTGGCGCGA

GCGGGCTGGCGCGAG

CGGGCTGGCGCGAGC

GGGCTGGCGCGAGCT

GGCTGGCGCGAGCTC

GCTGGCGCGAGCTCG

CTGGCGCGAGCTCGG

TGGCGCGAGCTCGGG

GGCGCGAGCTCGGGG

GCGCGAGCTCGGGGG

CGCGAGCTCGGGGGG

GCGAGCTCGGGGGGC

CGAGCTCGGGGGGCT

GAGCTCGGGGGGCTT

AGCTCGGGGGGCTTG

GCTCGGGGGGCTTGG

CTCGGGGGGCTTGGG

TCGGGGGGCTTGGGT

CGGGGGGCTTGGGTC

GGGGGGCTTGGGTCC

GGGGGCTTGGGTCCC

GGGGCTTGGGTCCCG

GGGCTTGGGTCCCGT

GGCTT3TGGTCCCGTG

GCTTGGGTCCCGTGG

CTTGGGTCCCGTGGT

TTGGGTCCCGTGGTG

TGGGTCCCGTGGTGC

GGGTCCCGTGGTGCG

GGTCCCGTGGTGCGC

GTCCCGTGGTGCGCT

TCCCGTGGTGCGCTG

CCCGTGGTGCGCTGC

CCGTGGTGCGCTGCG

CGTGGTGCGCTGCGA

GTGGTGCGCTGCGAG

TGGTGCGCTGCGAGC

GG-TGCGCTGCGAGCC

GTGCGCTGCGAGCCG

TGCGCTGCGAGCCGT

GCGCTGCGAGCCGTG

CGCTGCGAGCCGTGC

GCTGCGAGCCGTGCG

CTGCGAGCCGTGCGAk

TGCGAGCCGTGCGAC

GCGAGCCGTGCGACG

CGAGCCGTGCGACGC

GAGCCGTGCGACGCG

AGCCGTGCGACGCGC

GCCGTGCGACGCGCG

CCGTGCGACGCGCGT

CGTGCGACGCGCGTG

GTGCGACGCGCGTGC

TGCGACGCGCGTGCA

GCGACGCGCGTGCAC

C;t CGCGCGTGCACT

GACGCGCGTGCACTG

ACGCGCGTGCACTGG

CGCGCGTGCACTGGC

GCGCGTGCACTGGCC

CGCGTGCACTGGCCC

GCGTGCACTGGCCCA

CGTGCACTGGCCCAG

GTGCACTGGCCCAGT

TGCACTGGCCCAGTG

GCACTGGCCCAGTGC

CACTGGCCCAGTGCG

ACTGGCCCAGTGCGC

CTGGCCCAGTGCGCG

TGGCCCAGTGCGCGC

GGCCCAGTGCGCGCC

GCCCAGTGCGCGCCT

CC CAGTG CGCG CCT C

CCAGTGCGCGCCTCC

CAGTGCGCGCCTCCG

AGTGCGCGCCTCCGC

I WO096101636 PTA9/01 PCT/AIJ95/00410 28

GTGCGCGCCTCCGCC

TGCGCGCCTCCGCCC

GCGCGCCTCCGCCCG

CGCGCCTCCGCCCGC

GCGCCTCCGCCCGCC

CGCCTCCGCCCGCCG

GCCTCCGCCCGCCGT

CCTCCGCCCGCCGTG

CTCCGCCCGCCGTGT

TCCGCCCGCCGTGTG

CCGCCCGCCGTGTGC

CGCCCGCCGTGTGCG

GCCCGCCGTGTGCGC

CCCGCCGTGTGCGCG

CCGCCGTGTGCGCGG

CGCCGTGTGCGCGGA

GCCGTGTGCGCGGAG

CCGTGTGCGCGGAGC

CGTGTGCGCGGAGCT

GTGTGCGCGGACCTG

TGTGCGCGGAGCTGG

GTGCGCGGAGCTGGT

TGCGCGGAGCTGGTG

GCGCGGAGCTGGTGC

CGCGGAGCTGGTGCG

GCGGAGCTGGTGCGC

CGGAGCTGGTGCGCG

GGAGCTGGTGCGCGA

GAGCTGGTGCGCGAG

AGCTGGTGCGCGAGC

GCTGGTGCGCGAGCC

CTGGTGCGCGAGCCG

TGGTGCGCGAGCCGG

GGTGCGCGAGCCGGG

GTGC"GCGAGCCGGGC

TGCGCGAGCCGGGCT

GCGCGAGCCGGGCTG

CGCGAGCCGGGCTGC

GCGAGCCGGGCTGCG

CGAGCCGGGCTGCGG

GAGCCGGGCTGCGGC

AGCCGGGCTGCGGCT

GCCGGGCTGCGGCTG

CCGGGCTGCGGCTGC

CGGGCTGCGGCTGCT

GGGCTGCGGCTGCTG

GGCTGCGGCTGCTGC

GCTGCGGCTGCTGCC

CTGCGGCTGCTGCCT

TGCGGCTGCTGCCTG

GCGGCTGCTGCCTGA

CGGCTGCTGCCTGAC

GGCTGCTGCCTGACG

GCTGCTGCCTGACGT

CTGCTGCCTGACGTG

TGCTGCCTGACGTGC

GCTGCCTGACGTGCG

CTGCCTGACGTGCGC

TGCCTGACGTGCGCA

GCCTGACGTGCGCAC

CCTGACGTGCGCACT

CTGACGTGCGCACTG

TGACGTGCGCACTGA

GACGTGCGCACTGAG

ACGTGCGCACTGAGC

CGTGCGCACTGAGCG

GTGCGCACTGAGCGA

TGCGCACTGAGCGAG

GCGCACTGAGCGAGG

CGCACTGAGCGAGGG

GCACTGAGCGAGGGC

CACTGAGCGAGGGCC

ACTGAGCGAGGGCCA

CTGAGCGAGGGCCAG

TGAGCGAGGGCCAGC

GAGCGAGGGCCAGCC

AGCGAGGGCCAGCCG

GCGAGGGCCAGCCGT

CGAGGGCCAGCCGTG

GAGGGCCAGCCGTGC

AGGGCCAGCCGTGCG

GGGCCAGCCGTGCGG

GGCCAGCCGTGCGGC

GCCAGCCGTGCGGCA

CCAGCCGTGCGGCAT

CAGCCGTGCGGCATC

AGCCGTGCGGCATCT

GCCGTGCGGCATCTA

CCGTGCGGCATCTAC

CGTGCGGCATCTACA

GTGCGG CAT CTACAC

TGCGGCATCTACACC

GCGGCATCTACACCG

CGGCATCTACACCGA

GGCATCTACACCGAG

GCATCTACACCGAGC

CATCTACACCGAGCG

ATCTACACCGAGCGC

TCTACACCGAGCGCT

CTACACCGAGCGCTG

TACACCGAGCGCTGT

ACACCGAGCGCTGTG

CACCGAGCGCTGTGG

ACCGAGCGCTGTGGC

CCGAGCGCTGTGGCT

CGAGCGCTGTGGCTC

GAGCGCTGTGGCTCC

AGCGCTGTGGCTCCG

GCGCTGTGGCTCCGG

CGCTGTGGCTCCGGC

GCTGTGGCTCCGGCC

CTGTGGCTCCGGCCT

TGTGGCTCCGGCCTT

GTGGCTCCGGCCTTC

TGGCTCCGGCCTTCG

GGCTCCGGCCTTCGC

GCTCCGGCCTTCGCT

CTCCGGCCTTCGCTG

TCCGGCCTTCGCTGC

CCGGCCTTCGCTGCC

CGGCCTTCGCTGCCA

GGCCTTCGCTGCCAG

GCCTTCGCTGCCAGC

CCTTCGCTGCCAGCC

CTTCGCTGCCAGCCG

TTCGCTGCCAGCCGT

TCGCTGCCAGCCGTC

CGCTGCCAGCCGTCG

GCTGCCAGCCGTCGC

CTGCCAGCCGTCGCC

TGCCAGCCGTCGCCC

GCCAGCCGTCGCCCG

CCAGCCGTCGCCCGA

CAGCCGTCGCCCGAC

AGCCGTCGCCCGACG

GCCGTCGCCCGACGA

C CGTCG C CCGACGAG

CGTCGCCCGACGAGG

GTCGCCCGACGAGGC

TCGCCCGACGAGGCG

CGCCCGACGAGGCGC

GCCCGACGAGGCGCG

CCCGACGAGGCGCGA

CCGACGAGGCGCGAC

CGACGAGGCGCGACC

GACGAGGCGCGACCG

ACGAGGCGCGACCGC

CGAGGCGCGACCGCT

GAGGCGCGACCGCTG

AGGCGCGACCGCTGC

GGCGCGACCGCTGCA

GCGCGACCGCTGCAG

CGCGACCGCTGCAGG

GCGACCGCTGCAGGC

CGACCGCTGCAGGCG

GACCGCTGCAGGCGC

ACCGCTGCAGGCGCT

CCGCTGCAGGCGCTG

CGCTGCAGGCGCTGC

GCTGCAGGCGCTGCT

CTGCAGGCGCTGCTG

TGCAGGCGCTGCTGG

GCAGGCGCTGCTGGA

CAGGCGCTGCTGGAC

AGGCGCTGCTGGACG

GGCGCTGCTGGACGG

GCGCTGCTGGACGGC

CGCTGCTGGACGGCC

WO 9610 1636 PTA9101 PCT/AU95/00410 29

GCTGCTGGACGGCCG

CTGCTGGACGGCCGC

TGCTGGACGGCCGCG

GCTGGACGGCCGCGG

CTGGACGGCCGCGGG

TGGACGGCCGCGGGC

GGACGGCCGCGGGCT

GACGGCCGCGGGCTC

ACGGCCGCGGGCTCT

CGGCCGCGGGCTCTG

GGCCGCGGGCTCTGC

GCCGCGGGCTCTGCG

CCGCGGGCTCTGCGT

CGCGGGCTCTGCGTC

GCGGGCTCTGCGTCA

CGGGCTCTGCGTCAA

GGGCTCTGCGTCAAC

GGCTCTGCGTCAACG

GCTCTGCGTCAACGC

CTCTGCGTCAACGCT

TCTGCGTCAACGCTA

CTGCGTCAACGCTAG

TGCGTCAACGCTAGT

GCGTCAACGCTAGTG

CGTCAACGCTAGTGC

GTCAACGCTAGTGCC

TCAACGCTAGTGCCG

CAACG-CTAGTGCCGT

AACGCTAGTGCCGTC

ACGCTAGTGCCGTCA

CGC'TAGTGCCGTCAG

GCTAiGTGCCGTCAGC CTAGTGCCGTCAGC C

TAGTGCCGTCAGCCG

AGTGCCGTCAGCCGC

GTGCCGTCAGCCGCC

TGCCGTCAGCCGCCT

GCCGTCAGCCGCCTG

CCGTCAGCCGCCTGC

CGTCAGCCGCCTGCG

GTCAGCCGCCTGCGC

TCAGCCGCCTGCGCG

CAGCCGCCTGCGCGC

AG CCG CCTG CGCGC C

GCCGCCTGCGCGCCT

C CG CCTG CGCG CCTA

CGCCTGCGCGCCTAC

GCCTGCGCGCCTACC

CCTGCGCGCCTACCT

CTGCGCGCCTACCTG

TGCGCGCCTACCTGC

GCGCGCCTACCTGCT

CGCGCCTACCTGCTG

GCGCCTACCTGCTGC

CGCCTACCTGCTGCC

GCCTACCTGCTGCCA

CCTACCTGCTGCCAG

CTACCTGCTGCCAGC

TACCTGCTGCCAGCG

ACCTGCTGCCAGCGC

CCTGCTGCCAGCGCC

CTGCTGCCAGCGCCG

TGCTGCCAGCGCCGC

GCTGCCAGCGCCGCC

CTGCCAGCGCCGCCA

TGCCAGCGCCGCCAG

GCCAGCGCCGCCAGC

CCAGCGCCGCCAGCT

CAGCGCCGCCAGCTC

AGCGCCGCCAGCTCC

GCGCCGCCAGCTCCA

CGCCGCCAGCTCCAG

GCCGCCAGCTCCAGG

CCGCCAGCTCCAGGA

CGCCAGCTCCAGGAA

GCCAGCTCCAGGAAA

CCAGCTCCAGGAAAT

CAGCTCCAGGAAATG

AGCTCCAGGAAATGC

GCTCCAGGAAATGCT

CTCCAGGAAATGCTA

TCCAGGAAATGCTAG

CCAGGAAATGCTAGT

CAGGAAATGCTAGTG

AGGAAATGCTAGTGA

GGAAATGCTAGTGAG

GAAATGCTAGTGAGT

AAATGCTAGTGAGTC

AATGCTAGTGAGTCG

ATGCTAGTGAGTCGG

TGCTAGTGAGTCGGA

GCTAGTGAGTCGGAG

CTAGTGAGTCGGAGG

TAGTGAGTCGGAGGA

AGTGAGTCGGAGGAA

GTGAGTCGGAGGAAG

TGAGTCGGAGGAAGA

GAGTCGGAGGAAGAC

AGTCGGAGGAAGACC

GTCGGAGGAAGACCG

TCGG-AGGATAGACCGC

CGGAGGAAGACCGCA

GGAGGAAGACCGCAG

GAGGAAGACCGCAGC

AGGAAGACCGCAGCG

GGAAGACCGCAGCGC

GAAGACCGCAGCGCC

AAGACCGCAGCGCCG

AGACCGCAGCGCCGG

GACCGCAGCGCCGGC

ACCGCAGCGCCGGCA

CCGCAGCGCCGGCAG

CGCAGCGCCGGCAGT

GCAGCGCCGGCAGTG

CAGCGCCGGCAGTGT

AGCGCCGGCAGTGTG

GCGCCGGCAGTGTGG

CGCCGGCAGTGTGGA

GCCGGCAGTGTGGAG

CCGGCAGTGTGGAGA

CGGCAGTGTGGAGAG

GGCAGTGTGGAGAGC

GCAGTGTGGAGAGCC

CAGTGTGGAGAGCCC

AGTGTGGAGAGCCCG

GTGTGGAGAGCCCGT

TGTGGAGAG C CCGT C

GTGGAGAGCCCGTCC

TGGAGAGCCCGTCCG

GGAGAGCCCGTCCGT

GAGAGCCCGTCCGTC

AGAGCCCGTCCGTCT

GAGCCCGTCCGTCTC

AGCCCGTCCGTCTCC

GCCCGTCCGTCTCCA

CCCGTCCGTCTCCAC-

CCGTCCGTCTCCAGC

CGTCCGTCTCCAGCA

GTCCGTCTCCAGCAC

TCCGTCTCCAGCACG

CCGTCTCCAGCACGC

CGTCTCCAGCACGCA

GTCTCCAGCACGCAC

TCTCCAGCACGCACC

CTCCAGCACGCACCG

TCCAGCACGCACCGG

CCAGCACGCACCGGG

CAGCACGCACCGGGT

AGCACGCACCGGGTG

GCACGCACCGGGTGT

CACGCACCGGGTGTC

ACGCACCGGGTGTCT

CGCACCGGGTGTCTG

GCACCGGGTGTCTGA

CACCGGGTGTCTGAT

ACCGGGTGTCTGATC

CCGGGTGTCTGATCC

CGGGTGTCTGATCCC

GGGTGTC"L2GATCCCA

GGTGTCTGATCCCAA

GTGTCTGATCCCAAG

TGTCTGATCCCAAGT

GTCTGATCCCAAGTT

TCTGATCCCAAGTTC

CTGATCCCAAGTTCC

TGATCCCAAGTTCCA

GATCCCAAGTTCCAC

ATCCCAAGTTCCACC

I WO 96/01636 PTA9/01 PCT/AU95/00410 30

TCCCAAGTTCCACCC

CCCAAGTTCCACCCC

CCAAGTTCCACCCCC

CAAGTTCCACCCCCT

AAGTTCCACCCCCTC

AGTTCCACCCCCTCC

GTTCCACCCCCTCCA

TTCCACCCCCTCCAT

T CCACC C CCT CCATT

CCACCCCCTCCATTC

CACCCCCTCCATTCA

ACCCCCTCCATTCAA

CCC CCT CCATTCAAA C CCC TC CATTCAAAG

CCCTCCATTCAAAGA

CCTCCATTCAAAGAT

CTCCATTCAAAGATA

TCCATTCAAAGATAA

CCATTCAAAGATAAT

CATTCAAAGATAATC

ATTCAAAGATAATCA

TTCAAAGATAATCAT

TCAAAGATAATCATC

CAAAGATAATCATCA

AAAGATAAT CAT CAT

AAGATAATCATCATC

AGATAATCATCATCA

GATAAT CAT CAT CAA

ATAATCATCATCAAG

TAAT CAT CAT CAAGA AAT CAT CATCAAGAA AT CAT CAT CAAGAAA

TCATCATCAAGAAAG

CAT CAT CAAGAAAGG

ATCATCAAGAAAGGG

TCATCAAGAAAGGGC

CATCAAGAAAGGGCA

ATCAAGAAAGGG CAT

TCAAGAAAGGGCATG

CAAGAAAGGGCATGC

AAGAAAGGGCATGCT

AGAAAGGGCATGCTA

GAAAGGGCATGCTAA

AAAGGGCATGCTAAA

AAGGGCATGCTAAAG

AGGGCATGCTAAAGA

GGGCATGCTAAAGAC

GGCATGCTAAAGACA

GCATGCTAAAGACAG

CATGCTAAAGACAGC

ATGCTAAAGACAGCC

TGCTAAAGACAGCCA

GCTAAAGACAGCCAG

CTAAAGACAGCCAGC

TAAAGACAGCCAGCG

AAAGACAGCCAGCGC

AAGACAGCCAGCGCT

AGACAGCCAGCGCTA

GACAGCCAGCGCTAC

ACAGCCAGCGCTACA

CAGCCAGCGCTACAA

AGCCAGCGCTACAAA

GCCAGCGCTACAAAG

CCAGCGCTACAAAGT

CAGCGCTACAAAGTT

AGCGCTACAAAGTTG

GCGCTACAAAGTTGA

CGCTACAAAGTTGAC

GCTACAAAGTTGACT

CTACAAAGTTGACTA

TACAAAGTTGACTAC

ACAAAGTTGACTACG

CAAAGTTGACTACGA

AAAGTTGACTACGAG

AAGTTGACTACGAGT

AGTTGACTACGAGTC

GTTGACTACGAGTCT

TTGACTACGAGTCTC

TGACTACGAGTCTCA

GACTACGAGTCTCAG

ACTACGAGTCTCAGA

CTACGAGTCTCAGAG

TACGAGTCTCAGAGC

ACGAGTCTCAGAGCA

CGAGTCTCAGAGCAC

GAGTCTCAGAGCACA

AGTCTCAGAGCACAG

GTCTCAGAGCACAGA

TCTCAGAGCACAGAT

CTCAGAGCACAGATA

TCAGAGCACAGATAC

CAGAGCACAGATACC

AGAGCACAGATACCC

GAG CACAGATACC CA

AGCACAGATACCCAG

GCACAGATACCCAGA

CACAGATACCCAGAA

ACAGATACCCAGAAC

CAGATACCCAGAACT

AGATACCCAGAACTT

GATACCCAGAACTTC

ATACCCAGAACTTCT

TACCCAGAACTTCTC

ACCCAGAACTTCTCC

CCCAGAACTTCTCCT

CCAGAACTTCTCCTC

CAGAACTTCTCCTCC

AGAACTTCTCCTCCG

GAACTTCTCCTCCGA

AACTTCTCCTCCGAG

ACTTCTCCTCCGAGT

CTTCTCCTCCGAGTC

TTCTCCTCCGAGTCC

TCTCCTCCGAGTCCA

CTCCTCCGAGTCCAA

TCCTCCGAGTCCAAG

CCTCCGAGTCCAAGC

CTCCGAGTCCAAGCG

TCCGAGTCCAAGCGG

CCGAGTCCAAGCGGG

CGAGTCCAAGCGGGA

GAGTCCAAGCGGGAG

AGTCCAAGCGGGAGA

GTCCAAGCGGGAGAC

TCCAAGCGGGAGACA

CCAAGCGGGAGACAG

CAAGCGGGAGACAGA

AAGCGGGAGACAGAA

AGCGGGAGACAGAAT

GCGGGAGACAGAATA

CGGGAGACAGAATAT

GGGAGACAGAATATG

GGAGACAGAATATGG

GAGACAGAATATGGT

AGACAGAATATGGTC

GACAGAATATGGTCC

ACAGAATATGGTCCC

CAGAATATGGTCCCT

AGAATATGGTCCCTG

GP.ATATGGTCCCTGC

AATATGGTCCCTGCC

ATATGGTCCCTGCCG

TATGGTCCCTGCCGT

ATGGTCCCTGCCGTA

TGGTCCCTGCCGTAG

GGTCCCTGCCGTAGA

GTCCCTGCCGTAGAG

TCCCTGCCGTAGAGA

CCCTGCCGTAGAGAA

CCTGCCGTAGAGAAA

CTGCCGTAGAGAAAT

TGCCGTAGAGAAATG

GCCGTAG.,AGAAATGG

CCGTAG;AGAAATGGA

CGTAGAGAAATGGAA

GTAGAGAAATGGAAG

TAGAGAAATGGAAGA

AGAGAAATGGAAGAC

GAGAAATGGAAGACA

AGAAATGGAAGACAC

GAAATGGAAGACACA

AAATGGAAGACACAC

AATGGAAGACACACT

ATGGAAGACACACTG

TGGAAGACACACTGA

GGAAGACACACTGAA

GAAGACACACTGAAT

AAGACACACTGAATC

WO 96/0 1636 PTA9/01 PCT/AU95/00410 31

AGACACACTGAATCA

GACACACTGAATCAC

ACACACTGAATCACC

CACACTGAATCACCT

ACACTGAATCACCTG

CACTGAATCACCTGA

ACTGAATCACCTGAA

CTrG7AATCACCTGAAG

TGAATCACCTGAAGT

GAATCACCTGAAGTT

AATCACCTG.AAGTTC

ATCACCTGAAGTTCC

TCACCTGAAGTTCCT

CACCTGAAGTTCCTC

ACCTGAAGTTCCTCA

CCTGAAGTTCCTCAA

CTGAAGTTCCTCAAT

TGAAGTTCCTCAATG

GAAGTTCCTCAATGT

AAGTTCCTCAATGTG

AGTTCCTCAATGTGC

GTTCCTCAATGTGCT

TTCCTCAATGTGCTG

TCCTCAATGTGCTGA

CCTCAATGTGCTGAG

CTCAATGTGCTGAGT

TCAATGTGCTGAGTC

CAATGTGCTGAGTCC

AATGTGCTGAGTCCC

ATGTGCTGAGTCCCA

TGTGCTGAGTCCCAG

GTGCTGAGTCCCAGG

TGCTGAGTCCCAGGG

GCTGAGTCCCAGGGG

CTGAGTCCCAGGGGT

TGAGTCCCAGGGGTG

GAGTCCCAGGGGTGT

AGTCCCAGGGGTGTA

GTCCCAGGGGTGTAC

TCCCAGGGGTGTACA

CCCAGGGGTGTACAC

CCAGGGGTGTACACA

CAGGGGTGTACACAT

AGGGGTGTACACATT

GGGGTGTACACATTC

GGGTGTACACATTCC

GGTGTACACATTCCC

GTGTACACATTCCCA

TGTACACATTCCCAA

GTACACATTCCCAAC

TACACATTCCCAACT

ACACATTCCCAACTG

CACATTCCCAACTGT

ACATTCCCAACTGTG

CATTCCCAACTGTGA

ATTCCCAACTGTGAC

TTCCCAACTGTGACA

TCCCAACTGTGACAA

CCCAACTGTGACAAG

CCAACTGTGACAAGA

CAACTGTGACAAGAA

AACTGTGACAAGAAG

ACTGTGACAAGAAGG

CTGTGACAAGAAGGG

TGTGACAAGAAGGGA

GTGACAAGAAGGGAT

TGACAAGAAGGGATT

GACAAGAAGGGATTT

ACAAGAAGGGATTTT

CAAGAAGGGATTTTA

AAGAAGGGATTTTAT

AGAAGGGATTTTATA

GAAGGGATTTTATAA

AAGGGATTTTATAAG

AGGGATTTTATAAGA

GGGATTTTATAAGAA

GGATTTTATAAGAAA

GATTTTATAAGAAAA

ATTTTATAAGAAAAA

TTTTATAAGAAAAAG

TTTATAAGAAAAAGC

TTATAA.GAAAAAGCA

TATAAGAAAAAGCAG

ATAAGAAAAAGCAGT

TAAGAAAAAGCAGTG

AAGAAAAAGCAGTGT

AGAAAAAGCAGTGTC

GAAAAAGCAGTGTCG

AAAAAGCAGTGTCGC

AAAAGCAGTGTCGCC

AAAGCAGTGTCGCCC

AAGCAGTGTCGCCCT

AGCAGTGTCGCCCTT

GCAGTGTCGCCCTTC

CAGTGTCGCCCTTCC

AGTGTCGCCCTTCCA

GTGTCGCCCTTCCAA

TGTCGCCCTTCCAAA

GTCGCCCTTCCAAAG

TCGCCCTTC'CAAAGG

CGCCCTTCCAAAGGC

GCCCTTCCAAAGGCA

CCCTTCCAAAGGCAG

CCTTCCAAAGGCAGG

CTTCCAAAGGCAGGA

TTCCAAAGGCAGGAA

TCCAAAGGCAGGAAG

CCAAAGGCAGGAAGC

CAAAGGCAGGAAGCG

AAAGGCAGGAAGCGG

AAGGCAGGAAGCGGG

AGGCAGGAAGCGGGG

GGCAGGAAGCGGGGC

GCAGGAAGCGGGGCT

CAGGAAGCGGGGCTT

AGGAAGCGGGGCTTC

GGAAGCGGGGCTTCT

GAAGCGGGGCTTCTG

AAGCGGGGCTTCTGC

AGCGGGGCTTCTGCT

GCGGGGCTTCTGCTG

CGGGGCTTCTGCTGG

GGGGCTTCTGCTGGT

GGGCTTCTGCTGGTG

GGCTTCTGCTGGTGT

GCTTCTGCTGGTGTG

CTTCTGCTGGTGTGT

TTCTGCTGGTGTGTG

TCTGCTGGTGTGTGG

CTGCTGGTGTGTGGA

TGCTGGTGTGTGGAT

GCTGGTGTGTGGATA

CTGGTGTGTGGATAA

TGGTGTGTGGATAAG

GGTGTGTGGATAAGT

GTGTGTGGATAAGTA

TGTGTGGATAAGTAT

GTGTGGATAAGTATG

TGTGGATAAGTATGG

GTGGATAAGTATGGG

TGGATAAGTATGGGC

GGATAAGTATGGGCA

GATAAGTATGGGCAG

ATAAGTATGGGCAGC

TAAGTATGGGCAGCC

AAGTATGGGCAGCCT

AGTATGGGCAGCCTC

GTATGGGCAGCCTCT

T.ATGGGCAGCCTCTC

ATGGGCAG CCT CTC C

TGGGCAGCCTCTCCC

GGGCAGCCTCTCCCA

GGCAGCCTCTCCCAG

GCAGCCTCTCCCAGG

CAGCCTCTCCCAGGC

AGCCTCTCCCAGGCT

GCCTCTCCCAGGCTA

CCTCTCCCAGGCTAC

CTCTCCCAGGCTACA

TCTCCCAGGCTACAC

CTCCCAGGCTACACC

TCCCAGGCTACACCA

CCCAGGCTACACCAC

CCAGGCTACACCACC

CAGGCTACACCACCA

AGGCTACACCACCAA

GGCTACACCACCAAG

GCTACACCACCAAGG

WO 96101636 PTA9/01 PCT/AU95/00410 32

CTACACCACCAAGGG

TACACCACCAAGGGG

ACACCACCAAGGGGA

CACCACCAAGGGGAA

ACCACCAAGGGGAAG

CCACCAAGGGGAAGG

CACCAAGGGGAAGGA

ACCAAGGGGAAGGAG

CCAAGGGGAAGGAGG

CAAGGGGAAGGAGGA

AAGGGGAAGGAGGAC

AGGGGAAGGAGGACG

GGGGAAGGAGGACGT

GGGAAGGAGGACGTG

GGAAGGAGGACGTGC

GAAGGAGGACGTGCA

AAGGAGGACGTGCAC

AGGAGGACGTGCACT

GGAGGACGTGCACTG

GAGGACGTGCACTGC

AGGACGTGCACTGCT

GGACGTGCACTGCTA

GACGTGCACTGCTAC

ACGTGCACTGCTACA

CGTGCACTGCTACAG

GTGCACTGCTACAGC

TGCACTGCTACAGCA

GCACTGCTACAGCAT

CACTGCTACAGCATG

ACTGCTACAGCATGC

CTGCTACAGCATGCA

TGCTACAGCATGCAG

GCTACAGCATGCAGA

CTACAGCATGCAGAG

TACAGCATGCAGAGC

ACAGCATGCAGAGCA

CAGCATGCAGAGCAA

AGCATGCAGAGCAAG

GCATGCAGAGCAAGT

CATGCAGAGCAAGTA

ATGCAGAGCAAGTAG

TGCAGAGCAAGTAGA

GCAGAGCAAGTAGAC

CAGAGCAAGTAGACG

AGAGCAAGTAGACGC

GAGCAPAGTAGACGCC

AGCAAGTAGACGCCT

GCAAGTAGACGCCTG

CAAGTAGACGCCTGC

AAGTAGACGCCTGCC

AGTAGACGCCTGCCG

GTAGACGCCTGCCGC

TAGACGCCTGCCGCA

AGACGCCTGCCGCAA

GACGCCTGCCGCAAG

ACGCCTGCCGCAAGT

CGCCTGCCGCAAGTT

GCCTGCCGCAAGTTA

CCTGCCGCAAGTTAA

CTGCCGCAAGTTAAT

TGCCGCAAGTTAATG

GCCGCAAGTTAAkTGT

CCGCAAGTTAATGTG

CGCAAGTTAATGTGG

GCAAGTTAATGTGGA

CAAGTTAATGTGGAG

AAGTTAATGTGGAGC

AGTTAATGTGGAGCT

GTTAATGTGGAGCTC

TTAATGTGGAGCTCA

TAATGTGGAGCTCAA

AATGTGGAGCTCAAA

ATGTGGAGCTCAAAT

TGTGGAGCTCAAATA

GTGGAGCTCAAATAT

TGGAGCTCAAATATG

GGAGCTCAAATATGC

GAGCTCAAATATGCC

AGCTCAAATATGCCT

GCTCAAATATGCCTT

CTCAAATATGCCTTA

TCAAATATGCCTTAT

CAAATATGCCTTATT

AAATATGCCTTATTT

AATATGCCTTATTTT

ATATGCCTTATTTTG

TATGCCTTATTTTGC

ATGCCTTATTTTGCA

TGCCTTATTTTGCAC

GCCTTATTTTGCACA

CCTTATTTTGCACAA

CTTATTTTGCACAAA

TTATTTTGCACAAAA

TATTTTGCACAAAAG

ATTTTGCACAAAAGA

TTTTGCACAAAAGzAC

TTTGCACAAAAGACT

TTGCACAAAAGACTG

TGCACAAAAGACTGC

GCACAAAAGACTGCC

CACAAAAGACTGCCA

ACAAAAGACTGCCAA

CAAAAGACTGCCAAG

AAAAGACTGCCAAGG

AAAGACTGCCAAGGA

AAGACTGCCAAGGAC

AGACTGCCAAGGACA

GACTGCCAAGGACAT

ACTGCCAAGGACATG

CTGCCAAGGACATGA

TGCCAAGGACATGAC

GCCAAGGACATGACC

CCAAGGACATGACCA

CAAGGACATGACCAG

AA.GGACATGACCAGC

AGGACATGACCAGCA

GGACATGACCAGCAG

GACATGACCAGCAGC

ACATGACCAGCAGCT

CATGACCAGCAGCTG

ATGACCAGCAGCTGG

TGACCAGCAGCTGGC

GACCAGCAGCTGGCT

ACCAGCAGCTGGCTA

CCAGCAGCTGGCTAC

CAGCAGCTGGCTACA

AGCAGCTGGCTACAG

GCAGCTGGCTACAGC

CAGCTGGCTACAGCC

AGCTGGCTACAGCCT

GCTGGCTACAGCCTC

CTGGCTACAGCCTCG

TGGCTACAGCCTCGA

GGCTACAGCCTCGAT

GCTACAGCCTCGATT

CTACAGCCTCGATTT

TACAGCCTCGATTTA

ACAGCCTCGATTTAT

CAGCCTCGATTTATA

AGCCTCGATTTATAT

GCCTCGATTTATATT

CCTCGATTTATATTT

CTCGATTTATATTTC

TCGATTTATATTTCT

CGATTTATATTTCTG

GATTTATATTTCTGT

ATTTATATTTCTGTT

TTTATATTTCTGTTT

TTATATTTCTGTTTG

TATATTTCTGTTTGT

ATATTTCTGTTTGT%"

TATTTCTGTTTGTGG

ATTTCTGTTTGTGGT

TTTCTGTTTGTGGTG

TTCTGTTTGTGGTGA

TCTGTTTGTGGTGAA

CTGTTTGTGGTGAAC

TGTTTGTGGTGAACT

GTTTGTGGTGAACTG

TTTGTGGTGAACTGA

TTGTGGTGAACTGAT

TGTGGTGAACTGATT

GTGGTGAACTGATTT

TGGTGAACTGATTTT

GGTGAACTGATTTTT

GTGAACTGATTTTTT

TGAACTGATTTTTTT

GAACTGATTTTTTTT

WO 96101636 PTA9/01 PCTIAU95/00410 33

AACTGATTTTTTTTA

ACTGATTTTTTTTAA

CTGATTTTTTTTA-A

TGATTTTTTTTAAAC

GATTTTTTTTAAACC

ATTTTTrTTTAAACCA

TTTTTTTTAAACCAA

TTTTTTTAAACCAAk% TTTTTTAAACCAAAG7

TTTTTAAACCAAAGT

TTTTAAACCAAAGTT

TTTAAACCAAAGTTT

TTAAACCAAAGTTTA

TAAACCAAAGTTTAG

AAA.CCAAAGTTTAGA

AACCAAAGTTTAGAA

ACCAAAGTTTAGAAA

CCAAAGTTTAGAAAG

CAAAGTTTAGAAAGA

AAAGTTTAGAAAGAG

AAGTTTAGAAAGAGG

AGTTTAGAAAGAGGT~

GTTTAGAAAGAGGTT

TTTAGAAAGAGGTTT

TTAGAAAGAGGTTTT

TAGAAAGAGGTTTTT

AGAAAGAGGTTTTTG

GAAAGAGGTTTTTGA

AAAGAGGTTTTTGAA

AAGAGGTTTTTGAAA

AGAGGTTTTTGAAAT

GAGGTTTTTGAAATG

AGGTTTTTGAAATGC

GGTTTTTGAAATGCC

GTTTTTGAAATGCCT

TTTTTGAAATGCCTA

TTTTGAAATGCCTAT

TTTGAAATGCCTATG

TTG-AAATGCCTATGG

TGAAATGCCTATGGT

GAAATGCCTATGGTT

AAATGCCTATGGTTT

AATGCCTATGGTTTC

ATGCCTATGGTTTCT

TGCCTATGGTTTCTT

GCCTATGGTTTCTTT

CCTATGGTTTCTTTG

CTATGGTT'J.'CTTTGA

TATGGTTTCTTTGAA

ATGGTTTCTTTGAAT

TGGTTTCTTTGAATG

GGTTTCTTTGAATGG

GTTTCTTTGAATGGT

TTTCTTTGAATGGTA

TTCTTTGAATGGTAA

TCTTTGAATGGTAAA

CTTTGAATGGTAAAC

TTTGAATGGTAAACT

TTGAATGGTAAACTT

TGAATGGTAAACTTG

GAATGGTAAACTTGA

AATGGTAAkACTTGAG

ATGGTAAACTTGAGC

TGGTAAACTTGAGCA

GGTAAACTTGAGCAT

GTAAACTTGAGCATC

TAAACTTGAGCATCT

AAACTTGAG CAT CTT

AACTTGAGCATCTTT

ACTTGAGCATCTTTT

CTTGAGCATCTTTTC

TTGAGCATCTTTTCA

TGAGCATCTTTTCAC

GAGCATCTTTTCACT

AGCATCTTTTCACTT

GCATCTTTTCACTTT

CATCTTTTCACTTTC

A.TCTTTTCACTTTCC

TCTTTTCACTTTCCA

CTTTTCACTTTCCAG

TTTTCACTTTCCAGT

TTTCACTTTCCAGTA

TTCACTTTCCAGTAG

TCACTTTCCAGTAGT

CACTTTCCAGTAGTC

ACTTTCCAGTAGTCA

CTTTCCAGTAGTCAG

TTTCCAGTAGTCAGC

TTCCAGTAGTCAGCA

TCCAGTAGTCAGCAA

CCAGTAGTCAGCAAA

CAGTAGTCAGCAAAG

AGTAGTCAGCAAAGA

GTAGTCAGCAAAGAG

TAGTCAGCAAAGAGC

AGTCAGCAAAGAGCA

GTCAGCAAAGAGCAG

TCAGCAAAGAGCAGT

CAGCAAAGAGCAGTT

AGCAAAGAGCAGTTT

GCAAA.GAGCAGTTTG

CAAAGAGCAGTTTGA

AAAGAGCAGTTTGAA

AAGAGCAGTTTGAAT

AGAGCAGTTTGAATT

GAGCAGTTTGAATTT

AGCAGTTTGAATTTT

GCAGTTTGAATTTTC

CAGTTTGAATTTTCT

AGTTTGAA.TTTTCTT

GTTTGAATTTTCTTG

TTTGAATTTTCTTGT

TTGAATTTTCTTGTC

TGAATTTTCTTGTCG

GAATTTTCTTGTCGC

AATTTTCTTGTCGCT

ATTTTCTTGTCGCTT

TTTTCTTGTCGCTTC

TTTCTTGTCGCTTCC

TTCTTGTCGCTTCCT

TCTTGTCGCTTCCTA

CTTGTCGCTTCCTAT

TTGTCGCTTCCTATC

TGTCGCTTCCTATCA

GTCGCTTCCTATCAA

TCGCTTCCTATCAAA

CGCTTCCTATCAAAA

GCTTCCTATCAAAAT

CTTCCTATCAAAAT."A

TTCCTATCAAAATAT

TCCTATCAAAATATT

CCTATCAAAATATTC

CTATCAAAATATTCA

TATCAAAATATTCAG

ATCAAAATATTCAGA

TCAAAATATTCAGAG

CAAAATATTCAGAGA

AAAATATTCAGAGAC

AAATATTCAGAGACT

AATATTCAGAGACTC

ATATTCAGAGACTCG

TP.TTCAGAGACTCGA

ATTCAGAGACTCGAG

TTCAGAGACTCGAGC

TCAGAGACTCGAGCA

CAGAG7ACTCGAGCAC

ACGACTCGAGCACA

GAGACTCGAGCACAG

AGACTCGAGCACAGC

GACTCGAGCACAGCA

ACTCGAGCACAGCAC

CTCGAGCACAGCACC

TCGAGCACAGCACCC

CGAGCACAGCACCCA

GAGCACAGCACCCAG,

AGCACAGCACCCAGA

GCACAGCACCCAGAC

CACAGCACCCAGACT

ACAGCACCCAGACTT

CAGCACCCAGACTTC

AGCACCCAGACTTCA

GCACCCAGA-DCTTCAT

CACCCAGACTTCATG

ACCCAGACTTCATGC

CCCAGACTTCATGCG

CCAGACTTCATGCGC

CAGACTTCATGCGCC

AGACTTCATGCGCCC

WO 96101636 PTA9101 PCT/AU95,",10410 34

GACTTCATGCGCCCG

ACTTCATGCGCCCGT

CTTCATGCGCCCGTG

'PTCATGCGCCCGTGG

TCATGCGCCCGTGGA

CATGCGCCCGTGGAA

ATGCGCCCGTGGAAT

TGCGCCCGTGGAATG

G CG C CCGTGGAATG C

CGCCCGTGGAATGCT

GCCCGTGGAATGCTC

CCCGTGGAATGCTCA

CCGTGGAATGCTCAC

CGTGGAATGCTCACC

GTGGAATGCTCACCA

TGGAATGCTCACCAC

GGAATGCTCACCACA

GAATGCTCACCACAT

AATGCTCACCACATG

ATGCTCACCACATGT

TGCTCACCACATGTT

G%7TCACCACATGTTG

CTCACCACATGTTGG

TC2ACCACATGTTGGT

CACCACATGTTGGTC

ACCACATGTTGGTCG

CCACATGTTGGTCGA

CACATGTTGGTCGAA

ACATGTTGGTCGAAG

CATGTTGGTCGAAGC

ATGTTGGTCGAAGCG

TGTTGGTCGAAGCGG

GTTGGTCGAAGCGGC

TTGGTCGAAGCGGCC

TGGTCGAAGCGGCCG

GGTCGAAGCGGCCGA

GTCGAACCGGCCGAC

TCGAAGCGGCCGACC

CGAAGCGGCCGACCA

GAAGCGGCCGACCAC

AAGCGGCCGACCACT

AGCGGCCGACCACTG

GCGGCCGACCACTGA

CGGCCGACCACTGAC

GGCCGACCACTGACT

GCCGACCACTGACTT

CCGACCACTGACTTT

CGACCACTGACTTTG

GACCACTGACTTTGT

ACCACTGACTTTGTG

CCACTGACTTTGTGA

CACTGACTTTGTGAC

ACTGACTTTGTGACT

CTGACTTTGTGACTT

TGACTTTGTGACTTA

GACTTTGTGACTTAG

ACTTTGTGACTTAGG

CTTTGTGACTTAGGC

TTTGTGACTTAGGCG

TTGTGACTTAGGCGG

TGTGACTTAGGCGGC

GTGACTTAGGCGGCT

TGACTTAGGCGGCTG

GACTTAGGCGGCTGT

ACTTAGGCGGCTGTG

CTTAGGCGGCTGTGT

TTAGGCGGCTGTGTT

TAGGCGGCTGTGTTG

AGGCGGCTGTGTTGC

GGCGGCTGTGTTGCC

GCGGCTGTGTTGCCT

CGGCTGTGTTGCCTA

GGCTGTGTTGCCTAT

GCTGTGTTGCCTATG

CTGTGTTGCCTATGT

TGTGTTGCCTATGTA

GTGTTGCCTATGTAG

TGTTGCCTATGTAGA

GTTGCCTATGTAGAG

TTGCCTATGTAGAGA

TGCCTATGTAGAGAA

GCCTATGTAGAGAAC

CCTATGTAGAGAACA

CTATGTAGAGAACAC

TATGTAGAGAACACG

ATGTAGAGAACACGC

TGTAGAGAACACGCT

GTAGAGAACACGCTT

TAGAGAACACGCTTC

AGAGAACACGCTTCA

GAGAACACGCTTCAC

AGAACACGCTTCACC

GAACACGCTTCACCC

AACACGCTTCACCCC

ACACGCTTCACCCCC

CACGCTTCACCCCCA

ACGCTTCACCCCCAC

CGCTTCACCCCCACT

GCTTCACCCCCACTC

CTTCACCCCCACTCC

TTCACCCCCACTCCC

TCACCCCCACTCCCC

CACCCCCACTCCCCG

ACCCCCACTCCCCGT

CCCCCACTCCCCGTA

CCCCACTCCCCGTAC

CCCACTCCCCGTACA

CCACTCCCCGTACAG

CACTCCCCGTACAGT

ACTCCCCGTACAGTG

CTCCCCGTACAGTGC

TCCCCGTACAGTGCG

CCCCGTACAGTGCGC

CCCGTACAGTGCGCA

CCGTACAGTGCGCAC

CGTACAGTGCGCACA

GTACAGTGCGCACAG

TACAGTGCGCACAGG

ACAGTGCGCACAGGC

CAGTGCGCACAGGCT

AGTGCGCACAGGCTT

C-TGCGCACAGGCTTT

TGCGCACAGGCTTTA

GCGCACAGGCTTTAT

CGCACAGGCTTTATC

GCACAGGCTTTATCG

CACAGGCTTTATCGA

ACAGGCTTTATCGAG

CAGGCTTTATCGAGA

AGGCTTTATCGAGAA

GGCTTTATCGAGAAT

GCTTTATCGAGAATA

CTTTATCGAGAATAG

TTTATCGAGAATAGG

TTATCGAGAATAGGA

TAT CGAGAATAGGAA

ATCGAGAATAGGAAA

TCGAGAATAGGAAAA

CGAGAATAGGAAAAC

GAGAATAGGAAAACC

AGAATAGGAAAACCT

GAATAGGAAAACCTT

AATAGGAAAACCTTT

ATAGGAAAACCTTTA

TAGGAAAACCTTTAA

AGGAAAACCTTTAAA

GGAAAA.CCTTTAAAC

GAAAACCTTTAAACC

AAAACCTTTAAACCC

AAACCTTTAAACCCC

AACCTTTAAACCCCG

ACCTTTAAACCCCGG

CCTTTAAACCCCGGT

CTTTAAACCCCGGTC

TTTAAACCCCGGTCA

TTAAACCCCGGTCAT

TAAACCCCGGTCATC

AAACCCCGGTCATCC

AACCCCGGTCATCCG

ACCCCGGTCATCCGG

CCCCGGTCATCCGGA

CCCGGTCATCCGGAC

CCGGTCATCCGGACA

CGGTCATCCGGACAT

GGTCATCCGGACATC

GTCATCCGGACATCC

TCATCCGGACATCCC

CATCCGGACATCCCA

WO 96/01636PC/9/041 PCT/AU95/00410 35

ATCCGGACATCCCAA

TCCGGACATCCCAAC

CCGGACATCCCAACG

CGGACATCCCAACGC

GGACATCCCAACGCA

GACATCCCAACGCAT

ACATCCCAACGCATG

CATCCCAACGCAPTGC

ATCCCAACGCATGCT

TCCCAACGC'"ATGCTC

CCCAACGCATGCTCC

CC-AACGCATGCTCCT

CAACGCATGCTCCTG

AACGCATGCTCCTGG

ACGCATGCTCCTGGA

CGCATGCTCCTGGzAG

GCATGCTCCTGGAGC

CATGCTCCTGGAGCT

ATGCTCCTGGAGCTC

TGCTCCTGGAGCTCA

GCTCCTGGAGCTCAC

CTCCTGGAGCTCACA

TCCTGGAGCTCACAG

CCTGGAGCTCACAGC

CTGGAGCTCACAGCC

TGGAGCTCACAGCCT

GGAGCTCACAGCCTT

GAG CT CACAG CCTTC

AGCTCACAGCCTTCT

GCTCACAGCCTTCTG

CTCACAGCCTTCTGT

TCACAGCCTTCTGTG

CACAGCCTTCTGTGG

ACAGCCTTCTGTGGT

CAGCCTTCTGTGGTG

AGCCTTCTGTGGTGT

GCCTTCTGTGGTGTC

CCTTCTGTGGTGTCA

CTTCTGTGGTGTCAT

TTCTGTGGTGTCATT

TCTGTGGTGTCATTT

CTGTGGTGTCATTTC

TGTGGTGTCATTTCT

GTGGTGTCATTTCTG

TGGTGTCATTTCTGA

GGTGTCATTTCTGAA

GTGTCATTTCTGAAA

TGTCATTTCTGAAAC

GTCATTTCTGAAACA

TCATTTCTGAAACAA

CATTTCTGAAACAAG

ATTTCTGAAACAAGG

TTTCTGAAACAAGGG

TTCTGAAACAAGGGC

TCTGAAACAAGGGCG

CTGAAACAAGGGCGT

TGA.ZACAAGGGCGTG

GAAACAAGGGCGTGG

AAACAAGGGCGTGGA

AACAAGGGCGTGGAT

ACAAGGGCGTGGATC

CAAGGGCGTGGATCC

AAGGG CGTGGAT CCC

AGGGCGTGGATCCCT

GGG CGTGGAT C CCT C

GGCGTGGATCCCTCA

GCGTGGATCCCTCAA

CGTGGATCCCTCAAC

GTGGATCCCTCAACC

TGGATCCCTCAACCA

GGAT C CCTCAAC CAA

GATCCCTCAACCAAG

ATCCCTCAACCAAGA

TCCCTCAACCAAGAA

CCCTCAACCAAGAAG

CCTCAACCAAGAAGA

CTCAACCAAGAAGAA

TCAACCAAGAAGAAT

CAACCAAGAAGAATG

AACCAAGAAGAATGT

ACCAAGAAGAATGTT

CCAAGAAGAATGTTT

CAAGAAGAATGTTTA

AAGAAGAATGTTTAT

AGAAGAATGTTTATG

GAAGAATGTTTATGT

AAGAATGTTTATGTC

AGAATGTTTATGTCT

GAATGT'ITATGTCTT

AATGTTTATGTCTTC

ATGTTTATGTCTTCA

TGTTTATGTCTTCAA

GTTTATGTCTTCAAG

TTTATGTCTTCAAGT

TTATGTCTTCAAGTG

TATGTCTTCAAGTGA

ATGTCTTCAAGTGAC

TGTCTTCAAGTGACC

GTCTTCAAGTGACCT

TCTTCAAGTGACCTG

CTTCAAGTGACCTGT

TTCAAGTGACCTGTA

TCAAGTGACCTGTAC

CAAGTGACCTGTACT

AAGTGACCTGTACTG

AGTGACCTGTACTGC

GTGACCTGTACTGCT

TGACCTGTACTGCTT

GACCTGTACTGCTTG

ACCTGTACTGCTTGG

CCTGTACTGCTTGGG

CTGTACTGCTTGGGG

TGTACTGCTTGGGGA

GTACTGCTTGGGGAC

TACTGCTTGGGGACT

ACTGCTTGGGGACTA

CTGCTTGGGGACTAT

TGCTTGGGGACTATT

GCTTGGGGACTATTG

CTTGGGGACTATTGG

TTGGGGACTATTGGA

TGGGGACTATTGGAG

GGGGACTATTGGAGA

GGGACTATTGGAGAA

GGACTATTGGAGAAA

GACTATTGGAGAAAA

ACTATTGGAGAAAAr2

CTATTGGAGAAAATA

TATTGG:AGAAAATAA

ATTGGAGAAAATAAG

TTGGAGAAAATAAGG

TGGAGAAAATAAGGT

GGAGI4AAATAAGGTG

GAGAAAATAAGGTGG

AGAAAATAAGGTGGA

GAAAATAAGGTGGAG

AAAATAAGGTGGAGT

AAATAAGGTGGAGTC

AATAAGGTGGAGTCC

ATAAGGTGGAGTCCT

TAAGGTGGAGTCCTA

AAGGTGGAGTCCTAC

AGGTGGAGTCCTACT

GGTGGAGTCCTACTT

GTGGAGTCCTACTTG

TGGAGTCCTACTTGT

GGAGTCCTACTTGTT

GAGTCCTACTTGTTT

AGTCCTACTTGTTTA

GTCCTACTTGTTTAA

TCCTACTTGTTTAAA

CCTACTTGTTTAAAA

CTACTTGTTTAAAAA

TACTTGTTTAAAAAA

ACTTGTTTAAAAAAT

CTTGTTTAAAAAATA

TTGTTTAAAAAATAT

TGTTTAAAAAATATG

GTTTAAAAAATATGI

TTTAAAAAATATGTA

TTAAAAAATATGTAT

TAAAAAATATGTATC

AAAAAATATGTATCT

AAAAATATGTATCTA

AAAATATGTATCTAA

AAATATGTATCTAAG

AATATGTATCTAAGA

ATATGTATCTAAGAA

WO 96/01636 PTA9/01 PCVAIJ95/00410 36

TATGTATCTAAGAAT

ATGTAiTCTAAGAATG

TGTATCTAAGAATGT

GTATCTAAGAATGTT

TATCTAAGAATGTTC

ATCTAAGAATGTTCT

TCTAAGAATGTTCTA

CTAAGAATGTTCTAG

TAAGAATGTTCTAGG

AAGAATGTTCTAGGG

AGAATGTTCTAGGGC

GAATGTTCTAGGGCA

AATGTTCTAGGGCAC

ATGTTCTAGGGCACT

TGTTCTAGGGCACTC

GTTCTAGGGCACTCT

TTCTAGGGCACTCTG

TCTAGGGCACTCTGG

CTAGGGCACTCTGGG

TAGGGCACTCTGGZGA

AGGGCACTCTGGGAA

GGGCACTCTGGGAAC

GGCACTCTGGGAACC

GCACTCTGGGAACCT

CACTCTGGGAACCTA

ACTCTGGGAACCTAT

CTCTGGGAACCTATA

TCTGGGAACCTATAA

CTGGGAACCTATAAA

TGGGAACCTATAAAG

GGGAACCTATAAAGG

GGAACCTATAAAGGC

GAACCTATAAAGGCA

AACCTATAAAGGCAG

ACCTATAAAGGCAGG

CCTATAAAGGCAGGT

CTATAAAGGCAGGTA

TATAAAGGCAGGTAT

ATAAAGGCAGGTATT

TAAAGGCAGGTATTT

AAAGGCAGGTATTTC

AAGGCAGGTATTTCG

AGGCAGGTATTTCGG

GGCAGGTATTTCGGG

GCAGGTATTTCGGGC

CAGGTATTTCGGGCC

AGGTATTTCGGGCCC

GGTATTTCGGGCCCT

GTATTTCGGGCC CT C

TATTTCGGGCCCTCC

ATTT CGGG CCCT CCT TTTCGGGCCCTCCT.rC

TTCGGGCCCTCCTCT

TCGGGCCCTCCTCTT

CGGGCCCTCCTCTTC

GGGCCCTCCTCTTCA

GGCCCT CCTCTTCAG

GCCCTCCTCTTCAGG

CCCTCCTCTTCAGGA

CCTCCTCTTCAGGAA

CTCCTCTTCAGGAAT

TCCTCTTCAGGAATC

CCTCTTCAGGAATCT

CTCTTCAGGAATCTT

TCTTCAGGAATCTTC

CTTCAGGAATCTTCC

TTCAGGAATCTTCCT

TCAGGAATCTTCCTG

CAGGAATCTTCCTGA

AGGAATCTTCCTGAA

GGAATCTTCCTGAAG

GAATCTTCCTGAAGA

AATCTTCCTGAAGAC

ATCTTCCTGAAGACA

TCTTCCTGAAGACAT

CTTCCTGAAGACATG

TTCCTGAAGACATGG

TCCTGAAGACATGGC

CCTGAAGACATGGCC

CTGAAGACATGGCCC

TGAAGACATGGCCCA

GAAGACATGGCCCAG

AAGACATGGCCCAGT

AGACATGGCCCAGTC

GACATGGCCCAGTCG

ACATGGCCCAGTCGA

CATGGCCCAGTCGAA

ATGGCCCAGTCGAAG

TGGCCCAGTCGAAGG

GGCCCAGTCGAAGGC

GCCCAGTCGAAGGCC

CCCAGTCGAAGGCCC

CCAGTCGAAGGCCC-A

CAGTCGAAGGCCCAG

AGTCGAAGGCCCAGG

GTCGAAGGCCCAGGA

TCGAAGGCCCAGGAT

CGAAGGCCCAGGATG

GAAGGCCCAGGATGG

AAGGCCCAGGATGGC

AGGCCCAGGATGGCT

GGCCCAGGATGGCTT

GCCCAGGATGGCTTT

CCCAGGATGGCTTTT

CCAGGATGGCTTTTG

CAGGATGGCTTTTGC

AGGATGGCTTTTGCT

GGATGGCTTTTGCTG

GATGGCTTTTGCTGC

ATGGCTTTTGCTGCG

TGGCTTTTGCTGCGG

GGCTTTTGCTGCGGC

GCTTTTGCTGCGGCC

CTTTTGCTGCGGCCC

TTTTGCTGCGGCCCC

TTTGCTGCGGCCCCG

TTGCTGCGGCCCCGT

TGCTGCGGCCCCGTG

GCTGCGGCCCCGTGG

CTGCGGCCCCGTGGG

TGCGGCCCCGTGGGG

GCGGCCCCGTGGGGT

CGGCCCCGTGGGGTA

GGCCCCGTGGGGTAG

GCCCCGTGGGGTAGG

CCCCGTGGGGTAGGA

CCCGTGGGGTAGGAG

CCGTGGGGTAGGAGG

CGTGGGGTAGGAGGG

GTGGGGTAGGAGGGA

TGGGGTAGGAGGGAC

GGGGTAGGAGGGACA

GGGTAGGAGGGACAG

GGTAGGAGGGACAGA

GTAGGAGGGACAGAG

TAGGAGGGACAGAGA

AGGAGGGACAGAGAG

GGAGGGACAGAGAGA

GAGGGACAGAGAGAC

AGGGACAGAGAGACG

GGGACAGAGAGACGG

GGACAGAGAGACGGG

GACAGAGAGACGGGA

ACAGAGAGACGGGAG

CAGAGAGACGGGAGA

AGAGAGACGGGAGAG

GAGAGACGGGAGAGT

AGAGACGGGAGAGTC

GAGACGGGAGAGTCA

AGACGGGAGAGTCAG

GACGGGAGAGTCAGC

ACGGGAGAGTCAGCC

CGGGAGAGTCAGCCT

GGGAGAGTCAGCCTC

GGAGAGTCAGCCTCC

GAGAGTCAGCCTCCA

AGAGTCAGCCTCCAC

GAGTCAGCCTCCACA

AGTCAGCCTCCACAT

GTCAGCCTCCACATT

TCAGCCTCCACATTC

CAGCCTCCACATTCA

AGCCTCCACATTCAG

GCCTCCACATTCAGA

CCTCCACATTCAGAG

CTCCACATTCAGAGG

TCCACATTCAGAGGC

CCACATTCAGAGGCA

WO 96101636 PTA9/01 PCT/AU95/00410 37

CACATTCAGAGGCAT

ACATTCAGAGGCATC

CATTCAGAGGCATCA

ATTCAGAGGCATCAC

TTCAGAGGCATCACA

TCAGAGGCATCACAA

CAGAGGCATCACAAG

AGAGGCATCACAAGT

GAGGCATCACAAGTA

AGGCATCACAAGTAA

GGCATCACAAGTAAT

GCATCACAAGTAATG

CATCACAAGTAATGG

ATCACAAGTAATGGC

TCACAAGTAATGGCA

CACAAGTAATGGCAC

ACAAGTAATGGCACA

CAAGTAATGGCACAA

AAGTAATGGCACAAT

AGTAATGGCACAATT

GTAATGGCACAA.TTC

TAATGGCACAATTCT

AATGGCACAATTCTT

ATGGCACAATTCTTC

TGGCACAATTCTTCG

GGCACAATTCTTCGG

GCACAATTCTTCGGA

CACAATTCTTCGGAT

ACAATTCTTCGGATG

CAATTCTTCGGATGA

AATTCTTCGGATGAC

ATTCTTCGGATGACT

TTCTTCGGATGACTG

TCTTCGGATGACTGC

CTTCGGATGACTGCA

TTCGGATGACTGCAG

TCGGATGACTGCAGA

CGGATGACTGCAGAA

GGATGACTGCAGAAA

GATGAC 2AGAAAA

ATGACTGCAGAAAAT

TGACTGCAGAAAATA

GACTGCAGAAAATAG

ACTGCAGAAAATAGT

CTGCAGAAAATAGTG

TGCAGAAAATAGTGT

GCAGAAAATAGTGTT

CAGAAAATAGTGTTT

AGAAAATAGTGTTTT

GAAAATAGTGTTTTG

AAAATAGTGTTTTGT

AAATAGTGTTTTGTA

AATAGTGTTTTGTAG

ki'AGTGTTTTGTAGT

TAGTGTTTTGTAGTT

AGTGTTTTGTAGTTC

GTGTTTTGTAGTTCA

TGTTTTGTAGTTCAA

GTTTTGTAGTTCAAC

TTTTGTAGTTCAACA

TTTGTAGTTCAACAA

TTGTAGTTCAACAAC

TGTAGTTCAACAACT

GTAGTTCAACAACTC

TAGTTCAACAACTCA

AGTTCAACAACTCAA

GTTCAA.CAACTCAAG

TTCAACAACTCAAGA

TCAACAACTCAAGAC

CAACAACTCAAGACG

AACAACTCAAGACGA

ACAACTCAAGACGAA

CAACTCAAGACGAAG

AACTCAAGACGAAGC

ACTCAAGACGAAGCT

CTCAAGACGAAGCTT

TCAAGACGAAGCTTA

CAAGACGAAGCTTAT

AAGACGAAGCTTATT

AGACGAAGCTTATTT

GACGAAGCTTATTTC

ACGAAGCTTATTTCT

CGAAGCTTATTTCTG

GAAGCTTATTTCTGA

AAGCTTATTTCTGAG

AGCTTATTTCTGAGG

GCTTATTTCTGAGGA

CTTATTTCTGAGGAT

TTATTTCTGAGGATA

TATTTCTGAGGATAA

ATTTCTGAGGATAA.G

TTTCTGAGGATAAGC

TTCTGAGGATAAGCT

TCTGAGGATAAGCTC

CTGAGGATAAGCTCT

TGAGGATAAGCTCTT

GAGGATAAGCTCTTT

AGGATAAGCTCTTTA

GGATAAGCTCTTTAA

GATAAGCTCTTTAAA

ATAAGCTCTTTAAAG

TAAGCTCTTTAAAGG

AAGCTCTTTAAAGGC

AGCTCTTTAAAGGCA

GCTCTTTAAAGGCAA

CTCTTTA-k!,' -GCAAA

TCTTTAAAGGCAAAG

CTTTAAAGGCAAAGC

TTTAAAGGCAAAGCT

TTAAAGGCAAAGCTT

TAAAGGCAAAGCTTT

AAAGGCAAAGCTTTA

AAGGCAAAGCTTTAT

AGGCAAAGCTTTATT

GGCAAAGCTTTATTT

GCAAAGCTTTATTTT

CAAAGCTTTATTTTC

AAAGCTTTATTTTCA

AAGCTTTATTTTCAT

AGCTTTATTTTCATC

GCTTTATTTTCATCT

CTTTATTTTCATCTC

TTTATTTTCATCTCT

TTATTTTCATCTCTC

TATTTTCATCTCTCA

ATTTTCATCTCTCAT

TTTTCATCTCTCATC

TTTCATCTCTCATCT

TTCATCTCTCATCTT

TCATCTCTCATCTTT

CATCTCTCATCTTTT

ATCTCTCATCTTTTG

TCTCTCATCTTTTGT

CTCTCATCTTTTGTC

TCTCATCTTTTGTCC

CTCATCTTTTGTCCT

TCATCTTTTGTCCTC

CATCTTTTGTCCTCC

AT CTTTTGTC CT CCT

TCTTTTGTCCTCCTT

CTTTTGTCCTCCTTA

TTTTGTCCTCCTTAG

TTTGTCCTCCTTAGC

TTGTCCTCCTTAGCA

TGTCCTCCTTAGCAC

GTCCTCCTTAGCACA

TCCTCCTTAGCACAA

CCTCCTTAGCACAAT

CTCCTTAGCACAATG

TCCTTAGCACAATGT

CCTTAGCACAATGTPA

CTTAGCACAATGTAA

TTAGCACAATGTAAA

TAGCACAATGTAPAA

AGCACAAkTGTAAAAA

GCACAATGTAAAAAA

CACAATGTAAAAAAG

ACAATGTAAAAAAGA

CAATGTAAAAAAGAA

AATGTAAAAAAGAAT

ATGTAAAAAAGAATA

TGTAAAAAAGAATAG

GTAAAAA7A.GAATAGT

TAAAAAAGAATAGTA

AAAAAAGAATAGTAA

AAAAAGAATAGTAAT

AAAAGAATAGTAATA

AAAGAATAGTAATAT

WO 96/0 1636PCA19/00 PCTiAU95/00410 38

AAGAATAGTAATATC

AGAATAGTAATATCA

GAATAGTAATATCAG

AATAGTAATATCAGA

ATAGTAATATCAGAA

TAGTAATATCAGAAC

AGTAATATCAGAACA

GTAATATCAGAACAG

TAATATCAGAACAGG

AAT.ATCAGAACAGGA

ATATCAGAACAGGAA

TATCAGAACAGGAAG

ATCAGAACAGGAAGG

TCAGAACAGGAAGGA

CAGAACAGGAAGGAG

AGAACAGGAAGGAGG

GAACAGGAAGGAGGA

AACAGGAAGGAGGAA

ACAGGAAGGAGGAAT

CAGGAAGGAGGAATG

AGGAAGGAGGAATGG

GGAAGGAGGAATGGC

GAAGGAGGAATGGCT

AAGGAGGAATGGCTT

AGGAGGAATGGCTTG

GGAGGAATGGCTTGC

GAG7GAATGGCTTGCT

AGGAATGGCTTGCTG

GGAATGGCTTGCTGG

GAATGGCTTGCTGGG

AATGGCTTGCTGGGG

ATGGCTTGCTGGGGA

TGGCTTGCTGGGGAG

GGCTTGCTGGGGAGC

GCTTGCTGGGGAGCC

CTTGCTGGGGAGCCC

TTGCTG'GGGAGCCCA

TGCTGGGGAGCC CAT

GCTGGGGAGCCCATC

CTGGGGAGCCCATCC

TGGGGAGCCCATCCA

GGGGAGCCCATCCAG

GGGAGCCCATCCAGG

GGAGCCCATCCAGGA

GAGCCCATCCAGGAC

AGCCCATCCAGGACA

GCCCATCCAGGACAC

CCCATCCAGGACACT

CCATCCAGGACACTG

CATCCAGGACACTGG

ATCCAGGACACTGGG

TCCAGGACACTGGGA

CCAGGACACTGGGAG

CAGGACACTGGGAGC

AGGACACTGGGAGCA

GGACACTGGGAGCAC

GACACTGGGAGCACA

ACACTGGGA.GCACAT

CACTGGGAGCACATA

ACTGGGAGCACATAG

CTGGGAGCACATAGA

TGGGAGCACATAGAG

GGGAGC-ACATAGAGA

GGAGCACATAGAGAT

GAGCACATAGAGATT

AGCACATAGAGATTC

GCACATAGAGATTCA

CACATAGAGATTCAC

ACATAGAGATTCACC

CATAGAGATTCACCC

ATAGAGATTCACCCA

TAGAGATTCACCCAT

AGAGATTCACCCATG

GAGATTCACCCATGT

AGATTCACCCATGTT

GATTCACCCATGTTT

ATTCACCCATGTTTG

TTCACCCATGTTTGT

TC7ACCCATGTTTGTT CA XCCATGTTTGTTG

ACCCATGTTTGTTGA

CCCATGTTTGTTGAA

CCATGTTTGTTGAAC

CATGTTTGTTGAACT

ATGTTTGTTGAACTT

TGTTTGTTGAACTTA

GTTTGTTGAACTTAG

TTTGTTGAACTTAGA

TTGTTGAACTTAGAG

TGTTGAACTTAG-AGT

GTTGAACTTAGAGTC

TTGAACTTAGAGTCA

TGAACTTAGAGTCAT

GAACTTAGAGTCATT

AACTTAGAGTCATTC

ACTTAGAGTCATTCT

CTTAGAGTCATTCTC

TTAGAGTCATTCTCA

TAGAGTCATTCTCAT

AGAGTCATTCTCATG

GAGTCATTCTCATGC

AGTCATTCTCATGCT

GTCATTCTCATGCTT

TCATTCTCATGCTTT

CATTCTCATGCTTTT

ATTCTCATGCTTTTC

TTCTCATGCTTTTCT

TCTCATGCTTTTCTT

CTCATGCTTTTCTTT

TCATGCTTTTCTTTA

CATGCTTTTCTTTAT

ATGCTmTTTCTTTATA

TGCTTTTCTTTATAA

GCTTTTCTTTATAAT

CTTTTCTTTATAATT

TTTTCTTTATAATTC

TTTCTTTATAATTCA

TTCTTTATAATTCAC

TCTTTATAATTCACA

CTTTATAATTCACAC

TTTATAATTCACACA

TTATAATTCACACAT

TATAATTCACACATA

ATAATTCACACATAT

TAATTCACACATATA

AATTCACACATATAT

ATTCACACATATATG

TTCACACATATATGC

TCACACAT.ATATGCA

CACACATATATGCAG

ACACATATATGCAGA

CACATATATGCAGAG

ACATATATGCAGAGA

CATATATGCAGAGAA

ATATATGCAGAGAAG

TATATGCAGAGAAGA

ATATGCAGAGAAGAT

TATGCAGAGAAGATA

ATGCAGAGAAGATAT

TGCAG-'AGAAGATEATG

GCAGAGAAGATATGT

CAGAGAAGATATGTT

AGAGAAGATATGTTC

GAGAAGATATGTTCT

AGAAGATATGTTCTT

GAAGATATGTTCTTG

AAGATATGTTCTTGT

AGATATGTTCTTGTT

GATATGTTCTTGTTA

ATATGTTCTTGTTAA

TATGTTCTTGTTAAC

ATGTTCTTGTTAACA

TGTTCTTGTTAACAT

GTTCTTGTTAACATT

TTCTTGTTAACATTG

TrTTGTTAACATTGT

CTTGTTAA.CATTGTA

TTGTTAACATTGTAT

TGTTAACATTGTATA

GTTAACATTGTATAC

TTAACATTGTATACA

TAACATTGTATACAA

AACATTGTATACAAC

ACATTGTATACAACA

CATTGTATACAACAT

ATTGTATACAACATA

TTGTATACAACATAG

TGTATACA.A2-ATAGC WO 96101636 WO 9601636PCT/A1J95100410 39 GTATACAACATA3GCC

TATACAACATAGCCC

ATACAACATAGCCCC

TACAACATAGCCCCA

ACAACATAGCCCCAA

CAACATAGCCCCAAA

AACATAGCCCCAAAT

ACATAGCCCCAAATA

CATAGCCCCAAATAT

ATAGCCCCAAATATA

TAG CCCCAAATATAG

AGCCCCAAATATAGT

GCCCCAAATATAGTA

CCCCAATATATAGTAA

CCCAAATATAGTAAG

CCAAATATAGTAAGA

CAAATATAGTAAGAT

AAATATAGTAAGATC

AATATAGTAAGATCT

ATATAGTAAGATCTA

TATAGTAAGATCTAT

ATAGTAAGATCTATA

TAGTAAGATCTATAC

AGTAAGATCTATACT

GTAAGATCTATACTA

TAAGATCTATACTAG

AAGATCTATACTAGA

AGATCTATACTAGAT

GATCTATACTAGATA

ATLcTATAcTAGATAA

TCTATACTAGATAAT

CTATACTAGATAATC

TATACTAGATAATCC

ATACTAGATAATCCT

TACTAGATAATCCTA

ACTAGATAATCCTAG

CTAGATAATCCTAGA

TAGATAATCCTAGAT

AGATAATCCTAGATG

GATAATCCTAGATGA

ATAATCCTAGATGA

TAATCCTAGATGAAA

AATCCTAGATGAAAT

ATCCTA07ATGAAATG

TCCTAGATGAI\ATGT

CCTAGATGAAATGTT

CTAGATGAAATGTTA

TAGATGAAATGTTAG

AGATGAA ~kTGTTAGA

GATGAAAIGTTAGAG

ATGAAATGTTAGAGA

TGAAATGTTAGAG,-AT

GAAATGTTAGAGATG

AAATGTTACAGATGC

AATGTTAGAGATGC-T

ATGTTAGAGATGCTA

TGTTAGAGATGCTAT

GTTAGAGATGCTATA

TTAGAGATGCTATAT

TAGAGATGCTATATG

AGAGATGCTATATGA

GAGATGCTATATGAT

AGATGCTATATGATA

GATGCTATATGATAC

ATGCTATATGATACA

TGCTATATGATACAA

GCTATATGATACAAC

CTATATGATACAACT

TATATGATACAACTC

ATATGATACAACTGT

TATGATIACAACTGTG

ATGATACAACTGTGG

TGATACAACTGTGGC

GATACAACTGTGGCC

ATACAACTGTGGCCA

TACAACTGTGGCCAT

ACAACTGTGGCCATG

CAACTGTGGCCATGA

AACTGTGGCCATGAC

ACTGTGGCCATCACT

CTGrGGCCATGACTG TGTGGCC-7TGACTGA

GTGGCCATGACTGAG

TGGCCATGACTGAGG

GGCCATGACTGAGGA

GCCATGACTGAGGAA

CCATGACTGAGGAAA.

CATGACTGAGGAAAG

ATGACTGAGGAAAGG

TGA"-TGAGGAAAGGA

GACTGAGGAAAGGAG

ACa"GAGGAAAGGAGC

CTGAGGAAAGGAGCT

TGAGGAAAGGAGCTC

GAGGAAAGGAGCTCA

AGGAAAGGAGCTCAC

GGAAAGGAGCTCACG

7AAAGGAGCTCACGC

AAAGGAGCTCACGCC

AAGGAGCTCACGCQC

AGGAGCTCACGCCCA

GGACCTCACGCCCAG

GAGCTCACGCCCAGA

AGCTCACGCCCAGAG

GCTCACGCCCAGAGA

CTCACGCCCAGAGAC

TCACGCCCAGAGACT

CACGCCCAGAGACTG

ACGCCCAGAGACTGG

CGCCCAGAGACTGGG

GCCCAGAGACTGGGC

CCCAGAGACTGGGCT

CCAGAGACTGGGCTG

CAGAGACi GGGCTGC

AGAGACTGGGCTGCT

GAGACTGGGCTGCTC

AGACTGGGCTGCTCT

GACTGGGCTGCTCTC

ACTGGGCTGCTCTCC

CTGGGCTGCTCTCCC

TGGGCTGCTCTCCCG

GGGCTcGCTCTCCCGG

GGCTGCTCTCCCGGA

GCTGCTCTCCCGGAG

CTGCTCTCCCGGAGG

TGCTCTjCCCGGAGGC

GCTCTCCCGGAGGCC

CTCTCCCGGAGGCCA

TCTCCCGGAGGCCAA

CTCCCGC-AGGCCAAA

TCCCGG7AGGCCAAAC CCCL3GAGGCCAAACC C CGGAGGC CAAAC CC

CGGAGGCCAAACCCA

GGAGGCCAAACCCAA

GAGGCCAAA"ZCCAAG

AGGCCAAACCCAAGA

GGCCAAACCCAAGAA

GCCAAACCCAAGALG

CCAAACCCAAGAAGG

CAAACCCAAGAAGGT

?\AACCCAAGAAGGTC

AACCCAAGAAGGTCT

ACCCAAGAAGGTCTG

CCCAA.GAi\GGTCTGG CCAAGAAG.7TCTXGGC

CAAGAAGGTCTGGCA

AAGAAGGTCTGGCAA

AGAAGGTCTGGCAAA

GAAGGTCTGGCAAAG

AAGGTCTGGCAAAGT

AGGTCTGGCAAAGTC

GGTCTGGCAAAGTCA

GTCTGGCAAAGTCAG

TCTGGCAAAGTCAGG

CTGGCAAAG.TCAGGC

TGGCAAAGTCAGGCT

GGCi.kAAGTCAGC-CTC GCAAAGTCAGGCTCrA CAAAGTCAGGCTC AG

AAAGTCAGGCTCAGG

AAGTCAGGCTCAGGG

AGTCAP.GGCTCAGGGA

GTCAGGCTCAGGGAG

TCAGGCTCAGGGAGA

CAGGCTCAGGGAGAC

AGGCTCAGGGAGACT

GGCTCAGGGAGACTC

WO 96/0 1636PTAUS041 PCr/AU95/00410 40

GCTCAGGGAGACTCT

CTCAGGGAGACTCTG

TCAGGGAGACTCTGC

CAGGGAGACTCTGCC

AGGGAGACTCTGCCC

GGGAGACTCTGCCCT

GGAGACTCTGCCCTG

GAGACTCTGCCCTGC

AGACTCTGCCCTGCT

GACTCTGCCCTGCTG

ACTCTGCCCTGCTGC

CTCTGCCCTGCTGCA

TCTGCCCTGCTGCAG

CTGCCCTGCTGCAGA

TGCCCTGCTGCAGAC

GCCCTGCTGCAGACC

CCCTGCTGCAGACCT

CCTGCTGCAGACCTC

CTGCTGCAGACCTCG

TGCTGCAGACCTCGG

GCTGCAGACCTCGGT

CTGCAGACCTCGGTG

TGCAGACCTCGGTGT

GCAGACCTCGGTGTG

CAGACCTCGGTGTGG

AGA2'CTCGGTGTGGA

GACCTCGGTGTGGAC

ACCTCGGTGTGGACA

CCTCGGTGTGGACAC

CTCGGTGTGGACACA

TCGGTGTGGACACAC

CGGTGTGGACACACG

GGTGT'JGACACACGC

GTGTGGACACACGCT

TGTGGACACACGCTG

GTGGACACACGCTGC

TGGACACACGCTGCA

GGACACACGCTGCAT

GACACACGCTGCATA

ACACACGCTGCATAG

CACACGCTGCATAGA

ACACGCTGCATAGAG

CACGCTGCATAGAGC

ACGCTGCATAGAGCT

CGCTGCATAGAGCTC

GCTGCATAGAGCTCT

CTGCATAGAGCTCTC

TGCAThkGAGCTCTCC

GCATAGAGCTCTCCT

CATAGAGCTCTCCTT

ATAGAGCTCTCCTTG

TAGAGCTCTCCTTGA

AGAGCTCTCCTTGAA

GAGCTCTCCTTGAAA

NGCTCTCCTTGAAAA

GCTCTCCTTGAAAAC

CTCTCCTTGAAAACA

TCTCCTTGAAAACAG

CTCCTTGAAAACAGA

TCCTTGAAAACAGAG

CCTTGAAAACAGAGG

CTTGAAAACAGAGGG

TTGAAAACAGAGGGG

TGAAAACAGAGGGGT

GAAAACAGAGGGGTC

AAAACAGAGGGGTCT

AAACAGAGGGGTCTC

AACAGAGGGGT CT CA

ACAGAGGGGTCTCAA

CAGAGGGGTCTCAAG

AGAGGGGTCTCAAGA

CAGGGGTCTCAAGAC

AGGGGTCTCAAGACA

GGGGTCTCAAGACAT

GGGTCTCAAGACATT

GGTCTCAAGACATTC

GTCTCAAGACATTCT

TCTCAAGACATTCTG

CTCAAGACATTCTGC

TCAAGACATTCTGCC

CAAGACATTCTGCCT

AAGACATTCTGCCTA

AGACATTCTGCCTAC

GACATTCTGCCTACC

ACATTCTGCCTACCT

CATTCTGCCTACCTA

ATTCTGCCTACCTAT

TTCTGCCTACCTATT

TCTGCCTACCTATTA

CTGCCTACCTATTAG

TGCCTACCTATTAGC

GCCTACCTATTAGCT

CCTACCTATTAGCTT

CTACCTATTAGCTTT

TACCTATTAGCTTTT

ACCTATTAGCTTTTC

CCTATTAGCTTTTCT

CTATTAGCTTTTCTT

TATTAGCTTTTCTTT

ATTAGCTTTTCTTTA

TTAGCTTTTCTTTAT

TAGCTTTTCTTTATT

AGCTTTTCTTTATTT

GCTTTTCTTTATTTT

CTTTTCTTTATTTTT

TTTTCTTTATTTTTT

TTTCTTTATTTTTTT

TTCTTTATTTTTTTA

TCTTTAT"JTTTTTAA

CTTTATTTTTTTAAC

TTTATTTTTTTAACT

TTATTTTTTTAACTT

TATTTTTTTAACTTT

ATTTTTTTAACTTTT

TTTTTTTAACTTTTT

TTTTTTAACTTTTTG

TTTTTAACTTTTTGG

TTTTAACTTTTTGGG

TTTAACTTTTTGGGG

TTAACTTTTTGGGGG

TA7kCTTTTTGGGGGG

AACTTTTTGGGGGGA

ACTTTTTGGGGGGAA

CTTTTTGGGGGGAAA

TTTTTGGGGGGAAAA

TTTTGGGGGGAAAAG

TTTGGGGGGAAAAGT

TTGGGGGGAAAAGTA

TGGGGGGAAAAGTAT

GGGGGGAAAAGTATT

GGGGGAAAAGTATTT

GGGGAAAAGTATTTT

GGGAAAAGTATTTTT

GGAAAAGTATTTTTG

GAJAAAGTATTTTTGA

AAAAGTATTTTTGAG

AAAGTATTTTTGAGA

AAGTATTTTTGAGAA

AGTATTTTTGAGAAG

GTATTTTTGAGAAGT

TATTTTTGAGAAGTT

A.CTTTTGAGAAGTTT

TTTTTGAGAAGTTTG

TTTTGAGAAGTTTGT

TTTGAGAAGTTTGTC

TTGAGAAGTTTGTCT

TGAGAAGTTTGTCTT

GAGAAGTTTGTCTTG

AGAAGTTTGTCTTGC

GAAGTTTGTCTTGCA

AAGTTTGTCTTGCAA

AGTTTGTCTTGCAAT

GTTTGTCTTGCAATG

TTTGTCTTGCAATGT

TTGTCTTGCAATGTA

TGTCTTGCAATGTAT

GTCTTGCAATGTATT

TCTTGCAATGTATTT

CTTGCAATGTATTTA

TTGCAATGTATTTAT

TGCA %TGTATTTATA

GCAATGTATTTATAA

CAATGTATTTATAAA

AATGTA\TTTATAAAT

ATG' AT rTATAAATA

TGTATTTATAAATAG

GTATTTATAAIATAGT

TATTTATAAATAGTA

IWO096101636 PCT/A1J95/00410 41

ATTTATAAATAGTAA

TTTATAAATAGTAAA

TTATAAATAGTAAAT

TATAA.ATAGTAAATA

ATAAATAGTAAATAA

TAAATAGTAAATAAA

AAATAGTAAATAAAG

AATAGTAAATAAAGT

ATAGTAAATAAAGTT

TAGTAAATAAAGTTT

AGTAAATAAAGTTTT

GTAAATAAAGTTTTT

TAAATAAAGTTTTTA

AAATAAAGTTTTTAC

AATAAAGTTTTTACC

ATAAAGTTTTTACCA

TAAAGTTTTTACCAT

AAAGTTTTTACCATT

EXAMPLE 8 ANTISENSE OLIGONUCLEOTIDES OF IGF-I RECEPTOR Antisense oligonucleotides to IGF-I may be selected from molecules capable of interacting with one or more of the following sense olig(-onucleotides:

TTTTTTTTTTTTTTG

TTTTTTTTTi.TTTTGA

TTTTTTTTTTTTGAG

TTTTTTTTTTGAGA

TTTTTTTTTTGAGAA

TTTTTTTTTGAGAAA

TTTTTTTTGAGAAAG

TTTTTTTGAGAAAGG

TTTTTTGAGAAAGGG

TTTTTGAGAAAGGGA

TTTTGAGAAAGGGAA

TTTGAGAAAGGGAAT

TTGAGAAAGGGAATT

TGAGAAAGGGAATTT

GAGAAAGGGAATTTC

AGAAAGGGAATTTCA

GAAAGGGAATTT CAT AAAGGGAATTT CAT C

AAGGGAATTTCATCC

AGGGAATTTCATCCC

GGGAATTTCATCCCA

GGAATTTCATCCCAA

GAATTTCATCCCAAA

AATTTCATCCCAAAT

ATTTCATCCCAAATA

TTTCATCCCAAATAA

TTCATCCCAAATAAA

TCATCCCAAATAAAA

CAT CCCAAATAAAAG

ATCCCAAATAAAAGG

TCCCAAATAAAAGGA

CCCAAATAAAAGGAA

C(:AAATAAAAGGAAT

CAAATAAAAGGAATG

AAATAAAAGGAATGA

AATAAAAGGAATGAA

ATAAAAGGAATGAAG

TAAAAGGAATGAAGT

AAAAGGAATGAAGTC

AAAGGAATGAAGTCT

AAGGAATGAAGTCTG

AGGAATGAAGTCTGG

GGAATGAAGTCTGGC

GAATGAAGTCTGGCT

AATGAAGTCTGGCTC

ATGAAGTCTGGCTCC

TGAAGTCTGGCTCCG

GAAGTCTGGCTCCGG

AAGTCTGGCTCCGGA

AGTCTGGCTCCGGAG

GTCTGGCTCCGGAGG

TCTGGCTCCGGAGGA

CTGGCTCCGGAGGAG

TGGCTCCGGAGGAGG

GGCTCCGGAGGAGGG

GCTCCGGAGGAGGGT

CTCCGGAGGAGGGTC

TCCGGAGGAGGGTCC

CCGGAGGAGGGTCCC

CGGAGGAGGGTCCCC

GGAGGAGGGTCCCCG

GAGGAGGGTCCCCGA

AGGAGGGTCCCCGAC

GGAGGGTCCCCGACC

GAGGGTCCCCGACCT

AGGGTCCCCGACCTC

GGGTCCCCGACCTCG

GGTCCCCGACCTCGC

GTCCCCGACCTCGCT

TCCCCGACCTCGCTG

CCCCGACCTCGCTGT

CCCGACCTCGCTGTG

CCGACCTCGCTGTGG

CGACCTCGCTGTGGG

GACCTCGCTGTGGGG

ACCTCGCTGTGGGGG

CCTCGCT'GTGGGGGC

CTCGCTGTGGGGGCT

TCGCTGTGGGGGCTC

CGCTGTGGGGGCTCC

GCTGTGGGGGCTCCT

WO 96/01636 PTA9/01 PCT/AU95/00410 42

CTGTGGGGGCTCCTG

TGTGGGGGCTCCTGT

GTGGGGGCTCCTGTT

TGGGGGCTCCTGTTT

GGGGGCTCCTGTTTC

GGGGCTCCTGTTTCT

GGGCTCCTGTTTCTC

GGCTCCTGTTTCTCT

GCTCCTGTTTCTCTC

CTCCTGTTTCTCTCC

TCCTGTTTCTCTCCG

CCTGTTTCTCTCCGC

CTGTTTCTCTCCGCC

TGTTTCTCTCCGCCG

GTTTCTCTCCGCCGC

TTTCTCTCCGCCGCG

TTCTCTCCGCCGCGC

TCTCTCCGCCGCGCT

CTCTCCGCCGCGCTC

TCTCCGCCGCGCTCT

CTCCGCCGCGCTCTC

TCCGCCGCGCTCTCG

CCGCCGCGCTCTCGC

CGCCGCGCTCTCGCT

GCCGCGCTCTCGCTC

CCGCGCTCTCGCTCT

CGCGCTCTCGCTCTG

GCGCTCTCGCTCTGG

CGCTCTCGCTCTGGC

GCTCTCGCTCTGGCC

CTCTCGCTCTGGCCG

TCTCGCTCTGGCCGA

CTCGCTCTGGCCGAC

TCGCTCTGGCCGACG

CGCTCTGGC2CGACGA

GCTCTGGCCGACGAG

CTCTGGCCGACGAGT

TCTGGCCGACGAGTG

CTGGCCGACGAGTGG

TGGCCGACGAGTGGA

GGCCGACGAGTGGAG

GCCGACGAGTGGAGA

CCGACGAGTGGAGAA

CGACGAGTGGAGAAA

GACGAGTGGAGAAAT

ACGAGTGGAGAAATC

CGAGTGGAGAAATCT

GAGTGGAGAAATCTG

AGTGGAGAAATCTGC

GTGGAGAAATCTGCG

TGGAGAAATCTGCGG

GGAGAAATCTGCGGG

GAGAA' 2-,CTGCGGGC Ar-~ %.TGCGGGCC Gi-ATCTGCGGGCCA

AAATCTGCGGGCCAG

AATCTGCGGGCCAGG

ATCTGCGGGCCAGGC

TCTGCGGGCCAGGCA

CTGCGGGCCAGGCAT

TGCGGGCCAGGCATC

GCGGGCCAGGCATCG

CGGGCCAGGCATCGA

GGGCCAGGCATCGAC

GGCCAGGCATCGACA

GCCAGGCATCGACAT

CCAGGCATCGACATC

CAGGCATCGACATCC

AGGCATCGACATCCG

GGCATCGACATCCGC

GCATCGACATCCGCA

CATCGACATCCGCAA

ATCGACATCCGCAAC

TCGACATCCGCAACG

CGACATCCGCAACGA

GACATCCGCAACGAC

ACATCCGCAACGACT

CATCCGCAACGACTA

ATCCGCAACGACTAT

TCCGCAACGACTATC

CCGCAACGACTATCA

CGCAACGACTATCAG

GCAACGACTATCAGC

CAACGACTATCAGCA

AACGACTATCAGCAG

ACGACTATCAGCAGC

CGACTATCAGCAGCT

GACTATCAGCAGCTG

ACTATCAGCAGCTGA

CTATCAGCAGCTGAA

TATCAGCAGCTGAAG

ATCAGCAGCTGAAGC

TCAGCAGCTGAAGCG

CAGCAGCTGAAGCGC

AGCAGCTGAAGCGCC

GCAGCTGAAGCGCCT

CAGCTGAAGCGCCTG

AGCTGAAGCGCCTGG

GCTGAAGCGCCTGGA

CTGAAGCGCCTGGAG

TGAAGCGCCTGGAGA

GAAGCGCCTGGAGAA

AAGCGCCTGGAGAAC

AGCGCCTGGAGAACT

GCGCCTGGAGAACTG

CGCCTGGAGAACTGC

GCCTGGAGAACTGCA

CCTGGAGAACTGCAC

CTGGAGAACTGCACG

TGGAGAACTGCACGG

GGAGAACTGCACGGT

GAGAACTGCACGGTG

AGAACTGCACGGTGA

GAACTGCACGGTGAT

AACTGCACGGTGATC

ACTGCACGGTGATCG

CTGCACGGTGATCGA

TGCACGGTGATCGAG

GCACGGTGATCGAGG

CACGGTGATCGAGGG

ACGGTGATCGAGGGC

CGGTGATCGAGGGCT

GGTGATCGAGGGCTA

GTGATCGAGGGCTAC

TGATCGAGGGCTACC

GATCGAGGGCTACCT

ATCGAGGGCTACCTC

TCGAGGGCTACCTCC

CGAGGGCTACCTCCA

GAGGGCTACCTCCAC

AGGGCTACCTCCACA

GGGCTACCTCCACAT

GGCTACCTCCACATC

GCTACCTCCACATCC

CTAC CT CCACAT CCT

TACCTCCACATCCTG

ACCTCCACATCCTGC

CCTCCACATCCTGCT

CTCCACATCCTGCTC

TCCACATCCTGCTCA

CCACATCCTGCTCAT

CACATCCTGCTCATC

ACATCCTGCTCATCT

CATCCTGCTCATCTC

AT CCTGCTCATCTCC

TCCTGCTCATCTCCA

CCTGCTCATCTCCAA

CTGCTCATCTCCAAG

TG CTCAT CT CCAAGG

GCTCATCTCCAAGGC

CTCATCTCCAAGGCC

TCATCTCCAAGGCCG

CATCTCCAAGGCCGA

ATCTCCAAGGCCGAG

TCTCCAAGGCCGAGG

CTCCAAGGCCGAGGA

TCCAAGGCCGAGGAC

CCAAGGCCGAGGACT

CAAGGCCGAGGACTA

AAGGCCGAGGACTAC

AGGCCGAGGACTACC

GGCCGAGGACTACCG

GCCGAGGACTACCGC

CCGAGGACTACCGCA

CGAGGACTACCGCAG

GAGGACTACCGCAGC

AGGACTACCGCAGCT

GGACTACCGCAGCTA

WO 96101636 CJU/040 PCI7.tAkU95/00410 43

GACTACCGCAGCTAC

ACTACCGCAGCTACC

CTACCGCAGCTACCG

TACCGCAGCTACCGC

ACCGCAGCTACCGCT

CCGCAGCTACCGCTT

CGCAGCTACCGCTTC

GCAGCTACCGCTTCC

CAGCTACCGCTTCCC

AGCTACCGCTTCCCC

GCTACCGCTTCCCCA

CTACCGCTTCCCCAA

TACCGCTTCCCCAAG

ACCGCTTCCCCAAGC

CCGCTTCCCCAAGCT

CG CTT CC CCAAG CT C

GCTTCCCCAAGCTCA

CTTCCCCAAGCTCAC

TTCCCCAAGCTCACG

TCCCCAAGCTCACGG

CCCCAAGCTCACGGT

CCCAAGCTCACGGTC

CCAAGCTCACGGTCA

CAAGCTCACGGTCAT

AAGCTCACGGTCATT

AGCTCACGGTCATTA

GCTCACGGTCATTAC

CTCACGGTCATTACC

TCACGGTCATTACCG

CACGGTCATTACCGA

ACGGTCATTACCGAG

CGGTCATTACCGAGT

GGTCATTACCGAGTA

GTCATTACCGAGTAC

TCATTACCGAGTACT

CATTACCGAGTACTT

ATTACCGAGTACTTG

TI ACCGAGTACTTGC TACCr-GAGTACTTGCT

ACCGAGTACTTGCTG

CCGAGTACTTGCTGC

CGAGTACTTGCTGCT

GAGTACTTGCTGCTG

AGTACTTGCTGCTGT

GTACTTGCTGCTGTT

TACTTGCTGCTGTTC

ACTTGCTGCTGTTCC

CTTGCTGCTGTTCCG

TTGCTGCTGTTCCGA

TGCTGCTGTTCCGAG

GCTGCTGTTCCGAGT

CTGCTGTTCCGAGTG

TGCTGTTCCGAGTGG

GCTGTTCCGAGTGGC

CTGTTCCGAG-TGGCT

TGTTCCGAGTGGCTG

GTTCCGAGTGGCTGG

TTCCGAGTGGCTGGC

TCCGAGTGGCTGGCC

CCGAGTGGCTGGCCT

CGAGTGGCTGGCCTC

GAGTGGCTGGCCTCG

AGTGGCTGGCCTCGA

GTGGCTGGCCTCGAG

TGGCTGGCCTCGAGA

GGCTGGCCTCGAGAG

GCTGGCCTCGAGAGC

CTGGCCTCGAGAGCC

TGGCCTCGAGAGCCT

GGCCTCGAGAGCCTC

GCCTCGAGAGCCTCG

CCTCGAGAGCCTCGG

CTCGAGAGCCTCGGA

TCGAGAGCCTCGGAG

CGAGAGCCTCGGAGA

GAGAGCCTCGGAGAC

AGAGCCTCGGAGACC

GAGCCTCGGAGACCT

AGCCTCGGAGACCTC

GCCTCGGAGACCTCT

CCTCGGAGACCTCTT

CTCGGAGACCTCTTC

TCGGAGACCTCTTCC

CGGAGACCTCTTCCC

GGAGACCTCTTCCCC

GAGACCTCTTCCCCA

AGACCTCTTCCCCAA

GACCTCTTCCCCAAC

ACCTCTTCCCCAACC

CCTCTTCCCCAACCT

CTCTTCCCCAACCTC

TCTTCCCCAACCTCA

CTTCCCCAACCTCAC

TTCCCCAACCTCACG

TCCCCAACCTCACGG

CCCCAACCTCACGGT

CCCAACCTCACGG'LC

CCAACCTCACGGTCA

CAACCTCACGGTCAT

AACCTCACGGTCATC

ACCTCACGGTCATCC

CCTCACGGTCATCCG

CTCACGGTCATCCGC

TCACGGTCATCCGCG

CACGGTCATCCGCGG

ACGGTCATCCGCGGC

CGGTCATCCGCGGCT

GGTCATCCGCGGCTG

GTCATCCGCGGCTGG

TCATCCGCGGCTGGA

CATCCGCGGCTGGAA

ATCCGCGGCTGGAAA

TCCGCGGCTGG.XAAC

CCGCGGCTGGAAACT

CGCGGCTGGAAACTC

GCGGCTGGAAACTCT

CGGCTGGAAACTCTT

GGCTGGAAACTCTTC

GCTGGAAACTCTTCT

CTGGAAACTCTTCTA

TGGAAACTCTTCTAC

GGAAACTCTTCTACA

GAAACTCTTCTACAA

AAACTCTTCTACAAC

AACTCTTCTACAACT

ACTCTTCTACAACTA

CTCTTCTACAACTAC

TCTTCTACAACTACG

CTTCTACAACTACGC

TTCTACAACTACGCC

TCTACAACTACGCCC

CTACAACTACGCCCT

TACAACTACGCCCTG

ACAACTACGCCCTGG

CAACTACGCCCTGGT

AACTNCGCCCTGGTC

ACTACGCCCTGGTCA

CTACGCCCTGGTCAT

TACGCCCTGGTCATC

ACGCCCTGGTCATCT

CGCCCTGGTCATCTT

GCCCTGGTCATCTTC

CCCTGGTCATCTTCG

CCTGGTCATCTTCGA

CTGGTCATCTT'CGAG

TGGTCATCTTCGAGA

GGTCATCTTCGAGAT

GTCATCTTCGAGATG

TCATCTTCGAGATGA

CATCTTCGAGATGAC

ATCTTCGAGATGACC

TCTTCGAGATGACCA

CTTCGAGATGACCAA

TTCGAGATGACCAAT

TCGAGATGACCAATC

CGAGATGACCAATCT

GAGATGACCAATCTC

AGATGACCAATCTCA

GATGACCAATCTCAA

ATGACCAATCTCAAG

TGACCAATCTCAAGG

GACCAATCTCAAGGA

ACCAATCTCAAGGAT

CCAATCTCAAGGATA

CAPJTCTCAAGGATAT

AATCTCAAGGATATT

ATCTCAAGGATATTG

TCTCAAGGATATTGG

WO 96101636 PTA9/01 PCT/AU95/00410 44

CTCAAGGATATTGGG

TCAAGGATATTGGGC

CAAGGATATTGGGCT

AAGGATATTGGGCTT

AGGATATTGGGCTTT

GGATATTGGGCTTTA

GATATTGGGCTTTAC

ATATTGGGCTTTACA

TATTGGGCTTTACAA

ATTGGGCTTTACAAC

TTGGGCTTTACAACC

TGGGCTTTACAACCT

GGGCTTTACAACCTG

GGCTTTACAACCTGA

GCTTTACAACCTGAG

CTTTACAACCTGAGG

TTTAU.AACCTGAGGA

TTACAACCTGAGGAA

TACAACCTGAGGAAC

ACAACCTGAGGAACA

CAACCTGAGGAACAT

AACCTGAGGAACATT

ACCTGAGGAACATTA

CCTGAGGAACATTAC

CTGAGGAACATTACT

TGAGGAACATTACTC

GAGGAACATTACTCG

AGGAACATTACTCGG

GGAACATTACTCGGG

GAACATTACTCGGGG

AACATTACTCGGGGG

ACATTACTCGGGGGG

CATTACTCGGGGGGC

ATTACTCGGGGGGCC

TTACTCGGGGGGCCA

TACTCGGGGGGCCAT

ACTCGGGGGGCCATC

CTCGGGGGGCCATCA

TCGGGGGGCCATCAG

CGGGGGGCCATCAGG

GGGGGGCCATCAGGA

GGGGGCCATCAGGAT

GGGGCCATCAGGATT

GGGCCATCAGGATTG

GG-CCATCAGGATTGA

GCCATCAGGATTGAG

CCATCAGGATTGAGA

CATCAGGATTGAGAA

ATCAGGATTGAGAAA

TCAGGATTGAGAAAA

CAGGATTGAGAAAAA

AGGATTGAGAAAAAT

GGATTGAGAAAAATG

GATTGAGAAAAATGC

ATTGAGAAAAATGCT

TTGAGAAAAATGCTG

TGAGAAAAATGCTGA

GAGAAAAATGCTGAC

AGAAAAATGCTGACC

GAAAAATGCTGACCT

.AAAAATGCTGACCTC

AAAATGCTGACCTCT

AAATGCTGACCTCTG

AATGCTGACCTCTGT

ATGCTGACCTCTGTT

TGCTGACCTCTGTTA

GCTGACCTCTGTTAC

CTGACCTCTGTTACC

TGACCTCTGTTACCT

GACCTCTGTTACCTC

ACCTCTGTTACCTCT

CCTCTGTTACCTCTC

CTCTGTTACCTCTCC

TCTGTTACCTCTCCA

CTGTTACCTCTCCAC

TGTTACCTCTCCACT

GTTACCI CTCCACTG

TTACCTCTCCACTGT

TACCTCTCCACTGTG

AL'CTCTCCACTGTGG

CCTCTCCACTGTGGA

CTCTCCACTGTGGAC

TCTCCACTGTGGACT

CTCCACTGTGGACTG

TCCACTGTGGACTGG

CCACTGTGGACTGGT

CACTGTGGACTGGTC

ACTGTGGACTGGTCC

CTGTGGACTGGT CC C

TGTGGACTGGTCCCT

GTGGACTGGTCCCTG

TGGACTGGTCCCTGA

GGACTGGTCCCTGAT

GACTGGTCCCTGATC

ACTGGTCCCTGATCC

CTGGTCCCTGATCCT

TGGTCCCTGATCCTG

GGTCCCTGATCCTGG

GTCCCTGATCCTGGA

TCCCTGATCCTGGAT

CCCTGATCCTGGATG

CCTGATCCTGGATGC

CTGATCCTGGATGCG

TGATCCTGGATGCGG

GATCCTGGATGCGGT

ATCCTGGATGCGGTG

TCCTGGATGCGGTGT

CCTGGATGCGGTGTC

CTGGATGCGGTGTCC

TGGATGCGGTGTCCA

GGATGCGGTGTCCAA

GATGCGGTGTCCAAT

ATGCGGTGTCCAATA

TGCGGTGTCCAATAA

GCGGTGTCCAATAAC

CGGTGTCCAATAACT

GGTGTCCAATAACTA

GTGTCCAATAACTAC

TGTCCAATAACTACA

GTCCAP.TAACTACAT

TCCAATAACTACATT

CCAATAACTACATTG

CAATAACTACATTGT

AATAACTACATTGTG

ATAACTACATTGTGG

TAACTACATTGTGGG

AACTACATTGTGGGG

ACTACATTGTGGGGA

CTACATTGTGGGGAA

TACATTGTGGGGAAT

ACATTGTGGGGAATfA

CATTGTGGGGAATAA

ATTGTGGGGAATAAG

TTGTGGGGAATAAGC

TGTGGGGAATAAGCC

GTGGGGAATAAGCCC

TGGGGAATAAGCCCC

GGGGAATAAGCCCCC

GGGAATAAGCCCCCA

GGAATAAGCCCCCAA

GAATAAGCCCCCAAA

AATAAGCCCCCAAAG

ATAAGCCCCCAAAGG

TAAGCCCCCAAAGGA

AAGCCCCCAAAGGAA

AGCCCCCAAAGGAAT

GCCCCCAAAGGAATG

CCCCCAAAGGAATGT

CCCCAAAGGAATGTG

CCCAAAGGAATGTGG

CCAAAGGAATGTGGG

CAAAGGAATGTGGGG

AAAGGAATGTGGGGA

AAGGAATGTGGGGAC

AGGAATGTGGGGACC

GGAATGTGGGGACCT

GAATGTGGGGACCTG

AATGTGGGGACCTGT

ATGTGGGGACCTGTG

TGTGGGGACCTGTGT

GTGGGGACCTGTGTC

TGGGGACCTGTGTCC

GGGGACCTGTGTCCA

GGGACCTGTGTCCAG

GGACCTGTGTCCAGG

GACCTGTGTCCAGGG

ACCTGTGTCCAGGGA

CCTGTGTCCAGGGAC

WO096/01636 PTA9101 PC17AU95100410 45

CTGTGTCCAGGG.ACC

TGTGTCCAGGGACCA

GTGTCCAGGGACCAT

TGTCCAGGGACCATG

GTCCAGGGACCATGG

TCCAGGGACCATGGA

CCAGGGACCATGGAG

CAGGGACCATGGAGG

AGGGACCATGGAGGA

GGGACCATGGAGGAG

GGACCATGGAGGAGA

GACCATGGAGGAGAA

ACCATGGAGGAGAAG

CCATGGAGGAGAAGC

CATGGAGGAGAAGCC

ATGGAGGAGAAGCCG

TGGAGGAGAAGCCGA

GGAGGAGAAGCCGAT

GAGGAGAAGCCGATG

AGGAGAAGCCGATGT

GGAGAAGCCGATGTG

GAGAAGCCGATGTGT

AGAAGCCGATGTGTG

GAAGCCGATGTGTGA

AAGCCGATGTGTGAG

AGCCGATGTGTGAGA

GCCGATGTGTIGAGAA

CCGATGTGTfiAGAAG

CGATGTGTGAGAAGA

GATGTGTGAGAAGAC

ATGTGTGAGAAGACC

TGTGTGAGAAGACCA

GTGTGAGAAGACCAC

TGTGAGAAGACCACC

GTGAGAAGACCACCA

TGAGAAGACCACCAT

GAGAAGACCACCATC

AGAAGACCACCATCA

GAAGACCACCATCAA

AAGAccAc CAT CAAC

AGACCACCATCAACA

GACCACCATCAACAA

ACCACCATCAACAAT

CCACCATCAACAATG

CACCATCAACAATGA

ACCATCAACAATGAG

CCATCAACAATGAGT

CATCAACAATGAGTA

ATCAACAATGAGTIC'

TCAACAATGAGTACA

CAACAATGAGTACAA

AACAATGAGTACAAC

ACAATGAGTACAACT

CAATGAGTACAACTA

AATGAGTACAACTAC

ATGAGTACAACTACC

TGAGTACAACTACCG

GAGTACAACTACCGC

AGTACAACTACCGCT

GTACAACTACCGCTG

TACAACTACCGCTGC

ACA.ACTACCGCTGCT

CAACTACCGCTGCTG

AACTACCGCTGCTGG

ACTACCGCTGCTGGA

CTACCGCTCCTGGAC

TACCGCTGCTGGACC

ACCGCTGCTGGACCA

CCGCTGCTGGACCAC

CGCTGCTGGACCACA

GCTGCTGGACCACAA

CTGCTGGACCACAAA

TGCTGGACCACAAAC

GCTGGACCACAAACC

CTGGACCACAAACCG

TGGACCACAAACCGC

GGACCACAAACCGCT

GACCACAAACCGCTG

ACCACAAACCGCTGC

CCACAAACCGCTGCC

CACAAACCGCTGCCA

ACAAACCGCTGCCAG

CAAACCGCTGCCAGA

AAACCGCTGCCAGA

AACCGCTGCCAGAAA

ACCGCTC'CCAGAAAA

CCGCTGCCAGAAAAT

CGCTGCCAGAAAATG

GCTGCCAGAAAATGT

CTGCCAGAAAATGTG

TGCCAGAAAATGTGC

GCCAGAAAATGTGCC

CCAGAAAATGTGCCC

CAGAAAATGTGCCCA

AGAAAATGTGCCCAA

GAAAATGTGCCCAAG

AAAATGTGCCCAAGC

AAATGTGCCCAAGCA

AATGTGCCCAAGCAC

ATGTGCCCAAGCACG

TGTGCCCAAGCACGT

GTGCCCAAGCACGTG

TGCCCAAGCACGTGT

GCCCAAGCACGTGTG

CCCAAGCACGTGTGG

CCAAGCACGTGTGGG

CAAGCACGTGTGGGA

AAGCACGTGTGGGAA

AGCACGTGTGGGA7IG

GCACGTGTGGGAAGC

CACGTGTGGGAAGCG

ACGTGTGGGAAGCGG

CGTGTGGGAAGCGGG

GTGTGGGAAGCGGGC

TGTGGGAAGCGGGCG

GTGGG.AAGCGGGCGT

TGGGAAGCGGGCGTG

GGGAAGCGGGCGTGC

GGAAGCGGGCGTGCA

GAAGCGGGCGTGCAC

AAGCGGGCGTGCACC

AGCGGGCGTGCACCG

GCGGGCGTGCACCGA

CGGGCGTGCACCGAG

GGGCGTGCACCGAGA

GGCGTGCACCGAGAA

GCGTGCACCGAGAAC

CGTGCACCGAGAACA

GTGCACCGAGAACAA

TGCACCGAGAACAAT

GCACCGAGAACAATG

CACCGAGAACAATGA

ACCGAGAACAATGAG

CCGAGAACAATGAGT

CGAGAACAATGAGTG

GAGAACAATGAGTGC

AGAACAATGAGTGCT

GAACAATGAGTGCTG

AACAATGAGTGCTGC

ACAATGAGTGCTGCC

CAATGAGTGCTGCCA

AATGAGTGCTGCCAC

ATGAGTGCTGCCACC

TGAGTGCTGCCACCC

GAGTGCTGCCACCCC

AGTGCTGCCACCCCG

GTGCTGCCACCCCGA

TGCTGCCACCCCGAG

GCTGCCACCCCGAGT

CTGCCACCCCGAGTG

TGCCACCCCGAGTGC

GCCACCCCGAGTGCC

CCACCCCGAGTGCCT

CACCCCGAGTGCCTG

ACCCCGAGTGCCTGG

CCC CGAGTGC CTGGG

CCCGAGTGCCTGGGC

CCGAGTGCCTGGGCA

CGAGTGCCTGGGCAG

GAGTGCCTGGGCAGC

AGTGCCTGGGCAGCT

GTGCCTGGGCAGCTG

TGCCTGGGCAGCTGC

GCCTGGGCAGCTGCA

CCTGGGCAGCTGCAG

CTGGGCAGCTGCAGC

TGGGCAGCTGCAGCG

GGGCAGCTGCAGCGC

WO 96/01636 PTA9/01 PCTIAI]95/00410 46

GGCAGCTGCAGCGCG

GCAGCTGCAGCGCGC

CAGCTGCAGCGCGCC

AGCTGCAGCGCGCCT

GCTGCAGCGCGCCTG

CTGCAGCGCGCCTGA

TGCAGCGCGCCTGAC

GCAGCGCGCCTGACA

CAGCGCGCCTGACAA

AGCGCC-CCTGACAAC

GCGCGCCTGACAACG

CGCGCCTGACAACGA

GCGCCTGACAACGAC

CGCCTGACAACGACA

GCCTGACAACGACAC

CCTGACAACGACACG

CTGACAACGACACGG

TGACAACGACACGGC

GACAACGACACGGCC

ACAACGACACGGCCT

CAACGACACGGCCTG

AACGACACGGCCTGT

ACGACACGGCCTGTG

CGACACGGCCTGTGT

GACACGGCCTGTGTA

ACACGGCCTGTGTAG

CACGGCCTGTGTAGC

ACGGCCTGTGTAGCT

CGGCCTGTGTAGCTT

GGCCTGTGTAGCTTG

GCCTGTGTAGCTTGC

C CTGTGTAG CTTGC C

CTGTGTAGCTTGCCG

TGTGTAGCTTGCCGC

GTGTAGCTTGCCGCC

TGTAGCTTGCCGCCA

GTAGCTTGCCGCCAC

TAGCTTGCCGCCACT

AGCTTGCCGCCACTA

GCTTGCCGCCACTAC

CTTGCCGCCACTACT

TTGCCGCCACTACTA

TGCCGCCACTACTAC

GCCGCCACTACTACT

CCGCCACTACTACTA

CGCCACTACTACTAT

GCCACTACTACTATG

CCAC'TACTACTATGC

CACTACTACTATGCC

ACTACTACTATGCCG

CTACTACTATGCCGG

TACTACTATGCCGGT

ACTACTATGCCGGTG

CTACTATGCCGGTGT

TACTATGCCGGTGTC

ACTATGCCGGTGTCT

CTATGCCGGTGTCTG

TATGCCGGTGTCTGT

ATGCCGGTGTCTGTG

TGCCGGTGTCTGTGT

GCCGGTGTCTGTGTG

CCGGTGTCTGTGTGC

CGGTGTCTGTGTGCC

GGTGTCTGTGTGCCT

GTGTCTGTGTGCCTG

TGTCTGTGTGCCTGC

GTCTGTGTGCCTGCC

TCTGTGTGCCTGCCT

CTGTGTGCCTGCCTG

TGTGTGCCTGCCTGC

GTGTGCCTGCCTGCC

TGTGCCTGCCTGCCC

GTGCCTGCCTGCCCG

TGCCTGCCTGCCCGC

GCCTGCCTGCCCGCC

CCTGCCTGCCCGCCC

CTGCCTGCCCGCCCA

TGC CTG C CCG CCCAA

GCCTGCCCGCCCAAC

CCTGCCCGCCCAACA

CTGCCCGCCCAACAC

TGCCCGCCCAACACC

GCCCGCCCAACACCT

CCCGCCCAACACCTA

CCGCCCAACACCTAC

CGCCCAACACCTACA

GCCCAACACCTACAG

CCCAACACCTACAGG

CCAACACCTACAGGT

CAACACCTACAGGTT

AACACCTACAGGTTT

ACACCTACAGGTTTG

CACCTACAGGTTTGA

ACCTACAGGTTTGAG

CCTACAGGTTTGAGG

CTACAGGTTTGAGGG

TACAGGTTTGAGGGC

ACAGGTTTGAGGGCT

CAGGTTTGAGGGCTG

AGGTTTGAGGGCTGG

GGTTTGAGGGCTGGC

GTTTGAGGGCTGGCG

TTTGAGGGCTGGCGC

TTGAGGGCTGGCGCT

TGAGGGCTGGCGCTG

GAGGGCTGGCGCTGT

AGGGCTGGCGCTGTG

GGGCTGGCGCTGTGT

GGCTGGCGCTGTGTG

GCTGGCGCTGTGTGG

CTGGCGCTGTGTGGA

TGGCGCTGTGTGGAC

GGCGCTGTGTGGACC

GCGCTGTGTGGACCG

CGCTGTGTGGACCGT

GCTGTGTGGACCGTG

CTGTGTGGACCGTGA

TGTGTGGACCGTGAC

GTGTGGACCGTGACT

TGTGGACCGTGACTT

GTGGACCGTGACTTC

TGGACCGTGACTTCT

GGACCGTGACTTCTG

GACCGTGACTTCTGC

ACCGTGACTTCTGCG

CCGTGACTTCTGCGC

CGTGACTTCTGCGCC

GTGACTTCTGCGCCA

TGACTTCTGCGCCAA

GACTTCTGCGCCAAC

ACTTCTGCGCCAACA

CTTCTGCGCCAACAT

TTCTGCGCCAACATC

TCTGCGCCAACATCC

CTG CG CCAACAT CCT

TGCGCCAACATCCTC

GCGCCAACATCCTCA

CGCCAACATCCTCAG

GCCAACATCCTCAGC

CCAACATCCTCAGCG

CAACATCCTCAGCGC

AACATCCTCAGCGCC

ACATCCTCAGCGCCG

CATCCTCAGCGCCGA

ATCCTCAGCGCCGAG

TCCTCAGCGCCGAGA

CCTCAGCGCCGAGAG

CT CAG CG CCGAGAGCC

TCAGCGCCGAGAGCA

CAGCGCCGAGAGCAG

AGCGCCGAGAGCAGC

GCGCCGAGAGCAGCG

CGCCGAGAGCAGCGA

GCCGAGAGCAGCGAC

CCGAGAGCAGCGACT

CGAGAGCAGCGACTC

GAGAGCAGCGACTCC

AGAGCAGCGACTCCG

GAGCAGCGACTCCGA

AGCAGCGACTCCGAG

GCAGCGACTCCGAGG

CAGCGACTCCGAGGG

AGCGACTCCGAGGGG

GCGACTCCGAGGGGT

CGACTCCGAGGGGTT

GACTCCGAGGGGTTT

ACTCCGAGGGGTTTG

CTCCGAGGGGTTTGT

WO 96101636 PCT/AU95/004WL 47

TCCGAGGGGTTTGTG

CCGAGGGGTTTGTGA

CGAGGGGTTTGTGAT

GAGGGGTTTGTGATC

AGGGGTTTGTGATCC

GGGGTTTGTGATCCA

GGGTTTGTGATCCAC

GGTTTGTGATCCACG

GTTTGTGATCCACGA

TTTGTGATCCACGAC

TTGTGATCCACGACG

TGTGATCCACGACGG

GTGATCCACGACGGC

TGATCCACGACGGCG

GATCCACGACGGCGA

A.TCCACGACGGCGAG

TCCACGACGGCGAGT

CCACGACGGCGAGTG

CACGACGGCGAGTGC

ACGACGGCGAGTGCA

CGACGGCGAGTGCAT

GACGGCGAGTGCATG

ACGGCGAGTGCATGC

CGGCGAGTGCATGCA

GGCGAGTGCATGCAG

GCGAGTGCATGCAGG

CGAGTGCATGCAGGA

GAGTGCATGCAGGAG

AGTGCATGCAGGAGT

GTGCATGCAGGAGTG

TGCATGCAGGAGTGC

GCATGCAGGAGTGCC

CATGCAGGAGTGCCC

ATGCAGGAGTGCCCC

TGCAGGAGTGCCCCT

GCAGGAGTGCCCCTC

CAGGAGTGCCCCTCG

AGGAGTGCCCCTCGG

GGAGTGCCCCTCGGG

GAGTGCCCCTCGGGC

AGTGCCCCTCGGGCT

GTGCCCCTCGGGCTT

TGCCCCTCGGGCTTC

GCCCCTCGGGCTTCA

CCCCTCGGGCTTCAT

CCCTCGGGCTTCATC

CCTCGGGCTTCATCC

CTCGGGCTTCATCCG

TCGGGCTTCATCCGC

CGGGCTTCATCCGCA

GGGCTTCATCCGCAA

GGCTTCATCCGCAAC

GCTTCATCCGCAACG

CTTCATCCGCAACGG

TTCATCCGCAACGGC

TCATCCGCAACGGCA

CATCCGCAACGGCAG

ATCCGCAACGGCAGC

TCCGCAACGGCAGCC

CCGCAAC2-GCAGCCA

CGCAACGGCAGCCAG

GCAACGGCAGCCAGA

CAACGGCAGCCAGAG

AACGGCAGCCAGAGC

ACGGCAGCCAGAGCA

CGGCAGCCAGAGCAT

GGCAGCCAGAGCATG

GCAGCCAGAGCATGT

CAGCCAGAGCATGTA

AGCCAGAGCATGTAC

GCCAGAGCATGTACT

CCAGAGCATGTACTG

CAGAGCATGTACTGC

AGAGCATGTACTGCA

GAGCATGTACTGCAT

AGCATGTACTGCATC

GCATGTACTGCATCC

CATGTACTGCATCCC

ATGTACTGCATCCCT

TGTACTGCATCCCTT

GTACTGCATCCCTTG

TACTGCATCCCTTGT

ACTGCATCCCTTGTG

CTGCATCCCTTGTGA

TGCATCCCTTGTGAA

G CAT C CCTTGTGAAG

CATCCCTTGTGAAGG

ATCCCTTGTGAAGGT

TCCCTTGTGAAGGTC

CCCTTGTGAAGGTCC

CCTTGTGAAGGTCCT

CTTGTGAAGGTCCTT

TTGTGAAGGTCCTTG

TGTGAAGGTCCTTGC

GTGAAGGTCCTTGCC

TGAAGGTC CTTG CCC

GAAGGTCCTTGCCCG

AAGGTCCTTGCCCGA

AGGTCCTTGCCCGAA

GGTCCTTGCCCGAAG

GTCCTTGCCCGAAGG

TCCTTGCCCGAAGGT

CCTTGCCCGAAGGTC

CTTGCCCGAAGGTCT

TTGCCCGAAGGTCTG

TGCCCGAAGGTCTGT

GCCCGAAGGTCTGTG

CCCGAAGGTCTGTGA

CCGAAGGTCTGTGAG

CGAAGGTCTGTGAGG

GAAGGTCTGTGAGGA

AAGGTCTGTGAGGAA

AGGTCTGTGAGGAAG

GGTCTGTGAGGAAGA

GTCTGTGAGGAAGAA

TCTGTGAGGAAGAAA

CTGTGAGGAAGAAAA

TGTGAGGAAGAAAAG

GTGAGGAAGAAAAGA

TGAGGAAGAAAAGAA

GAGGAAGAAAAGAAA

AGGAAGAAAAGAAAA

GGAAGAAAAGAAAAC

GAAGAAAAGAAAACA

AAGAAAAGAAAACAA

AGAAAAGAAAACAAA

GAAAAGAAAACAAAG

AAAAGAAAACAAAGA

AAAGAAAACAAAGAC

AAGAAAACAAAGACC

AGAAAACAA7AGACCA GAAAACAAAGAC CAT

AAAACAAAGACCATT

AAACAAAGACCATTG

AACAAAGACCATTGA

ACAAAGACCATTGAT

CAAAGACCATTGATT

AAAGACCATTGATTC

AAGACCATTGATTCT

AGACCATTGATTCTG

GACCATTGATTCTGT

ACCATTGATTCTGTT

CCATTGATTCTGTTA

CATTGATTCTGTTAC

ATTGATTCTGTTACT

TTGATTCTGTTACTT

TGATTCTGTTACTTC

GATTCTGTTACTTCT

ATTCTGTTACTTCTG

TTCTGTTACTTCTGC

TCTGTTACTTCTGCT

CTGTTACTTCTGCTC

TGTTACTTCTGCTCA

GTTACTTCTGCTCAG

TTACTTCTGCTCAGA

TACTTCTGCTCAGAT

ACTTCTGCTCAGATG

CTTCTGCTCAGATGC

TTCTGCTCAGATGCT

TCTGCTCAGATGCTC

CTGCTCAGATGCTCC

TGCTCAGATGCTCCA

GCTCAGATGCTCCAA

CTCAGATGCTCCAAG

TCAGATGCTCCAAGG

CAGATGCTCCAAGGA

AGATGCTCCAAGGAT

GATGCTCCAAGGATG

l PCT/AU95/0041 0 I WO 96/01636 48

ATGCTCCAAGGATGC

TGCTCCAAGGATGCA

GCTCCAAGGATGCAC

CTCCAAGGATGCACC

TCCAAGGATGCACCA

CCAAGGATGCACCAT

CAAGGATGCACCATC

AAGGATGCACCATCT

AGGATGCACCATCTT

GGATGCACCATCTTC

GATGCACCATCTTCA

ATGCACCATCTTCAA

TGCACCATCTTCAAG

GCACCATCTTCAAGG

CACCATCTTCAAGGG

ACCATCTTCAAGGGC

CCATCTTCAAGGGCA

CATCTTCAAGGGCAA

ATCTTCAAGGGCAAT

TCTTCAAGGGCAATT

CTTCAAGGGCAATTT

TTCAAGGGCAATTTG

TCAAGGGCAATTTGC

CAAGGGCAATTTGCT

AAGGGCAATTTGCTC

AGGGCAATTTGCTCA

GGGCAATTTGCTCAT

GGCAATTTGCTCATT

GCAATTTGCTCATTA

CAATTTGCTCATTAA

AATTTGCTCATTAAC

ATTTGCTCATTAACA

TTTGCTCATTAACAT

TTGCTCATTAACATC

TGCTCATTAACATCC

GCTCAT."TAACATCCG

CTCATTAACATCCGA

TCATTAACATCCGAC

CATTAACATCCGACG

ATTAACATCCGACGG

TTAACATCCGACGGG

TAACATCCGACGGGG

AACATCCGACGGGGG

ACATCCGACGGGGGA

CATCCGACGGGGGAA

ATCCGACGGGGGAAT

TCCGACGGGGGAATA

CCGACGGGGGAATAA

CGACGGGGGAATAAC

GACGGGGGAATAACA

ACGGGGGAATAACAT

CGGGGGAATAACATT

GGGGGAATAACATTG

GGGGAATAACATTGC

GGGAATAACATTGCT

GGAATAACATTGCTT

GAATAACATTGCTTC

AATAACATTGCTTCA

ATAACATTGCTTCAG

TAACATTGCTTCAGA

AACATTGCTTCAGAG

ACATTGCTTCAGAGC

CATTGCTTCAGAGCT

ATTGCTTCAGAGCTG

TTGCTTCAGAGCTGG

TGCTTCAGAGCTGGA

GCTTCAGAGCTGGAG

CTTCAGAGCTGGAGA

TTCAGAGCTGGAGAA

TCAGAGCTGGAGAAC

CAGAGCTGGAGAACT

AGAGCTGGAGAACTT

GAGCTGGAGAACTTC

AGCTGGAGAACTTCA

GCTGGAGAACTTCAT

CTGGAGAACTTCATG

TGGAGAACTTCATGG

GGAGAACTTCATGGG

GAGAACTTCATGGGG

AGAACTTCATGGGGC

GAACTTCATGGGGCT

AACTTCATGGGGCTC

ACTTCATGGGGCTCA

CTT CATGGGGCT CAT

TTCATGGGGCTCATC

TCATGGGGCTCATCG

CATGGGGCTCATCGA

ATGGGGCTCATCGAG

TGGGGCTCATCGAGG

GGGGCTCATCGAGGT

GGGCTCATCGAGGTG

GGCTCATCGAGGTGG

GCTCATCGAGGTGGT

CTCATCGAGGTGGTG

TCATCGAGGTGGTGA

CATCGAGGTGGTGAC

ATCGAGGTGGTGACG

TCGAGGTGGTGACGG

CGAGGTGGTGACGGG

GAGGTGGTGACGGGC

AGGTGGTGACGGGCT

GGTGGTGACGGGCTA

GTGGTGACGGGCTAC

TGGTGACGGGCTACG

GGTGACGGGCTACGT

GTGACGGGCTACGTG

TGACGGGCTACGTGA

GACGGGCTACGTGAA

ACGGGCTACGTGAAG

CGGGCTACGTGCkAGA

GGGCTACGTGAAGAT

GGCTACGTGAAGATC

GCTACGTGAAGATCC

CTACGTGAAGATCCG

TACGTGAAGATCCGC

ACGTGAAGATCCGCC

CGTGAAGATCCGCCA

GTGAAGATCCGCCAT

TGAAGATCCGCCATT

GAAGATCCGCCATTC

AAGATCCGCCATTCT

AGATCCGCCATTCTC

GATCCGCCATTCTCA

ATCCGCCATTCTCAT

TCCGCCATTCTCATG

CCGCCATTCTCATGC

CGCCATTCTCATGCC

GCCATTCTCATGCCT

CCATTCTCATGCCTT

CaTTCTCATGCCTTG

ATTCTCATGCCTTGG

TTCTCATGCCTTGGT

TCTCATGCCTTGGTC

CTCATGCCTTGGTCT

T CATG CCTTGGT CT C

CATGCCTTGGTCTCC

ATGCCTTGGTCTCCT

TGCCTTGGTCTCCTT

GCCTTGGTCTCCTTG

CCTTGGTCTCCTTGT

CTTGGTCTCCTTGTC

TTGGTCTCCTTGTCC

TGGTCTCCTTGTCCT

GGTCTCCTTGTCCTT

GTCTCCTTGTCCTTC

TCTCCTTGTCCTTCC

CTCCTTGTCCTTCCT

TCCTTGTCCTTCCTA

CCTTGTCCTTCCTAA

CTTGTCCTTCCTAAA

TTGTCCTTCCTAAAA

TGTCCTTCCTAAAAA

GTCCTTCCTAAAAAA

TCCTTCCTAAAAAAC

CCTTCCTAAAAAACC

CTTCCTAAAAAACCT

TTCCTAAAAAACCTT

TCCTAAAAAACCTTC

CCTAAAAAACCTTCG

CTAAAAAACCTTCGC

TAAAAAACCTTCGCC

AAAAAACCTTCGCCT

AAAAACCTTCGCCTC

AAAACCTTCGCCTCA

AAACCTTCGCCTCAT

AACCTTCGCCTCATC

ACCTTCGCCTCATCC

CCTTCGCCTCATCCT

I WO 96101636 PTA9101 PCT/AU95/00410 49

CTTCGCCTCATCCTA

TTCGCCTCATCCTAG

TCGCCTCATCCTAGG

CGCCTCATCCTAGGA

GCCTCATCCTAGGAG

CCTCATC2CTAGGAGA

CTCATCCTAGGAGAG

TCATCCTAGGAGAGG

CAT CCTAGGAGAGGA

ATCCTAGGAGAGGAG

TCCTAGGAGAGGAGC

CCTAGGAGAGGAGCA

CTAGGAGAGGAGCAG

TAGGAGAGGAGCAGC

AGGAGAGGAGCAGCT

GGAGAGGAGCAGCTA

GAGAGGAGCAGCTAG

AGAGGAGCAGCTAGA

GAGGAGCAGCTAGAA

AGGAGCAGCTAGAAG

GGAGCAGCTAGAAGG

GAGCAGCTAGAAGGG

AGCAGCTAGAAGGGA

GCAGCTAGAAC-GGAA

CAGCTAGAAGGGAAT

AGCTAGAAGGGAATT

GCTAGAAGGGAATTA

CTAGAAGGGAATTAC

TAGAAGGGAATTACT

AGAAGGGAATTACTC

GAAGGGAATTACTCC

AAGGGAATTACTCCT

AGGGAATTACTCCTT

GGGAATTACTCCTTC

GGAATTACTCCTTCT

GAATTACTCCTTCTA

AATTACTCCTTCTAC

ATTACTCCTTCTACG

TTACTCCTTCTACGT

TACTCCTTCTACGTC

ACTCCTTCTACGTCC

CTCCT'TCTACGTCCT

TCCTTCTACGTCCTC

CCTTCTACGTCCTCG

CTTCTACGTCCTCGA

TTCTACGTCCTCGAC

TCTACGTCCTCGACA

CTACGTCCTCGACAA

TACGTCCTCGACAAC

ACGTCCTCGACAACC

CGTCCTCGACAACCA

GTCCTCGACAACCAG

TCCTCGACAACCAGA

CCTCGACAWCCAGAA

CTCGACAACC.A-GAAC

TCGACAACCAGAA-'CT

CGACAACCAGAACTT

GACAACCAGAACTTG

ACAACCAGAACTTGC

CAACCAGAACTTGCA

AACCAGAACTTGCAG

ACCAGAACTTGCAGC

CCAGAACTTGCAGCA

CAGAACTTGCAGCAA

AGAACTTGCAGCAAC

GAACTTGCAGCAP CT

AACTTGCAGCAACTG

ACTTGCAGCAACTGT

CTTGCAGCAACTGTG

TTGCAGCAACTGTGG

TGCAGCAACTGTGGG

GCAGCAACTGTGGGA

CAGCAACTGTGGGAC

AGCAACTGTGGGACT

GCAACTGTGGGACTG

CAACTGTGGGACTGG

AACTGTGGGACTGGG

ACTGTGGGACTGGGA

CTGTGGGACTGGGAC

TGTGGGACTGGGACC

GTGGGACTGGGACCA

TGGGACTGGGACCAC

GGGACTGGGACCACC

GGACTGGGACCACCG

GACTGGGACCACCGC

ACTGGGACCACCGCA

CTGGGACCACCGCAA

TGGGACCACCGCAAC

GGGACCACCGCAACC

GGACCACCGCAACCT

GACCACCGCAACCTG

ACCACCGCAACCTGA

CCACCGCAACCTGAC

CACCGCAACCTGACC

ACCGCAACCTGACCA

CCGCAACCTGACCAT

CGCAACCTGACCATC

GCAACCTGACCATCA

CAACCTGACCATCAA

AACCTGACCATCAAA

ACCTGACCATCAAAG

CCTGACCATCAAAGC

CTGACCATCAAAGCA

TGACCATCAAAGCAG

GACCATCAAAGCAGG

ACCATCAAAGCAGGG

CCATCAAAGCAGGGA

CATCAA-AGCAGGGAA

ATCAAAGCAGGGAAA

TCAAAGCACGGGAAAA

CAAAGCAGGGAAAAT

AAAGCAGGGAAAATG

AAGCAGGGAAAATGT

AGCAGGGAAAATGTA

GCAGGGAAAATGTAC

CAGGGAAAATGTACT

AGGGAAAATGTACTT

GGGAAAATGTACTTT

GGAAAATGTACTTTG

GAAAATGTACTTTGC

AAAATGTACTTTGCT

AAATGTACTTTGCTT

AATGTACTTTGCTTT

ATGTACTTTGCTTTC

TGTACTTTGCTTTCA

GTACTTTGCTTTCAA

TACTTTGCTTTCAA.T

ACTTTGCTTTCAATC

CTTTGCTTTCAATCC

TTTGCTTTCAATCCC

TTGCTTTCAATCCCA

TGCTTTCAATCCCAA

GCTTTCAATCCCAAA

CTTTCAATCCCAAAT

TTTCAATCCCAAATT

TTCAATCCCAAATTA

TCAATCCCAAATTAT

CAATCCCAAATTATG

AATCCCAAATTATGT

ATCCCAAATTATGTG

TCCCAAATTATGTGT

CCCAAATTATGTGTT

CCAAATTATGTGTTT

CAAATTATGTGTTTC

AAATTATGTGTTTCC

AATTATGTGTTTCCG

ATTATGTGTTTCCGA

TTATGTGTTTCCGAA

TATGTGTTTCCGAAA

ATGTGTTTCCGAAAT

TGTGTTTCCGAAATT

GTGTTTCCGAAATTT

TGTTTCCGAAATTTA

GTTTCCGAAATTTAC

TTTCCGAAATTTACC

TTCCGAAATTTACCG

TCCGAAATTTACCGC

CCGAAATTTACCGCA

CGAAATTTACCGCAT

GAAATTTACCGCATG

AAATTTACCGCATGG

AATTTACCGCATGGA

ATTTACCGCATGGAG

TTTACCGCATGG.iGG

TTACCGCATGGAGGA

TACCGCATGGAGGAA

ACCGCATGGAGGAAG

CCGCATGGAGGAAGT

WO 96101636PC/US040 PCT/AU95100410 50

CGCATGGAGGAAGTG

GCATGGAGGAAGTGA

CATGGAGGAAGTGAC

ATGGAGGAAGTGACG

TGGAGGAAGTGACGG

GGAGGAAGTGACGGG

GAGGAAGTGACGGGG

AGGAAGTGACGGGGA

GGAAGTGACGGGGAC

GAAGTGACGGGGACT

AAGTGACGGGGACTA

AGTGACGGGGACTAA

GTGACGGGGACTAAA

TGACGGGGACTAAAG

GACGGGGACTAAAGG

ACGGGGACTAAAGGG

CGGGGACTAAAGGGC

GGGGACTAAAGGGCG

GGGACTAAAGGGCGC

GGACTAAAGGGCGCC

GACTAAAGGGCGCCA

ACTAAAGGGCGCCAA

CTAAAGGGCGCCAAA

TAAAGGGCGCCAAAG

AAAGGGCGCCAAAGC

AAGGGCGCCAAAGCA

AGGGCGCCAAAGCAA

GGGCGCCAAAGCAAA

GGCGCCAAAGCAAAG

GCGCCAAAGCAAAGG

CGCCAAAGCAAAGGG

GCCAAAGCAAAGGGG

CCAAAGCAAAGGGGA

CAAAGCAAAGGGGAC

AAAGCAAAGGGGACA

AAGCAAAGGGGACAT

AGCAAAGGGGACATA

GCAAAGGGGACATAA

CAAAGGGGACATAAA

AAAGGGGACATAAAC

AAGGGGACATAAACA

AGGGGACATAAACAC

GGGGACATAAACACC

GGGACATAAACACCA

GGACATAAACACCAG

GACATAAACACCAGG

ACATAAACACCAGGA

CATAAACACCAGGAA

ATAAACACCAGGAAC

TAAACACCAGGAACA

AAACACCAGGAACAA

AACACCAGGAACAAC

ACACCAGGAACAACG

CACCAGGAACAACGG

ACCAGGAACAACGGG

CCAGGAACAACGGGG

CAGGAACAACGGGGA

AGGAACAACGGGGAG

GGAACAACGGGGAGA

GAACAACGGGGAGAG

AACAACGGG--GAGAGA

ACAACGGGGAGAGAG

CAACGGGGAGAGAGC

AACGGGGAGAGAGCC

ACGGGGAGAGAGCCT

CGGGGAGAGAGCCTC

GGGGAGAGACCCTCC

GGGAGAGAGCCTCCT

GGAGAGAGCCTCCTG

GAGAGAGCCTCCTGT

AGAGAGCCTCCTGTG

GAGAGCCTCCTGTGA

AGAGCCTCCTGTGAA

GAG CCT CCTGTGAAA

AGCCTCCTGTGAAAG

GCCTCCTGTGAAAGT

CCTCCTGTGAAAGTG

CTCCTGTGAAAGTGA

TCCTGTGAAAGTGAC

CCTGTGAAAGTGACG

CTGTG'CAAAGTGACGT

TGTGAAakGTGACGTC

GTGAAAGTGACGTCC

TGAAAGTGACGTCCT

GAAAGTGACGTCCTG

AAAGTGACGTCCTGC

AAGTGACGTCCTGCA

AGTGACGTCCTGCAT

GTGACGTCCTGCATT

TGACGTCCTGCATTT

GACGTCCTGCATTTC

ACGTCCTGCATTTCA

CGTCCTGCATTTCAC

GTCCTGCATTTCACC

TCCTGCATTTCACCT

CCTGCATTTCACCTC

CTGCATTTCACCTCC

TGCATTTCACCTCCA

GCATTTCACCTCCAC

CATTTCACCTCCACC

ATTTCACCTCCACCA

TTTCACCTCCACCAC

TTCACCTCCACCACC

TCACCTCCACCACCA

CACCTCCACCACCAC

ACCTCCACCACCACG

CCTCCACCACCACGT

CTCCACCACCACGTC

TCCACCACCACGTCG

CCACCACCACGTCGA

CACCACCACGTCGAA

ACCACCACGTCGAAG

CCACCACGTCGAAGA

CACCACGTCGAAGAA

ACCACGTCGAAGAAT

CCACGTCGAAGAATC

CACGTCGAAGAATCG

ACGTCGAAGAATCGC

CGTCGAAGAATCGCA

GTCGAAGAATCG CAT

TCGAAGAATCGCATC

CGAAGAATCGCATCA

GAAGAATCGCATCAT

AAGAAT CG CAT CAT C

AGAATCGCATCATCA

GAATCGCATCATCAT

AATCGCATCATCATA

ATCGCATCATCATAA

TCGCATCATCATAAC

CGCATCATCATAACC

GCATCATCATAACCT

CATCATCATAACCTG

ATCATCATAACCTGG

TCATCATAACCTGGC

CATCATAACCTGGCA

ATCATAACCTGGCAC

TCATAACCTGGCACC

CATAACCTGGCACCG

ATAACCTGGCACCGG

TAACCTGGCACCGGT

AACCTGGCACCGGTA

ACCTGGCACCGGTAC

CCTGGCACCGGTACC

CTGGCACCGGTACCG

TGGCACCGGTACCGG

GGCACCGGTACCGGC

GCACCGGTACCGGCC

CACCGGTACCGGCCC

AC CGGTAC CGGC CC C

CCGGTACCGGCCCCC

CGGTACCGGCCCCCT

GGTAC CGG CC C CCTG

GTACCGGCCCCCTGA

TACCGGCCCCCTGAC

ACCGGCCCCCTGACT

CCGGCCCCCr.TGACTA

CGGCCCCCTGACTAC

GGCCCCCTGACTACA

GCCCCCTGACTACAG

CCCCCTGACTACAGG

CCCCTGACTACAGGG

CCCTGACTACAGGGA

CCTGACTACAGGGAT

CTGACTACAGGGATC

TGACTACAGGGATCT

GACTACAGGGATCTC

ACTACAGGGATCTCA

CTACAGGGATCTCAT

I

WO 96/01636 T/19/00 PCr/AU95/00410 51

TACAGGGATCTCATC

ACAGGGATCTCATCA

CAGGGATCTCATCAG

AGGGATCTCATCAGC

GGGATCTCATCAGCT

OjGATCTCATCAGCTT

GATCTCATCAGCTTC

ATCTCATCAGCTTCA

TCTCATCAGCTTCAC

CTCATCAGCTTCACC

TCATCAGCTTCACCG

CATCAGCTTCACCGT

ATCAGCTTCACCGTT

TCAGCTTCACCGTTT

CAGCTTCACCGTTTA

AGCTTCACCGTTTAC

GCTTCACCGTTTACT

CTTCACCGTTTACTA

TTCACCGTTTACTAC

TCACCGTTTACTACA

CACCGTTTACTACAA

ACCGTTTACTACAAG

CCGTTTACTACAAGG

CGTTTACTACAAGGA

GTTTACTACAAGGAA

TTTACTACAAGGAAG

TTACTACAAGGAAGC

TACTACAAGGAAGCA

ACTACAAGGAAGCAC

CTACAAGGAAGCACC

TACAAGGAAGCACCC

ACAAGGAAGCACCCT

CAAGGAAGCACCCTT

AAGGAAGCACCCTTT

AGGAAGCACCCTTTA

GGAAGCACCCTTTAA

GAAGCACCCTTTAAG

AAGCACCCTTTAAGA

AGCACCCTTTAAGAA

GCACCCTTTAAGAAT

CACCCTTTAAGAATG

ACCCTTTAAGAATGT

CCCTTTAAGAATGTC

CCTTTAAGAATGTCA

CTTTAAGAATGTCAC

TTTAAGAATGTCACA

TTAAGAATGTCACAG

TAAGAATGTCACAGA

AAGAATGTCACAGAG

AGAATGTCACAGAGT

GAATGTCACAGAGTA

AATGTCACAGAGTAT

ATGTCACAGAGTATG

TGTCACAGAGTATGA

GTCACAGAGTATGAT

TCACAGAGTATGATG

CACAGAGTATGATGG

ACAGAGTATGATGGG

CAGAGTATGATGGGC

AGAGTATGATGGGCA

GAGTATGATGGGCAG

AGTATGATGGGCAGG

GTATGATGGGCAGGA

TATGATGGGCAGGAT

ATGATGGGCAGGATG

TGATGGGCAGGATGC

GATGGGCAGGATGCC

ATGGGCAGGATGCCT

TGGGCAGGATGCCTG

GGGCAGGATGCCTGC

GGCAGGATGCCTGCG

GCAGGATGCCTGCGG

CAGGATGCCTGCGGC

AGGATGCCTGCGGCT

GGATGCCTGCGGCTC

GATGCCTGCGGCTCC

ATGCCa'GCGGCTCCA

TGCCTGCC-GCTCCAA

GCCTGCGGCTCCAAC

CCTGCGGCTCCAACA

CTGCGGCTCCAACAG

TGCGGCTCCAACAGC

GCGGCTCCAACAGCT

CGGCTCCAACAGCTG

GGCTCCAACAGCTGG

GCTCCAACAGCTGGA

CTCCAACAGCTGGAA

TCCAACAGCTGGAAC

CCAACAGCTGGAACA

CAACAGCTGGAACAT

AACAGCTGGAACATG

ACAGCTGGAACATGG

CAGCTGGAACATGGT

AGCTGGAACATGGTG

GCTGGAACATGGTGG

CTGGAACATGGTGGA

TGGAACATGGTGGAC

GGAACATGGTGGACG

GAACATGGTGGACGT

AACATGGTGGACGTG

ACATGGTGGACGTGG

CATGGTGGACGTGGA

ATGGTOGACGTGGAC

TGGTGGACGTGGACC

GGTGGACGTGGACCT

GTGGACGTGGACCTC

TGGACGTGGACCTCC

GGACGTGGACCTCCC

GACGTGGACCTCCCG

ACGTGGACCTCCCGC

CGTGGACCTCCCGCC

GTGGACCTCCCGCCC

TGGACCTCCCGCCCA

GGACCTCCCGCCCAA

GACCTCCCGCCCAAC

ACCTCCCGCCCAACA

CCTCCCGCCCAACAA

CTCCCGCCCAACAAG

TCCCGCCCAACAAGG

CCCGCCCAACAAGGA

CCGCCCAACAAGGAC

CGCCCAACAAGGACG

GCCCAACAAGGACGT

CCCAACAAGGACGTG

CCAACAAGGACGTGG

CAACAAGGACGTGGOA

AACA-AGGACGTGGAG

ACAAGGACGTGGAGC

CAAGGACGTGGAGCC

AAGGACGTGGAGCCC

AGGACGTGGAGCCCG

GGACGTGGAGCCCGG

GACGTGGAGCCCGGC

ACGTGGAGCCCGGCA

CGTGGAGCCCGGCAT

GTGGAGCCCGGCATC

TGGAG C CCGGCAT CT

GGAGCCCGGCATCTT

GAGCCCGGCATCTTA

AGCCCGGCATCTTAC

GCCCGGCATCTTACT

CCCGGCATCTTACTA

CCGGCATCTTACTAC

CGGCATCTTACTACA

GGCATCTTACTACAT

GCATCTTACTACATG

CATCTTACTACATGG

ATCTTACTACATGGG

TCTTACTACATGGGC

CTTACTACATGGGCT

TTACTACATGGGCTG

TACTACATGGGCTGA

ACTACATGGGCTGAA

CTACATGGGCTGAAG

TACATGGGCTGAAGC

ACATGGGCTGAAGCC

CATGGGCTGAA&GCCC

ATGGGCTGAAGCCCT

TGGGCTGAAGCCCTG

GGGCTGAAGCCCTGG

GGCTGAAGCCCTGGA

GCTGAAGCCCTGGAC

CTGAAGCCCTGGACT

TGAAGCCCTGGACTC

GAAGCCCTGGACTCA

AAGCCCTGGACTCAG

AGCCCTGGACTCAGT

GCCCTGGACTCAGTA

WO 96101636PC/9/041 PCT/AU95/00410 52

CCCTGGACTCAGTAC

CCTGGACTCAGTACG

CTGGACTCAGTACGC

TGGACTCAGTACGCC

GGACTCAGTACGCCG

GACTCAGTACGCCGT

ACTCAGTACGCCGTT

CTCAGTACGCCGTTT

TCAGTACGCCGTTTA

CAGTACGCCGTTTAC

AGTACGCCGTTTACG

GTACGCCGTTTACGT

TACGCCGTTTACGTC

ACGCCGTTTACGTCA

CGCCGTTTACGTCAA

GCCGTTTACGTCAAG

CCGTTTACGTCAAGG

CGTTTACGTCAAGGC

GTTTACGTCAAGGCT

TTTACGTCAAGGCTG

TTACGTCAAGGCTGT

TACGTCAAGGCTGTG

ACGTCAAGGCTGTGA

CGTCAAGGCTGTGAC

GTCAAGGCTGTGACC

TCAAGGCTGTGACCC

CAAGGCTGTGACCCT

AAGGCTGTGACCCTC

AGG CTGTGAC CCT CA

GGCTGTGACCCTCAC

GCTGTGACCCTCACC

CTGTGACCCTCACCA

TGTGACCCTCACCAT

GTGACCCTCACCATG

TGACCCTCACCATGG

GACCCTCACCATGGT

ACCCTCACCATGGTG

CCCTCACCATGGTGG

CCTCACCATGGTGGA

CTCACCATGGTGGAG

TCACCATGGTGGAGA

CACCATGGTGGAGAA

ACCATGGTGGAGAAC

CCATGGTGGAGAACG

CATGGTGGAGAACGA

ATGGTGGAGAACGAC

TGGTGGAGAACGACC

GGTGGAGAACGACCA

GTGGAGAACGACCAT

TGGAGAA.CGACCATA

GGAGAACGACCATAT

GAGAACGACCATATC

AGAACGACCATATCC

GAACGACCATATCCG

AACGACCATATCCGT

ACGACCATATCCGTG

CGACCATATCCGTGG

GACCATATCCGTGGG

ACCATATCCGTGGGG

CCATATCCGTGGGGC

CATATCCGTGGGGCC

ATATCCGTGGGGCCA

TATCCGTGGGGCCAA

ATCCGTGGGGCCAAG

TCCGTGGGGCCAAGA

CCGTGGGGCCAAGAG

CGTGGGGCCAAGAGT

GTGGGGCCAAGAGTG

TGGGGCCAAGAGTGA

GGGGCCAAGAGTGAG

GGGCCAAGAGTGAGA

GGCCAAGAGTGAGAT

GCCAAGAGTGAGATC

CCAAGAGTGAGATCT

CAAGAGTGAGATCTT

AAGAGTGAGATCTTG

AGAGTGAGATCTTGT

GAGTGAGATCTTGTA

AGTGAGATCTTGTAC

GClGAGATCTTGTACA

TGAGATCTTGTACAT

GAGATCTTGTACATT

AGATCTTGTACATTC

GATCTTGTACATTCG

ATCTTGTACATTCGC

TCTTGTACATTCGCA

CTTGTACATTCGCAC

TTGTACATTCGCACC

TGTACATTCGCACCA

GTACATTCGCACCAA

TACATTCGCACCAAT

ACATTCGCACCAATG

CATTCGCACCAATGC

ATTCGCACCAATGCT

TTCGCACCAATGCTT

TCGCACCAATGCTTC

CGCACCAATGCTTCA

GCACCAATGCTTCAG

CACCAATGCTTCAGT

ACCAATGCTTCAGTT

CCAATGCTTCAGTTC

CAATGCTTCAGTTCC

AATGCTTCAGTTCCT

ATGCTTCAGTTCCTT

TGCTTCAGTTCCTTC

GCTTCAGTTCCTTCC

CTTCAGTTCCTTCCA

TTCAGTTCCTTCCAT

TCAGTTCCTTCCATT

CAGTTCCTTCCATTC

AGTTCCTTCCATTCC

GTTCCTTCCATTCCC

TTCCTTCCATTCCCT

TrCCTTCCATTCCCTT

CCTTCCATTCCCTTG

CTTCCATTCCCTTGG

TTCCATTCCCTTGGA

TCCATTCCCTTGGAC

CCATTCCCTTGGACG

CATTCCCTTGGACGT

ATTCCCTTGGACCTT

TTCCCTTGGACGTTC

TCCCTTGGACGTTCT

CCCTTGGACGTTCTT

CCTTCGACGTTCTTT

CTTGGACGTTCTTTC

TTGGACGTTCTTTCA

TGGACGTTCTTTCAG

GGACGTTCTTTCAGC

GACGTTCTTTCAGCA

ACGTTCTTTCAGCAT

CGTTCTTTCAGCATC

GTTCTTTCAGCATCG

TTCTTTCAGCATCGA

TCTTTCAGCATCGAA

CTTTC-AGCATCGAAC

TTTCAGCATCGAACT

TTCAGCATCGAACTC

TCAGCATCGAACTCC

r'-rCATCGAACTCCT

\TCGAACTCCTC

A'CGAACTCCTCT

CATCGAACTCCTCTT

ATCGAACTCCTCTTC

TCGAACTCCTCTTCT

CGAACTCCTCTTCTC

GAACTCCTCTTCTCA

AACTCCTCTTCTCAG

ACTCCTCTTCTCAGT

CTCCTCTTCTCAGTT

TCCTCTTCTCAGTTA

CCTCTTCTCAGTTAA

CTCTTCTCAGTTAAT

TCTTCTCAGTTAATC

CTTCTCAGTTAATCG

TTCTCAGTTAATCGT

TCTCAGTTAATCGTG

CTCAGTTAATCGTGA

TCAGTTAATCGTGAA

CAGTTAATCGTGAAG

AGTTAATCGTGAAGT

GTTAATCGTGAAGTG

TTAATCGTGAAGTGG

TAATCGTGAAGTGGA

AATCGTGAAGTGGAA

ATCGTGAAGTGGAAC

TCGTGAAGTGGAACC

CGTGAAG' rGGAACCC WO 96101636 WO 9601636PCT/AU9/00430f .53

GTGAAGTGGAACCCT

TGAAGTGGAACC CT C

GAAGTGGAACCCTCC

AAGTGGAACCCTCCC

AGTGC-AACCCTCCCT

GTGGAACCCTCCCTC

TGGAACCCTCCCTCT

GGAACC CT CCCTCT C

GAACCCTC-CCTCTCT

AACCCTCCCTCTCTG

ACCCTCCCTCTCTGC

CCCTCCCTCTCTGCC

CCTCCCTCTCTGCCC

CTCCCTCTCTGCCCA

TCCCTCTCTGCCCAA

CCCTCTCTGCCCAAC

CCTCTCTGCCCAACG

CTCTCTGCCCAACGG

T'C 'CTGCCCAACGGC

CTCTGCCCAACGGCA

TCTGCCCAACGGCAA

CTGCCCAACGGCAAC

TGCCCAAkCGGC&ACC

GCCCAACGGCAACCT

CCCAACGGCAACCTG

CCAACGGCAACCTGA7.

CAACGGCAACCTGAG

AACGGCAACCTGAGT

ACGGCAACCTG:'AGTT

CGGCAACCTGAGTTA

GGCAACCTGAGTTAC

GCAA.CCTGAGTTACT

CAACCTGAGTTACTA

AACCTGAGTTACTAC

ACCTGAGTTACTACA

CCTGAGTTACTACAT

CTGAGTTACTACATT

TGAGTTACTACATTG

GAGTTACTACATTGT

AGTTACTACATTGTG

GTTACTACATTGTGC

TTACTACATTGTGCG

TACTACATTGTGCGC

ACTACATTGTGCGCT

CTACATTGTGCGCTG

TAkCATTGTGCGCTGG

ACATTGTGCGCTGGC

CATTGTGCGCTGGCA

ATTGTGCGCTGGCAG7

TTGTGCGCTGGCAGC

TGTGCGCTGGCAGCG

GTGCGCTGGCAGCGG

TGCGCTGGCAGCGGC

GCGCTGGCAGCGGCA

CGCTGGCAGCGGCAG

GCTGGCAGCGGCAGC

CTGGCAGCGGCAGCC

TGGCAGCGCGCAGCCT

GGCAGCGGCAGCCTC

GCAGCGGCAGCCTCA

CAGCGGCAGCCTCAG

AGCGGCAGCCTCAGG

GCGGCAGCCTCAGGA

CGGCAGCCTCAGGAC

GGCAGCCTCAGGACG

GCAGCCTCAGGACGG

CAGCCTCAGGACGGC

AGCCTCAGGACGGCT

GCCTCAGGACGGCTA

CCTCAGGACGGCTAC

CTCAGGACGGCTACC

TCAGGACGGCTACCT

CAGGACGOCTACCTT

AGGACGCGCTACCTTT

GGACGGCTACCTTTA

GACGGCTACCTTTAC

ACGGCTACCTTTACC

CGGCTACCTTTACCG

GGCTACCTTTACCGG

GCTACCTTTACCGGC

CTACCTTTACCGGCA

TACCTTTACCGGCAC

ACCTTTACCGGCACA

CCTTTACCGGCACAA

CTTTACCGGCACAAT

TTTACCGGCACAATT

TTACCGGCACAkATTZ'

'ACCGGCACAATTAC

ACCGGCACAATTACT

CCGGCACAATTACTG

CGGCACAATTACTGC

GGCACAATTACTGCT

GCACAATTACTGCTC

CACAATTACTGCTCC

ACAATTACTGCTCCA

CAATTACTGCTCCAA

AATTACTGCTCCAAA

ATTACTGCTCCAAAG

TTACTGCTCCAAAGA

TACTGCTCCAAAGAC

ACTGCTCCAAAGACA

CTGCTCCAAAGACAA

TGCTCCAAAGACAAA

GCTCCAAAGACAAAA

CTCCAAAGACAAAAT

TCCAAAGACAAAATC

CCAAAGACAAAATCC

CAAAGACAAAATCCC

AAAGACAAAATCCCC

AAGACAAAATCCCCA

AGACAAAATCCCCATf

GACAAAATCCCCATC

ACAAAATCCCCATCA

CAAAATCCCCATCAG

AAAATCCCCATCAGG

AAATCCCCATCAGGA

AATCCCCATCAGGAA

ATCCCCATCAGGAAG

TCCCCATCAGGAAGT

CCCCATCAGGAAGTA

CCCATCAGGAAGTAT

CCATCAGGAAGTATG

CATCAGGAAGTATGC

ATCAGGAAGTATGCC

TCAGGAAGI',TGCCG

CAGGAAGTATGCCGA

AGGAAGTATGCCGAC

GGAAGTAdTGCCGACG-:

C-AAGTATGCCGACGG

AAGTATGCCGACGGC

AGTATGCCGACGGCA

GTATGCCGACGGCAC

TATGCCGACGGCACC

ATGCCGACGGCACCA

TGCCGACGGCACCAT

GCCGACGGCACCATC

CCGACGGCACCATCG

CGACGGCI,.CCATCGA

GACGGCACCATCGAC

ACGGCACCATCGACA

C.JGCACCATCGACAT

GGCADCCATCGACATT

GCA CCATCGACATTG

CACCATCGACATTGA

ACCATCGACATTGAG

CCATCGACATTGAG

CATCGACATTCAGGA

ATCGACATTGAGGAG

TCGACATTGAGGAGG,-

CGACATTGAGGAG.GT

GACATTGAGGAGGTC

AC'ATTGAGGAGGTCA

(CAT"4TGAGGAGGTCAC 'j",-,G7GAGGTCACAi

TTGAGC-AGGTCACAG

TGAGGAGGTCACAGA

GAGGA.GGTCACAGAG

AGGAGGTCACAGAC;A

GGAGGTCACAGAGAA

GAGGTCACAGAGAAC

AGGTCACAGAGAACC

GGTCACAGAGAACCC

GTCACAGAGAACCCC

TCACAGAGAACCCCA

CACAGAGAACCCCAA,

ACAGAGAACCCCAAG

CINGJAGAAC C CCAAGA

AGAGAACCCCAAGAC

pCTAU95IOO4 WO 96/0 1636 54

GAGAACCCCAAGACT

AGAACCCCAAGACTG

GAACCCCAAGACTGA

AACCCCAAGACTGAG

ACCCCAAGACTGAGG

CCCCAAGACTGAGGT

CCCAAGACTGAGGTG

CCAAGACTGAGGTGT

CAAGACTGAGGTGTG

AAGACTGAGGTGTGT,

AGACTGAGGTGTGTG

GACTGAGGTGTGTGG

ACTGAGGTGTGTGGT

CTGAGGTGTGTGGTG

TGAGGTGTGTGGTGG

GAGGTGTGTGGTGGG

AGGTGTGTGGTGGGG

GGTGTGTGGTGGGGA

GTGTGTGGTGGGGAG

TGTGTGGTGGGGAGA

GTGTGGTGGGGAG.AA

TGTGGTGGGGAGAAA

GTGGTGGGGAGAAAG

TGGTGGGGAGAAAGG

GGTGGGGAGAAAGGG

GTGGGGAGAAAGGGC

TGGGGAGAAAGGGCC

GGGGAGAAAGGGCCT

GGGAGAAAGGGCCTT

GGAGAAAGGGCCTTG

GAGAAAGGGCCTTGC

AGAAAGGGCCTTGCT

GAAAGGGCCTTGCTG

AAAGGGCCTTGCTGC

AAGGGCCTTGCTGCG

AGGGCCTTGCTGCGC

GGGCCTTGCTGCGCC

GGCCTTGCTGCGCCT

GCCTTGCTGCGCCTG

CCTTGCTGCGCCTGC

CTTGCTGCG-;CCTGCC

TTGCTGCGCCTGCCC

TGCTGCGCCTGCCCC

GCTGCGCCTGCCCCA

CTGCGCCTGCCCCAA

TGCGCCTGCCCCAAA

GCGCCTGCCCCAAAA

CGCCTGCCCCAAAAC

GCCTGCCCCAAAACT

CCTGCCCCAAAACTG

CTGCCCCAAAACTGA

TGCCCCAAAACTGAA

GCCCCAAAACTGAAG

CC CCAAAACTGAAG C

CCCAAAACTGAAGCC

CCAAAACTGAAGCCG

CAAAACTGAAGCCGA

AAAACTGAAGCCGAG

AAACTGAAGCCGAGA

AACTGAAGCCGAGAA

ACTGAAGCCGAGAAG

CTGAAGCCGAGAAGC

TGAAGCCGAGAAGCA

GAAGCCGAGAAGCAG

AAGCCGAGAAGCAGG

AGCCGAGAAGCAGGC

GCCGAGAAGCAGGCC

CCGAGAAGCAGGCCG

CGAGAAGCAGGCCGA

GAGAAGCAGGCCGAG

AGAAGCAGGCCGAGA

GAAGCAGGCCGAGAA

AAGCAGGCCGAGAAG

AGCAGGCCGAGAAGG

GCAGGCCGAGAAGGA

CAGGCCGAGAAGGAG

AGGCCGAGAAGGAGG

GGCCGAGAAGGAGGA

GCCGAGAAGGAGGAG

CCGAGAAGGAGGAGG

CGAGAA.GGAGGAGGC

GAGAAGGAGGAGGCT

AGAAGGAGGAGGCTG

GAAGGAGGAGGCTGA

AAGGAGGAGGCTGAA

AGGAGGAGGCTGAAT

GGAGGAGGCTGAATA

GAGGAGGCTGAATAC

AGGAGGCTGAATACC

GGAGGCTGAATACCG

GAGGCTGAATACCGC

AGGCTGAATACCGCA

GGCTGAATACCGCAA

GCTGAATACCGCAAA

CTGAATACCGCAAAG

TGAATACCGCAAAGT

GAATACCGCAAAGTC

AATACCGCAAAGTCT

ATACCGCAAAGTCTT

TACCGCAAAGTCTTT

ACCGCAAAGTCTTTG

CCGCAAAG2TCTTTGA

CGCAAAGTCTTTGAG

GCP.AAGTCTTTGAGA

CAAAGTCTTTGAGAA

AAAGTCTTTGAGAAT

AAGTCTTTGAGAATT

AGTCTTTGAGAATTT

GTCTTTG-AGAATTTC

TCTTTGAGAATTTCC

CTTTGAGAATTTCCT

TTTGAGAATTTCCTG

TTGAGAATTTCCTGC

TGAGAATTTCCTGCA

GAGAATTTCCTGCAC

AGAATTTCCTGCACA

GAATTTCCTGCACAA

AATTTCCTGCACAAC

ATTTCCTGCACAACT

TTTCCTGCACAACTC

TTCCTGCACAACTCC

TCCTGCACAACTCCA

CCTGCACAACTCCAT

CTGCACAACTCCATC

TGCACAACTCCATCT

GCACAACTCCATCTT

CACAACTCCATCTTC

ACAACTCCATCTTCG

CAACTCCATCTTCGT

AACTCCATCTTCGTG

ACTCCATCTTCGTGC

CTCCATCTTCGTGCC

TCCATCTTCGTGCCC

CCATCTTCGTGCCCA

CATCTTCGTGCCCAG

ATCTTCGTGCCCAGA

TCTTCGTGCCCAGAC

CTTCGTGCCCAGACC

TTCGTGCCCAGACCT

TCGTGCCCAGACCTG

CGTGCCCAGACCTGA

GTGCCCAGACCTGAA

TGCCCAGACCTGAAXA

GCCCAGACCTGAAAG

CCCAGACCTGAAAGG

CCAGACCTGAAAGGA

CAGACCTGAAAGGAA

AGACCTGAAAGGAAG

GACCTGAAAGGAAGC

ACCTGAAAGGAAGCG

CCTGAAAGGAAGCGG

CTGAAAGGAAGCGGA

TGAAAGGAAGCGGAG

GAAAGGAAGCGGAGA

AAAGGAAGCGGAGAG

AAGGAAGCGGAGAGA

AGGAAGCGGAGAGAT

GGAAGCGGAGAGATG

GAAGCGGAGAGATGT

AAGCGGAGAGATGTC

AGCGGAGAGATGTCA

GCGGAGAGATGTCAT

CGGAGAGATGTCATG

GGAGAGATGTCATGC

GAGAGATGTCATGCA

AGAGATGTCATGCAA

GAGATGTCATGCAAG

AGATGTCATGCAAGT

WO 9610 1636PCIJ9I41 PCT/AU95/00410 55

GATGTCATGCAAGTG

ATGTCATGCAAGTGG

TCTCATGCAAGTGGC

GTCATGCAAGTGGCC

TCATGCAAGTGGCCA

CATGCAAGTGGCCAA

ATGCAAGTGGCCAAC

TGCAAGTGGCCAACA

GCAAGTGGCCAACAC

CAAGTGGCCAACACC

AAGTGGCCAACACCA

AGTGGCCAACACCAC

GTGGCCAACACCACC

TGGCCAACACCACCA

GGCCAACACCACCAT

GCCAACACCACCATG

CCAACACCACCATGT

CAACACCACCATGTC

AACACCACCATGTCC

ACACCACCATGTCCA

CACCACCATGTCCAG

ACCACCATGTCCAGC

CCACCATGTCCAGCC

CACCATGTCCAGCCG

ACCATGTCCAGCCGA

CCATGTCCAGCCGAA

CATGTCCAGCCGAAG

ATGTCCAGCCGAAGC

TGTCCAGCCGAAGC:A

GTCCAGCCGAAGCAG

TCCAGCCGAAGCAGG

CCAGCCGAAGCAGGA

CAGCCGAAGCAGGAA

AGCCGAAGCAGGAAC

GCCGAAGCAGGAACA

CCGAAGCAGGAACAC

CGAAGCAGGAACACC

GAAGCAGGAACACCA

AAGCAGGAACACCAC

AGCAGGAACACC-ACG

GCAGGAACACCACGG

CAGGAACACCACGGC

AGGAACACCACGGCC

GGAACACCACGGCCG

GAACACCACGGCCGC

AACACCACGGCCGCA

ACACCACGGCCGCAG

CACCACGGCCGCAGA

ACCACGGCCGCAGAC

CCACGGCCGCAGACA

CACGGCCGCAGACAC

ACGGCCGCAGACACC

CGGCCGCAGACACCT

GGCCGCAGACACCTA

GCCGCAGACACCTAC

CCGCAGACACCTACA

CGCAGACACCTACAA

GCAGACACCTACAAC

CAGACACCTACAACA

AGACACCTACAACAT

GACACCTACAACATC

ACACCTACAACATCA

CACCTACAACATCAC

ACCTACAACATCACC

CCTACAACATCACCG

CTACAACATCACCGA

TACAACATCACCGAC

ACAACATCACCGACC

CAACATCACCGACCC

AACATCACCGACCCG

ACATCACCGACCCGG

CATCACCGACCCGGA

ATCACCGACCCGGAA

TCACCGACCCGGAAG

CACCGACCCGGAAGA

ACCGACCCGGAAGAG

CCGACCCGGAAGAGC

CGACCCGGAAGAGCT

GACCCGGAAGAGCTG

ACCCGGAAGAGCTGG

CCCGGAAGAGCTGGA

CCGGAAGAGCTGGAG

CGGAAGAGCTGGAGA

GGAAGAGCTGGAGAC

GAAGAGCTGGAGACA

AAGAGCTGGAGACAG

AGAGCTGGAGACAGA

GAGCTGGAGACAGAG

AGCTGGAGACAGAGT

GCTGGAGACAGAGTA

CTGG.XGACAGAGTAC

TGGAGACAGAGTACC

GGAGACAGAGTACCC

GAGACAGAGTACCCT

AGACAGAGTACCCTT

GACAGAGTACCCTTT

ACAGAGTACCCTTTC

CAGAGTACCCTTTCT

AGAGTACCCTTTCTT

GAGTACCCTTTC7TT AGTACCCTT'fC-TTTG

GTACCCTTTCTTTGA

TACCCTTTCTTTGAG

ACCCTTTCTTTGAGA

CCCTTTCTTTGAGAG

CCTTTCTTTGAGAGC

CTTTCTTTGAGAGCA

TTTCTTTGAGAGCAG

TTCTTTGAGAGCAGA

TCTTTGAGAGCAGAG

CTTTGAGAGCAGAGT

TTTGAGAGCAGAGTG

TTGAGAGCAGAGTGG

TGAGAGCAGAGTGGA

GAGAGCAGAGTGG-AT

AGAGCAGAGTGGATA

GAGCAGAGTGGATAA

AGCAGAGTGGATAAC

GCAGAGTGGATAACA

CAGAGTGGATAACAA

AGAGTGGATAACAAG

GAGTGGATAACAAGG

AGTGGATAACAAGGA

GTGGATAACAAGGAG

TGGATAACAAGGAGA

GGATAACAAGGAGAG

GATAACAAGGAGAGA

ATAACAAGGAGAGAA

TAACAAGGAGAGAAC

AACAAGGAGAGAACT

ACAA.GGAGAGAACTG

CAAGGAGAGAACTGT

AAGGAGAGAACTGTC

AGGAGAGAACTGTCA

GGAGAGAACTGTCAT

GAGAGAACTGTCATT

AGAGAACTGTCATTT

GAGAACTGTCATTTC

AGAACTGTCATTTCT

GAACT3"TCATTTCTA

AACTGTCATTTCTAA

ACTGTCATTTCTAAC

CTGTCATTTCTAACC

TGTCATTTCTAACCT

GTCATTTCTAACCTT

TCATTTCTAACCTTC

CATTTCTAACCTTCG

ATTTCTAACCTTCGG

TTTCTAACCTTCGGC

TTCTAACCTTCGGCC

TCTAACCTTCGGCCT

CTAACCTTCGGCCTT

TAACCTTCGGCCTTT

AACCTTCGGCCTTTC

ACCTTCGGCCTTTCA

CCTTCGGCCTTTCAC

CTTCGGCCTTTCACA

TTCGGCCTTTCACAT

TCGGCCTTTCACATT

CGGCCTTTCACATTG

GGCCTTTCACATTGT

GCCTTTCACATTGTA

CCTTTCACATTGTAC

CTTTCACATTGTACC

TTTCACATTGTACCG

TTCACATTGTACCGC

TCACATTGTACCGCA

CACATTGTACCGCAT

m WO 96101636 PTA9101 PCT/AU95,100410 56

ACATTGTACCGCATC

CATTGTACCGCATCG

ATTGTACCGCATCGA

TTGTACCGCATCGAT

TGTACCGCATCGATA

GTACCGCATCGATAT

TACCGCATCGATATC

ACCGCATCGATATCC

CCGCATCGATATCCA

CGCATCGATATCCAC

GCATCGATATCCACA

CATCGATATCCACAG

ATCGATATCCACAGC

TCGATATCCACAGCT

CGATATCCACAGCTG

GATATCCACAGCTGC

ATATCCACAGCTGCA

TATCCACAGCTGCAA

ATCCACAGCTGCAAC

TCCACAGCTGCAACC

CCACAGCTGCAACCA

CACAGCTGCAACCAC

ACAGCTGCAACCACG

CAGCTGCAACCACGA

AGCTGCAACCACGAG

GCTGCAACCACGAGG

CTGCAACCACGAG.GC

TGCAACCACGAGGCT

GCAACCACGAGGCTG

CAACCACGAGGCTGA

AACCACGAGGCTGAG

ACCACGAGGCTGAGA

CCACGAGGCTGAGAA

CACGAGGCTGAGAAG

ACGAGGCTGAGAAGC

CGAGGCTGAGAAGCT

GAGGCTGAGAAGCTG

AGGCTGAGAAGCTGG

GGCTGAGAAGCTGGG

GCTGAGAAGCTGGGC

CTGAGAAGCTGGGCT

TGAGAAGCTGGGCTG

GAGAAGCTGGGCTGC

AGAAkGCTGGGCTGCA

GAAGCTGGGCTGCAG

AAGCTGGGCTGCAGC

AGCTGGGCTGCAGCG

GCTGGGCTGCAGCGC

CTGGGCTGCAGCGCC

TGGGCTGCAGCGCCT

GGGCTGCAGCGCCTC

GGCTG CAGCG CCTC C

GCTGCAGCGCCTCCA

CTGCAGCGCCTCCAA

TGCAGCGCCTCCAAC

GCAGCGCCTCCAACT

CAGCGCCTCCAACTT

AGCGCCTCCAACTTC

GCGCCTCCAACTTCG

CGCCTCCAACTTCGT

GCCTCCAACTTCGTC

CCTCCAACTTCGTCT

CTCCAACTTCGTCTT

TCCAACTTCGTCTTT

CCAACTTCGTCTTTG

CAACTTCGTCTTTGC

AACTTCGTCTTTGCA

ACTTCGTCTTTGCAA

CTTCGTCTTTGCAAG

TTCGTCTTTGCAAGG

TCGTCTTTGCAAGGA

CGTCTTTGCAAGGAC

GTCTTTGCAAGGACT

TCTTTGCAAGGACTA

CTTTGCAAGGACTAT

TTTGCAAGGACTATG

TTGCAAGGACTATGC

TGCAAGGACTATGC2

GCAAGGACTATGCCC

CAAGGACTATGCCCG

AAGGACTATGCCCGC

AGGACTATGCCCGCA

GGACTATGCCCGCAG

GACTATGCCCGCAGA

ACTATGCCCGCAGAA

CTATGCCCGCAGAAG

TATGCCCGCAGAAGG

ATGCCCGCAGAAGGA

TGCCCGCAGAAGGAG

GCCCGCAGAAGGAGC

CCCGCAGAAGGAGCA

CCGCAGAAGGAGCAG

CGCAGAAGGAG'2AGA

GCAGAAGGAGCAGAT

CAGAAGGAGCAGATG

AGAAGGAGCAGATGA

GAAGGAGCAGATGAC

AAGGAGCAGATGACA

AGGAGCAGATGACAT

GGAGCAGATGACATT

GAGCAGATGACATTC

AGCAGATGACATTCC

GCAGATGACATTCCT

CAGATGACATTCCTG

AGATGACATTCCTGG

GATGACATTCCTGGG

ATGACATTCCTGGGC

TGACATTCCTGGGCC

GACATTCCTGGGCCA

ACATTCCTGGGCCAG

CATTCCTGGGCCAGT

ATTCCTGGGCCAGTG

TTCCTGGGCCAGTGA

TCCTGGGCCAGTGAC

CCTGGGCCAGTGACC

CTGGGCCAGTGACCT

TGGGCCAGTGACCTG

GGGCCAGTGACCTGG

GGCCAGTGACCTGGG

GCCAGTGACCTGGGA

CCAGTGACCTGGGAG

CAGTGACCTGGGAGC

AGTGACCTGGGAGCC

GTGACCTGGGAGCCA

TGACCTGGGAGCCAA

GACCTGGGAGCCAAG

ACCTGGGAGCCAAGG

CCTGGGAGCCAAGGC

CTGGGAGCCAAGGCC

TGGGAGCCAAGGCCT

GGGAGCCAAGGCCTG

GGAGCCAAGGCCTGA

GAGCCAAGGCCTGAA

AG CCAAGG CCTGAAA

GCCAAGGCCTGAAAA

CCAAGGCCTGAAAAC

CAAGGCCTGAAAACT

AAGGCCTGAAAACTC

AGGCCTGAAAACTCC

GGCCTGAAAACTCCA

GCCTGAAAACTCCAT

CCTGAAAACTCCATC

CTGAAAACTCCATCT

TGAAAACTCCATCTT

GAAAACTCCATCTTT

AAAACTCCATCTTTT

AAACTCCATCTTTTT

AACTCCATCTTTTTA

ACTCCATCTTTTTAA

CTC CAT CTTTTTAAA

TCCATCTTTTTAAAG

CCATCTTTTTAAAGT

CATCTTTTTAAAGTG

ATCTTTTTAAAGTGG

TCTTTTTAAAGTGGC

CTTTTTAAAGTGGCC

TTTTTAAAGTGGCCG

TTTTAAAGTGGCCOG

TTTAAAGTGGCCGGA

TTAAAGTGGCCGGAA

TAAAGTGGCCGGAAC

AAAGTGGCCGGAACC

AAGTGGCCGGAACCT

AGTGGCCGGAACCTG

GTGGCCGGAACCTGA

TGGCCGGAACCTGAG

GGCCGGAACCTGAGA

GCCGGAACCTGAGAA

m WO 96/0 1636 PTA9101 PCT/AU95/00410 57

CCGGAACCTGAGAAT

CGGAACCTGAGAATC

GGAACCTGAGAATCC

GAACCTGAGAATCCC

AACCTGAGAATCCCA

ACCTGAGAATCCCAA

CCTGAGAATCCCAAT

CTGAGAATCCCAATG

TGAGAATCCCAATGG

GAGAATCCCAATGGA

AGAATCCCAATGGAT

GAATCCCAATGGATT

APATCCCAATGGATTG

ATCCCAATGGATTGA

TCCCAATGGATTGAT

CCCAATGGATTGATT

CCAATGGATTGATTC

CAATGGATTGATTCT

AATGGATTGATTCTA

ATGGATTGATTCTAA

TGGATTGATTCTAAT

GGATTGATTCTAATG

GATTGATTCTAATGT

ATTGATTCTAATGTA

TTGATTCTAA.TGTAT

TGATTCTAATGTATG

GATTCTAATGTATGA

ATTCTAATGTATGAA

TTCTAATGTATGAAA

TCTAATGTATGAAAT

CTAATGTATGAAATA

TAATGTATGAAATAA

AATGTATGAAATAAA

ATGTATGAAATAAAA

TGTATGAAATAAAAT

GTATGAAATAAAATA

TATGAAATAAAATAC

ATGAAATAAAATACG

TGAAATAAAATACGG

GAAATAAAATACGGA

AAATAAAATACGGAT

AATAAAATACGGATC

ATAAAATACGGATCA

TAAAATACGGATCAC

AAAATACGGATCACA

AAATACGGATCACAA

AATACGGATCACAAG

ATACGGATCACAAGT

TACGGATCACAAGTT

ACGGATCACAAGTTG

CGGATCACAAGTTGA

GGATCACAAGTTGAG

GATCACAAGTTGAGG

ATCACAAGTTGAGGA

TCACAAGTTGAGGAT

CACAAGTTGAGGATC

ACAAGTTGAGGATCA

CAAGTTGAGGATCAG

AAGTTGAGGATCAGC

AGTTGAGGATCAGCG

GTTGAGGATCAGCGA

TTGAGGATCAGCGAG

TGAGGATCAGCGAGA

GAGGATCAGCGAGAA

AGGATCAGCGAGAAT

GGATCAGCGAGAATG

GATCAGCGAGAATGT

ATCAGCGAGAATGTG

TCAGCGAGAATGTGT

CAGCGAGAATGTGTG

AGCGAGAATGTGTGT

GCGAGAATGTGTGTC

CGAGAATGTGTGTCC

GAGAATGTGTGTCCA

AGAATGTGTGTCCAG

GAATGTGTGTCCAGA

AATGTGTGTCCAGAC

ATGTGTGTCCAGACA

TGTGTGTCCAGACAG

GTGTGTCCAGACAGG

TGTGTCCAGACAGGA

GTGTCCAGACAGGAA

TGTCCAGACAGGAAT

GTCCAGACAGGAATA

TCCAGACAGGAATAC

CCAGACAGGAATACA

CAGACAGGAATACAG

AGA P-AGGAATACAGG

GACAGGAATACAGGA

ACAGGAATACAGGAA

CAGGAATACAGGAAG

AGGAATACAGGAAGT

GGAATACAGGAAGTA

GAATACAGGAAGTAT

AATACAGGAAGTATG

ATACACGGAAGTATGG

TACAGGAAGTATGGA

ACAGGAAGTATGGAG

CAGGAAGTATGGAGG

AGGAAGTATGGAGGG

GGAAGTATGGAGGGG

GAAGTATGGAGGGGC

AAGTATGGAGGGGCC

AGTATGGAGGGGCCA

GTATGGAGGGGCCAA

TATGGAGGGGCCAAG

ATGGAGGGGCCAAGC

TGGAGGGGCCAAGCT

GGAGGGGCCAAGCTA

GAGGGGCCAAGCTAA

AGGGGCCAAGCTAAA

GGGGCCAAGCTAAAC

GGGCCAAGCTAAACC

GGCCAAGCTAAACCG

GCCAAGCTAAACCGG

CCAAGCTAAACCGGC

CAAGCTAAACCGGCT

AAGCTAAACCGGCTA

AGCTAAACCGGCTAA

GCTAAACCGGCTAAA

CTAAACCGGCTAAAC

TAAACCGGCTAAACC

AAACCGGCTAAACCC

AACCGGCTAAACCCG

ACCGGCTAAACCCGG

CCGGCTAAACCCGGG

CGGCTAAACCCGGGG

GGCTAAACCCGGGGA

GCTAAACCCGGGGAA

CTAAACCCGGGGAAC

TAAACCCGGGGAACUT

AAACCCGGGGAACTA

AACCCGGGGAACTAC

ACCCGGGGAACTACA

CCCGGGGAACTACAC

CCGGGGAACTACACA

CGGGGAACTACACAG

GGGGAACTACACAGC

GGGAACTACACAGCC

GGAACTACACAGCCC

GAACTACACAGCCCG

AACTACACAGCCCGG

ACTACACAGCCCGGA

CTACAC-AGCCCGGAT

TACACAGCCCGGATT

ACACAGCCCGGATTC

CACAGCCCGGATTCA

ACAGCCCGGATTCAG

CAGCCCGGATTCAGG

AGCCCGGATTCAGGC

GCCCGGATTCAGGCC

CCCGGATTCAGGCCA

CCGGATTCAGGCCAC

CGGATTCAGGCCACA

GGATTCAGGCCACAT

GATTCAGGCCACATC

ATTCAGGCCACATCT

TTCAGGCCACATCTC

TCAGGCCACATCTCT

CAGGCCACATCTCTC

AGGCCACATCTCTCT

GGCCACATCTCTCTC

GCCACATCTCTCTCT

CCACATCTCTCTCTG

CACATCTCTCTCTGG

ACATCTCTCTCTGGG

CATCTCTCTCTGGGA

ATCTCTCTCTGGGAA

WO 96/01636PcI9IO40 PCT/AU95/00410 58

TCTCTCTCTGGGAAT

CTCTCTCTGGGAATG

TCTCTCTGGGAATGG

CTCTCTGGGAATGGG

TCTCTGGGAATGGGT

CTCTGGGAATGGGTC

TCTGGGAATGGGTCG

CTGGGAATGGGTCGT

TGGGAATGGGTCGTG

GGGAATGGGTCGTGG

GGAATGGGTCGTGGA

GAATGGGTCGTGGAC

AATGGGTCGTGGACA

ATGGGTCGTGGACAG

TGGGTCGTGGACAGA

GGGTCGTGGACAGAT

GGTCGTGGACAGATC

GTCGTGGACAGATCC

TCGTGGACAGATCCT

CGTGGACAGATCCTG

GTGGACAGATCCTGT

TGGACAGATCCTGTG

GGACAGATCCTGTGT

GACAGATCCTGTGTT

ACAGATCCTGTGTTC

CAGATCCTGTGTTCT

AGATCCTGTGTTCTT

GATCCTGTGTTCTTC

AT CCTGTGTTCTT CT

TCCTGTGTTCTTCTA

CCTGTGTTCTTCTAT

CTGTGTTCTTCTATG

TGTGTTCTTCTATGT

GTGTTCTTCTATGTC

TGTTCTTCTATGTCC

GTTCTTCTATGTCCA

TTCTTCTATGTCCAG

TCTTCTATGTCCAGG

CTTCTATGTCCAGGC

TTCTATGTCCAGGCC

TCTATGTCCAGGCCA

CTATGTCCAGGCCAA

TATGTCCAGGCCAAA

ATGTCCAGGCCAAAA

TGTCCAGGCCAAAAC

GTCCAGGCCAAAACA

TCCAGGCCAAAAkCAG

CCAGGCCAAAACAGG

CAGGCCAAAACAGGA

AGGCCAAAACAGGAT

GGCCAAAACAGGATA

GCCAAAACAGGATAT

CCAAAACAGGATATG

CAAAACAGGATATGA

AAAACAGGATATGAA

AAACAGGATATGAAA

AACAGGATATGAAAA

ACAGGATATGAAAAC

CAGGATATGAAAACT

AGGATATGAAAACTT

GGATATGAAAACTTC

GATATGAAAACTTCA

ATATGAAAACTTCAT

TATGAAAACTTCATC

ATGAAAACTTCATCC

TGAAAACTTCATCCA

GAAAACTTCATCCAT

AAAACTTCATCCATC

AAACTTCATCCATCT

AACTTCATCCATCTG

ACTTCATCCATCTGA

CTTCATCCATCTGAT

TTCATCCATCTGATC

TCATCCATCTGATCA

CATCCATCTGATCAT

ATCCATCTGATCATC

TCCATCTGATCATCG

CCATCTGATCATCGC

CATCTGATCATCGCT

ATCTGATCATCGCTC

TCTGATCATCGCTCT

CTGAT CAT CGCTCTG

TGATCATCGCTCTGC

GATCATCGCTCTGCC

ATCATCGCTCTGCCC

TCATCGCTCTGCCCG

CATCGCTCTGCCCGT

ATCGCTCTGCCCGTC

TCGCTCTGCCCGTCG

CGCTCTGCCCGTCGC

GCTCTGCCCGTCGCT

CTCTGCCCGTCGCTG

TCTGCCCGTCGCTGT

CTGCCCGTCGCTGTC

TGCCCGTCGCTGTCC

GCCCGTCGCTGTCCT

CCCGTCGCTGTCCTG

CCGTCGCTGTCCTGT

CGTCGCTGTCCTGTT

GTCGCTGTCCTGTTG

TCGCTGTCCTGTTGA

CGCTGTCCTGTTGAT

GCTGTCCTGTTGATC

CTGTCCTGTTGATCG

TGTCCTGTTGATCGT

GTCCTGTTGATCGTG

TCCTGTTGATCGTGG

CCTGTTGATCGTGGG

CTGTTGATCGTGGGA

TGTTGATCGTGGGAG

GTTGATCGTGGGAGG

TTGATCGTGGGAGGG

TGATCGTGGGAGGGT

GATCGTGGGAGGGTT

ATCGTGGGAGGGTTG

TCGTGGGAGGGTTGG

CGTGGGAGGGTTGGT

GTGGGAGGGTTGGTG

TGGGAGGGTTGGTGA

GGGAGGGTTGGTGAT

GGAGGGTTGGTGATT

GAGGGTTGGTGATTA

AGGGTTGGTGATTAT

GGGTTGGTGATTATG

GGTTGGTGATTATGC

GTTGGTGATTATGCT

TTGGTGATTATGCTG

TGGTGATTATGCTGT

GGTGATTATGCTGTA

GTGATTATGCTGTAC

TGATTATGCTGTACG

GATTATGCTGTACGT

ATTATGCTGTACGTC

TTATGCTGTACGTCT

TATGCTGTACGTCTT

ATGCTGTACGTCTTC

TGCTGTACGTCTTCC

GCTGTACGTCTTCCA

CTGTACGTCTTCCAT

TGTACGTCTTCCATA

GTACGTCTTCCATAG

TACGTCTTCCATAGA

ACGTCTTCCATAGAA

CGTCTTCCATAGAAA

GTCTTCCATAGAAAG

TCTTCCATAGAAAGA

CTTCCATAGAAAGAG

TTCCATAGAAAGAGA

TCCATAGAAAGAGAA

CCATAGAAAGAGAAA

CATAGAAAGAGAAAT

ATAGAAAGAGAAATA

TAGAAAGAGAAATAA

AGAAAGAGAAATAAC

GAAAGAGAAATAACA

AAAGAGAAATAACAG

AAGaAGAAATAACAGC

AGAGAAATAACAGCA

GAGAAATAACAGCAG

AGAAATAACAGCAGG

GAAATAACAGCAGGC

AAATAACAGCAGGCT

AATAACAGCAGGCTG

ATAAC!AGCAGGCTGG

TAACAGCAGGCTGGG

AACAGCAGGCTGGGG

ACAGCAGGCTGGGGA

CAGCAGGCTGGGGAA

WO 96101636 PTA9IOI PCT/AU95/00410 59

AGCAGGCTGGGGAAT

GCAGGCTGGGGAATG

CAGGCTGGGGAATGG

AGGCTGGGGAATGGA

GGCTGGGGAATGGAG

GCTGGGGAATGGAGT

CTGGGGAATGGAGTG

TGGGGAATGGAGTGC

GGGGAATGGAGTGCT

GGGAATGGAGTGCTG

GGAATGGAGTGCTGT

GAATGGAGTGCTGTA

AATGGAGTGCTGTAT

ATGGAGTGCTGTATG

TGGAGTGCTGTATGC

GGAGTGCTGTATGCC

GAGTGCTGTATGCCT

AGTGCTGTATGCCTC

GTGCTGTATGCCTCT

T'GCTGTATGCCTCTLG

GCTGTATGCCTCTGT

CTGTATGCCTCTGTG

TGTATGCCTCTGTGA

GTATGCCTCTGTGAA

TATGCCTCTGTGAAC

ATGCCTCTGTGAACC

TGCCTCTGTGAACCC

GCCTCTGTGAACCCG

CCTCTGTGAACCCGG

CTCTGTGAACCCGGA

TCTGTGAACCCGGAG

CTGTGAACCCGGAGT

TGTGAACCCGGAGTA

GTGAACCCGGAGTAC

TGAACCCGGAGTACT

GAACCCGGAGTACTT

AACCCGGAGTACTTC

ACCCGGAGTACTTCA

CCCGGAGTACTTCAG

CCGGAGTACTTCAGC

CGGAGTACTTCAGCG

GGAGTACTTCAGCGC

GAGTACTTCAGCGCT

AGTACTTCAGCGCTG

GTACTTCAGCGCTGC

TACTTCAGCGCTGCT

ACTTCAGCGCTGCTG

CTTCAGCGCTGCTGA

TTCAGCGCTGCTGAT

TCAGCGCTGCTGATG

CAGCGCTGCTGATGT

AGCGCTGCTGATGTG

GCGCTGCTGATGTGT

CGCTGCTGATGTGTA

GCTGCTGATGTGTAC

CTGCTGATGTGTACG

TGCTGATGTGTACGT

GCTGATGTGTACGTT

CTGATGTGTACGTTC

TGATGTGTACGTTCC

GATGTGTACGTTCCT

ATGTGTACGTTCCTG

TGTGTACGTTCCTGA

GTGTACGTTCCTGAT

TGTACGTTCCTGATG

GTACGTTCCTGATGA

TACGTTCCTGATGAG

ACGTTCCTGATGAGT

CGTTCCTGATGAGTG

GTTCCTGATGAGTGG

TTCCTGATGAGTGGG

TCCTGATGAGTGGGA

CCTGATGAGTGGGAG

CTGATGAGTGGGAGG

TGATGAGTGGGAGGT

GATGAGTGGGAGGTG

ATGAGTGGGAGGTGG

TGAGTGGGAGGTGGC

GAGTGGGAGGTGGCT

AGTGGGAGGTGGCTC

GTGGGAGGTGGCTCG

TGGGAGGTGGCTCGG

GGGAGGTGGCTCGGG

GGAGGTGGCTCGGGA

GAGGTGGCTCGGGAG

AGGTGGCTCGGGAGA

GGTGGCTCGGGAGAA

GTGGCTCGGGAGAAG

TGGCTCGGGAGAAGA

GGCTCGGGAGAAGAT

GCTCGGGAGAAGATC

CTCGGGAGAAGATCA

TCGGGAGAAGATCAC

CGGGAGAAGATCACC

GGGAGAAGATCACCA

GGAGAAGATCACCAT

GAGAAGATCACCATG

AGAAGATCACCATGA

GAAGATCACCATGAG

AAGATCACCATGAGC

AGATCACCATGAGCC

GATCACCATGAGCCG

ATCACCATGAGCCGG

TCACCATGAGCCGGG

CACCATGAGCCGGGA

ACCATGAGCCGGGAA

CCATGAGCCGGGAAC

CATGAGCCGGGAACT

ATGAGCCGGGAACTT

TGAGCCGGGAACTTG

GAGCCGGGAACTTGG

AGCCGGGAACTTGGG

GCCGGGAACTTGGGC

CCGGGAACTTGGGCA

CGGGAACTTGGGCAG

GGGAACTTGGGCAGG

GGAACTTGGGCAGGG

GAACTTGGGCAGGGG

AACTTGGGCAGGGGT

ACTTGGGCAGGGGTC

CTTGGGCAGGGGTCG

TTGGGCAGGGGTCGT

TGGGCAGGGGTCGTT

GGGCAGGGC £CGTTT

GGCAGGGGTCGTTTG

GCAGGGGTCGTTTGG

CAGGGGTCGTTTGGG

AGGGGTCGTTTGGGA

GGGGTCGTTTGGGAT

GGGTCGTTTGGGATG

GGTCGTTTGGGATGG

GTCGTTTGGGATGGT

TCGTTTGGGATGGTC

CGTTTGGGATGGTCT

GTTTGGGATGGTCTA

TTTGGGATGGTCTAT

TTGGGATGGTCTATG

TGGGATGGTCTATGA

GGGATGGTCTATGAA

GGATGGTCTATGAAG

GATGGTCTATGAAGG

ATGGTCTATGAAGGA

TGGTCTATGAAGGAG

GGTCTATGAAGGAGT

GTCTATGAAGGAGTT

TCTATGAAGGAGTTG

CTATGAAGGAGTTGC

TATLGAAGGAGTTGCC

ATGAAGGAGTTGCCA

TGAAGGAGTTGCCAA

GAAGGAGTTGCCAAG

AAGGAGTTGCCAAGG

AGGAGTTGCCAAGGG

GGAGTTGCCAAGGGT

GAGTTGCCAAGGGTG

AGTTGCCAAGGGTGT

GTTGCCAAGGGTGTG

TTGCCAAGGGTGTGG

TGCCAAGGGTGTGGT

GCCAAGGGTGTGGTG

CCAAGGGTGTGGTGA

CAAGGGTGTGGTGAA

AAGGGTGTGGTGAAA

AGGGTGTGGTGAAAG

GGGTGTGGTGAAAGA

GGTGTGGTGAAAGAT

GTGTGGTGAAAGATG

TGTGGTGAAAGATGA

PCTALJ95OO410 WO 96/0 1636 60

GTGGTGAAAGATGAA

TGGTGAAAGATGAAC

GGTGAAAGATGAACC

GTGAAAGATGAACCT

TGAAAGATGAACCTG

GAAAGAJ.GAACCTGA

AAAGATGAACCTGAA

AAGATGAACCTGAAA

AGATGAACCTGAAAC

GATGAACCTGAAACC

ATGAACCTGAAACCA

TGAACCTGAAACCAG

GAACCTGAAACCAGA

AACCTGAAACCAGAG

ACCTGAAACCAGAGT

CCTGAAACCAGAGTG

CTGAAACCAGAGTGG

TGAAACCAGAGTGGC

GAAACCAGAGTGGCC

AAACCAGAGTGGCCA

AACCAGAGTGGCCAT

ACCAGAGTGGCCATT

CCAGAGTGGCCATTA

CAGAGTGGCCATTAA

AGAGTGGCCATTAAA

GAGTGGCCATTAAAA

AGTGGCCATTAPAAAC

GTGGCCATTAAAACA

TGGCCATTAAAACAG

GGCCATTAAAACAGT

GCCATTAAAACAGTG

CCATTAAAACAGTGA

CATTAAAACAGTGAA

ATTAAAACAGTGAAC

TTAAAACAGTGAACG

TAAAACAGTGAACGA

AAAACAGTGAACGAG

AAACAGTGAACGAGG

AACAGTGAACgAGGC

ACAGTGAACGAGGCC

CAGTGAACGAGGCCG

AGTGAACGAGGCCGC

GTGAACGAGGCCGCA

TGAACGAGGCCGCAA

GAACGAGGCCGCAAG

AACGAGGCCGCAAGC

ACGAGGCCGCAAGCA

CGAGGCCGCAAGCAT

GAGGCCGCAAGCATG

AGGCCGCAAGCATGC

GGCCGCAAGCATGCG

GCCGCAAGCATGCGT

CCGCAAGCATGCGTG

CGCAAGCATGCGTGA

GCAAGCATGCGTGAG

CAAGCATGCGTGAGA

AAGCATGCGTGAGAG

AGCATGCGTGAGAGG

GCATGCGTGAGAGGA

CATGCGTGAGAGGAT

ATGCGTGAGAGGATT

TGCGTGAGAGGATTG

GCGTGAGAGGATTGA

CGTGAGAGGATTGAG

GTGAGAGGATTGAGT

TGAGAGGATTGAGTT

GAGAGGATTGAGTTT

AGAGGATTGAGTTTC

GAGGATTGAGTTTCT

AGGATTGAGTTTCTC

GGATTGAGTTTCTCA

GATTGAGTTTCTCAA

ATTGAGTTTCTCAAC

TTGAGTTTCTCAACG

TGAGTTTCTCAACGA

GAG7'TTCTCAACGAA AG7TTTCTCAACGAAG

GTTTCTCAACGAAGC

TTTCTCAACGAAGCT

TTCTCAACGAAGCTT

TCTCAACGAAGCTTC

CTCAACGAAGCTTCT

TCAACGAAGCTTCTG

CAACGAAGCTTCTGT

AACGAAGCTTCTGTG

ACGAAGCTTCTGTGA

CGAAGCTTCTGTGAT

GAAGCTTCTGTGATG

AAGCTTCTGTGATGA

AGCTTCTGTGATGAA

GCTTCTGTGATGAAG

CTTCTGTGATGAAGG

TTCTGTGATGAAGGA

TCTGTGATGAAGGAG

CTGTGATGAAGGAGT

TGTGATGAAGGAGTT

GTGATGAAGGAGTTC

TGATGAAGGAGTTCA

GATGAAGGAGTTCAA

ATGAAGGAGTTCAAT

TGAAGGAGTTCAATT

GAAGGAGTTCAATTG

AAGGAGTTCAATTGT

AGGAGTTCAATTGTC

GGAGTTCAATTGTCA

GAGTTCAATTGTCAC

AGTTCAATTGTCACC

GTTCAATTGTCACCA

TTCAA.TTGTCACCAT

TCAATTGTCACCATG

CAATTGTCACCATGT

AATTGTCACCATGTG

ATTGTCACCATGTGG

TTGTCACCATGTGGT

TGTCACCATGTGGTG

GTCACCATGTGGTGC

TCACCATGTGGTGCG

CACCATGTGGTGCGA

ACCATGTGGTGCGAT

CCATGTGGTGCGATT

CATGTGGTGCGATTG

ATGTGGTGCGATTGC

TGTGGTGCGATTGCT

GTGGTGCGATTGCTG

TGGTGCGATTGCTGG

GGTGCGATTGCTGGG

GTGCGATTGCTGGGT

TGCGATTGCTGGGTG

GCGATTGCTGGGTGT

CGATTGCTGGGTGTG

GATTGCTGGGTGTGG

ATTGCTGGGTGTGGT

TTGCTGGGTGTGGTG

TGCTGGGTGTGGTGT

GCTGGGTGTGGTGTC

CTGGGTGTGGTGTCC

TGGGTGTGGTGTCCC

GGGTGTGGTGTCCCA

GGTGTGGTGTCCCAA

GTGTGGTGTCCCAAG

TGTGGTGTCCCAAGG

GTGGTGTCCCAAGGC

TGGTGTCCCAAGGCC

GGTGTCCCAAGGCCA

GTGTCCCAAGGCCAG

TGTCCCAAGGCCAGC

GTCCCAAGGCCAGCC

TCCCAAGGCCAGCCA

CCCAAGGCCAGCCAA

CCAAGGCCAGCCAAC

CAAGGCCAGCCAACA

AAGGCCAGCCAACAC

AGGCCAGCCAACACT

GGCCAGCCAACACTG

GCCAGCCAACACTGG

CCAGCCAACACTGGT

CAGCCAACACTGGTC

AGCCAACACTGGTCA

GCCAACACTGGTCAT

CCAACACTGGTCATC

CAACACTGGTCATCA

AACACTGGTCATCAT

ACACTGGTCATCATG

CACTGGTCATCATGG

ACTGGTCATCATGGA

CTGGTCATCATGGAA

TGGTCATC-ATGGAAC

GGTCATCATGGAACT

I

I WO096101636 PTA9101 PCT/AU95/00410 61

GTCATCATGGAACTG

TCATCATGGAACTGA

CATCATGGAACTGAT

ATCATGGAACTGATG

TCATGGAACTGATGA

CATGGAACTGATGAC

ATGGAACTGATGACA

TGGAACTGATGACAC

GGAACTGATGACACG

GAACTGATGACACGG

AACTGATGACACGGG

ACTGATGACACGGGG

CTGATGACACGGGGC

TGATGACACGGGGCG

GATGACACGGGGCGA

ATGACACGGGGCGAT

TGACACGGGGCGATC

GACACGGGGCGATCT

ACACGGGGCGATCTC

CACGGGGCGATCTCA

ACGGGGCGATCTCAA

CGGGGCGATCTCAAA

GGGGCGATCTCAAA2-.

GGGCGATCTCAAAAG

GGCGATCTCAAAAGT

GCGATCTCAAAAGTT

CGATCTCAAAAGTTA

GATCTCAAAAGTTAT

ATCTCAAAAGTTATC

TCTCAAAAGTTATCT

CTCAAAAGTTATCTC

TCAAAAGTTATCTCC

CAAAAGTTATCTCCG

AAAAGTTATCTCCGG

AAAGTTATCTCCGGT

AAGTTATCTCCGGTC

AGTTATCTCCGGTCT

GTTATCTCCGGTCTC

TTATCTCCGGTCTCT

TATCTCCGGTCTCTG

AT CT CCGGT CTCTGA

TCTCCGGTCTCTGAG

CTCCGGTCTCTGAGG

TCCGGTCTCTGAGGC

CCGGTCTCTGAGGCC

CGGTCTCTGAGGCCA

GGTCTCTGAGGCCAG

GTCTCTGAGGCCAGA

TCTCTGAGGCCAGAA

CTCTGAGGCCAGAAA

TCTGAGGCCAGAAAT

CTGAGGCCAGAAATG

TGAGGCCAGAAATGG

GAGGCCAGAAATGGA

AGGCCAGA-ZATGGAG

GGCCAGAAATGGAGA

GCCAGAAATGGAGAA

CCAGAAATGGAGAAT

CAGAAATGGAGAATA

AGAAATGGAGAATAA

GAAATGGAGAATAAT

AAATGGAGAATAATC

AATGGAGAATAATCC

ATGGAGAATAATCCA

TGGAGAATAATCCAG

GGAGAATAATCCAGT

GAGAATAATCCAGTC

AGAATAATCCAGTCC

GAATAATCCAGTCCT

AATAATCCAGTCCTA

ATAATCCAGTCCTAG

TAATCCAGTCCTAGC

AATCCAGTCCTAGCA

ATCCACTCCTAGCAC

TCCAGTCCTAGCACC

CCAGTCCTAGCACCT

CAGTCCTAGCACCTC

AGTCCTAGCACCTCC

GTCCTAGCACCTCCA

TCCTAGCACCTCCAA

CCTAGCACCTCCAAG

CTAGCACCTCCAAGC

TAGCACCTCCAAGCC

AGCACCTCCAAGCCT

GCACCTCCAAGCCTG

CACCTCCAAGCCTGA

ACCTCCAAGCCTGAG

CCTCCAAGCCTGAGC

CTCCAAGCCTGAGCA

TCCAAGCCTGAGCAA

CCAAGCCTGAGCAAG

CAAGCCTGAGCAAGA

AAGCCTGAGCAAGAT

AGCCTGAGCAAGATG

GCCTGAGCAAGATGA

CCTGAGCAAGATGAT

CTGAGCAAGATGATT

TGAGCAAGATGATTC

GAGCAAGATGATTCA

AGCAAGATGATTCAG

GCAAGATGATTCAGA

CAAGATGATTCAGAT

AAGATGATTCAGATG

AGATGATTCAGATGG

GATGATTCAGATGGC

ATGATTCAGATGGCC

TGATTCAGATGGCCG

GATTCAGATGGCCGG

ATTCAGATGGCCGGA

TTCAGATGGCCGGAG

TCAGATGGCCGGAGA

CAGATGGCCGGAGAG

AGATGGCCGGAGAGA

GATGGCCGGAGAGAT

ATGGCCGGAGAGATT

TGGCCGGAGAGATTG

GGCCGGAGAGATTGC

GCCGGAGAGATTGCA

CCGGAGAGATTGCAG

CGGAGAGATTGCAGA

GGAGAGATTGCAGAC

GAGAGATTGCAGACG

AGAGATTGCAGACGG

GAGATTGCAGACGGC

AGATTGCAGACGGCA

GATTG CAGACGG CAT

ATTGCAGACGGCATG

TTGCAGACGGCATGG

TGCAGACGGCATGGC

GCAGACGGCATGGCA

CAGACGGCATGGCAT

AGACGGCATGGCATA

GACGGCATGGCATAC

ACGGCATGGCATACC

CGGCATGGCATACCT

GGCATGGCATACCTC

GCATGGCATACCTCA

CATGGCATACCTCAA

ATGGCATACCTCAAC

TGGCATACCTCAACG

GGCATACCTCAACGC

GCATACCTCAACGCC

CATACCTCAACGCCA

ATACCTCAACGCCAA

TACCTCAACGCCAAT

ACCTCAACGCCAATA

CCTCAACGCCAATAA

CTCAACGCCAATAAG

TCAACGCCAATAAGT

CAACGCCAATAAGTT

AACGCCAATAAGTTC

ACGCCAATAAGTTCG

CGCCAATAAGTTCGT

GCCAATAAGTTCGTC

CCAATAAGTTCGTCC

CAATAAGTTCGTCCA

AATAAGTTCGTCCAC

ATAAGTTCGTCCACA

TAAGTTCGTCCACAG

AAGTTCGTCCACAGA

AGTTCGTCCACAGAG

GTTCGTCCACAGAGA

TTCGTCCACAGAGAC

TCGTCCACAGAGACC

CGTCCACAGAGACCT

GTCCACAGAGACCTT

TCCACAGAGACCTTG

CCACAGAGACCTTGC

WO 96/01636 PTA9/01 PCT/A'U95/00410 62

CACAGAGACCTTGCT

ACAGAGACCTTGCTG

CAGAGACCTTGCTGC

AGAGACCTTGCTGCC

GAGACCTTGCTGCCC

AGACCTTGCTGCCCG

GACCTTGCTGCCCGG

AC CTTGCTG C CCGGA C CTTG CTG C CCGGAA

CTTGCTGCCCGGAAT

TTGCTGCCCGGAATT

TGCTGCCCGGAATTG

GCTGCCCGGAATTGC

CTGCCCGGAATTGCA

TGCCCGGAATTGCAT

GCCCGGAATTGCATG

CCCGGAATTGCATGG

CCGGAATTGCATGGT

CGGAATTGCATGGTA

GGAATTGCATGGTAG

GAATTGCATGGTAGC

AATTGCATGGTAGCC

ATTGCATGGTAGCCG

TTGCATGGTAGCCGA

TGCATGGTAGCCGAA

GCATGGTAGCCGAAG

CATGGTAGCCGAAGA

ATGGTAGCCGAAGAT

TGGTAGCCGAAGATT

GGTAGCCGAAGATTT

GTAGCCGAAGATTTC

TAGCCGAAGATTTCA

AGCCGAAGATTTCAC

GCCGAAGATTTCACA

CCGAAGATTTCACAG

CGAAGATTTCACAGT

GAAGATTTCACAGTC

AAGATTTCACAGTCA

AGATTTCACAGTCAA

GATTTCACAGTCAAA

ATTTCACAGTCAAA

TTTCACAGTCAAAAT

TTCACAGTCAAAATC

TCACAGTCAAAATCG

CACAGTCAAAATCGG

ACAGTCAAAATCGGA

CAGTCAAAATCGGAG

AGTCAAAATCGGAGA

GTCAAAATCGGAGAT

TCAAAATCGGAGATT

CAAAATCGGAGATTT

AAAATCGGAGATTTT

AAATCGGAGATTTTG

AATCGGAGATTTTGG

ATCGGAGATTTTGGT

TCGGAGATTTTGGTA

CGGAGATTTTGGTAT

GGAGATTTTGGTATG

GAGATTTTGGTATGA

AGATTTTGGTATGAC

GATTTTGGTATGACG

ATTTTGGTATGACGC

TTTTGGTATGACGCG

TTTGGTATGACGCGA

TTGGTATGACGCGAG

TGGTATGACGCGAGA

GGTATGACGCGAGAT

GTATGACGCGAGATA

TATGACGCGAGATiAT

ATGACGCGAGATATC

TGACGCGAGATATCT

GACGCGAGATATCTA

ACGCGAGATATCTAT

CGCGAGATATCTATG

GCGAGATATCTATGA

CGAGATATCTATGAG

GAGATATCTATGAGA

AGATATCTATGAGAC

GATATCTATGAGACA

ATATCTATGAGACAG

TAT CTATGAGACAGA

ATCTATGAGACAGAC

TCTATGAGACAGACT

CTATGAGACAGACTA

TATGAGACAGACTAT

ATGAGACAGACTATT

TGAGACAGACTATTA

GAGACAGACTATTAC

AGACAGACTATTACC

GACAGACTATTACCG

ACAGACTATTACCGG

CAGACTATTACCGGA

AGACTATTACCGGAA

GACTATTACCGGAAA

ACTATTACCGGAAAG

CTATTACCGGAAAGG

TATTACCGGAAAGGA

ATTACCGGAAAGGAG

TTACCGGAAAGGAGG

TACCGGAAAGGAGGC

ACCGGAAAGGAGGCA

CCGGAAAGGAGGCAA

CGGAAAGGAGGCAAA

GGAAAGGAGGCAAAG

GAAAGGAGGCAAAGG

AAAGGAGGCAAAGGG

AAGGAGGCAAAGGGC

ACGAGGCAAAGGGCT

GGAGGCAAAGGGC'-TG

GAGGCAAAGGGCTGC

AGGCAAAGGGCTGCT

GGCAAAGGGCTGCTG

GCAAAGGGCTGCTGC

CAAAGGGCTGCTGCC

AAAGGGCTGCTGCCC

AAGGGCTGCTGCCCG

AGGGCTGCTGCCCGT

GGGCTGCTGCCCGTG

GGCTGCTGCCCGTGC

GCTGCTGCCCGTGCG

CTGCTGCCCGTGCGC

TGCTGCCCGTGCGCT

GCTGCCCGTGCGCTG

CTGCCCGTGCGCTGG

TGCCCGTGCG'CTGGA

GCCCGTGCGCTGGAT

CCCGTGCGCTGGAtTG

CCGTGCGCTGGATGT

CGTGCGCTGGATGTC

GTGCGCTGGATGTCTr

TGCGCTGGATGTCTC

GCGCTGGATGT CT CC

CGCTGGATGTCTCCT

GCTGGATGTCTCCTG

CTGGATGTCTCCTGA

TGGATGTCTCCTGAG

GGATGTCTCCTGAGT

GATGTCTCCTGAGTC

ATGTCTCCTGAGTCC

TGTCTCCTGAGTCCC

GTCTCCTGAGTCCCT

TCTCCTGAGTCCCTC

CTCCTGAGTCCCTCA

TCCTGAGTCCCTCAA

CCTGAGTCCCTCAAG

CTGAGTCCCTCAAGG

TGAGTCCCTCAAGGA

GAGTCCCTCAAGGAT

AGTCCCTCAAGGATG

GTCCCTCAAGGATGG

TCCCTCAAGGATGGA

CC CTCAAGGATGGAG

CCTCAAGGATGGAGT

CTCAAGGATGGAGTC

TCAAGGATGGAGTCT

CAAGGATGGAGTCTT

AAGGATGGAGTCTTC

AGGATGGAGTCTTCA

GGATGGAGTCTTCAC

GATGGAGTCTTCACC

ATGGAGTCTTCACCA

TGGAGTCTTCACCAC

GGAGTCTTCACCACT

GAGTCTTCACCACTT

AGTCTTCACCACTTA

GTCTTCACCACTTAC

TCTTCACC-ACTTACT

CTTCACCACTTACTC

WO 96101636 PTA9101 PCT/AU9510041 0 63

TTCACCACTTACTCG

TCACCACTTACTCGG

CACCACTTACTCGGA

ACCACTTACTCGGAC

CCACTTACTCGGACG

CACTTACTCGGACGT

ACTTACTCGGACGTC

CTTACTCGGACGTCT

TTACTCGGACGTCTG

TACTCGGACGTCTGG

ACTCGGACGTCTGGT

CTCGGACGTCTGGTC

TCGGACGTCTGGTCC

CGGACGTCTGGTCCT

GGACGTCTGGTCCTT

GACGTCTGGTCCTTC

ACGTCTGGTCCTTCG

CGTCTGGTCCTTCGG

GTCTGGTCCTTCGGG

TCTGGTCCTTCGCGG

CTGGTCCTTCGGGGT

TGGTCCTTCGGGGTC

GGTCCTTCGGGGTCG

GTCCTTCGGGGTCGT

TCCTTCGGGGTCGTC

CCTTCGGGGTCGTCC

CTTCGGGGTCGTCCT

TTCGGGGTCGTCCTC

TCGGGGTCGTCCTCT

CGGGGTCGTCCTCTG

GGGGTCGTCCTCTGG

GGGTCGTCCTCTGGG

GGTCGTCCTCTGGGA

GTCGTCCTCTGGGAG

TCGTCCTCTGGGAGA

CGTCCTCTGGGAGAT

GTCCTCTGGGAGATC

TCCTCTGGGAGATCG

CCTCTGGGAGATCGC

CTCTGGGAGATCGCC

TCTGGGAGATCGCCA

CTGGGAGATCGCCAC

TGGGAGATCGCCACA

GGGAGATCGCCACAC

GGAGATCGCCACACT

GAGATCGCCACACTG

AGATCGCCACACTGG

GATCGCCACACTGGC

ATCGCCACACTGGCC

TCGCCACACTGGCCG

CGCCACACTGGCCGA

GCCACACTGGCCGAG

CCACACTGGCCGAGC

CACACTGGCCGAGCA

ACACTGGCCGAGCAG

CACTGGCCGAGCAGC

ACTGGCCGAGCAGCC

CTGGCCGAGCAGCCC

TGGCCGAGCAGCCCT

GGCCGAGCAGCCCTA

GCCGAGCAGCCCTAC

CCGAGCAGCCCTACC

CGAGCAGCCCTACCA

GAGCAGCCCTACCAG

AGCAGCCCTACCAGG

GCAGCCCTACCAGGG

CAGCCCTACCAGGGC

AGCCCTACCAGGGCT

GCCCTACCAGGGCTT

CCCTACCAGGGCTTG

CCTACCAGGGCTTGT

CTACCAGGGCTTGTC

TACCAGGGCTTGTCC

ACCAGGGCTTGTCCA

CCAGGGCTTGTCCAA

CAGGGCTTGTCCAAC

AGGGCTTGTCCAACG

GGGCTTGTCCAACGA

GGCTTGTCCAACGAG

GCTTGTCCAACGAGC

CTTGTCCAACGAGCA

TTGTCCAACGAGCAA

TGTCCAACGAGCAAG

GTCCAACGAGCAAGT

TCCAACGAGCAAGTC

CCAACGAGCAAGTCC

CAACGAGCAAGTCCT

AACGAGCAAGTCCTT

ACGAGCAAGTCCTTC

CGAGCAAGTCCTTCG

GAGCAAGTCCTTCGC

AGCAAGTCCTTCGCT

GCAAGTCCTTCGCTT

CAAGTCCTTCGCTTC

AAGTCCTTCGCTTCG

AGTCCTTCGCTTCGT

GTCCTTCGCTTCGTC

TCCTTCGCTTCGTCA

CCTTCGCTTCGTCAT

CTTCGCTTCGTCATG

TTCGCTTCGTCATGG

TCGCTTCGTCATGGA

CGCTTCGTCATGGAG

GCTTCGTCATGGAGG

CTTCGTCATGGAGGG

TTCGTCATGGAGGGC

TCGTCATGGAGGGCG

CGTCATGGAGGGCGG

GTCATGGAGOGCGGC

TCATGGAGGGCGGCC

CATGGAGGGCGGCCT

ATGGAGGGCGGCCTT

TGGAGGGCGGCCTTC

GGAGGGCGGCCTTCT

GAGGGCGGCCTTCTG

AGGGCGGCCTTC'IGG

GGGCGGCCTTCTGGA

GGCGGCCTTCTGGAC

GCGGCCTTCTGGACA

CGGCCTTCTGGACAA

GGCCTTCTGGACAAG

GCCTTCTGGACAAGC

CCTTCTGGACAAGCC

CTTCTGGACAAGCCA

TTCTGGACAAGCCAG

TCTGGACAAGCCAGA

CTGGACAAGCCAGAC

TGGACAAGCCAGACA

GGACAAGCCAGACAA

GACAAGCCAGACAAC

ACAAGCCAGACAACT

CAAGCCAGACAACTG

AAGCCAGACAACTGT

AGCCAGACAACTGTC

GCCAGACAACTGTCC

CCAGACAACTGTCCT

CAGACAACTGTCCTG

AGACAACTGTCCTGA

GACAACTGTCCTGAC

ACAACTGTCCTGACA

CAACTGTCCTGACAT

AACTGTCCTGACATG

ACTGTCCTGACATGC

CTGTCCTGACATGCT

TGTCCTGACATGCTG

GTCCTGACATGCTGT

TCCTGACATGCTGTT

CCTGACATGCTGTTT

CTGACATGCTGTTTG

TGACATGCTGTTTGA

GACATGCTGT'TTGAA

ACATGCTGTTTGAAC

CATGCTGTTTGAACT

ATGCTGTTTGAACTG

TGCTGTTTGAACTGA

GCTGTTTGAACTGAT

CTGTTTGAACTGATG

TGTTTGAACTGATGC

GTTTGAACTGATGCG

TTTGAACTGATGCGC

TTGAACTGATGCGCA

TGAACTGATGCGCAT

GAACTGATGCGCATG

AACTGATGCGCATGT

ACTGATGCGCATGTG

CTGATGCGCATGTGC

TGATGCGCATGTGCT

GATGCGCATGTGCTG

WO 9610 1636 PTA9/01 PCT/AU95/00410 64

ATGCGCATGTGCTGG

TGCGCATGTGCTGGC

GCGCATGTGCTGGCA

CGCATGTGCTGGCAG

GCATGTGCTGGCAGT

CATGTGCTGGCAGTA

ATGTGCTGGCAGTAT

TGTGCTGGCAGTATA

GTGCTGGCAGTATAA

TGCTGGCAGTATAAC

GCTGGCAGTATAACC

CTGGCAGTATAACCC

TGGCAGTATAACCCC

GGCAGTATAACCCCA

GCAGTATAACCCCAA

CAGTATAACCCCAAG

AGTATAACCCCAAGA

GTATAACCCCAAGAT

TATAACCCCAAGATG

ATAACCCCAAGATGA

TAACCCCAAGATGAG

AACCCCAAGATGACG

ACCCCAAGATGAGGC

CCCCAAGATGAGGCC

CCCAAGATGAGGCCT

CCAAGATGAGGCCTT

CAAGATGAGGCCTTC

AAGATGAGGCCTTCC

AGATGAGGCCTTCCT

GATGAGGCCTTCCTT

ATGAGGCCTTCCTTC

TGAGGCCTTCCTTCC

GAGGCCTTCCTTCCT

AGGCCTTCCTTCCTG

GGCCTTCCTTCCTGG

GCCTTCCTTCCTGGA

CCTTCCTTCCTGGAG

CTTCCTTCCTGGAGA

TTCCTTCCTGGAGAT

TCCTTCCTGGAGATC

CCTTCCTGGAGATCA

CTTCCTGGAGATCAT

TTCCTGGAGATCATC

TCCTGGAGATCATCA

CCTGGAGATCATCAG

CTGGAGATCATCAGC

TGGAGATCATCAGCA

GGAGATCATCAGCAG

GAGATCATCAGCAGC

AGATCATCAGCAGCA

GAT CAT CAGCAGCAT

ATCATCAGCAGCATC

TCATCAGCAGCATCA

CAT CAG CAG CAT CAA

ATCAGCAGCATCAAA

TCAGCAGCATCAAAG

CAGCAGCATCAAAGA

AGCAGCATCAA.,%GAG

GCAGCATCAAAGAGG

CAGCATCAAAGAGGA

AGCATCAAAGAGGAG

GCATCAAAGAGGAGA

CAT CAAAGAGGAGAT

ATCAAAGAGGAGATG

TCAAAGAGGAGATGG

CAAAGAGGAGATGGA

AAAGAGGAGATGGAG

AAGAGGAGATGGAGC

AGAGGAGATGGA' GCC

GAGGAGATGGAGCCT

AGGAGATGGAGCCTG

GGAGATGGAGCCTGG

GAGATGGAGCCTGGC

AGATGGAGCCTGGCT

GATGGAGCCTGGCTT

ATGGAGCCTGGCTTC

TGGAGCCTGGCTTCC

GGAGCCTGGCTTCCG

GAGCCTGGCTTCCGG

AGCCTGGCTTCCGGG

GCCTGGCTTCCGGGA

CCTGGCTTCCGGGAG

CTGGCTTCCGGGAGG

TGGCTTCCGGGAGGT

GGCTTCCGGGAGGTC

GCTTCCGGGAGGTCT

CTTCCGGGAGGTCTC

TTC CGGGAGGT CTC C

TCCGGGAGGTCTCCT

CCGGGAGGTCTCCTT

CGGGAGGTCTCCTTC

GGGAGGTCTCCTTCT

GGAGGTCTCCTTCTA

GAGGTCTCCTTCTAC

AGGTCTCCTTCTACT

GGTCTCCTTCTACTA

GTCTCCTTCTACTAC

TCTCCTTCTACTACA

CTCCTTCTACTACAG

TCCTTCTACTACAGC

CCTTCTACTACAGCG

CTTCTACTACAGCGA

TTCTACTACAGCGAG

TCTACTACAGCGAGG

CTACTACAGCGAGGA

TACTACAGCGAGGAG

ACTACAGCGAGGAGA

CTACAGCGAGGAGAA

TACAGCGAGGAGAAC

ACAGCGAGGAG-AACA

CAGCGAGGAGAACAA

AGCGAGGAGAACAAG

GCGAGGAGAACAAGC

CGAGGAGAACAAGCT

GAGGAGAACAAGCTG

AGGAGAACAAGCTGC

GGAGAACAAGCTGCC

GAGAACAAGCTGCCC

AGAACAAGCTGCCCG

GAACAAGCTGCCCGA

AACAAGCTGCCCGAG

ACAAGCTGCCCGAGC

CAAGCTGCCCGAGCC

AAGCTGCCCGAGCCG

AGCTGCCCGAGCCGG

GCTGCCCGAGCCGGA

CTGCCCGAGCCGGAG

TGCCCGAGCCGGAGG

GCCCGAGCCGGAGGA

CCCGAGCCGGAGGAG

CCGAGCCGGAGGAGC

CGAGCCGGAGGAGCT

GAGCCGGAGGAGCTG

AGCCGGAGGAGCTGG

GCCGGAGGAGCTGGA

CCGGAGGAGCTGGAC

CGGAGGAGCTGGACC

GGAGGAGCTGGACCT

GAGGAGCTGGACCTG

AGGAGCTGGACCTGG

GGAGCTGGACCTGGA

GAGCTGGACCTGGAG

AGCTGGACCTGGAGC

GCTGGACCTGGAGCC

CTGGACCTGGAGCCA

TGGACCTGGAGCCAG

GGACCTGGAGCCAGA

GACCTGGAGCCAGAG

ACCTGGAGCCAGAGA

CCTGGAGCCAGAGAA

CTGGAGCCAGAGAAC

TGGAGCCAGAGAACA

GGAGCCAGAGAACAT

GAGCCAGAGAACATG

AGCCAGAGAACATGG

GCCAGAGAACATGGA

CCAGAGAACATGGAG

CAGAGAACATGGAGA

AGAGAACATGGAGAG

GAGAACATGGAGAGC

AGAACATGGAGAGCG

GAACATGGAGAGCGT

AACATGGAGAGCGTC

ACATGGAGAGCGTCC

CATGGAGAGCGTCCC

ATGGAGAGCGTCCCC

TGGAGAGCGTCCCCC

GGAGAGCGTCCCCCT

WO 96/01636 WO 96/ 1636PCTAU95OO4 65

GAGAGCGTCCCCCTG

AGAGCGTCCCCCTGG

GAGCGTCCCCCTGGA

AGCGTCCCCCT"7GAC

GCGTCCCCCTGGACC

CGTCCCCCTGGACCC

GTCCCCCTGGACCCC

TCCCCCTGGACCCCT

CCCCCTGGACCCCTC

CCCCTGGACCCCTCG

CCCTGGACCCCTCGG

C CTGGAC C CCTCGG C

CTGGACCCCTCGGCC

TGGACCC CT CGG CCT

GGACCCCTCGGCCTC

GACCCCTCGGCCTCC

ACCCCTCGGCCTCCT

CCCCTCGGCCTCCTC

CCCTCGGCCTCCTCG

CCTCGGCCTCCTCGT

CTCGGCCTCCTCGTC

TCGGCCTCCTCGTCC

CGGCCTCCTCGTCCT

GGCCTCCTCGTCCTC

GCCTCCTCGTCCTCC

CCTCCTCGTCCTCCC

CTCCTCGTCCTCCCT

TCCTCGTCCTCCCTG

CCTCGTCCTCCCTGC

CTCGTCCTCCCTGCC

TCGTCCTCCCTGCCA

CGTCCTCCCTGCCAC

GTCCTCCCTGCCACT

TCCTCCCTGCCACTG

CCTCCCTGCCACTGC

CTCCCTGCCACTGCC

TCCCTGCCACTGCCC

CCCTGCCACTGCCCG

CCTGCCACTGCCCGA

CTGCCACTGCCCGAC

TGCCACTGCCCGACA

GCCACTGCCCGACAG

CCACTGCCCGACAGA

CACTGCCCGACAGAC

ACTGCCCGACAGACA

CTGCCCGACAGACAC

TGCCCGACAGACACT

GCCCGACAGACACTC

CCCGACAGACACTCA

CCGACAGACACTCAG

CGACAGACACTCAGG

GACAGACACTCAGGA

ACAGACACTCAGGAC

CAGACACTCAGGACA

AGACACTCAGGACAC

GACACTCAGGACACA

ACACTCAGGACACAA

CACTCAGGACACAAG

ACTCAGGACACAAGG

CTCAGGACACAAGGC

TCAGGACACAAGGCC

CAGGACACAAGGCCG

AGGACACAAGGCCGA

GGACACAAGGCCGAG

GACACAAGGCCGAGA

ACACAAGGCCGAGAA

CACAAGGCCGAGAAC

ACAAGGCCGAGAACG

CAAGGCCGAGAACGG

AAGGCCGAGAACGGC

AGGCCGAGAAkCGGCC

GGCCGAGAACGGCCC

CCCGAGAACGGCCC C

CCGAGAACGCCCCCG

CGAGAACGCCCCCC

GAGAACGGCCCCGCC

AGAACGGCCCCGGCC

GA7ACGCCCCCGGCC C

AACGGCCCCGGCCCT

ACGGCCCCGGCCCTG

CGGCCCCGGCCCTCG

GGCCCCGGCCCTGGG

GCCCCGGCCCTGCGGG

CCCCGGCCCTGGGGT

CCCGGCCCTGGGGTG

CCGGCCCTGGGGTGC

CGGCCCTGGGGTGCT

GGCCCTGGCTGCTG

GCCCTGGGGTGCTGG

CCCTGGGGTGCTGGT

CCTGC-GTGCTGGTC

CTGGGGTGCTGGTCC

TGGGGTGCTGGTCCT

GGGGTCCTGGTCCTC

GGGTGCTGCTCCTCC

GGTGCTGGTCCTCCG

GTGCTGGTCCTCCGC

TGCTGGTCCTCCGCG

GCTGGTCCTCCGCGC

CTGGTCCTCCGCGCC

TGGTCCTCCGCGCCA

GGTCCTCCGCGCCAG

GTCCTCCGCGCCAC

TCCTCCGCGCCAGCT

CCTCCGCGCCAGCTT

CTCCGCGCCAGCTTC

TCCGCGCCAGCTTCG

CCGCGCCAGCTTCGA

CGCGCCAGCTTCGAC

GCGCCAGCTTCGACG

CGCCAGCTTCGACGA

GCCAGCTTCGACGAG

CCACCTTCGACGAGA

CAGCTTCGACGAGAG

AGCTTCGACGAGAGA

GCTTCGACGACAGAC

CTTCGACGAGAGACA

TTCGACGAGAGACAG

TCGACGAGAGACAGC

CGACGAGAGACAGCC

GACCAGAGACAGCCT

ACGAGAGACAGCCTT

CGAGAGACAGCCTTA

GAGAGACAGCCTTAC

AGAGACAGCCTTACG

GAGACAGCCTTACGC

AGACAGCCTTACGCC

GACAGCCTTACGCCC

ACAGCCTTACGCCCA

CACCCTTACGCCCAC

AGCCTTACCCCCACA

GCCTTACGCCCACAT

CCTTACGCCCACATG

CTTACGCCCACATGA

TTACGCCCACATGAA

TACGCCCACATGAAC

ACGCCCACATGAACG

CGCCCACATGAACGG

CCC CACATGAACCG

CC'CACATGAACGGGG

CCACATGAACGCGGGC

CACATGAACGGGGGC

ACATGAACGGGGGCC

CATGAACGCGCCG

,XTGAACGGCGCCC

TGAACGGGGGCCGCA

GAACGCGCCGCAA

AACGGGGGCCGCAAG

ACGGGGGCCGCAAGA

CGGGGCCCCAAGAA

GGGGCCGCAAGAAC

GCGGCCGCAAGAACG

CCCCCGCAAGAACGA

GGCCGCAAGAACGAG

CCCCAAGAACGAGC

CCGCAAGAACGAC

CGCAAGAACGAGCGG

GCAAGAACGAGCGGG

CAACAACGAGCGGGC

AAGAACGAGCGGGCC

AGAACGAGCGGGCCT

GAACGAGCGGGCCTT

AACGAGCGGGCCTTG

ACCAGCGCCTTGC

CGAGCGGCCTTGCC

GACCGGCCTTGCCG

AGCGGGCCTTGCCGC

GCGGCCTTGCCGCT

I

PCTIAU95/00410 WO 96101636 66

CGGGCCTTGCCGCTG

GGGCCTTGCCGCTGC

GGCCTTGCCGCTGCC

GCCTTGCCGCTGCCC

CCTTGCCGCTGCCCC

CTTGCCGCTGCCCCA

TTGCCGCTGCCCCAG

TGCCGCTGCCCCAGT

GCCGCTGCCCCAGTC

CCGCTGCCCCAGTCT

CGCTGCCCCAGTCTT

GCTG CC CCAGTCTT C

CTGCCCCAGTCTTCG

TGCCCCAGTCTTCGA

GCCCCAGTCTTCGAC

CCCCAGTCTTCGACC

CCCAGTCTTCGACCT

CCAGTCTTCGACCTG

CAGTCTTCGACCTGC

AGTCTTCGACCTGCT

GTCTTCGACCTGCTG

TCTTrCGACCTGCTGA

CTTCGACCTGCTGAT

TTCGACCTGCTGATC

TCGACCTGCTGATCC

CGACCTGCTGATCCT

GACCTGCTGATCCTT

ACCTGCTGATCCTTG

CCTGCTGATCCTTGG

CTGCTGATCCTTGGA

TGCTGATCCTTGGAT

GCTGATCCTTGGATC

CTGATCCTTGGATCC

TGATCCTTGGATCCT

GATCCTTGGATCCTG

ATCCTTGGATCCTGA

TCCTTGGATCCTGAA

CCTTGGATCCTGAAT

CTTGGATCCTGAATC

TTGGATCCTGAATCT

TGGATCCTGAATCTG

GGATCCTGAATCTGT

GATCCTGAATCTGTG

ATCCTGAATCTGTGC

TCCTGAATCTGTGCA

CCTGAATCTGTGCAA

CTGAATCTGTGCAAA

TGAATCTGTGCAAAC

GAATCTGTGCAAACA

AATCTGTGCAAPACAG

ATCTGTGCAAACAGT

TCTGTGCAAACAGTA

CTGTGCAAACAGTAA

TGTGCAAACAGTAAC

GTGCAAACAGTAACG

TGCAAACAGTAACGT

GCAAACAGTAACGTG

CAAACAGTAACGTGT

AAACAGTAACGTGTG

AACAGTAACGTGTGC

ACAGTAACGTGTGCG

CAGTAACGTGTGCGC

AGTAACGTGTGCGCA

GTAACGTGTGCGCAC

TAACGTGTGCGCACG

AACGTGTGCGCACGC

ACGTGTGCGCACGCG

CGTGTGCGCACGCGC

GTGTGCGCACGCGCA

TGTGCGCACGCGCAG

GTGCGCACGCGCAGC

TGCGCACGCGCAGCG

GCGCACGCGCAGCGG

CGCACGCGCAGCGGG

GCACGCGCAGCGGGG

CACGCGCAGCGGGGT

ACGCGCAGCGGGGTG

CGCGCAGCGGGGTGG

GCGCAGCGGGGTGGG

CGCAGCGGGGTGGGG

GCAGCGGGGTGGGGG

CAGCGGGGTGGGGGG

AGCGGGGTGGGGGGG

GCGGGGTGGGGGGGG

CGGGGTGGGGGGGGA

GGGGTGGGGGGGGAG

GGGTGGGGGGGGAGA

GGTGGGGGGGGAGAG

GTGGGGGGGGAGAGA

TGGGGGGGGAGAGAG

GGGGGGGGAGAGAC37\

GGGGGGGAGAGAGAG

GGGGGGAGAGAGAGT

GGGGGAGAGAGAGTT

GGGGAGAGAGAGTTT

GGGAGAGAGAGTTTT

GGAGAGAGAGTTTTA

GAGAGAGAGTTTTAA

AGAGAGAGTTTTAAC

GAGAGAGTTTTAACA

AGAGAGTTTTAACAA

GAGAGTTTTAACAAT

AGAGTTTTAACAATC

GAGTTTTAACAATCC

AGTTTTAACAATCCA

GTTTTAACAATCCL .T

TTTTAACAATCCATT

TTTAACAATCCATTC

TTAACAATCCATTCA

TAACAATCCATTC-AC

AACAATCCATTCACA

ACAATCCATTCACAA

CAATCCATTCACAAG

AATCCATTCACAAGC

ATCCATTCACAAGCC

TCCATTCACAAGCCT

CCATTCACAAGCCTC

CATTCACAAGCCTCC

ATTCACAAGCCTCCT

TTCACAAGCCTCCTG

TCACAAGCCTCCTGT

CACAAGCCTCCTGTA

ACAAGCCTCCTGTAC

CAAGCCTCCTGTACC

AAGCCTCCTGTACCT

AGCCTCCTGTACCTC

GCCTCCTGTACCTCA

CCTCCTGTACCTCAG

CTCCTGTACCTCAGT

TCCTGTACCTCAGTG

CCTGTACCTCAGTGG

CTGTACCTCAGTGGA

TGTACCTCAGTGGAT

GTACCTCAGTGGATC

TACCTCAGTGGATCT

ACCTCAGTGGATCTT

CCTCAGTGGATCTTC

CTCAGTGGATCTTCA

TCAGTGGATCTTCAG

CAGTGGATCTTCAGT

AGTGGATCTTCAGTT

GTGGATCTTCAGTTC

TGGATCTTCAGTTCT

GGATCTTCAGTTLCTG

GATCTTCAGTTCTGC

AT CTT CAGTT CTGC C

TCTTCAGTTCTGCCC

CTTCAGTTCTGCCCT

TTCAGTTCTGCCCTT

TCAGTTCTGCCCTTG

CAGTTCTGCCCTTGC

AGTTCTGCCCTTGCT

GTTCTGCCCTTGCTG

TTCTGCCCTTGCTGC

TCTGCCCTTGCTGCC

CTGCCCTTGCTGCCC

TGCCCTTGCTGCCCG

GCCCTTGCTGCCCGC

CCCTTGCTGCCCGCG

CCTTGCTGCCCGCGG

CTTGCTGCCCGCGGG

TTGCTGCCCGCGGGA

TGCTGCCCGCGGGAG

GCTGCCCGCGGGAGA

CTGCCCGCGGG.XGAC

TGCCCGCGGGAGACA

GCCCGCGGGAGACAG

CCCGCGGGAGACAGC

WO 96101636PC/U541 PCUAU95100410 67

CCGCGGGAGACAGCT

CGCGGGAGACAGCTT

GCGGGAGACAGCTTC

CGGGAGACAGCTTCT

GGGAGACAGCTTCTC

GGAGAC"AGCTTCTCT

GAGACAGCTTCTCTG

AGACAGCTTCTCTGC

GACAGC7TCTCTGCA

ACAGCTTCTCTGCAG

CAGCTTCTCTGCAGT

AGCTTCTCTGCAGTA

GCTTCTCTGCAGTAA

CTTCTCTGCAGTAAA

TTCTCTGCAGTAAAA

TCTCTGCAGTAAAAC

CTCTGCAGTAAAACA

TCTGCAGTAAAACAC

CTGCAGTAAAACACA

TGCAGTAAAACACAT

GCAGTAAAACACATT

CAGTAAAACACATTT

AGTAAAACACATTTG

GTAAAACACATTTGG

TAAAACACATTTGGG

AAAACACATTTGGGA

AAACACATTTGGGAT

AACACATTTGGGATG

ACACATTTGGGATGT

CACATTTGGGATGTT

ACATTTGGGATGTTC

CATTTGGGATGTTCC

ATTTGGGATGTTCCT

TTTGGG,'ATGTTCCTT

TTGGGATGTTCCTTT

TGGGATGTTCCTTTT

GGGATGTTCCTTTTT

GGATGTTCCTTTTTT

GATGTTCCTTTTTTC

ATGTTCCTTTTTTCA

TGTTCCTTTTTTCAA

GTTCCTTTTTTCAAT

TTCCTTTTTTCAATA

TCCTTTTTTCAATAT

CCTTTTTTCAATATG

CTTTTTTCAATATGC

TTTTTTCAATATGCA

TTTTTCAATATGCAA

TTTTCAATATGCAAG

TTTCAATATGCAAGC

TTCAATATGC-AAGCA

TCAATATGCAAGCAG

CAATATGCAAGCAGC

AATATGCAAGCAGCT

ATATGCAAGCAGCTT

TATGCAAGiCAGCTTT

ATGCAAGCAGCTTTT

TGCAAGCAGCTTTTT

GCAPAGCAGCTTTTTA

CAAGCAGCTTTTTAT

AAGCAGCTTTTTATT

AGCAGCTTTTTATTC

G CAG CTTTTTATTC C

CAGCTTTTTATTCCC

AGCTTTTTATTCCCT

GCTTTTTATTCCCTG

CTTTTTATTCCCTGC

TTTTTATTCCCTGCC

TTTTATTCCCTGCCC

TTTATTCCCTGCCCA

TTATTC 2TGCCCAA

TATTCCCTGCCCAAA

ATTCCCTGCCCAAAC

TTCCCTGCCCAAACC

T CCCTG CC CAAACC C

CCCTGCCCAAACCCT

CCTGCCCAAACCCTT

CTGCCCAAACCCTTA

TGCCCAAACCCTTAA

GCCCAAACCCTTAAC

CCCAAACCCTTAACT

CCAAACCCTTAACTG~

CAZV 'CTTAACTGA AN? TTAACTGAC AA, -TAACTGACA

ACCCTTAACTGACAT

CCCTTAACTGACATG

CCTTAAFTGACATGG

CTTAACTGACATGGG

TTAACTGACATGGGC

TAACTGACATGGGCC

AACTGACATGGGCCT

ACTGACATGGGCCTT

CTGACATGGGCCTTT

TGACATGGGCCTTTA

GACATGGGCCTTTAA

ACATGGGCCTTTAAG

CATGGGCCTTTAAGA

ATGGGCCTTTAAGAA

TGGGCCTTTAAGAAC

GGGCCTTTAAGAACC

GGCCTTTAAGAACCT

GCCTTTAAGAACCTT

CCTTTAAGAACCTTA

CTTTAAGAACCTTAA

TTTAAGAACCTITAAT

TTAAGAACCTTAATG

TAAGAACCTTAATGA

AAG1AACCTTAATGAC

AGAACCTTAATGACA

G.Z2ACCTTAATGACAA

AACCTTAATGACAAC

ACCTTAATGACAACA

C.CTTAATGACAACAC

CTTAATGACAACACT

TTAATGACAACaCTT

TAATGACAACACTTA

AATGACAACACT'TAA

ATGCrzi.AACACrTTAAT

TGACAACACTTAATA

GACAACACTTAATAG

ACAACACTTAATAGC

CAACACTTAATAGCA

AACACTTAATAGCAA

ACACTTAATAGCAAC

CACTTAATAGCAACA

ACTTAATAGCAACAG

CTTAATAGCAACAGA

TTAATAGCAACAGAG

TA2U TAG CAACAGAGC' AA TAG CAA CP.AC2.M'ZC

ATAGCAACACIAGCAC

TAGCAACAGACTCACT

AGCAACAG? qCACTT GCAACAGAGCiACTTG

CAACAGAGCACTTGA

AACAGAGUACTTGAG

ACAGAGCACTTGAGA

CAGAGCACTTGAGINA

AGAGCACTTGAGAAC

GAGCACTTGAGAACC

AGCACTTGAGAACCA

GCACTTGAGAACCAG

CACTTGAGAACCAGT

ACTTGAGAACCAGTC

CTTGAG7-ACCAGTCT

TTC'AGAACCAGTCTC

TGAGAACCAGTCTCC

GAGAACCAGTCTCCT

AC-AACCAGTCTCCTC

GAACCAGTCTCCTCA

AACCAGTCTCCTCAC

ACCAGTCTCCTCACT

CCAGTCTCCTCACTC

CAGTC-TCCTCACTCIT

AGTCTCCTCACTCTG

GTCTCCTCACTCTC:,T

TCTCCTCACTrCTGTC

CTCCTCACTCTGTCC

TCCTCACTCTGTCC

CCTCACTCTGTCCCT

C-TCACTCTGTCCCTG

TCACTrCTGTCCCTGT C AC "r s"G TCC CT GT C

ACTC'TGTCCCTGTCC

CTCTGTCCCTGT.CCT

TCTGTC'-'CTGTCCTT

CTGTCCCTGTCCTTC

WO 96101636 CTA9IO41 PCT/AU95/00410 68

TGTCCCTGTCCTTCC

GTCCCTGTCCTTCCC

TCCCTGTCCTTCCCT

CCCTGTCCTTCCCTG

CCTGTCCTTCCCTGT

CTGTCCT&TCCCTGTT

TGTCCTTCCCTGTTC

GTCCTTCCCTGTTCT

TCCTTCCCTGTTCTC

CCTTCCCTGTTCTCC

CTTCCCTGTTCTCCC

TTCCCTGTTCTCCCT

TCCCTGTTCTCCCTT

CCCTGTTCTCCCTTT

CCTGTTCTCCCTTTC

CTGTTCTCCCTTTCT

TGTTCTCCCTTTCTC

GTTCTCCCTTTCTCT

TTCTCCCTTTCTCTC

TCTCCCTTTCTCTCT

CTCCCTTTCTCTCTC

TCCCTTTCTCTCTCC

CCCTTTCTCTCTCCT

CCTTTCTCTCTCCTC

CTTTCTCTCTCCTCT

TTTCTCTCTCCTCTC

TTCTCTCTCCTCTCT

TCTCTCTCCTCTCTG

CTCTCTCCTCTCTGC

TCTCTCCTCTCTGCT

CTCTCCTCTCTGCTT

TCTCCTCTCTGCTTC

CTCCTCTCTGCTTCA

TCCTCTCTGCTTOAT

CCTCTCTGCTTCATA

CTCTCTGCTTCATAA

TCTCTGCTTCATAAC

CTCTGCTTCATAACG

TCTGCTTCATAACGG

CTGCTTCATAACGGA

TGCTTCATAACGGAA

GCTTCATAACGGAAA

C7"TCATAACGGAAAA

TTCATAACGGAAAAA

TCATAACGGAAAAAT

CATAACGGAAAAATA

ATAACGGAAAAATAA

TAACGGAAAAATAAT

AACGGAAAAATAATT

ACGGAAAAATAATTG

CGGAAAAATAATTGC

GGAAAAATAATTGCC

GAAAAATAATTGCCA

AAAAATAATTGCCAC

AAAATAATTGCCACA

AAATAATTGCCACAA

AATAATTGCCACAAG

ATAATTGCCACAAGT

TAATTGCCACAAGTC

AATTGCCACAZAGTCC

ATTGCCACAAGTCCA

TTGCCACAAGTCCAG

TGCCACAAGTCCAGC

GCCACAAGTCCAGCT

CCACAAGTCCAGCTG

CACAAGTCCAGCTGG

ACAAGTCCAGCTGGG

CAAGTCCAGCTGGGA

AAGTCCAGCTGGGAA

AGTCCAGCTGGGAAG

GTCCAGCTGGGAAGC

TCCAGCTGGGAAGCC

CCAGCTGGGAAGCCC

CAGCTGGGAAGCCCT

AGCTGGGAAGCCCTT

GCTGGGAAGCCCTTT

CTGGGAAGCCCTTTT

TGGGAAGCCCTTTTT

GGGAAGCCCTTTTTA

GGAAGCCCTTTTTAT

GAAGCCCTTTTTATC

AAGCCCTTTTTATCA

AGCCCTTTTTATCAG

GCCCTTTTTATCAGT

CCCTTTTTATCAGTT

CCTTTTTA:TCAGTTT

CTTTTTATCAGTTTG

TTTTTATCAGTTTGA

TTTTATCAGTTTGAG

TTTATCAGTTTGAGG

TTATCAGTTTGAGGA

TATCAGTTTGAGGAA

ATCAGTTTGAGGAAG

TCAGTTTGAGGAAGT

CAGTTTGAGGAAGTG

AGTTTGAGGAAGTGG

GTTTGAGGAAGTGGC

TTTGAGGAAGTGGCT

TTGAGGAAGTGGCTG

TGAGGAAGTGGCTGT

GAGGAAGTGGCTGTC

AGGAAGTGGCTGTCC

GGAAGTGGCTGTCCC

GAAGTGGCTGTCCCT

AAGTGGCTGTCCCTG

'kGTGGCTGTCCCTGT

GTGGCTGTCCCTGTG

TGGCTGTCCCTGTGG

GGCTGTCCCTGTGGC

GCTGTCCCTGTGGCC

CTGTCCCTGTGGCCC

TGTCCCTGTGGCCCC

GTCCCTGTGGCCCCA

TCCCTGTGGCCCCAT

CCCTGTGGCCCCATC

CCTGTGGCCCCATCC

CTGTGGCCCCATCCA

TGTGGCCCCATCCAA

GTGGCCCCATCCAAC

TGGCCCCATCCAACC

GGCCCCATCCAACCA

GCCCCATCCAACCAC

CCCCATCCAACCACT

CCCATCCAACCACTG

CCATCCAACCACTGT

CATCCAACCACTGTA

ATCCAACCACTGTAC

TCCAACCACTGTACA

CCAACCACTGTACAC

CAACCACTGTACACA

AACCACTGTACACAC

ACCACTGTACACACC

CCACTGTACACACCC

CACTGTACACACCCG

ACTGTACACACCCGC

CTGTACACACCCGCC

TGTACACACCCGCCT

GTACACACCCGCCTG

TACACACCCGCCTGA

ACACACCCGCCTGAC

CACACCCGCCTGACA

ACACCCGCCTGACAC

CACCCGCCTGACACC

ACCCGCCTGACACCG

CCCGCCTGACACCGT

CCGCCTGACACCGTG

CGCCTGACACCGTGG

GCCTGACACCGTGGG

CCTGACACCGTGGGT

CTGACACCGTGGGTC

TGACACCGTGGGTCA

GACACCGTGGGTCAT

ACACCGTGGGTCATT

CACCGTGGGTCATTA

ACCGTGGGTCATTAC

CCGTGGGTCATTACA

CGTGGGTCATTACAA

GTGGGTCATTACAAA

TGGGTCATTACAAAA

GGGTCATTACAAAAA

GGTCATTACAAAAAA

GTCATTACAAAAAAA

TCATTACAAAAAAAC

CATTACAAAAAAACA

ATTACAAAAAAACAC

TTACAAAAAAACACG

TACAAAAAAACACGT

ACAAAAAAACACGTG

WO 96101636 PTA9IOI PCT/AU95/00410 69

CAAAAAAACACGTGG

AAAAAAACACGTGGA

AAAAAACACGTGGAG

AAAAACACGTGGAGA

AAAACACGTGGAGAT

AAACACGTGGAGATG

AACACGTGGAGATGG

ACACGTGGAGATGGA

CACGTGGAGATGGAA

ACGTGGAGATGGAAA

CGTGGAGATGGAAAT

GTGGAGATGGAAATT

TGGAGATGGAAATTT

GGAGATGGAAATTTT

GAGATGGAAATTTTT

AGATGGAAATTTTTA

GATGGAAATTTTTAC

ATGGAAATTTTTACC

TGGAAATTTTTACCT

GGAAATTTTTACCTT

GAAATTTTTACCTTT

AAATTTTTACCTTTA

AATTTTTACCTTTAT

ATTTTTACCTTTATC

TTTTTACCTTTATCT

TTTTACCTTTATCTT

TTTACCTTTATCTTT

TTACCTTTATCTTTC

TACCTTTATCTTTCA

ACCTTTATCTTTCAC

CCTTTATCTTTCACC

CTTTrATCTTTCACCT

TTTATCTT.TCACCTT

TTATCTTTCACCTTT

TATCTTTCACCTTTC

ATCTTTCACCTTTCT

TCTTTCACCTTTCTA

CTTTCACCTTTCTAG

TTTCACCTTTCTAGG

TTCACCTTTCTAGGG

TCACCTTTCTAGGGA

CACCTTTCTAGGGAC

ACCTTTCTAGGGACA

CCTTTCTAGGGACAT

CTTTCTAGGGACATG

TTTCTAGGGACATGA

TTCTAGGGACATGAA

TCTAGGGACATGAAA

CTAGGGACATGAAAT

TAGGGACATGAAATT

AGGGACATGAAATTT

GGGACATGAAATTTA

GGACATGAAATTTAC

GACATGAAATTTACA

ACATGAAATTTACAA

CATGAAATTTACAAA

ATGAAATTTACAAAG

TGAAATTTACAAAGG

GAAATTTACAAAGGG

AAATTTACAAAGGGC

AATTTACAAAGGGCC

ATTTACAAAGGGCCA

TTTACAAAGGGCCAT

TTACAAAGGGCCATC

TACAAAGGGCCATCG

ACAAAGGGCCATCGT

CAAAGGGCCATCGTT

AAAGGGCCATCGTTC

AAGGGCCATCGTTCA

AGGGCCATCGTTCAT

GGGCCATCGTTCATC

GGCCATCGTTCATCC

GCCATCGTTCATCCA

CCATCGTTCATCCAA

CATCGTTCATCCAAG

ATCGTTCATCCAAGG

TCGTTCATCCAAGGC

CGTTCATCCAAGGCT

GT9'CATCCAAGGCTG

TTCATCCAAGGCTGT

TCATCCAAGGCTGTT

CATCCAAGGCTGTTA

ATCCAAGGCTGTTAC

TCCAAGGCTGTTACC

CCAAGGCTGTTACCA

CAAGGCTGTTACCAT

AAGGCTGTTACCATT

AGGCTGTTrACCATTT

GGCTGTTACCATTTT

GCTGTTACCATTTTA

CTGTTACCATTTTAA

TGTTACCATTTTAAC

GTTACCATTTTAACG

TTACCATTTTAACGC

TACCATTTTAACGCT

ACCATTTTAACGCTG

CCATTTTAACGCTGC

CATTTTAACGCTGCC

ATTTTAACGCTGCCT

TTTTAACGCTGCCTA

TTTAACGCTGCCTAA

TTAACGCTGCCTAAT

TAACGCTGCCTAATT

AACGCTGCCTAATTT

ACGCTGCCTAATTTT

CGCTGCCTAATTTTG

GCTGCCTAATTTTGC

CTGCCTAATTTTGCC

TGCCTAATTTTGCCA

GCCTAATTTTGCCAA

CCTAATTTTGCCAAA

CTAATTTTGCCAAAA

TAATTTTGCCAAAAT

AATTTTGCCAAAATC

ATTTTGCCAAAATCC

TTTTGCCAAAATCCT

TTTGCCAAAATCCTG

TTGCCAAAATCCTGA

TGCCAAAATCCTGAA

C CCAAAAT C CTGAAC

CCAAAATCCTGAACT

CAAAATCCTGAACTT

AAAATCCTGAACTTT

AAATCCTGAACTTTC

AATCCTGAACTTTCT

ATCCTGAACTTTCTC

TCCTGAACTTTCTCC

CCTGAACTTTCTCCC

CTGAACTTTCT CCCT

TGAACTTTCTCCCTC

GAACTTTCTCCCTCA

AACTTTCTCCCTCAT

ACTTTCTCCCTCATC

CTTTCTCCCTCATCG

TTTCTCCCTCATCGG

TTCTCCCTCATCGGC

T CT CCCT CAT CGG CC CTCC CT CAT CGG CC C

TCCCTCATCGGCCCG

CCCTCATCGGCCCGG

CCTCATCGGCCCGGC

CTCATCGGCCCGGCG

TCATCGGCCCGGCGC

CATCGGCCCGGCGCT

ATCGGCCCGGCGCTG

TCGGCCCGGCGCTGA

CGGCCCGGCGCTGAT

GGCCCGGCGCTGATT

GCCCGGCGCTGATTC

CCCGGCGCTGATTCC

CCGGCGCTGATTCCT

CGGCGCTGATTCCTC

GGCGCTGATTCCTCG

G CCCTGATT CCT CGT

CGCTGATTCCTCGTG

GCTGATTCCTCGTGT

CTGATTCCTCGTGTC

TCATTCCTCGTGTCC

GATTCCTCGTGTCCG

ATTC CT CGTGT C CC

TTCCTCGTGTCCGGA

TCCTCGTGTCCGGAG

CCTCGTGTCCGGAG

CTCGTGTCCGGAGGC

TCGTGTCCGGAGGCA

CGTGTCCGGAGGCAT

GTGTCCGGAGGCATG

TGTCCGGAGGCATGG

pCT/AU95/004 WO 96/01636 70 GTCCGGAGGCATiGGG

TCCGGAGGCATGGGT

CCGGAGGCATGGGTG

CGGAGGCATGGGTGA

GGAGGCATGGGTGAG

GAGGCATGGGTGAGC

AGGCATGGGTGAGCA

GGCATGGGTGAGCAT

GCATGGGTGAGCATG

CATGGGTGAGCATGG

ATGGGTGAGCATGGC

TGGGTGAGCATGGCA

GGGTGAGCATGGCAG

GGTGAGCATGGCAGC

GTGAGCATGGCAGCT

TGAGCATGGCAGCTG

GAGCATGGCAGCTGG

AGCATGGCAGCTGGT

GCATGGCAGCTGGTT

CATGGCAGCTGGTTG

ATGGCAGCTGGTTGC

TGGCAGCTGGTTGCT

GGCAGCTGGTTGCTC

GCAGCTGGTTGCTCC

CAGCTGGTTGCTCCA

AGCTGGTTGCTCCAT

GCTGGTTGCTCCATT

CTGGTTGCTCCATTT

TGGTTGCTCCATTTG

GGTTGCTCCATTTGA

GTTGCTCCATTTGAG

TTGCTCCATTTGAGA

TGCTCCATTTGAGAG

GCTCCATTTGAGAGA

CTCCATTTGAGAGAC

TCCATTTGAGAGACA

CCATTTGAGAGACAC

CATTTGAGAGACACG

ATTTGAGAGACACGC

TTTGAGAGACACGCT

TTGAGAGACACGCTG

TGAGAGACACGCTGG

GAGAGACACGCTGGC

AGAGACACGCTGGCG

GAGACACGCTGGCGA

AGACACGCTGGCGAC

GACACGCTGGCGACA

ACACGCTGGCGACAC

CACGCTGGCGACACA

ACGCTGGCGACACAC

CGCTGGCGACACACT

GCTGGCGACACACTC

CTGGCGACACACTCC

TGGCGACACACTCCG

GGCGACACACTCCGT

GCGACACACTCCGTC

CGACACACTCCGTCC

GACACACTCCGTCCA

ACACACTCCGTCCAT

CACACTCCGTCCATC

ACACTCCGTCCATCC

CACTCCGTCCATCCG

ACTCCGTCCATCCGA

CTCCGTCCATCCGAC

TCCGTCCATCCGACT

CCGTCCATCCGACTG

CGTCCATCCGACTGC

GTCCATCCGACTGCC

TCCATCCGACTGCCC

CCATCCGACTGCCCC

CATCCGACTGCCCCT

ATCCGACTGCCCCTG

TCCGACTGCCCCTGC

CCGACTGCCCCTGCT

CGACTGCCCCTGCTG

GACTGCCCCTGCTGT

ACTGCCCCTGCTGTG

CTGCCCCTGCTGTGC

TGCCCCTGCTGTGCT

GCCCCTGCTGTGCTG

CCCCTGCTGTGCTGC

CCCTGCTGTGCTGCT

CCTGCTGTGCTGCTC

CTGCTGTGCTGCTCA

TGCTGTGCTGCTCAA

GCTGTGCTGCTCAAG

CTGTGCTGCTCAAGG

TGTGCTGCTCAAGGC

GTGCTGCTCAAGGCC

TGCTGCTCAAGGCCA

GCTGCTCAAGGCCAC

CTGCTCAAGGCCACA

TGCTCAAGGCC-ACAG

GCTCAAGGCCACAGG

CTCAAGGCCACAGGC

TCAAGGCCACAGGCA

CAAGGCCACAGGCAC

AAGGCCACAGGCACA

AGGCCACAGGCACAC

GGCCACAGGCACACA

GCCACAGGCACACAG

CCACAGGCACACAGG

CACAGGCACACAGGT

ACAGGCACACAGGTC

CAGGCACACAGGTCT

AGGCACACAGGTCTC

GGCACACAGGTCTCA

GCACACAGGTCTCAT

CACACAGGTCTCATT

ACACAGGTCTCATTG

CACAGGTCTCATTGC

ACAGGTCTCATTGCT

CAGGTCTCATTGCTT

AGGTCTCATTGCTTC

GGTCTCATTGCTTCT

GTCTCATTGCTTCTG

TCTCATTGCTTCTGA

CTCATTGCTTCTG7%C

TCATTGCTTCTGACT

CATTGCTTCTGACTA

ATTGCTTCTGACTAG

TTGCTTCTGACTAGA

TGCTTCTGACTAGAT

GCTTCTGACTAGATT

CTTCTGACTAGATTA

TTCTGACTAGATTAT

TCTGACTAGATTATT

CTGACTAGATTATTA.

TGACTAGATTATTAT

GACTAGATTATTATT

ACTAGATTATTATTT

CTAGATTATTATTTG

TAGATTATTATTTGG

AGATTATTATTTGGG

GATTATTATTTGGGG

ATTATTATTTGGGGG

TTATTATTTGGGGGA

TATTATTTGGGGGAA

ATTATTTGGGGGAAC

TTATTTGGGGGAACT

TATTTGGGGGAACTG

ATTTGGGGGAACTGG

TTTGGGGGAACTGGA

TTGGGGGAACTGGAC

TGGGGGAACTGGACA

GGGGGAACTGGACAC

GGO2AACTGGACACA

GGGAACTGGACACAA

GGAACTGGACACAAT

GAACTGGACACAATA

AACTGGACACAATAG

ACTGGACACAATAGG

CTGGACACAATAGGT

TGGACACAATAGGTC

GGACACAATAGGTCT

GACACAATAGGTCTT

ACACAATAGGTCTTT

CACAATAGGTCTTTC

ACAATAGGTCTTTCT

CAATAGGTCTTTCTC

AATAGGTCTTTCTCT

ATAGGTCTTTCTCTC

TAGGTCTTTCT, £CA

AGGTCTTTCTCTCAG

GGTCTTTCTCTCAGT

GTCTTTCTCTCAGTG

TCTTTCTCTCAGTGA

CTTTCTCTCAGTGAA

WO 965101636 WO 9~iO1636 CT/AU95/00410 -71

TTTCTCTCAGTGAAG

TTCTCTCAGTGAAGG

TCTCTCAGTGAAGGT

CTCTCAGTGAAGGTG

TCTCAGTGAAGGTGG

CTCAGTGAAGGTGGG

TCAGTGAAGGTGGGG

CAGTGAAGGTGGGGA

AGTGAAGGTGGGGAG

GTGAAGGTGGGGAGA

TGAAGGTGGGGAGAA

GAAGGTGGGGAGAAG

AAGGTGGGGAGAAGC

AGGTGGGGAGAAGCT

GGTGGGGAGAAGCTG

GTGGGGAGAAkGCTGA

TGGGGAGAAGCTGAA

GGGGAGAAGCTGAAC

GGGAGAAGCTGAACC

GGAGAAGCTGAACCG

GAGAAGCTGAACCGG

AGAAGCTGAACCGGC

EXAMPLE 9 INHIBITION OF IGF-I BINDING BY ANTISENSE OLIGONUCLEOTIDES TO IGF-I RECEPTOR Sub-confluent HaCaT cells were treated as described above with phosphorothioate oligonucleotides IGFR-AS (antisense: 5'-ATCTCTCCGCTTCCTTTC-3'; [SEQ ID NO.

10]; ref 13) and IGFR.S (sense control: 5'-GAAAGGAAGCGGAGAGAT-3'; [SEQ ID NO. 11]; ref 13) IGF-I binding to the cell monolayers; was then measured as 12 11-IGF-I.

EXAMPLE INHIBITION OF IGFBP-3 PRODUCTION USING ANTISENSE

OLIGONJJCLEOTIDES

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 t Keratinocyte-SFM" (Gibco) to exclude the influence of exogenous IGFBPs. Oligos were synthesised as phosphorothioate (nucleaseresistant) derivatives (Bresatec, South Australia) and were as follows: antisense: AS2, 5'-GCGCCCGCTGCATGACGCCTGCAAC-3' (IGFBP-3 start codon); controls: II PCT/AU95/00410 WO 96/01636 -72- 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 AS oligos were added to HaCaT monolayers in 0.5ml 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 in which 100p1 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 1 25 I-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 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 125 I-IGF-I (30,000cpm/well) at 4"C.

EXAMPLE 11 INHIBITION OF IGFBP-2 PRODUCTION USING RIBOZYMES Experiments involving ribozymes are generally conducted as described in Interaitonal Patent Application No. WO 89/05852 and in Haselhoff and Gerlach 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).

M

L

WO 96/01636 PCT/AU95/00410 73 EXAMPLE 12 INHIBITION OF IGFBP-3 PRODUCTION USING RIBOZYMES The methods described in Example 11 are used for the screening of ribozymes which inhibit IGFBP-3 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 13 INHIBITION OF IGF-1 PRODUCTION USING RIBOZYMES The methods described in Example 11 are used for the screening of ribozymes which inhibit IGF-1 production. The activity of the ribozymes is determined as in Example 11.

EXAMPLE 14 INHIBITION OF IGF-1 RECEPTOR PRODUCTION USING RIBOZYMES 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.

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.

WO 96101636 PCT/AU95/00410 74

REFERENCES:

1. Sara V Physiological Reviews 70: 591-614, 1990.

2. Rechier MM and Brown AL Growth Regulation 2: 55-68, 1992.

3. Clemmons DR Growth Regn 2: 80, 1992.

4. Oakes SR, KM Haynes, MJ Waters, AC Herington and GA Werther J Clin Endocrinol Metab 73: 1368-1373, 1992.

Camacho-Hiibner C et al. J Biol Chemn 267:- 11949-11956) 1992.

6. Neely KB et al. .J Inv Derm 96: 104, 199 1.

7. Ts'O POP, Aurelian L, Chang E and Miller PS. Nonionic oligonucleotide analogs (Matagen TM) as anticodic agents in duplex and triplex formation. in "Antisense Strategies", Annals of the New York Academy of Sciences 660:159- 177 (Baserga R and Denhardt DT, eds.), 1993.

8. Haseloff J and Gerlach L Nature 334: 586-591, 1988.

9. Boukamp P, Petrussevska RT, Breitkreuz D, Hornung J, Markham A, Fusenig NE. J1 Cell Biol 106.: 761-771, 1988.

Rheinwald and Green Cell 6: 33 1-344, 1975.

11. Hossenlopp P, Seurin D, Segovia. Quinson B, Hardouin 5, Binoux M. A4nal Biochem 154: 138-143, 1986.

PCT/AU95/00410 WO 96101636 75 12. Spratt SK, Tatsuno GP, Yamanaka M4K, Ark BC, Detmer J, Mascarenhas D, Flynn J, Talkington-Yerser C, Spencer EM. Growth Factors 3: 63-72, 1990.

13. Pietrzkowski, Z, Sell C, Lammners R, tjllrich A and Baserga R. Mol CeIl Biol.

12: 3883-3889, 1992.

14. Schulz J, Dettlaff 5, Fritzsche U, Harms U, Schiebel H, Derer W, Fusenig NE, Hulsen A and Bohm M. ImmunoL. Meth. 167: 1-13, 1994.

Baker BS, Brent L, Valdimarsson H, Powles AV, Al-Imara L, Walker M and Fry L. Brit. J Bermatol 126: 105-110, 1992.

16. Nanney LB et al J. Invest. Berinatol 98: 296-301, 1992.

17. Sundberg JP et a? inmunol. Investigations 22: 389-401, 1993.

18. Sundberg JP et al J Invest. Dermatol 102: 781-788, 1994.

M

WO 96/01636 PCT/AU95/00410 -76- SEQUENCE LISTING GENERAL INFORMATION: APPLICANT (countries other than US): ROYAL CHILDREN'S HOSPITAL RESEARCH FOUNDATION (US only): George A WERTHER and Christopher J WRAIGHT (ii) TITLE OF INVENTION: A METHOD FOR THE PROPHYLAXIS AND/OR TREATMENT OF PROLIFERATIVE AND/ORINFLAMMATORY SKIN DISORDERS (iii) NUMBER OF SEQUENCES: 11 (iv) CORRESPONDENCE ADDRESS: ADDRESSEE: DAVIES COLLISON CAVE STREET: 1 LITTLE COLLINS STREET CITY: MELBOURNE STATE: VICTORIA COUNTRY: AUSTRALIA ZIP: 3000 COMPUTER READABLE FORM: MEDIUM TYPE: Floppy disk COMPUTER: IBM PC compatible OPERATING SYSTEM: PC-DOS/MS-DOS SOFTWARE: PatentIn Release Version #1.25 (vi) CURRENT APPLICATION DATA: APPLICATION NUMBER: PCT INTERNATIONAL FILING DATE: 06-JUL-1995 (vii) PRIOR APPLICATION DATA: APPLICATION NUMBER: PM6725/94 FILING DATE: 08-JUL-1994 (viii) ATTORNEY/AGENT INFORMATION: NAME: HUGHES, Dr E JOHN L REFERENCE/DOCKET NUMBER: EJH/EK (ix) TELECOMMUNICATION INFORMATION: TELEPHONE: +61 3 9254 2777 TELEFAX: +61 3 9254 2770 WO 96101636 PCUA'U95/00410 77 INFORMATION FOR SEQ ID NO:1: SEQUENCE CHARACTERISTICS: LENGTH: 1433 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1: ATTCGGGGCG AGGGAGGAGG AAGAAGCGGA GGAGGCGGCT CCCGCTCGCA GGGCCGTGCA 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 CGCAGIGCC 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 WO096/01636 PCr/AU95/00410 78 INFORMATION FOR SEQ ID NO:2: SEQUENCE CHARACTERISTICS: LENGTH: 2474 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: CTCAGCGCCC AGCCGCTTCC TGCCTGGATT CCACAGCTTC GCGCCGTGTA CTGTCGCCCC ATCCCTGCGC GCCCAGCCTG CCAAGCAGCG TGCCCCGGTT GCAGGCGTCA TGCAGCGGGC GCGACCCACG CTCTGGGCCG CTGCGCTGAC GGCGCGGGCT GGCGCGAGCT CGGGGGGCTT CGCGCGTGCA CTGGCCCAGT GCGCGCCTCC GCCGGGCTGC GGCTGCTGCC CACCGAGCGC TGTGGCTCCG GCAGGCGCTG CTGGACGGCC CGCCTACCTG CTGCCAGCGC CAGCGCCGGC AGTGTGGAGA.

GTTCCACCCC CTCCATTCAA GCGCTACAAA GTTGACTACG CAAGCGGGAG ACAGAATATG GAAGTTCCTC AATGTGCTGA ATTTTATAAG AAAAAGCAGT TGTGGATAAG TATGGGCAGC CTGCTACAGC ATGCAGAGCA CCTTATTTTG CACAAAAGAC ATATTTCTGT TTGTGGTC& AATGCCTATG GTTTCTTTGA AAAGAGCAGT TTGAATTTTC CACCCAGACT TCATGCGCCC TGACTTTGTG ACTTAGGCGG CCGTACAGTG CGCACAGGCT

TGACGTGCGC

GCCTTCGCTG

GCGGGCTCTG

CGCCAGCTCC

GCCCGTCCGT

AGATAATCAT

AGTCTCAGAG

GTCCCTGCCG

GTCCCAGGGG

GTCGCCCTTC

CTCTCCCAGG

TCTGCTG(3TG CTGCTCCGCG GGCCGCCGGT GGGTCCCGTG GTGCGCTGCG AGCCGTGCGA GCCCGCCGTG TGCGCGGAGC TGGTGCGCGA ACTGAGCGAG GGCCAGCCGT GCGGCATCTA CCAGCCGTCG CCCGACGAGG CGCGACCGCT CGTCAACGCT AGTGCCGTCA GCCGCCTGCG AGGAAATGCT AGTGAGTCGG AGGAAGACCG CTCCAGCACG CACCGGGTGT CTGATCCCAA CATCAAGAAA GGGCATGCTA AAGACAGCCA CACAGATACC CAGAACTTCT Cr- .'CGAGTC TAGAGAAATG GAAGACACAC TGAATCACCT TGTACACATT CCCAACTGTG ACAAGAAGGG CAAAGGCAGG AAGCGGGGCT TCTGCTGGTG CTACACCACC AAGGGGAAGG AGGACGTGCA 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 1140 1200 1260 1320 1380 1440 AGTAGACGCC TGCCGCAAGT TAATGTGGAG CTCAAATATG TGCCAAGGAC ATGACCAGCA GCTGGCTACA GCCTCGATTT CTGATTTTTT TTAAACCAAA GTTTAGAAAG AGGTTTTTGA ATGGTAAACT TGAGCATCTT TTCACTTTCC AGTAGTCAGC TTGTCGCTTC CTATCAAAAT ATTCAGAGAC TCGAGCACAG GTGGAATGCT CACCACATGT TGGTCGAAGC GGCCGACCAC CTGTGTTGCC TATGTAGAGA ACACGCTTCA CCCCCACTCC TTATCGAGAA TAGGAAAACC TTTAAACCCC GGTCATCCGG 0 PCT/AU95/00410 WO 96101636 79 ACATCCCAAC GCATGCTCCT GGAGCTCACA GCCTTCTGTG GTGTCATTTC TGAAACAAGG GCGTGGATCC CTCAACCAAG AAGAATGTTT ATGTCTTCAA GTGACCTGTA CTGCTTGGGG ACTATTGGAG AAAATAAGGT GGAGTCCTAC TTGTTTAAAA AATATGTATC TAAGAATGTT CTAGGGCACT CTGGGAACCT ATAAAGGCAG GTATTTCGGG CCCTCCTCTT CAGGAATCTT CCTGAAGACA TGGCCCAGTC GAAGGCCCAG GATGGCTTTT GCTGCGGCCC CGTGGGGTAG GAGGGACAGA GAGACGGGAG AGTCAGCCTC CACATTCAGA GGCATCACAA GTAATGGCAC AATTCTTCGG ATGACTGCAG AAAATAGTGT TTTGTAGTTC AACAACTCAA GACGAAGCTT ATTTCTGAGG ATAAGCTCTT TAAAGGCAAA GCTTTATTTT CATCTCTCAT CTTTTGTCCT CCTTAGCACA ATGTAAAAAA GAATAGTAAT GGGAGCCCAT CCAGGACACT GGGAGCACAT GTCATTCTCA TGCTTTTCTT TATAATTCAC AACATTGTAT ACAACATAGC CCCAAATATA AATGTTAGAG ATGCTATATG ATACAACTGT AGAGACTGGG CTGCTCTCCC GGAGGCCAAA GGAGACTCTG CCCTGCTGCA GACCTCGGTG AAACAGAGGG GTCTCAAGAC ATTCTGCCTA ATCAGAACAG GAAGGAGGAA TGGCTTGCTG AGAGATTCAC CCATGTTTGT TGAACTTAGA ACATATATGC AGAGAAGATA TGTTCTTGTT GTAAGATCTA TACTAGATAA TCCTAGATGA GGCCATGACT GAGGAAAGGA GCTCACGCCC CCCAAGAAGG TCTGGCAAAG TCAGGCTCAG TGGACACACG CTGCATAGAG CTCTCCTTGA CCTATTAGCT TTTCTTTATT TTTTTAACTT 1500 1560 1620 1680 1740 '1800 1860 1920 1980 2040 2100 2160 2220 2280 2340 2400 2460 2474 TTTGGGGGGA AAAGTATTTT TGAGAAGTTT GTCTTGCAAT GTATTTATAA ATAGTAAATA AAGTTTTTAC CATT IWO 96101636 PCT/AU9/00410 80 INFORMATION FOR SEQ ID NO i3: SEQUENCE CHARACTERISTICS: CA) LENGTH: 4989 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: TTTTTTTTTrT TTTTGAGAAA GGGAATTTCA TCCCAAATAA AAGGAATGAA GTCTGGCTCC GGAGGAGGGT CCCCGACCTC GCTGTGGGGG CTCCTGTTTC' TCTCCGCCGC GCTCTCGCTC TGGCCGACGA GTGGAGAAAT CTGCGGGCCA GGCATCGACA TCCGCAACGA CTATCAGCAG CTGAAGCGCC TGG GAACTG CACGGTGATC GAGGGCTACC TCCACATCCT GCTCATCTCC AAGGCCGAGG ACTACCGCAG CTACCGCTTC CCCAAGCTCA CGGTCATTAC CTGCTGTTCC GAGTGGCTGG ATCCGCGGCT GGAAACTCTT )AGGATATTG GGCTTTACAA AATGCTGACC TCTGTTACCT AATAACTACA TTGTGGGGAA ATGGAGGAGA AGCCGATGTG TGGACCACAA ACCGCTG(CCA GAGAACAATG AGTGCTGCCA ACGGCCTGTG TAGCTTGCCG CCCAACACCT ACAGGTTTGA CTCAGCGCCG AGAGCAGCGA GAGTGCCCCT CGGGCTTCAT GGTCCTTGCC CGAAGGTCTG

CCTCGAGAGC

CTACAACTAC

CCTGAGGAAC

CTCCACTGTG

TAAGCCCCCA

TGAGAAGACC

GAAAATGTGC

CCCCGAGTGC

CCACTACTAC

GGGCTGGCGC

CTCCGAGGGG

CTCGGAGACC TCTTCCCCAA.

GCCCTGGTCA

ATTACTCGGG

GACTGGTCCC

AAGG(iATGT

ACCATCAACA

CCAAGCACGT

CTGGGCAGCT

TATGCCGGTG

TGTGTGGACC

TTTGTGATCC

TCTTCGAGAT

GGGCCATCAG

TGATCCTGGA

GGGACCTGTG

ATGAGTACAA

GTGGGAAGCG

GCAGCGCGCC

TCTGTGTGCC

GTGACTTCTG

ACGACGGCGA

CGAGTACTTG

CCTCACGGTC

GACCAATCTC

GATTGAGAAA

TGCGGTGTCC

TCCAGGGACC

CTACCGCTGC

GGCGTGCACC

TGACAACGAC

TGCCTGCCCG

(7GCCAACATC

GTGCATGCAG

120 180 240 300 360 420 480 540 600 660 720 780 840 900 960 1020 1080 21l40 1200 1260 1320 1380 CCGCAACGGC AGCCAGAGCA TGTACTGCAT CCCTTGTGA.A TGAGGAAGAA AAGAAAACAA AGACCATTGA TTCTGTTACT

TCTGCTCAGA

CGGGGGAATA

GGCTACGTGA

CGCCTCATCC

CAGAACTTGC

TGCTCCAAGG ATGCACCATC TTCAAGGGCA ATTTGCTCAT TAACATCCGA ACATTGCTTC AGAGCTGGAG AACTTCATGG GGCTCATCGA GGTGGTGACG AGATCCGCCA TTCTCATGCC TTGGTCTCCT TGTCCTTCCT AAAAAACCTT TAGGAGAGGA GCAGCTAGAA GGGAATTACT CCTTCTACGT CCTCGACAAC AGCAACTGTG GGACTGGGAC CACCGCAACC TGACCATCAA AGCAGGGAAA m WO 96/01636PTJ9SQ41 PCT/A'U95100410 81 ATGTACTTTG CTTTCAATCC CAAATTATGT CTTTCCGAAA TTTACCGCAT GGAGGAAGTG 1440 ACGGGGACTA AAGGGCGCCA AAGCAAAGGG GACATAAACA CCAGGAACAA CGGGGAGAGA 1500 GCCTCCTGTG AAAGTGACGT CCTGCATTTC ACCTCCACCA CCACGTCGAA GAATCGCATC 1560 ATCATAACCT GGCACCGGTA CCGGCCCCCT GACTACAGGG ATCTCATCAG CTTCACCGTT 1.620 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 GArAAAATCC 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 GAAATAAAALT ACGGATCACA AGTTGAGGAT CAGCGAGAAT GTGTGTCCAG ACAGGAATAC 2700 AGGAAGTATG GAGGGGCCAA GCTAAACCGG CTAAACCCGG GGAACTACAC AGCCCGGATT 2760 CAGGCCACAT CTCTCTCTGG GAATGGGTCG TGGACAGATC CTGTGTTCTT CTATGTCCAG 2820 GCCAAAACAG GATATGAAAA CTTCATCCAT CTGATCATCG CTrTGCCCGT 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 WO 96101636 PCTAU1J9O4 82 CTGGGTGTGG TGTCCCAAGG CCAGCCAACA CTGGTCATCA TGGAACTGAT GAC.ACGGGGC 3300 GATCTCAAAA GTTATCTCCG GTCTCTGAGG CCAGAAATGG AGAATAATCC AGTCCTAGCA 3360 CCTCCAAGCC TGAGCAAGAT GATTCAGATG GCCGGAGAGA TTGCAGACGG CATGOCATAC 3420 CTCAACGCCA ATAAGTTCGT CCACAGAGAC CTTGCTGCCC GGAATTGCAT GGTAGCCGAA 3480 GATTTCACAG TCAAAATCGG AGATTTTGGT ATGACGCGAG ATATCTATGA GACAGACTAT 3540 TACCGGAAAG GAGGCAA\GG 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 CATCAGrCAGC 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 GAGACAGC 4080 TACGCCCACA TGAACGGGGG CCGCAAGMAC 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 AGGAhtGTGGC 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 TGAGCN~TGGC AGCTGGTTGC TCCATTTGAG AGACACGCTG GCGACACACT CCGTCCATCC 4860 GACTGCCCCT GCTGTGCTGC TCAAGGCCAC AGGCACACAG GTCTCATTGC TTCTGACTAG 4920 ATTATTATTT GGGGGAACTG GACACAATAG GTCTTTCTCT CAGTGAAGGT GGGGAGAAGC 4980 TGAACCGGC 4989 WO 96/01636 PCT/AU95/00410 83 INFORMATION FOR SEQ ID NO:4: SEQUENCE CHARACTERISTICS: LENGTH: 25 base pairs TYPE: nuclei- acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4: GCGCCCGCTG CATGACGCCT GCAAC INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 24 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID CGGGCGGCTC ACCTGGAGCT GGCG 24 INFORMATION FOR SEQ ID NO:6: SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6: AGGCGGCTGA CGGCACTA 18 INFORMATION FOR SEQ ID NO:7: SEQUENCE CHARACTERISTICS: LENGTH: 19 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7: CAGGCGTCAT GCAGCGGGC WO 96/01636 PCT/AU95/00410 84 INFORMATION FOR SEQ ID NO:8: SEQUENCE CHARACTERISTICS: LENGTH: 25 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8: CGGAGATGCC GCATGCCAGC GCAGG INFORMATION FOR SEQ ID NO:9: SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9: GACAGCGTCG GAGCGATC 18 INFORMATION FOR SEQ ID SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID ATCTCTCCGC TTCCTTTC 18 INFORMATION FOR SEQ ID NO:11: SEQUENCE CHARACTERISTICS: LENGTH: 18 base pairs TYPE: nucleic acid STRANDEDNESS: single TOPOLOGY: linear (ii) MOLECULE TYPE: cDNA (xi) SEQUENCE DESCRIPTION: SEQ ID NO11:: GAAAGGAAGC GGAGAGAT 18

Claims (14)

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 or chemical analogue thereof capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation and/or inflammation.

2. A method according to claim 1 wherein the proliferative or inflammatory skin disorder is psoriasis, ichthyosis, pityriasis, rubra, pilaris, serborrhoea, keloids, keratosis, neoplasias, scleroderma, warts, benign growths or cancers of the skin.

3. A method according to claim 2 wherein the skin condition is psoriasis.

4. A method according to claim 1 or 3 wherein the mammal is a human. A method according to claim 1 or 3 wherein the nucleic acid molecule is capable of inhibiting, reducing or otherwise interfering with IGF-I-interaction with its receptor. S

6. A method according to claim 7 wherein the nucleic acid molecule is an antisense 0

7. A method according to claim 6 w herein the nucleic acid molecule is an antisense Smolecule capable of reducing expression of a gene encoding IGFBP-, -5 re or -6.

8. A method according to claim 7 wherein the nucleic acid molecule is an antisense molecule capable of reducing expression of a gene encoding IGFBP-2 or IGFBP-3. .\OPJTDOVPTIO CIA 3/9I -86-

9. A method according to claim 8 wherein the antisense molecule is at least about nucleotides in length and is capable of interaLting with at least one sequence selected from the list set forth in Example 6 or Example 7. A method according to claim 8 wherein the antisense molecule comprises the nucleotide sequence: 5'-ATCTCTCCGCTTCCTTTC-3' [SEQ ID NO:

11. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridising to or forming a heterodupliex or otherwise interacting with an RNA molecule directed from a gene corresponding to a genomic form of SEQ ID NO:1 and/or SEQ ID NO:2 and which thereby reduces or inhibits translation of said RNA molecule, when used in accordance with the method of claim 1.

12. A nucleic acid molecule accordi .g to claim 11 wherein said molecule is capable of interacting with at least one nucleotide sequence selected from the list set forth in Example S6 and Example 7.

13. A nucleic acid molecule according to claim 12 comprising the nucleotide sequence: 5'-ATCTCTCCGCTTCCTTTC-3' [SEQ ID

14. A method of ameliorating the effects of psoriasis, 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 comprising a polynucleotide capable of interacting with mRNA directed from an IGF-I gene, and IGF-I receptor gene or a gene encoding an IGFBP. A method according to claim 14 wherein the IGFBP is IGFBP-2 or IGFBP-3. P:OPEKRWDOPCT4IO CLA 103J96

87- 16. A method according to claim 14 or 15 wherein the mammal is a human. 17. A method according to claim 16 wherein the nucleic acid molecule is capable of interacting with a nucleotide sequence selected from the list set forth in Example 6 or Example 7. 18. A method according to claim 17 wherein the nucleic acid molecule comprises the nucleotide sequence: 5'-ATCTCTCCGCTTCCTTTC-3' [SEQ ID 19. A pharmaceutical composition for topical administration when used in accordance with the method of claim 1 or 14 said composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation said composition further comprising one or more pharmaceutically acceptable carriers and/or diluents. 99* S: 20. A pharmaceutical composition according to claim 19 wherein the nucleic acid molecule is an antisense molecule to a gene encoding IGF-I, IGF-I-receptor or an IGFBP. 21. A pharmaceutical composition according to claim 20 wherein the nucleic acid C molecule is capable of targeting a gene encoding IGFBP-2 and/or IGFBP-3. 22. A pharmaceutical composition according to claim 20 capable of interacting with at least one nucleotide sequence set forth in Example 6 or Example 7. 23. 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 SEQ ID NO: 1 or SEQ ID NO:2 wherein said catalytic domain is capable of cleaving said target mRNA sequence to reduce or inhibit IGF-I mediated cell proliferation or inflammation. MOPHRUMMRDO\PCr4iQCIA 3OrJ

88- 24. A method according to any one of claims 1 to 10 or 14 to 18 or a nucleic acid molecule according to any one of claims 11 to 13 or a pharmaceutical composition according to any one of claims 19 to 22 or a ribozyme according to claim 23 substantially as hereinbefore described with reference to the Figures and/or Examples. Dated this 30th day of March, 1998 Royal Children's Hospital Research Foundation by its Patent Attorneys DAVIES COLLISON CAVE a *a o. a* •e a* 6 I