JP2003502383A - Method for prevention and / or treatment of medical disorders - Google Patents

Abstract

  (57) [Summary] The present invention relates generally to methods for preventing and / or treating skin disorders, especially proliferative and / or inflammatory skin disorders, and to genetic molecules useful therein. The invention is particularly directed to genetics that modulate the interaction of growth factors and their receptors on epidermal keratinocytes to inhibit, reduce, or otherwise reduce stimulation of this layer of cells. About molecules. The present invention contemplates in most preferred embodiments a method for the prevention and / or treatment of psoriasis.

Description

Detailed Description of the Invention

FIELD OF THE INVENTION The present invention relates generally to methods of preventing and / or treating medical disorders, specifically proliferative and / or inflammatory skin disorders, and genetic molecules useful therein. Specifically, the present invention regulates the interaction of growth factors with their receptors on cells such as epidermal keratinocytes to inhibit, reduce or otherwise reduce stimulation of epidermal cells. Relating to genetic molecules capable of The present invention, in a particularly preferred embodiment, contemplates a method of preventing and / or treating a psoriasis condition or a neovascularization condition such as retinal neovascularization. The invention further relates to such genetic molecules in adjunctive therapy of epidermal hyperplasia, such as when combined with UV treatment, to promote apoptosis of cancer cells, especially cancer cells containing keratinocytes.

[0002] In the background herein invention, the bibliographic details of the publications referred to in number, it is summarized at the end of this specification.

References herein to prior art are not, and are to be construed, as a form of recognition or suggestion that the prior art forms part of general common sense in Australia or any other country. Should not be.

Psoriasis and other similar conditions are common diseases, proliferative and / or inflammatory traumatic skin disorders that affect or have the potential to affect a significant proportion of the population. This condition results from hyperproliferation of basal keratinocytes in the epidermal layer of the skin, associated with inflammation of the underlying dermis. While a range of treatments have been developed, there are no treatments that are completely effective and without adverse side effects. The underlying cause of psoriasis is elusive, but this condition arises, at least in part, from local overexpression of growth factors, as well as their interaction with receptors that become more abundant during psoriasis. There is consensus that it supports the proliferation of keratinocytes via the keratinocyte receptors found.

One of the important groups of growth factors is the dermis-derived insulin-like growth factor that supports keratinocyte proliferation. Specifically, IGF-I and IGF-II are ubiquitous peptides each having a strong mitogenic effect on a wide range of cells. IGF-type molecules are also known as "progressors" that promote "reactive" cells during DNA synthesis.
These IGFs act through a type I receptor, a common receptor known as the IGF-I receptor, which is linked to tyrosine kinases. They are synthesized in mesenchymal tissues including the dermis and act on neighboring cells originating from mesoderm, endoderm or ectoderm. Regulation of their synthesis involves hepatic growth hormone (GH), which is poorly defined in most tissues [1].

A particular protein, called the IGF binding protein (IGFBP), is a tissue IG
It appears to be involved in autocrine / paracrine control of F availability [2]. So far, six IGFBPs have been identified. The exact effect of IGFBPs was not clear, and the effects observed in vitro were either inhibitory or stimulatory, depending on the experimental method used [3]. However, some IGFBPs
There is some evidence that it is involved in the targeting of -I to its cell surface receptor.

Skin, including the epidermis and the underlying dermis, has GH receptors on fibroblasts of the dermis [4]. Fibroblasts synthesize IGF-I as well as IGFBP-3, -4, -5 and -6 [5], which may be involved in targeting IGF-I to coated epidermis and neighboring cells. The major epidermal cell type, keratinocytes, does not synthesize IGF-I, but has the IGF-I receptor and thus responds to IGF-I [6].

Thus, it is clear that IGF-I and other growth promoting molecules are responsible for, or at least are involved in, a range of skin cell activities. In accordance with the present invention, we have found that abnormalities in the normal function of these molecules or in their interaction with their receptors are important in a variety of medical disorders such as proliferative and / or inflammatory skin disorders. It was proved that it was a factor. Thus, targeting these molecules or other molecules that promote the function of these molecules or the interaction of these molecules with their receptors, such as in conditions of skin diseases and conditions with neovascularization, etc. It has been proposed to ameliorate the effects of abnormal activity during or leading to other medical conditions. In addition, these molecules can also be used to promote apoptosis of target cells, and can be useful as an adjunct therapy for epidermal hyperplasia.

[0009] Overview nucleotide and amino acid sequences of the invention, the sequence Doteiko, namely, (SEQ ID NO: 1)
, (SEQ ID NO: 2) and the like. The sequence listing is given at the end of the description.

Throughout this specification, unless the context demands otherwise, “comprise”
The word or variations such as "comprises" or "comprising" mean the inclusion of the specified element or integer or group of elements or integers, but any other element or integer or element or It will be understood that this does not mean exclusion of groups of integers.

Accordingly, one aspect of the invention contemplates a method of ameliorating the effects of a medical disorder in a mammal, such as a proliferative and / or inflammatory skin disorder. The method comprises the steps of proliferating and / or inflamed skin or proliferating and / or inflamed skin or cells otherwise involved in the medical disorder and cells mediated by growth factors. Contacting with an effective amount of a nucleic acid molecule or chemical analogue thereof that can inhibit or otherwise reduce proliferation and / or inflammation and / or other medical disorders.

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

According to this embodiment, a method of ameliorating the effects of proliferative and / or inflammatory skin disorders, such as psoriasis, which comprises treating proliferating and / or inflamed skin or proliferative and / or inflammatory skin Contacting Possible Skin with an Effective and Effective Amount of UV Treatment of Nucleic Acid Molecules or Chemical Analogs That Can Inhibit or otherwise Reduce IGF-I-Mediated Cell Proliferation and / or Inflammation A method is provided that includes steps.

According to this embodiment, in a particularly preferred aspect there is provided a ribozyme comprising a hybridizing region and a catalytic region. Here, the hybridizing region is the target mR transcribed from the genomic gene corresponding to (SEQ ID NO: 1) or (SEQ ID NO: 2).
Is capable of hybridizing to at least a portion of the NA sequence and the catalytic domain is the target mR
The NA sequence can be cleaved to reduce or inhibit IGF-I mediated cell proliferation and / or inflammation and / or other medical disorders.

Yet another aspect of the present invention is, for example, IGF-I, its receptor, or IGFB.
Cosuppression is intended to reduce expression or inhibit translation of endogenous genes encoding IGFBPs such as P-2 and / or IGFBP-3. In co-suppression, a second copy of the endogenous gene or a substantially similar copy or analog of the endogenous gene is introduced intracellularly after local administration. As with antisense molecules, ribozyme-defining nucleic acid molecules or nucleic acid molecules useful for co-suppression may first be protected, such as by the use of nonionic backbones.

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

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

A further aspect of the invention contemplates an agent comprising a nucleic acid molecule as defined above as useful in the treatment of proliferative and / or inflammatory skin disorders such as psoriasis or other medical disorders. To do.

The present invention further contemplates the use of genetic molecules, especially antisense molecules that inhibit the anti-apoptotic activity of the IGF-I receptor.

Detailed Description of the Preferred Embodiments The present invention in part promotes the use of molecules, especially genetic molecules, and more specifically the expression of growth factors, their receptors and / or growth factors. It is based on the use of antisense molecules to regulate sequences at low levels.

Accordingly, one aspect of the invention contemplates a method of ameliorating the effects of a medical disorder in a mammal, such as a proliferative and / or inflammatory skin disorder. This method involves the growth of proliferating skin and / or inflamed skin or cells that are proliferative and / or inflamed skin or otherwise involved in the medical disorder and growth factor mediated proliferation of cells. And / or contacting with an effective amount of a nucleic acid molecule or chemical analogue thereof that can inhibit or otherwise reduce inflammation and / or other medical disorders.

Growth factor-mediated cell proliferation and inflammation is also called epidermal hyperplasia, and these and other medical disorders include IGF-I, keratinocyte growth factor (KGF), transforming growth factor-α (TGFα). , Tumor necrosis factor-α (TNFα), interleukins-1, -4, -6 and -8 (IL-1, IL-4, IL-, respectively).
6 and IL-8), basal fibroblast growth factor (bFGF) or a combination of one or more of the above, but can be mediated by any number of molecules. The present invention particularly relates to IGF-I and its receptor (IGF-I receptor) and IGF
Described and exemplified with reference to IGFBP, which is a -I promoting molecule. Because targeting these molecules according to the methods contemplated herein gives the best results thus far. However, this is any growth factor or cytokine-like molecule involved in the proliferation of skin cells, such as the molecule and / or their receptors and / or their promoting molecules for which the present invention is intended, its receptor. Alternatively, it is carried out with the understanding that it also extends to IGFBP-like promoting molecules.

According to this preferred embodiment, a method of ameliorating the effects of a medical disorder, such as a proliferative and / or inflammatory skin disorder in a mammal, which comprises proliferating skin and / or inflamed skin or Cells that are prone to proliferation and / or inflammation, or cells that are otherwise involved in the medical disorder, and IGF-I mediated cell proliferation and / or inflammation and / or other medical disorders can be inhibited, or Methods are provided that include the step of contacting with an effective amount of a nucleic acid molecule or chemical analogue thereof that can be otherwise reduced.

The invention is described in particular by psoriasis as a proliferative skin disorder. However, the invention relates to psoriasis, ichthyosis, pityriasis erythematosus piriformis (“PRP”), seborrhea,
Spans a range of proliferative and / or inflammatory skin disorders or epidermal hyperplasia, including but not limited to keloids, keratoses, neoplasia, and scleroderma, warts, benign growths and cancers of the skin . INDUSTRIAL APPLICABILITY The present invention relates to excessive neovascularization such as neovascularization of retina, brain lining, and skin, hyperproliferation of blood vessel inside, renal disease, atherosclerosis, hyperplasia of intestinal epithelium or malignant tumor mediated by IGF1. It extends to a range of other disorders such as, but not limited to, growth factor mediated malignancies, such as neovascularization conditions.

In addition, low level regulation of IGF-I receptors is useful as an adjunct treatment for epidermal hyperplasia. According to this aspect of the invention, the IGF-I receptor is known to elicit distinct intracellular signals that prevent apoptosis [19]. In keratinocytes, IGF-I receptor activation was shown to protect UV-irradiated cells from apoptosis [20]. In another cell type, some IGF-I receptors expressed by this cell correlated with tumorigenic and apoptosis resistance [21]. As a result, in accordance with the present invention, inactivating IGF-I receptors on cells such as epidermal keratinocytes has three important consequences: (i) acute epidermal hyperplasia after UV. It has been suggested to increase the risk of oncogenic transformation of keratinocytes [22]. Reducing the expression of IGF-I receptors in the epidermis may reduce the incidence of epidermal hyperplasia after UV exposure and may generally promote normalization of the disorder and a reduced risk of carcinogenesis. is there. (Ii) Inhibition of the anti-apoptotic effect of the IGF-I receptor enhances reversal of epidermal thickening and promotes normalization of differentiation. Topically administered or injected IGF-as adjunctive therapy
I-Receptor Antisense UV by Increasing Epidermal Layer Apoptosis
Enhances the reduction in epidermal thickening observed with treatment. (Iii) When cells damage DNA, cells that survive keratinocyte survival, ie, apoptosis, appear to appear. Such mutations can occur within the tumor suppressor region. As a result, the use of antisense therapy screens rarely mutated keratinocytes, thus reducing the incidence of cancerous and squamous basal cells.

According to this embodiment, there is provided a method of ameliorating the effects of proliferative and / or inflammatory skin disorders such as psoriasis. The method can inhibit proliferating and / or inflamed or proliferative and / or inflamed skin and IGF-I mediated cell proliferation and / or inflammation or other Contacting with an effective amount of the nucleic acid molecule or chemical analogue thereof that can be reduced by the method.

The UV treatment and nucleic acid molecule or chemical analogue thereof can be administered in any order or can be performed simultaneously. This method is particularly useful for the treatment of psoriasis by the combination of UV treatment and antisense treatment. Antisense therapy is preferably directed to the IGF-I receptor.

In a preferred embodiment, the present invention is a method of ameliorating the effects of psoriasis or other medical disorders, wherein the skin is growing or proliferative skin or cells associated with said disorder are mediated by IGF-I. Said method comprising the step of contacting with an effective amount of a nucleic acid molecule or a chemical analogue thereof which is capable of inhibiting or otherwise reducing the proliferation of cells or ameliorating said medical disorder.

The present invention can be applied to humans, domestic animals (eg, horse, sheep, cow, goat, pig, donkey), laboratory test animals (eg, rabbit, mouse, guinea pig), companion animals (eg, cat, dog). And any mammal, including, but not limited to, captive wildlife. However, the invention is not only directed to the medical disorders intended above, but in particular to proliferative and / or inflammatory skin disorders such as psoriasis in humans.

Aspects of the invention contemplated herein specifically include one or more suitable nucleic acid molecules that can inhibit, reduce, or otherwise interfere with IGF-mediated cell proliferation and / or inflammation. For topical application. More specifically, the nucleic acid molecule is IGF-
Targets the interaction of I with its receptor. Therefore, the nucleic acid molecule is conveniently an antagonist of the interaction of IGF-I with its receptor. The nucleic acid molecule antagonist is an antisense molecule to a molecule such as, but not limited to, IGF-I receptor, IGF-I itself, or IGFBP, which is capable of promoting interaction between IGF-I and its receptor. Is the most convenient.

As far as the invention relates to IGFBPs, the preferred molecules are IGFBP-2, -3,-
4, -5 and -6. Most preferred molecules are IGFBP-2 and IGFBP-
It is 3.

The nucleotide sequences of IGFBP-2 and IGFBP-3 are (SEQ ID NO:
1) and (SEQ ID NO: 2) of FIG. 2 respectively. According to a particularly preferred aspect of the present invention, it can hybridize with an mRNA molecule directed from the gene corresponding to the genomic form of SEQ ID NO: 1 and / or SEQ ID NO: 2, form a heteroduplex or otherwise. Provided is a nucleic acid molecule comprising at least about 10 nucleotides capable of interacting, thereby reducing or inhibiting translation of the mRNA molecule. Preferably, the nucleic acid molecule is at least about 15 nucleotides in length, more preferably at least about 20-25 nucleotides in length. However, the invention extends to nucleic acid molecules of any length, including 100-200 nucleotide molecules in length corresponding to the full length or near full length of the gene.

The nucleotide sequence of the antisense molecule is SEQ ID NO: 1 or SEQ ID NO:
The two regions or parts may be matched exactly or may differ by substitutions, deletions and / or additions of one or more nucleotides. However, when the nucleic acid molecule is m
A requirement is to reduce its translation into an active protein by interacting with the RNA molecule.

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

The nucleic acid molecule in the form of an antisense molecule may be linear or covalently closed circular and single-stranded or partially double-stranded. The double-stranded molecule may form a triple helix with the target mRNA or target gene. The molecule may be protected by several means, such as by using a nonionic backbone or phosphorothioate linkages, eg from nucleases. A convenient nonionic backbone contemplated herein is an ethylphosphotriester bond or a 2'-O-methylribosyl derivative. A particularly useful modification is the method of modifying the DNA backbone by introducing phosphorothioate bonds between the nucleotides. Alternatively or additionally, the pyrimidine base is modified by the introduction of C-5 propyne substitution. This modification has been proposed to enhance the stability of the double helix [23]. The invention extends to any chemical modifications to the bases and / or RNA or DNA backbones. Reference to a "chemical analog" of a nucleic acid molecule includes reference to a modified base, nucleotide, nucleoside or phosphate backbone.

Examples of suitable oligonucleotide analogues are conveniently described in Tuo et al.
7]. Further suitable examples of oligonucleotide analogues and chemical modifications can be found in reference 2
5 to 31.

In addition, the antisense molecule of the present invention can target the IGF-I gene itself or its receptor, or a multivalent antisense molecule can be constructed, or at least two or IGFBP, IGF-I and / Or Separate molecules targeting the IGF-I receptor can be administered. Examples of suitable antisense molecules that can target the IGF-I receptor are those capable of interacting with sequences selected from the table in Example 8.
One particularly useful antisense molecule is 5'-ATCTCTCCGCTTCCTT.
TC-3 '(SEQ ID NO: 10).

[0038]   Other particularly useful antisense molecules are: # 27 UCCGGAGCCAGACUU # 64 CACAGUUGCUGCAAG # 78 UCUCCGCUUCCUUUC # 28 AGCCCCCACACGCGAG # 32 GCCUUGGAGAUGAGC # 40 UAACAGAGGUCAGCA # 42 GGAUCAGGGGACCAGU # 46 CGGCAAGCUACACAG # 50 GGCAGGGCAGGCACAC Is.

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

A particularly preferred embodiment of the present invention is a method of ameliorating the effects of psoriasis or other medical disorders, which comprises growing or proliferating skin or cells associated with said medical disorder and IGF-. Contemplated is a method comprising contacting with an effective amount of one or more nucleic acid molecules or chemical analogues thereof that can inhibit or otherwise reduce cell mediated by I or otherwise ameliorate the medical disorder. To do. Where one or more of the molecules is
IGF-I gene, IGF-I receptor gene or IGFBP-2 and / or IG
It includes a polynucleotide capable of interacting with mRNA directed by a gene encoding IGFBPs such as FBP-3.

The nucleic acid molecule is preferably an antisense molecule. Particularly useful antisense molecule is a # 27 UCCGGAGCCAGACUU # 64 CACAGUUGCUGCAAG # 78 UCUCCGCUUCCUUUC # 28 AGCCCCCACAGCGAG # 32 GCCUUGGAGAUGAGC # 40 UAACAGAGGUCAGCA # 42 GGAUCAGGGACCAGU # 46 CGGCAAGCUACACAG # 50 GGCAGGCAGGCACAC.

[0042]   An even more useful molecule is selected from # 27, # 64 and # 78.

According to one aspect of the invention, the nucleic acid molecule is topically applied in an aqueous solution or with a cream, ointment, oil or other suitable carrier and / or diluent. More generally, multiple applications within the range of hourly, hourly, daily, daily, weekly or monthly, or some other suitable time intervals are required, but the severity of the condition. Or a single application may be sufficient depending on the emergency. The treatment may include only the application of the nucleic acid molecule, or the treatment may be other treatments for the proliferative and / or inflammatory disorders of the skin to be treated or microbial infection, bleeding and the formation of various eruptions. It may be applied with treatment for other related conditions including.

As an alternative to, or in conjunction with, antisense therapy, the invention may be described, for example, in I
A nucleic acid molecule as a ribozyme or a nucleic acid molecule containing the ribozyme including a minizyme for a molecule such as GF-I, its receptor, or IGFBP, particularly IGFBP-2 and -3. Ribozymes are synthetic nucleic acid molecules that have highly specific endoribonuclease activity. In particular, these are the target RNs in the nucleotide sequence.
A hybridizing region complementary to at least part of A is included. Ribozymes are well described in Hazelov and Gerach [8] and in International Patent Application WO 89/05852. The present invention relates to IGF-I, its receptor or IGFBP-2 and / or IG.
M identified by genes encoding one or more IGFBPs such as FBP-3
It covers ribozymes that target RNA.

According to this embodiment, in a particularly preferred aspect there is provided a ribozyme comprising a hybridizing region and a catalytic region. Here, the hybridizing region is the target mR transcribed from the genomic gene corresponding to (SEQ ID NO: 1) or (SEQ ID NO: 2).
Is capable of hybridizing to at least a portion of the NA sequence and the catalytic domain is the target mR
IGF-I-mediated cell proliferation and / or inflammation and / or cleavage of NA sequences
Or it can reduce or inhibit other medical disorders.

Yet another aspect of the present invention is, for example, IGF-I, its receptor, or IGFBP.
-2 and / or co-suppression to reduce the expression of endogenous genes encoding IGFBPs such as IGFBP-3 or to inhibit translation. In co-suppression, a second copy of the endogenous gene or a substantially similar copy or analog of the endogenous gene is introduced intracellularly after local administration. As with antisense molecules, ribozyme-defining nucleic acid molecules or nucleic acid molecules useful for co-suppression may first be protected, such as by the use of nonionic backbones.

The effectiveness of the nucleic acid molecules of the invention can be conveniently tested and screened using in vitro systems containing basal keratinocyte cell lines. Particularly useful systems include the HaCaT cell line described by Boukamp et al. [9]. In one assay, IGF-I is added to oligonucleotide-treated HaCaT cell lines. In another assay, proliferation of oligonucleotide-treated HaCaT cells is observed on a feed layer of irradiated 3T3 fibroblasts. Using such an in vitro assay, antisense oligonucleotides to IGFBP-3 can be labeled, for example, with Ha
It is observed to inhibit the production of IGFBP-3 by CaT cells. Other suitable animal models include the nude mouse / human skin explant model (15; 16) and the "flaky skin" mouse model (17; 18). In a nude mouse model, microdermatome biopsies of psoriatic lesions are collected from volunteers under local anesthesia and then transplanted into congenital athymic (nude) mice. These transplanted human skin grafts retain a characteristic hyperproliferative epidermis for 6-8 weeks. These are established models for testing the efficacy of locally applied psoriasis treatments. In the "flaky skin" mouse model, this fsn / fsn mutation results in mice with skin that resembles human psoriasis. This mouse, or other mutant mice with a similar phenotype, is a further in vitro model for testing the efficacy of topically applied psoriasis treatments.

Another aspect of the invention is a pharmaceutical composition for topical administration, which comprises IGF such as psoriasis
A composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing cell proliferation mediated by -I and one or more pharmaceutically acceptable carriers and / or diluents is contemplated.
This nucleic acid molecule is an antisense molecule against IGF-I, IGF-I receptor or IGFBPs such as IGFBP-2 and / or IGFBP-3, or contains ribozymes against one or more of these targets, Alternatively, it is preferably a molecule suitable for co-suppression of one or more of these targets. The composition is IGF-
I, its receptor or a single species of nucleic acid molecule capable of targeting one of the IGFBPs such as IGFBP-2 or IGFBP-3, or IGF-I, its receptor or IGFBP-2 and / or IGFBP-. It may be a multivalent molecule capable of targeting two or more IGFBPs such as 3.

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

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

Topical solutions are prepared by mixing the required amount of the nucleic acid molecule compound with the various other ingredients enumerated above in a suitable solvent, followed by sterilization by filtration if necessary.

The active agent may be absorbed intraperitoneally, intramuscularly, or through the lining of epithelial or mucosal skin,
Alternatively, it may be administered alternatively by intravenous, subcutaneous, nasal drip, suppository, or transdermal means, among other suitable routes of administration, including absorption via nasal, oral, vaginal, rectal or gastrointestinal administration. sell. For convenience, reference 24 may be referred to.

As used herein, “pharmaceutically acceptable carrier and / or diluent” includes any and all solvents, dispersion solvents, aqueous solutions, coatings, antibacterial and antifungal agents, etc. Tonicity agents, absorption delaying agents and the like are included. The use of such media and agents for pharmaceutically active substances is well known in the art. Their use in pharmaceutical compositions is intended except to the extent that any conventional vehicle or drug is incompatible with the active ingredient.
Supplementary active ingredients can also be included in the composition. For convenience, the nucleic acid molecules of the invention are stored in lyophilized form and reconstituted before use.

Yet another aspect of the invention contemplates the use of nucleic acid molecules in the manufacture of a medicament for the treatment of proliferative and / or inflammatory skin disorders or other medical disorders mediated by growth factors. . This proliferative and / or inflammatory skin disorder is generally psoriasis or other medical disorders mentioned above, wherein the nucleic acid molecule is IGF-I, IGF-I receptor and / or IGFBP-2 and / or Targets IGFBPs such as IGFBP-3.

A further aspect of the invention is an agent useful in the treatment of proliferative and / or inflammatory skin disorders such as psoriasis or other medical disorders and comprising a nucleic acid molecule as defined above. Intent.

The present invention contemplates the use of genetic molecules, especially antisense molecules that inhibit the anti-apoptotic activity of the IGF-I receptor. Such use is suitable as an adjunct treatment for epidermal hyperplasia, such as in certain cancer treatments as well as in combination with UV treatment.

[0057]   The invention is further described by the following non-limiting examples.

Example 1 The differentiated human keratinocyte cell line HaCaT [9] was used in an in vitro assay. Cells at passages 33 to 36 were treated with 5% v / v CO ₂ , 3 in keratinocyte-SFM (Gibco) containing EGF supplemented with bovine pituitary extract.
It was maintained as a monolayer culture at 7 ° C. The medium containing fetal bovine serum was avoided due to its high content of IGF-I binding protein in serum.

Feeding layer plates of lethal irradiated 3T3 fibroblasts were prepared as described by Reinwald and Green [10].

Example 2 Cells were grown in 2 cm ² wells for up to 4 days after confluence with daily keratinocyte-SFM medium exchange, then this medium was
25 mM Hepes, 0.19% w / v sodium bicarbonate, 0.03% w / v glutamine (Sigma Chemical Co., USA), 50 IU / ml penicillin and 50 μg / ml streptomycin (Flow Laboratories)) DMEM (Cytosystems, Inc.) Australia)
I changed to. Twenty-four hours later, IGF-I or tIGF-I was added to the wells in triplicate at a designated concentration in 0.5 ml of fresh DMEM containing 0.02% v / v bovine serum albumin (Sigma's molecular biology grade). Incubated for an additional 21 hours. Next, [3H
] -Thymidine (0.1 μCi / well) was added and the cells were incubated for an additional 3 hours. The medium was then aspirated and the cells were washed once with ice cold PBS, ice cold 10% v / v.
Washed twice with TCA. The TCA-precipitated monolayer was then mixed with 0.25M NaOH (
(200 μl / well), solubilized, transferred to a scintillation vial, and measured for radioactivity by liquid scintillation counting (Pharmacia Vallac 1410 liquid scintillation counter).

Example 3 HaCaT conditioned medium (250 μL) was concentrated by adding 750 μL cold ethanol, incubating at −20 ° C. for 2 hours, and centrifuging at 16,000 g for 20 minutes at 4 ° C. The obtained pellets were subjected to the Laemli method (1970) according to
Air dried, completely resuspended in non-reduced Laemmli sample buffer, heated to 90 ° C. for 5 minutes and separated on 12% w / v SDS-PAGE. 25mM of separated protein
Electrophoresis was performed on nitrocellulose membranes (0.45 mm, Schleicher and Schul, Germany) in a buffer containing Tris, 192 mM glycine and 20% v / v methanol. The IGFBPs were then visualized by the technique of Hossenlop et al. [11] using [ ¹²⁵ I] -IGF-I, followed by autoradiography. Autoradiographs were scanned on a BioRad model GS-670 image densitometer and band densities were measured using the Molecular Analyst program.

Example 4 Phosphorothioate oligodeoxynucleotides were synthesized by Bresatech, Inc. of Adelaide, South Australia. The following antisense sequences were used: BP3AS2: 5'-GCG CCC GCT GCA TGA CGC C
TG CAA C-3 '(SEQ ID NO: 4), which is human IGFBP-3mRN
A 25-mer complementary to the start codon region of A, BP3AS3: 5'-CGG GCG GCT CAC CTG GAG C
TG GCG-3 '(SEQ ID NO: 5), which is the 24mer complementary to the exon 1 / intron 1 splice site, BP3AS4: 5'-AGG CGG CTG ACG GCA CTA-3.
'(SEQ ID NO: 6), which is an 18-mer complementary to the coding sequence region that lacks RNA secondary structure and oligonucleotide dimerization (using the computer software "Oligo for Pissi") . BP3AS4 was used as a control because it was found to have no effect on the inhibition of IGFBP-3 synthesis. The following additional control oligonucleotide sequences were used: BP3S: 5'-CAG GCG TCA TGC AGC GGG C.
-3 '(SEQ ID NO: 7), which is an 18-mer sense control sequence equivalent to the start codon region, BP3AS2NS: 5'-CGG AGA TGC CGC ATG CCA.
GCG CAG G-3 '(SEQ ID NO: 8), which is the same GC as BP3AS2
A 25-mer random sequence with content, BP3AS4NS: 5'-GAC AGC GTC GGA GCG ATC
-3 '(SEQ ID NO: 9), an 18-mer optionally extracted sequence with the same GC content as BP3AS4NS. The design of the oligonucleotide was based on the human IGFBP-3 cDNA sequence of Splat et al. [12].

Cells were 2 cm ² with daily 0.5 ml keratinocyte-SFM medium exchange. After culturing in the wells for up to 1 day after confluence, medium exchange of keratinocyte-SFM was performed every day for another 4 days. Then, daily, 0.5 ml of fresh keratinocyte-SFM was added for a further 7 days, but when the medium was added, 5 μL of oligonucleotide PBS solution was added to the specified final concentration, and then the oligonucleotide was mixed. The wells were shaken to 24 cells after final addition
Incubated for hours and harvested media for IGFBP assay. The cells were then trypsinized and counted in a Coulter Industrial D counter from Coulter Bedfordshire, England. The difference in cell number after oligonucleotide treatment was less than 10%.

Example 5 HaCaT cells secrete mainly IGFBP-3 (> 95%), the only other IGFBP detectable in HaCaT conditioned medium is IGFBP-4 (<5%). The effect of antisense oligonucleotides on IGFBP-3 and IGFBP-4 synthesis was tested at two concentrations, 5 μM and 0.5 μM. IGFBP-
Two oligonucleotides were used, BP3AS2 and BP3AS3, which are antisense molecules to the 3 mRNA start site and the intron1 / exon1 splice site. As a control, a sense oligonucleotide corresponding to the start site was used. As shown in FIGS. 4A and 4B, at 5 μM all oligonucleotides caused a significant reduction in IGFBP-3 synthesis compared to untreated cells, but these two antisense oligonucleotides were compared to the sense control. Then about 50% I
It inhibited GFBP-3 synthesis (Fig. 4B). The antisense oligonucleotide to the start codon appeared to be the more effective of the two, the difference being more pronounced at the low concentration of 0.5 μM. IG secreted by HaCaT cells
In FBP-4 cells, it is difficult to reproduce a band on a Western ligand blot, but densitometry allows appropriate ratio quantification. As a result, IGFBP-4
An important observation was made that the level of A was not affected by the addition of oligonucleotides to the cells, suggesting that the observed inhibitory effect on IGFBP-3 was specific.

The more effective of these two antisense oligonucleotides, BP
To further investigate the inhibitory effect of 3AS2, the inhibition by this oligonucleotide at 0.5 μM was compared to several control oligonucleotides. In this, 0.5 μM
One antisense oligonucleotide to IGFBP-3 that has been shown to be ineffective in. As shown in FIGS. 5A and 5B, BP3AS2
Is again inhibitory and is the most non-specific inhibitory control oligonucleotide
It produced IGFBP-3 levels of approximately 50% of the randomized equivalent of 3AS2. Other control oligonucleotides were IGFB at 0.5 μM compared to untreated cells
It did not cause a reduction in P-3 levels. Similar to BP3AS2 itself, the fact that this control oligonucleotide, BP3AS2NS, has the highest potential Tm of the three control oligonucleotides used in this experiment could be significant, and could be non-specific to non-target mRNAs. The probability of forming specific base pairs is increased. However, the fact that BP3AS2 does not inhibit the secretion of IGFBP-4 suggests that this oligonucleotide is selective even compared to the most closely related protein that is likely to be present in the cell line.

Example 6 Antisense oligonucleotides against IGFBP2 can be selected from molecules capable of interacting with one or more of the following sense oligonucleotides.

[0067] 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 AGGCGGCTCCCGCTC GGCGGCTCCCGCTCG GCGGCTCCCGCTCGC CGGCTCCCGCTCGCA GGCTCCCGCTCGCAG GCTCCCGCTCGCAGG CTCCCGCTCGCAGGG TCCCGCTCGCAGGGC CCCGCTCGCAGGGCC CCGCTCGCAGGGCCG CGCTCGCAGGGCCGT GCTCGCAGGGCCGTG CTCGCAGGGCCGTGC TCGCAGGGCCGTGCA

[0068] CGCAGGGCCGTGCAC GCAGGGCCGTGCACC CAGGGCCGTGCACCT AGGGCCGTGCACCTG GGGCCGTGCACCTGC GGCCGTGCACCTGCC GCCGTGCACCTGCCC CCGTGCACCTGCCCG CGTGCACCTGCCCGC GTGCACCTGCCCGCC TGCACCTGCCCGCCC GCACCTGCCCGCCCG CACCTGCCCGCCCGC ACCTGCCCGCCCGCC 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

[0069] CCGCGCCGCGCTGCC CGCGCCGCGCTGCCG GCGCCGCGCTGCCGA CGCCGCGCTGCCGAC GCCGCGCTGCCGACC CCGCGCTGCCGACCG CGCGCTGCCGACCGC GCGCTGCCGACCGCC CGCTGCCGACCGCCA GCTGCCGACCGCCAG CTGCCGACCGCCAGC TGCCGACCGCCAGCA GCCGACCGCCAGCAT CCGACCGCCAGCATG CGACCGCCAGCATGC GACCGCCAGCATGCT ACCGCCAGCATGCTG CCGCCAGCATGCTGC CGCCAGCATGCTGCC GCCAGCATGCTGCCG CCAGCATGCTGCCGA CAGCATGCTGCCGAG AGCATGCTGCCGAGA GCATGCTGCCGAGAG CATGCTGCCGAGAGT ATGCTGCCGAGAGTG TGCTGCCGAGAGTGG GCTGCCGAGAGTGGG CTGCCGAGAGTGGGC TGCCGAGAGTGGGCT GCCGAGAGTGGGCTG CCGAGAGTGGGCTGC CGAGAGTGGGCTGCC GAGAGTGGGCTGCCC AGAGTGGGCTGCCCC GAGTGGGCTGCCCCG AGTGGGCTGCCCCGC GTGGGCTGCCCCGCG TGGGCTGCCCCGCGC GGGCTGCCCCGCGCT GGCTGCCCCGCGCTG GCTGCCCCGCGCTGC CTGCCCCGCGCTGCC TGCCCCGCGCTGCCG GCCCCGCGCTGCCGC CCCCGCGCTGCCGCT

[0070] CCCGCGCTGCCGCTG CCGCGCTGCCGCTGC CGCGCTGCCGCTGCC GCGCTGCCGCTGCCG CGCTGCCGCTGCCGC GCTGCCGCTGCCGCC CTGCCGCTGCCGCCG TGCCGCTGCCGCCGC GCCGCTGCCGCCGCC CCGCTGCCGCCGCCG CGCTGCCGCCGCCGC GCTGCCGCCGCCGCC CTGCCGCCGCCGCCG TGCCGCCGCCGCCGC GCCGCCGCCGCCGCT CCGCCGCCGCCGCTG CGCCGCCGCCGCTGC GCCGCCGCCGCTGCT CCGCCGCCGCTGCTG CGCCGCCGCTGCTGC GCCGCCGCTGCTGCC 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

[0071] CTGCTGCTACTGGGC TGCTGCTACTGGGCG GCTGCTACTGGGCGC CTGCTACTGGGCGCG TGCTACTGGGCGCGA GCTACTGGGCGCGAG CTACTGGGCGCGAGT TACTGGGCGCGAGTG ACTGGGCGCGAGTGG CTGGGCGCGAGTGGC TGGGCGCGAGTGGCG GGGCGCGAGTGGCGG GGCGCGAGTGGCGGC GCGCGAGTGGCGGCG CGCGAGTGGCGGCGG GCGAGTGGCGGCGGC CGAGTGGCGGCGGCG GAGTGGCGGCGGCGG AGTGGCGGCGGCGGC GTGGCGGCGGCGGCG TGGCGGCGGCGGCGG GGCGGCGGCGGCGGG GCGGCGGCGGCGGGG CGGCGGCGGCGGGGC GGCGGCGGCGGGGCG GCGGCGGCGGGGCGC CGGCGGCGGGGCGCG GGCGGCGGGGCGCGC GCGGCGGGGCGCGCG CGGCGGGGCGCGCGC GGCGGGGCGCGCGCG GCGGGGCGCGCGCGG CGGGGCGCGCGCGGA GGGGCGCGCGCGGAG GGGCGCGCGCGGAGG GGCGCGCGCGGAGGT GCGCGCGCGGAGGTG CGCGCGCGGAGGTGC GCGCGCGGAGGTGCT CGCGCGGAGGTGCTG GCGCGGAGGTGCTGT CGCGGAGGTGCTGTT GCGGAGGTGCTGTTC CGGAGGTGCTGTTCC GGAGGTGCTGTTCCG GAGGTGCTGTTCCGC AGGTGCTGTTCCGCT GGTGCTGTTCCGCTG GTGCTGTTCCGCTGC TGCTGTTCCGCTGCC GCTGTTCCGCTGCCC

[0072] 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

[0073] CCGCCGGTTGCGCCG CGCCGGTTGCGCCGC 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

[0074] ATGCCATGCGCGGAG TGCCATGCGCGGAGC GCCATGCGCGGAGCT CCATGCGCGGAGCTC CATGCGCGGAGCTCG 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

[0075] TGCGCCCGGCTGGAG GCGCCCGGCTGGAGG CGCCCGGCTGGAGGG 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

[0076] CAGGGGCTGCGCTGC AGGGGCTGCGCTGCT GGGGCTGCGCTGCTA GGGCTGCGCTGCTAT GGCTGCGCTGCTATC GCTGCGCTGCTATCC CTGCGCTGCTATCCC TGCGCTGCTATCCCC GCGCTGCTATCCCCA CGCTGCTATCCCCAC GCTGCTATCCCCACC CTGCTATCCCCACCC TGCTATCCCCACCCG GCTATCCCCACCCGG CTATCCCCACCCGGG TATCCCCACCCGGGC ATCCCCACCCGGGCT TCCCCACCCGGGCTC CCCCACCCGGGCTCC CCCACCCGGGCTCCG CCACCCGGGCTCCGA CACCCGGGCTCCGAG ACCCGGGCTCCGAGC CCCGGGCTCCGAGCT CCGGGCTCCGAGCTG CGGGCTCCGAGCTGC GGGCTCCGAGCTGCC GGCTCCGAGCTGCCC GCTCCGAGCTGCCCC CTCCGAGCTGCCCCT TCCGAGCTGCCCCTG CCGAGCTGCCCCTGC CGAGCTGCCCCTGCA GAGCTGCCCCTGCAG AGCTGCCCCTGCAGG GCTGCCCCTGCAGGC CTGCCCCTGCAGGCG TGCCCCTGCAGGCGC GCCCCTGCAGGCGCT CCCCTGCAGGCGCTG CCCTGCAGGCGCTGG CCTGCAGGCGCTGGT CTGCAGGCGCTGGTC TGCAGGCGCTGGTCA GCAGGCGCTGGTCAT CAGGCGCTGGTCATG AGGCGCTGGTCATGG GGCGCTGGTCATGGG GCGCTGGTCATGGGC CGCTGGTCATGGGCG GCTGGTCATGGGCGA

[0077] CTGGTCATGGGCGAG TGGTCATGGGCGAGG GGTCATGGGCGAGGG GTCATGGGCGAGGGC TCATGGGCGAGGGCA CATGGGCGAGGGCAC ATGGGCGAGGGCACT TGGGCGAGGGCACTT GGGCGAGGGCACTTG GGCGAGGGCACTTGT GCGAGGGCACTTGTG CGAGGGCACTTGTGA GAGGGCACTTGTGAG AGGGCACTTGTGAGA GGGCACTTGTGAGAA GGCACTTGTGAGAAG GCACTTGTGAGAAGC CACTTGTGAGAAGCG ACTTGTGAGAAGCGC CTTGTGAGAAGCGCC TTGTGAGAAGCGCCG TGTGAGAAGCGCCGG GTGAGAAGCGCCGGG TGAGAAGCGCCGGGA GAGAAGCGCCGGGAC AGAAGCGCCGGGACG GAAGCGCCGGGACGC AAGCGCCGGGACGCC AGCGCCGGGACGCCG GCGCCGGGACGCCGA CGCCGGGACGCCGAG GCCGGGACGCCGAGT CCGGGACGCCGAGTA CGGGACGCCGAGTAT GGGACGCCGAGTATG GGACGCCGAGTATGG GACGCCGAGTATGGC ACGCCGAGTATGGCG CGCCGAGTATGGCGC GCCGAGTATGGCGCC CCGAGTATGGCGCCA CGAGTATGGCGCCAG GAGTATGGCGCCAGC AGTATGGCGCCAGCC GTATGGCGCCAGCCC TATGGCGCCAGCCCG ATGGCGCCAGCCCGG TGGCGCCAGCCCGGA GGCGCCAGCCCGGAG GCGCCAGCCCGGAGC CGCCAGCCCGGAGCA

[0078] GCCAGCCCGGAGCAG CCAGCCCGGAGCAGG CAGCCCGGAGCAGGT AGCCCGGAGCAGGTT GCCCGGAGCAGGTTG CCCGGAGCAGGTTGC CCGGAGCAGGTTGCA CGGAGCAGGTTGCAG GGAGCAGGTTGCAGA GAGCAGGTTGCAGAC AGCAGGTTGCAGACA GCAGGTTGCAGACAA CAGGTTGCAGACAAT AGGTTGCAGACAATG GGTTGCAGACAATGG GTTGCAGACAATGGC TTGCAGACAATGGCG TGCAGACAATGGCGA GCAGACAATGGCGAT CAGACAATGGCGATG AGACAATGGCGATGA GACAATGGCGATGAC ACAATGGCGATGACC CAATGGCGATGACCA AATGGCGATGACCAC ATGGCGATGACCACT TGGCGATGACCACTC GGCGATGACCACTCA GCGATGACCACTCAG CGATGACCACTCAGA GATGACCACTCAGAA ATGACCACTCAGAAG TGACCACTCAGAAGG GACCACTCAGAAGGA ACCACTCAGAAGGAG CCACTCAGAAGGAGG CACTCAGAAGGAGGC ACTCAGAAGGAGGCC CTCAGAAGGAGGCCT TCAGAAGGAGGCCTG CAGAAGGAGGCCTGG AGAAGGAGGCCTGGT GAAGGAGGCCTGGTG AAGGAGGCCTGGTGG AGGAGGCCTGGTGGA GGAGGCCTGGTGGAG GAGGCCTGGTGGAGA AGGCCTGGTGGAGAA GGCCTGGTGGAGAAC GCCTGGTGGAGAACC CCTGGTGGAGAACCA

[0079] CTGGTGGAGAACCAC TGGTGGAGAACCACG GGTGGAGAACCACGT GTGGAGAACCACGTG TGGAGAACCACGTGG GGAGAACCACGTGGA GAGAACCACGTGGAC AGAACCACGTGGACA GAACCACGTGGACAG AACCACGTGGACAGC ACCACGTGGACAGCA CCACGTGGACAGCAC 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 GCAGTGCTGGCCGGA CAGTGCTGGCCGGAA

[0080] AGTGCTGGCCGGAAG GTGCTGGCCGGAAGC TGCTGGCCGGAAGCC GCTGGCCGGAAGCCC CTGGCCGGAAGCCCC TGGCCGGAAGCCCCT GGCCGGAAGCCCCTC GCCGGAAGCCCCTCA CCGGAAGCCCCTCAA CGGAAGCCCCTCAAG GGAAGCCCCTCAAGT GAAGCCCCTCAAGTC AAGCCCCTCAAGTCG AGCCCCTCAAGTCGG GCCCCTCAAGTCGGG CCCCTCAAGTCGGGT CCCTCAAGTCGGGTA CCTCAAGTCGGGTAT CTCAAGTCGGGTATG TCAAGTCGGGTATGA CAAGTCGGGTATGAA AAGTCGGGTATGAAG AGTCGGGTATGAAGG GTCGGGTATGAAGGA TCGGGTATGAAGGAG CGGGTATGAAGGAGC GGGTATGAAGGAGCT GGTATGAAGGAGCTG GTATGAAGGAGCTGG TATGAAGGAGCTGGC ATGAAGGAGCTGGCC TGAAGGAGCTGGCCG GAAGGAGCTGGCCGT AAGGAGCTGGCCGTG AGGAGCTGGCCGTGT GGAGCTGGCCGTGTT GAGCTGGCCGTGTTC AGCTGGCCGTGTTCC GCTGGCCGTGTTCCG CTGGCCGTGTTCCGG TGGCCGTGTTCCGGG GGCCGTGTTCCGGGA GCCGTGTTCCGGGAG CCGTGTTCCGGGAGA CGTGTTCCGGGAGAA GTGTTCCGGGAGAAG TGTTCCGGGAGAAGG GTTCCGGGAGAAGGT TTCCGGGAGAAGGTC TCCGGGAGAAGGTCA CCGGGAGAAGGTCAC

[0081] CGGGAGAAGGTCACT GGGAGAAGGTCACTG GGAGAAGGTCACTGA GAGAAGGTCACTGAG 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 GGCAAGGGTGGCAAG GCAAGGGTGGCAAGC CAAGGGTGGCAAGCA AAGGGTGGCAAGCAT AGGGTGGCAAGCATC GGGTGGCAAGCATCA GGTGGCAAGCATCAC GTGGCAAGCATCACC TGGCAAGCATCACCT GGCAAGCATCACCTT GCAAGCATCACCTTG CAAGCATCACCTTGG AAGCATCACCTTGGC AGCATCACCTTGGCC GCATCACCTTGGCCT CATCACCTTGGCCTG ATCACCTTGGCCTGG TCACCTTGGCCTGGA

[0082] CACCTTGGCCTGGAG ACCTTGGCCTGGAGG CCTTGGCCTGGAGGA CTTGGCCTGGAGGAG TTGGCCTGGAGGAGC TGGCCTGGAGGAGCC GGCCTGGAGGAGCCC GCCTGGAGGAGCCCA CCTGGAGGAGCCCAA CTGGAGGAGCCCAAG TGGAGGAGCCCAAGA GGAGGAGCCCAAGAA GAGGAGCCCAAGAAG AGGAGCCCAAGAAGC GGAGCCCAAGAAGCT GAGCCCAAGAAGCTG AGCCCAAGAAGCTGC GCCCAAGAAGCTGCG CCCAAGAAGCTGCGA CCAAGAAGCTGCGAC CAAGAAGCTGCGACC AAGAAGCTGCGACCA AGAAGCTGCGACCAC GAAGCTGCGACCACC AAGCTGCGACCACCC AGCTGCGACCACCCC GCTGCGACCACCCCC CTGCGACCACCCCCT TGCGACCACCCCCTG GCGACCACCCCCTGC CGACCACCCCCTGCC GACCACCCCCTGCCA ACCACCCCCTGCCAG CCACCCCCTGCCAGG CACCCCCTGCCAGGA ACCCCCTGCCAGGAC CCCCCTGCCAGGACT CCCCTGCCAGGACTC CCCTGCCAGGACTCC CCTGCCAGGACTCCC CTGCCAGGACTCCCT TGCCAGGACTCCCTG GCCAGGACTCCCTGC CCAGGACTCCCTGCC CAGGACTCCCTGCCA AGGACTCCCTGCCAA GGACTCCCTGCCAAC GACTCCCTGCCAACA ACTCCCTGCCAACAG CTCCCTGCCAACAGG TCCCTGCCAACAGGA

[0083] CCCTGCCAACAGGAA CCTGCCAACAGGAAC CTGCCAACAGGAACT TGCCAACAGGAACTG GCCAACAGGAACTGG CCAACAGGAACTGGA CAACAGGAACTGGAC AACAGGAACTGGACC ACAGGAACTGGACCA CAGGAACTGGACCAG AGGAACTGGACCAGG GGAACTGGACCAGGT GAACTGGACCAGGTC AACTGGACCAGGTCC ACTGGACCAGGTCCT CTGGACCAGGTCCTG TGGACCAGGTCCTGG GGACCAGGTCCTGGA GACCAGGTCCTGGAG ACCAGGTCCTGGAGC CCAGGTCCTGGAGCG CAGGTCCTGGAGCGG AGGTCCTGGAGCGGA GGTCCTGGAGCGGAT GTCCTGGAGCGGATC TCCTGGAGCGGATCT CCTGGAGCGGATCTC CTGGAGCGGATCTCC TGGAGCGGATCTCCA GGAGCGGATCTCCAC GAGCGGATCTCCACC AGCGGATCTCCACCA GCGGATCTCCACCAT CGGATCTCCACCATG GGATCTCCACCATGC GATCTCCACCATGCG ATCTCCACCATGCGC TCTCCACCATGCGCC CTCCACCATGCGCCT TCCACCATGCGCCTT CCACCATGCGCCTTC CACCATGCGCCTTCC ACCATGCGCCTTCCG CCATGCGCCTTCCGG CATGCGCCTTCCGGA ATGCGCCTTCCGGAT TGCGCCTTCCGGATG GCGCCTTCCGGATGA CGCCTTCCGGATGAG GCCTTCCGGATGAGC CCTTCCGGATGAGCG

[0084] 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 CTCCCTGCACATCCC TCCCTGCACATCCCC CCCTGCACATCCCCA CCTGCACATCCCCAA CTGCACATCCCCAAC TGCACATCCCCAACT GCACATCCCCAACTG CACATCCCCAACTGT ACATCCCCAACTGTG CATCCCCAACTGTGA ATCCCCAACTGTGAC TCCCCAACTGTGACA CCCCAACTGTGACAA CCCAACTGTGACAAG CCAACTGTGACAAGC CAACTGTGACAAGCA

[0085] AACTGTGACAAGCAT ACTGTGACAAGCATG CTGTGACAAGCATGG TGTGACAAGCATGGC GTGACAAGCATGGCC TGACAAGCATGGCCT GACAAGCATGGCCTG ACAAGCATGGCCTGT CAAGCATGGCCTGTA AAGCATGGCCTGTAC AGCATGGCCTGTACA GCATGGCCTGTACAA CATGGCCTGTACAAC ATGGCCTGTACAACC TGGCCTGTACAACCT GGCCTGTACAACCTC GCCTGTACAACCTCA CCTGTACAACCTCAA CTGTACAACCTCAAA TGTACAACCTCAAAC GTACAACCTCAAACA TACAACCTCAAACAG ACAACCTCAAACAGT CAACCTCAAACAGTG AACCTCAAACAGTGC ACCTCAAACAGTGCA CCTCAAACAGTGCAA CTCAAACAGTGCAAG TCAAACAGTGCAAGA CAAACAGTGCAAGAT AAACAGTGCAAGATG AACAGTGCAAGATGT ACAGTGCAAGATGTC CAGTGCAAGATGTCT AGTGCAAGATGTCTC GTGCAAGATGTCTCT TGCAAGATGTCTCTG GCAAGATGTCTCTGA CAAGATGTCTCTGAA AAGATGTCTCTGAAC AGATGTCTCTGAACG GATGTCTCTGAACGG ATGTCTCTGAACGGG TGTCTCTGAACGGGC GTCTCTGAACGGGCA TCTCTGAACGGGCAG CTCTGAACGGGCAGC TCTGAACGGGCAGCG CTGAACGGGCAGCGT TGAACGGGCAGCGTG GAACGGGCAGCGTGG

[0086] AACGGGCAGCGTGGG ACGGGCAGCGTGGGG CGGGCAGCGTGGGGA GGGCAGCGTGGGGAG GGCAGCGTGGGGAGT GCAGCGTGGGGAGTG CAGCGTGGGGAGTGC AGCGTGGGGAGTGCT GCGTGGGGAGTGCTG CGTGGGGAGTGCTGG GTGGGGAGTGCTGGT TGGGGAGTGCTGGTG GGGGAGTGCTGGTGT GGGAGTGCTGGTGTG GGAGTGCTGGTGTGT GAGTGCTGGTGTGTG AGTGCTGGTGTGTGA GTGCTGGTGTGTGAA TGCTGGTGTGTGAAC GCTGGTGTGTGAACC CTGGTGTGTGAACCC GGTGTGTGAACCCCA GTGTGTGAACCCCAA TGTGTGAACCCCAAC GTGTGAACCCCAACA TGTGAACCCCAACAC GTGAACCCCAACACC TGAACCCCAACACCG GAACCCCAACACCGG AACCCCAACACCGGG ACCCCAACACCGGGA CCCCAACACCGGGAA CCCAACACCGGGAAG CCAACACCGGGAAGC CAACACCGGGAAGCT AACACCGGGAAGCTG ACACCGGGAAGCTGA CACCGGGAAGCTGAT ACCGGGAAGCTGATC CCGGGAAGCTGATCC CGGGAAGCTGATCCA GGGAAGCTGATCCAG GGAAGCTGATCCAGG GAAGCTGATCCAGGG AAGCTGATCCAGGGA AGCTGATCCAGGGAG GCTGATCCAGGGAGC CTGATCCAGGGAGCC TGATCCAGGGAGCCC GATCCAGGGAGCCCC

[0087] ATCCAGGGAGCCCCC TCCAGGGAGCCCCCA CCAGGGAGCCCCCAC CAGGGAGCCCCCACC AGGGAGCCCCCACCA GGGAGCCCCCACCAT GGAGCCCCCACCATC GAGCCCCCACCATCC AGCCCCCACCATCCG GCCCCCACCATCCGG CCCCCACCATCCGGG CCCCACCATCCGGGG CCCACCATCCGGGGG CCACCATCCGGGGGG CACCATCCGGGGGGA ACCATCCGGGGGGAC CCATCCGGGGGGACC CATCCGGGGGGACCC ATCCGGGGGGACCCC TCCGGGGGGACCCCG CCGGGGGGACCCCGA CGGGGGGACCCCGAG GGGGGGACCCCGAGT GGGGGACCCCGAGTG GGGGACCCCGAGTGT GGGACCCCGAGTGTC GGACCCCGAGTGTCA GACCCCGAGTGTCAT ACCCCGAGTGTCATC CCCCGAGTGTCATCT CCCGAGTGTCATCTC CCGAGTGTCATCTCT CGAGTGTCATCTCTT GAGTGTCATCTCTTC AGTGTCATCTCTTCT GTGTCATCTCTTCTA TGTCATCTCTTCTAC GTCATCTCTTCTACA TCATCTCTTCTACAA CATCTCTTCTACAAT ATCTCTTCTACAATG TCTCTTCTACAATGA CTCTTCTACAATGAG TCTTCTACAATGAGC CTTCTACAATGAGCA TTCTACAATGAGCAG TCTACAATGAGCAGC CTACAATGAGCAGCA TACAATGAGCAGCAG ACAATGAGCAGCAGG CAATGAGCAGCAGGA

[0088] AATGAGCAGCAGGAG ATGAGCAGCAGGAGG TGAGCAGCAGGAGGC GAGCAGCAGGAGGCT AGCAGCAGGAGGCTT GCAGCAGGAGGCTTG CAGCAGGAGGCTTGC AGCAGGAGGCTTGCG GCAGGAGGCTTGCGG CAGGAGGCTTGCGGG AGGAGGCTTGCGGGG GGAGGCTTGCGGGGT GAGGCTTGCGGGGTG AGGCTTGCGGGGTGC GGCTTGCGGGGTGCA GCTTGCGGGGTGCAC CTTGCGGGGTGCACA TTGCGGGGTGCACAC TGCGGGGTGCACACC 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

[0089] 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 GCCCCCCGCCCCTCT CCCCCCGCCCCTCTC CCCCCGCCCCTCTCC CCCCGCCCCTCTCCA CCCGCCCCTCTCCAA CCGCCCCTCTCCAAA CGCCCCTCTCCAAAC GCCCCTCTCCAAACA CCCCTCTCCAAACAC CCCTCTCCAAACACC CCTCTCCAAACACCG CTCTCCAAACACCGG TCTCCAAACACCGGC CTCCAAACACCGGCA TCCAAACACCGGCAG CCAAACACCGGCAGA CAAACACCGGCAGAA AAACACCGGCAGAAA AACACCGGCAGAAAA ACACCGGCAGAAAAC CACCGGCAGAAAACG ACCGGCAGAAAACGG CCGGCAGAAAACGGA CGGCAGAAAACGGAG GGCAGAAAACGGAGA

[0090] GCAGAAAACGGAGAG CAGAAAACGGAGAGT AGAAAACGGAGAGTG GAAAACGGAGAGTGC AAAACGGAGAGTGCT AAACGGAGAGTGCTT AACGGAGAGTGCTTG ACGGAGAGTGCTTGG CGGAGAGTGCTTGGG GGAGAGTGCTTGGGT GAGAGTGCTTGGGTG AGAGTGCTTGGGTGG GAGTGCTTGGGTGGT AGTGCTTGGGTGGTG GTGCTTGGGTGGTGG TGCTTGGGTGGTGGG GCTTGGGTGGTGGGT CTTGGGTGGTGGGTG TTGGGTGGTGGGTGC TGGGTGGTGGGTGCT GGGTGGTGGGTGCTG GGTGGTGGGTGCTGG GTGGTGGGTGCTGGA TGGTGGGTGCTGGAG GGTGGGTGCTGGAGG GTGGGTGCTGGAGGA TGGGTGCTGGAGGAT GGGTGCTGGAGGATT GGTGCTGGAGGATTT GTGCTGGAGGATTTT TGCTGGAGGATTTTC GCTGGAGGATTTTCC CTGGAGGATTTTCCA TGGAGGATTTTCCAG GGAGGATTTTCCAGT GAGGATTTTCCAGTT AGGATTTTCCAGTTC GGATTTTCCAGTTCT GATTTTCCAGTTCTG ATTTTCCAGTTCTGA TTTTCCAGTTCTGAC TTTCCAGTTCTGACA TTCCAGTTCTGACAC TCCAGTTCTGACACA CCAGTTCTGACACAC CAGTTCTGACACACG AGTTCTGACACACGT GTTCTGACACACGTA TTCTGACACACGTAT TCTGACACACGTATT CTGACACACGTATTT

[0091]
TGACACACGTATTTA GACACACGTATTTAT ACACACGTATTTATA CACACGTATTTATAT ACACGTATTTATATT CACGTATTTATATTT ACGTATTTATATTTG CGTATTTATATTTGG GTATTTATATTTGGA TATTTATATTTGGAA ATTTATATTTGGAAA TTTATATTTGGAAAG TTATATTTGGAAAGA TATATTTGGAAAGAG ATATTTGGAAAGAGA TATTTGGAAAGAGAC ATTTGGAAAGAGACC TTTGGAAAGAGACCA TTGGAAAGAGACCAG TGGAAAGAGACCAGC GGAAAGAGACCAGCA GAAAGAGACCAGCAC AAAGAGACCAGCACC AAGAGACCAGCACCG AGAGACCAGCACCGA GAGACCAGCACCGAG AGACCAGCACCGAGC GACCAGCACCGAGCT ACCAGCACCGAGCTC CCAGCACCGAGCTCG CAGCACCGAGCTCGG AGCACCGAGCTCGGC GCACCGAGCTCGGCA CACCGAGCTCGGCAC ACCGAGCTCGGCACC CCGAGCTCGGCACCT CGAGCTCGGCACCTC GAGCTCGGCACCTCC AGCTCGGCACCTCCC GCTCGGCACCTCCCC CTCGGCACCTCCCCG TCGGCACCTCCCCGG CGGCACCTCCCCGGC GGCACCTCCCCGGCC GCACCTCCCCGGCCT CACCTCCCCGGCCTC ACCTCCCCGGCCTCT CCTCCCCGGCCTCTC CTCCCCGGCCTCTCT TCCCCGGCCTCTCTC CCCCGGCCTCTCTCT

[0092] CCCGGCCTCTCTCTT CCGGCCTCTCTCTTC CGGCCTCTCTCTTCC GGCCTCTCTCTTCCC GCCTCTCTCTTCCCA CCTCTCTCTTCCCAG CTCTCTCTTCCCAGC TCTCTCTTCCCAGCT CTCTCTTCCCAGCTG TCTCTTCCCAGCTGC CTCTTCCCAGCTGCA TCTTCCCAGCTGCAG CTTCCCAGCTGCAGA TTCCCAGCTGCAGAT TCCCAGCTGCAGATG CCCAGCTGCAGATGC CCAGCTGCAGATGCC CAGCTGCAGATGCCA AGCTGCAGATGCCAC GCTGCAGATGCCACA CTGCAGATGCCACAC TGCAGATGCCACACC GCAGATGCCACACCT CAGATGCCACACCTG AGATGCCACACCTGC GATGCCACACCTGCT ATGCCACACCTGCTC TGCCACACCTGCTCC GCCACACCTGCTCCT CCACACCTGCTCCTT CACACCTGCTCCTTC ACACCTGCTCCTTCT CACCTGCTCCTTCTT ACCTGCTCCTTCTTG CCTGCTCCTTCTTGC CTGCTCCTTCTTGCT TGCTCCTTCTTGCTT GCTCCTTCTTGCTTT CTCCTTCTTGCTTTC TCCTTCTTGCTTTCC CCTTCTTGCTTTCCC CTTCTTGCTTTCCCC TTCTTGCTTTCCCCG TCTTGCTTTCCCCGG CTTGCTTTCCCCGGG TTGCTTTCCCCGGGG TGCTTTCCCCGGGGG GCTTTCCCCGGGGGA CTTTCCCCGGGGGAG TTTCCCCGGGGGAGG TTCCCCGGGGGAGGA

[0093] TCCCCGGGGGAGGAA CCCCGGGGGAGGAAG CCCGGGGGAGGAAGG CCGGGGGAGGAAGGG CGGGGGAGGAAGGGG GGGGGAGGAAGGGGG GGGGAGGAAGGGGGT GGGAGGAAGGGGGTT GGAGGAAGGGGGTTG GAGGAAGGGGGTTGT AGGAAGGGGGTTGTG GGAAGGGGGTTGTGG GAAGGGGGTTGTGGT AAGGGGGTTGTGGTC AGGGGGTTGTGGTCG GGGGGTTGTGGTCGG GGGGTTGTGGTCGGG GGGTTGTGGTCGGGG GGTTGTGGTCGGGGA GTTGTGGTCGGGGAG TTGTGGTCGGGGAGC TGTGGTCGGGGAGCT GTGGTCGGGGAGCTG TGGTCGGGGAGCTGG GGTCGGGGAGCTGGG GTCGGGGAGCTGGGG TCGGGGAGCTGGGGT CGGGGAGCTGGGGTA GGGGAGCTGGGGTAC GGGAGCTGGGGTACA GGAGCTGGGGTACAG GAGCTGGGGTACAGG AGCTGGGGTACAGGT GCTGGGGTACAGGTT CTGGGGTACAGGTTT TGGGGTACAGGTTTG GGGGTACAGGTTTGG GGGTACAGGTTTGGG GGTACAGGTTTGGGG GTACAGGTTTGGGGA TACAGGTTTGGGGAG ACAGGTTTGGGGAGG CAGGTTTGGGGAGGG AGGTTTGGGGAGGGG GGTTTGGGGAGGGGG GTTTGGGGAGGGGGA TTTGGGGAGGGGGAA TTGGGGAGGGGGAAG TGGGGAGGGGGAAGA GGGGAGGGGGAAGAG GGGAGGGGGAAGAGA

[0094] GGAGGGGGAAGAGAA GAGGGGGAAGAGAAA AGGGGGAAGAGAAAT GGGGGAAGAGAAATT GGGGAAGAGAAATTT GGGAAGAGAAATTTT GGAAGAGAAATTTTT GAAGAGAAATTTTTA AAGAGAAATTTTTAT AGAGAAATTTTTATT GAGAAATTTTTATTT AGAAATTTTTATTTT GAAATTTTTATTTTT AAATTTTTATTTTTG AATTTTTATTTTTGA ATTTTTATTTTTGAA TTTTTATTTTTGAAC TTTTATTTTTGAACC TTTATTTTTGAACCC TTATTTTTGAACCCC TATTTTTGAACCCCT ATTTTTGAACCCCTG TTTTTGAACCCCTGT TTTTGAACCCCTGTG TTTGAACCCCTGTGT TTGAACCCCTGTGTC TGAACCCCTGTGTCC GAACCCCTGTGTCCC AACCCCTGTGTCCCT ACCCCTGTGTCCCTT CCCCTGTGTCCCTTT CCCTGTGTCCCTTTT CCTGTGTCCCTTTTG CTGTGTCCCTTTTGC TGTGTCCCTTTTGCA GTGTCCCTTTTGCAT TGTCCCTTTTGCATA GTCCCTTTTGCATAA TCCCTTTTGCATAAG CCCTTTTGCATAAGA CCTTTTGCATAAGAT CTTTTGCATAAGATT TTTTGCATAAGATTA TTTGCATAAGATTAA TTGCATAAGATTAAA TGCATAAGATTAAAG GCATAAGATTAAAGG CATAAGATTAAAGGA ATAAGATTAAAGGAA TAAGATTAAAGGAAG AAGATTAAAGGAAGG

[0095] AGATTAAAGGAAGGA GATTAAAGGAAGGAA ATTAAAGGAAGGAAA TTAAAGGAAGGAAAA TAAAGGAAGGAAAAG AAAGGAAGGAAAAGT

Example 7 Antisense oligonucleotides to IGFBP3 can be selected from molecules capable of interacting with one or more of the following sense oligonucleotides.

[0097] CTCAGCGCCCAGCCG TCAGCGCCCAGCCGC CAGCGCCCAGCCGCT AGCGCCCAGCCGCTT GCGCCCAGCCGCTTC CGCCCAGCCGCTTCC GCCCAGCCGCTTCCT CCCAGCCGCTTCCTG CCAGCCGCTTCCTGC CAGCCGCTTCCTGCC AGCCGCTTCCTGCCT GCCGCTTCCTGCCTG CCGCTTCCTGCCTGG CGCTTCCTGCCTGGA GCTTCCTGCCTGGAT CTTCCTGCCTGGATT TTCCTGCCTGGATTC TCCTGCCTGGATTCC CCTGCCTGGATTCCA CTGCCTGGATTCCAC TGCCTGGATTCCACA GCCTGGATTCCACAG CCTGGATTCCACAGC CTGGATTCCACAGCT TGGATTCCACAGCTT GGATTCCACAGCTTC GATTCCACAGCTTCG ATTCCACAGCTTCGC TTCCACAGCTTCGCG TCCACAGCTTCGCGC CCACAGCTTCGCGCC CACAGCTTCGCGCCG ACAGCTTCGCGCCGT CAGCTTCGCGCCGTG AGCTTCGCGCCGTGT GCTTCGCGCCGTGTA CTTCGCGCCGTGTAC TTCGCGCCGTGTACT TCGCGCCGTGTACTG CGCGCCGTGTACTGT GCGCCGTGTACTGTC CGCCGTGTACTGTCG

[0098] GCCGTGTACTGTCGC CCGTGTACTGTCGCC CGTGTACTGTCGCCC GTGTACTGTCGCCCC TGTACTGTCGCCCCA GTACTGTCGCCCCAT TACTGTCGCCCCATC ACTGTCGCCCCATCC CTGTCGCCCCATCCC TGTCGCCCCATCCCT GTCGCCCCATCCCTG TCGCCCCATCCCTGC CGCCCCATCCCTGCG GCCCCATCCCTGCGC CCCCATCCCTGCGCG CCCATCCCTGCGCGC CCATCCCTGCGCGCC CATCCCTGCGCGCCC ATCCCTGCGCGCCCA TCCCTGCGCGCCCAG CCCTGCGCGCCCAGC CCTGCGCGCCCAGCC CTGCGCGCCCAGCCT TGCGCGCCCAGCCTG GCGCGCCCAGCCTGC CGCGCCCAGCCTGCC GCGCCCAGCCTGCCA CGCCCAGCCTGCCAA GCCCAGCCTGCCAAG CCCAGCCTGCCAAGC CCAGCCTGCCAAGCA CAGCCTGCCAAGCAG AGCCTGCCAAGCAGC GCCTGCCAAGCAGCG CCTGCCAAGCAGCGT CTGCCAAGCAGCGTG TGCCAAGCAGCGTGC GCCAAGCAGCGTGCC CCAAGCAGCGTGCCC CAAGCAGCGTGCCCC AAGCAGCGTGCCCCG AGCAGCGTGCCCCGG

[0099] GCAGCGTGCCCCGGT CAGCGTGCCCCGGTT AGCGTGCCCCGGTTG GCGTGCCCCGGTTGC CGTGCCCCGGTTGCA GTGCCCCGGTTGCAG TGCCCCGGTTGCAGG GCCCCGGTTGCAGGC CCCCGGTTGCAGGCG CCCGGTTGCAGGCGT CCGGTTGCAGGCGTC CGGTTGCAGGCGTCA GGTTGCAGGCGTCAT GTTGCAGGCGTCATG TTGCAGGCGTCATGC TGCAGGCGTCATGCA GCAGGCGTCATGCAG CAGGCGTCATGCAGC AGGCGTCATGCAGCG GGCGTCATGCAGCGG GCGTCATGCAGCGGG CGTCATGCAGCGGGC GTCATGCAGCGGGCG TCATGCAGCGGGCGC CATGCAGCGGGCGCG ATGCAGCGGGCGCGA TGCAGCGGGCGCGAC GCAGCGGGCGCGACC CAGCGGGCGCGACCC AGCGGGCGCGACCCA GCGGGCGCGACCCAC CGGGCGCGACCCACG GGGCGCGACCCACGC GGCGCGACCCACGCT GCGCGACCCACGCTC CGCGACCCACGCTCT GCGACCCACGCTCTG CGACCCACGCTCTGG GACCCACGCTCTGGG ACCCACGCTCTGGGC CCCACGCTCTGGGCC CCACGCTCTGGGCCG

[0100]
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 TCCGCGGGCCGCCGG CCGCGGGCCGCCGGT CGCGGGCCGCCGGTG GCGGGCCGCCGGTGG CGGGCCGCCGGTGGC GGGCCGCCGGTGGCG GGCCGCCGGTGGCGC GCCGCCGGTGGCGCG CCGCCGGTGGCGCGG CGCCGGTGGCGCGGG GCCGGTGGCGCGGGC CCGGTGGCGCGGGCT CGGTGGCGCGGGCTG

[0101] 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 GGCTTGGGTCCCGTG GCTTGGGTCCCGTGG CTTGGGTCCCGTGGT TTGGGTCCCGTGGTG TGGGTCCCGTGGTGC GGGTCCCGTGGTGCG GGTCCCGTGGTGCGC GTCCCGTGGTGCGCT TCCCGTGGTGCGCTG CCCGTGGTGCGCTGC CCGTGGTGCGCTGCG CGTGGTGCGCTGCGA GTGGTGCGCTGCGAG TGGTGCGCTGCGAGC GGTGCGCTGCGAGCC GTGCGCTGCGAGCCG TGCGCTGCGAGCCGT GCGCTGCGAGCCGTG CGCTGCGAGCCGTGC GCTGCGAGCCGTGCG CTGCGAGCCGTGCGA TGCGAGCCGTGCGAC GCGAGCCGTGCGACG

[0102] CGAGCCGTGCGACGC GAGCCGTGCGACGCG AGCCGTGCGACGCGC GCCGTGCGACGCGCG CCGTGCGACGCGCGT CGTGCGACGCGCGTG GTGCGACGCGCGTGC TGCGACGCGCGTGCA GCGACGCGCGTGCAC CGACGCGCGTGCACT GACGCGCGTGCACTG ACGCGCGTGCACTGG CGCGCGTGCACTGGC GCGCGTGCACTGGCC CGCGTGCACTGGCCC GCGTGCACTGGCCCA CGTGCACTGGCCCAG GTGCACTGGCCCAGT TGCACTGGCCCAGTG GCACTGGCCCAGTGC CACTGGCCCAGTGCG ACTGGCCCAGTGCGC CTGGCCCAGTGCGCG TGGCCCAGTGCGCGC GGCCCAGTGCGCGCC GCCCAGTGCGCGCCT CCCAGTGCGCGCCTC CCAGTGCGCGCCTCC CAGTGCGCGCCTCCG AGTGCGCGCCTCCGC GTGCGCGCCTCCGCC TGCGCGCCTCCGCCC GCGCGCCTCCGCCCG CGCGCCTCCGCCCGC GCGCCTCCGCCCGCC CGCCTCCGCCCGCCG GCCTCCGCCCGCCGT CCTCCGCCCGCCGTG CTCCGCCCGCCGTGT TCCGCCCGCCGTGTG CCGCCCGCCGTGTGC CGCCCGCCGTGTGCG GCCCGCCGTGTGCGC CCCGCCGTGTGCGCG CCGCCGTGTGCGCGG CGCCGTGTGCGCGGA GCCGTGTGCGCGGAG CCGTGTGCGCGGAGC CGTGTGCGCGGAGCT GTGTGCGCGGAGCTG TGTGCGCGGAGCTGG

[0103] GTGCGCGGAGCTGGT TGCGCGGAGCTGGTG GCGCGGAGCTGGTGC CGCGGAGCTGGTGCG GCGGAGCTGGTGCGC CGGAGCTGGTGCGCG GGAGCTGGTGCGCGA GAGCTGGTGCGCGAG AGCTGGTGCGCGAGC GCTGGTGCGCGAGCC CTGGTGCGCGAGCCG TGGTGCGCGAGCCGG GGTGCGCGAGCCGGG GTGCGCGAGCCGGGC 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

[0104] ACTGAGCGAGGGCCA CTGAGCGAGGGCCAG TGAGCGAGGGCCAGC GAGCGAGGGCCAGCC AGCGAGGGCCAGCCG GCGAGGGCCAGCCGT CGAGGGCCAGCCGTG GAGGGCCAGCCGTGC AGGGCCAGCCGTGCG GGGCCAGCCGTGCGG GGCCAGCCGTGCGGC GCCAGCCGTGCGGCA CCAGCCGTGCGGCAT CAGCCGTGCGGCATC AGCCGTGCGGCATCT GCCGTGCGGCATCTA CCGTGCGGCATCTAC CGTGCGGCATCTACA GTGCGGCATCTACAC 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

[0105] CCTTCGCTGCCAGCC CTTCGCTGCCAGCCG TTCGCTGCCAGCCGT TCGCTGCCAGCCGTC CGCTGCCAGCCGTCG GCTGCCAGCCGTCGC CTGCCAGCCGTCGCC TGCCAGCCGTCGCCC GCCAGCCGTCGCCCG CCAGCCGTCGCCCGA CAGCCGTCGCCCGAC AGCCGTCGCCCGACG GCCGTCGCCCGACGA CCGTCGCCCGACGAG 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 GCTGCTGGACGGCCG CTGCTGGACGGCCGC TGCTGGACGGCCGCG GCTGGACGGCCGCGG CTGGACGGCCGCGGG TGGACGGCCGCGGGC

[0106] GGACGGCCGCGGGCT GACGGCCGCGGGCTC ACGGCCGCGGGCTCT CGGCCGCGGGCTCTG GGCCGCGGGCTCTGC GCCGCGGGCTCTGCG CCGCGGGCTCTGCGT CGCGGGCTCTGCGTC GCGGGCTCTGCGTCA CGGGCTCTGCGTCAA GGGCTCTGCGTCAAC GGCTCTGCGTCAACG GCTCTGCGTCAACGC CTCTGCGTCAACGCT TCTGCGTCAACGCTA CTGCGTCAACGCTAG TGCGTCAACGCTAGT GCGTCAACGCTAGTG CGTCAACGCTAGTGC GTCAACGCTAGTGCC TCAACGCTAGTGCCG CAACGCTAGTGCCGT AACGCTAGTGCCGTC ACGCTAGTGCCGTCA CGCTAGTGCCGTCAG GCTAGTGCCGTCAGC CTAGTGCCGTCAGCC TAGTGCCGTCAGCCG AGTGCCGTCAGCCGC GTGCCGTCAGCCGCC TGCCGTCAGCCGCCT GCCGTCAGCCGCCTG CCGTCAGCCGCCTGC CGTCAGCCGCCTGCG GTCAGCCGCCTGCGC TCAGCCGCCTGCGCG CAGCCGCCTGCGCGC AGCCGCCTGCGCGCC GCCGCCTGCGCGCCT CCGCCTGCGCGCCTA CGCCTGCGCGCCTAC GCCTGCGCGCCTACC CCTGCGCGCCTACCT CTGCGCGCCTACCTG TGCGCGCCTACCTGC GCGCGCCTACCTGCT CGCGCCTACCTGCTG GCGCCTACCTGCTGC CGCCTACCTGCTGCC GCCTACCTGCTGCCA CCTACCTGCTGCCAG

[0107] 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 TCGGAGGAAGACCGC CGGAGGAAGACCGCA GGAGGAAGACCGCAG GAGGAAGACCGCAGC AGGAAGACCGCAGCG GGAAGACCGCAGCGC GAAGACCGCAGCGCC AAGACCGCAGCGCCG

[0108] AGACCGCAGCGCCGG GACCGCAGCGCCGGC ACCGCAGCGCCGGCA CCGCAGCGCCGGCAG CGCAGCGCCGGCAGT GCAGCGCCGGCAGTG CAGCGCCGGCAGTGT AGCGCCGGCAGTGTG GCGCCGGCAGTGTGG CGCCGGCAGTGTGGA GCCGGCAGTGTGGAG CCGGCAGTGTGGAGA CGGCAGTGTGGAGAG GGCAGTGTGGAGAGC GCAGTGTGGAGAGCC CAGTGTGGAGAGCCC AGTGTGGAGAGCCCG GTGTGGAGAGCCCGT TGTGGAGAGCCCGTC GTGGAGAGCCCGTCC TGGAGAGCCCGTCCG GGAGAGCCCGTCCGT GAGAGCCCGTCCGTC AGAGCCCGTCCGTCT GAGCCCGTCCGTCTC AGCCCGTCCGTCTCC GCCCGTCCGTCTCCA CCCGTCCGTCTCCAG CCGTCCGTCTCCAGC CGTCCGTCTCCAGCA GTCCGTCTCCAGCAC TCCGTCTCCAGCACG CCGTCTCCAGCACGC CGTCTCCAGCACGCA GTCTCCAGCACGCAC TCTCCAGCACGCACC CTCCAGCACGCACCG TCCAGCACGCACCGG CCAGCACGCACCGGG CAGCACGCACCGGGT AGCACGCACCGGGTG GCACGCACCGGGTGT CACGCACCGGGTGTC ACGCACCGGGTGTCT CGCACCGGGTGTCTG GCACCGGGTGTCTGA CACCGGGTGTCTGAT ACCGGGTGTCTGATC CCGGGTGTCTGATCC CGGGTGTCTGATCCC GGGTGTCTGATCCCA

[0109] GGTGTCTGATCCCAA GTGTCTGATCCCAAG TGTCTGATCCCAAGT GTCTGATCCCAAGTT TCTGATCCCAAGTTC CTGATCCCAAGTTCC TGATCCCAAGTTCCA GATCCCAAGTTCCAC ATCCCAAGTTCCACC TCCCAAGTTCCACCC CCCAAGTTCCACCCC CCAAGTTCCACCCCC CAAGTTCCACCCCCT AAGTTCCACCCCCTC AGTTCCACCCCCTCC GTTCCACCCCCTCCA TTCCACCCCCTCCAT TCCACCCCCTCCATT CCACCCCCTCCATTC CACCCCCTCCATTCA ACCCCCTCCATTCAA CCCCCTCCATTCAAA CCCCTCCATTCAAAG CCCTCCATTCAAAGA CCTCCATTCAAAGAT CTCCATTCAAAGATA TCCATTCAAAGATAA CCATTCAAAGATAAT CATTCAAAGATAATC ATTCAAAGATAATCA TTCAAAGATAATCAT TCAAAGATAATCATC CAAAGATAATCATCA AAAGATAATCATCAT AAGATAATCATCATC AGATAATCATCATCA GATAATCATCATCAA ATAATCATCATCAAG TAATCATCATCAAGA AATCATCATCAAGAA ATCATCATCAAGAAA TCATCATCAAGAAAG CATCATCAAGAAAGG ATCATCAAGAAAGGG TCATCAAGAAAGGGC CATCAAGAAAGGGCA ATCAAGAAAGGGCAT TCAAGAAAGGGCATG CAAGAAAGGGCATGC AAGAAAGGGCATGCT AGAAAGGGCATGCTA

[0110] 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

[0111] GAGCACAGATACCCA 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 GAATATGGTCCCTGC AATATGGTCCCTGCC ATATGGTCCCTGCCG TATGGTCCCTGCCGT ATGGTCCCTGCCGTA

[0112] TGGTCCCTGCCGTAG GGTCCCTGCCGTAGA GTCCCTGCCGTAGAG TCCCTGCCGTAGAGA CCCTGCCGTAGAGAA CCTGCCGTAGAGAAA CTGCCGTAGAGAAAT TGCCGTAGAGAAATG GCCGTAGAGAAATGG CCGTAGAGAAATGGA CGTAGAGAAATGGAA GTAGAGAAATGGAAG TAGAGAAATGGAAGA AGAGAAATGGAAGAC GAGAAATGGAAGACA AGAAATGGAAGACAC GAAATGGAAGACACA AAATGGAAGACACAC AATGGAAGACACACT ATGGAAGACACACTG TGGAAGACACACTGA GGAAGACACACTGAA GAAGACACACTGAAT AAGACACACTGAATC AGACACACTGAATCA GACACACTGAATCAC ACACACTGAATCACC CACACTGAATCACCT ACACTGAATCACCTG CACTGAATCACCTGA ACTGAATCACCTGAA CTGAATCACCTGAAG TGAATCACCTGAAGT GAATCACCTGAAGTT AATCACCTGAAGTTC ATCACCTGAAGTTCC TCACCTGAAGTTCCT CACCTGAAGTTCCTC ACCTGAAGTTCCTCA CCTGAAGTTCCTCAA CTGAAGTTCCTCAAT TGAAGTTCCTCAATG GAAGTTCCTCAATGT AAGTTCCTCAATGTG AGTTCCTCAATGTGC GTTCCTCAATGTGCT TTCCTCAATGTGCTG TCCTCAATGTGCTGA CCTCAATGTGCTGAG CTCAATGTGCTGAGT TCAATGTGCTGAGTC

[0113] 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

[0114] ATTTTATAAGAAAAA TTTTATAAGAAAAAG TTTATAAGAAAAAGC TTATAAGAAAAAGCA TATAAGAAAAAGCAG ATAAGAAAAAGCAGT TAAGAAAAAGCAGTG AAGAAAAAGCAGTGT AGAAAAAGCAGTGTC GAAAAAGCAGTGTCG AAAAAGCAGTGTCGC AAAAGCAGTGTCGCC AAAGCAGTGTCGCCC AAGCAGTGTCGCCCT AGCAGTGTCGCCCTT GCAGTGTCGCCCTTC CAGTGTCGCCCTTCC AGTGTCGCCCTTCCA GTGTCGCCCTTCCAA TGTCGCCCTTCCAAA GTCGCCCTTCCAAAG TCGCCCTTCCAAAGG 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

[0115] CTGCTGGTGTGTGGA TGCTGGTGTGTGGAT GCTGGTGTGTGGATA CTGGTGTGTGGATAA TGGTGTGTGGATAAG GGTGTGTGGATAAGT GTGTGTGGATAAGTA TGTGTGGATAAGTAT GTGTGGATAAGTATG TGTGGATAAGTATGG GTGGATAAGTATGGG TGGATAAGTATGGGC GGATAAGTATGGGCA GATAAGTATGGGCAG ATAAGTATGGGCAGC TAAGTATGGGCAGCC AAGTATGGGCAGCCT AGTATGGGCAGCCTC GTATGGGCAGCCTCT TATGGGCAGCCTCTC ATGGGCAGCCTCTCC TGGGCAGCCTCTCCC GGGCAGCCTCTCCCA GGCAGCCTCTCCCAG GCAGCCTCTCCCAGG CAGCCTCTCCCAGGC AGCCTCTCCCAGGCT GCCTCTCCCAGGCTA CCTCTCCCAGGCTAC CTCTCCCAGGCTACA TCTCCCAGGCTACAC CTCCCAGGCTACACC TCCCAGGCTACACCA CCCAGGCTACACCAC CCAGGCTACACCACC CAGGCTACACCACCA AGGCTACACCACCAA GGCTACACCACCAAG GCTACACCACCAAGG CTACACCACCAAGGG TACACCACCAAGGGG ACACCACCAAGGGGA CACCACCAAGGGGAA ACCACCAAGGGGAAG CCACCAAGGGGAAGG CACCAAGGGGAAGGA ACCAAGGGGAAGGAG CCAAGGGGAAGGAGG CAAGGGGAAGGAGGA AAGGGGAAGGAGGAC AGGGGAAGGAGGACG

[0116] 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 GAGCAAGTAGACGCC AGCAAGTAGACGCCT GCAAGTAGACGCCTG CAAGTAGACGCCTGC AAGTAGACGCCTGCC AGTAGACGCCTGCCG GTAGACGCCTGCCGC TAGACGCCTGCCGCA AGACGCCTGCCGCAA GACGCCTGCCGCAAG ACGCCTGCCGCAAGT CGCCTGCCGCAAGTT GCCTGCCGCAAGTTA CCTGCCGCAAGTTAA CTGCCGCAAGTTAAT TGCCGCAAGTTAATG GCCGCAAGTTAATGT CCGCAAGTTAATGTG

[0117] 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 TTTTGCACAAAAGAC TTTGCACAAAAGACT TTGCACAAAAGACTG TGCACAAAAGACTGC GCACAAAAGACTGCC CACAAAAGACTGCCA ACAAAAGACTGCCAA CAAAAGACTGCCAAG AAAAGACTGCCAAGG AAAGACTGCCAAGGA AAGACTGCCAAGGAC AGACTGCCAAGGACA GACTGCCAAGGACAT ACTGCCAAGGACATG CTGCCAAGGACATGA TGCCAAGGACATGAC GCCAAGGACATGACC CCAAGGACATGACCA CAAGGACATGACCAG

[0118] AAGGACATGACCAGC 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 ATATTTCTGTTTGTG TATTTCTGTTTGTGG ATTTCTGTTTGTGGT TTTCTGTTTGTGGTG TTCTGTTTGTGGTGA TCTGTTTGTGGTGAA CTGTTTGTGGTGAAC TGTTTGTGGTGAACT GTTTGTGGTGAACTG TTTGTGGTGAACTGA TTGTGGTGAACTGAT TGTGGTGAACTGATT GTGGTGAACTGATTT TGGTGAACTGATTTT GGTGAACTGATTTTT

[0119] GTGAACTGATTTTTT TGAACTGATTTTTTT GAACTGATTTTTTTT AACTGATTTTTTTTA ACTGATTTTTTTTAA CTGATTTTTTTTAAA TGATTTTTTTTAAAC GATTTTTTTTAAACC ATTTTTTTTAAACCA TTTTTTTTAAACCAA TTTTTTTAAACCAAA TTTTTTAAACCAAAG TTTTTAAACCAAAGT TTTTAAACCAAAGTT TTTAAACCAAAGTTT TTAAACCAAAGTTTA TAAACCAAAGTTTAG AAACCAAAGTTTAGA AACCAAAGTTTAGAA ACCAAAGTTTAGAAA CCAAAGTTTAGAAAG CAAAGTTTAGAAAGA AAAGTTTAGAAAGAG AAGTTTAGAAAGAGG AGTTTAGAAAGAGGT GTTTAGAAAGAGGTT TTTAGAAAGAGGTTT TTAGAAAGAGGTTTT TAGAAAGAGGTTTTT AGAAAGAGGTTTTTG GAAAGAGGTTTTTGA AAAGAGGTTTTTGAA AAGAGGTTTTTGAAA AGAGGTTTTTGAAAT GAGGTTTTTGAAATG AGGTTTTTGAAATGC GGTTTTTGAAATGCC GTTTTTGAAATGCCT TTTTTGAAATGCCTA TTTTGAAATGCCTAT TTTGAAATGCCTATG TTGAAATGCCTATGG TGAAATGCCTATGGT GAAATGCCTATGGTT AAATGCCTATGGTTT AATGCCTATGGTTTC ATGCCTATGGTTTCT TGCCTATGGTTTCTT GCCTATGGTTTCTTT CCTATGGTTTCTTTG CTATGGTTTCTTTGA

[0120] TATGGTTTCTTTGAA ATGGTTTCTTTGAAT TGGTTTCTTTGAATG GGTTTCTTTGAATGG GTTTCTTTGAATGGT TTTCTTTGAATGGTA TTCTTTGAATGGTAA TCTTTGAATGGTAAA CTTTGAATGGTAAAC TTTGAATGGTAAACT TTGAATGGTAAACTT TGAATGGTAAACTTG GAATGGTAAACTTGA AATGGTAAACTTGAG ATGGTAAACTTGAGC TGGTAAACTTGAGCA GGTAAACTTGAGCAT GTAAACTTGAGCATC TAAACTTGAGCATCT AAACTTGAGCATCTT AACTTGAGCATCTTT ACTTGAGCATCTTTT CTTGAGCATCTTTTC TTGAGCATCTTTTCA TGAGCATCTTTTCAC GAGCATCTTTTCACT AGCATCTTTTCACTT GCATCTTTTCACTTT CATCTTTTCACTTTC ATCTTTTCACTTTCC TCTTTTCACTTTCCA CTTTTCACTTTCCAG TTTTCACTTTCCAGT TTTCACTTTCCAGTA TTCACTTTCCAGTAG TCACTTTCCAGTAGT CACTTTCCAGTAGTC ACTTTCCAGTAGTCA CTTTCCAGTAGTCAG TTTCCAGTAGTCAGC TTCCAGTAGTCAGCA TCCAGTAGTCAGCAA CCAGTAGTCAGCAAA CAGTAGTCAGCAAAG AGTAGTCAGCAAAGA GTAGTCAGCAAAGAG TAGTCAGCAAAGAGC AGTCAGCAAAGAGCA GTCAGCAAAGAGCAG TCAGCAAAGAGCAGT CAGCAAAGAGCAGTT

[0121] AGCAAAGAGCAGTTT GCAAAGAGCAGTTTG CAAAGAGCAGTTTGA AAAGAGCAGTTTGAA AAGAGCAGTTTGAAT AGAGCAGTTTGAATT GAGCAGTTTGAATTT AGCAGTTTGAATTTT GCAGTTTGAATTTTC CAGTTTGAATTTTCT AGTTTGAATTTTCTT GTTTGAATTTTCTTG TTTGAATTTTCTTGT TTGAATTTTCTTGTC TGAATTTTCTTGTCG GAATTTTCTTGTCGC AATTTTCTTGTCGCT ATTTTCTTGTCGCTT TTTTCTTGTCGCTTC TTTCTTGTCGCTTCC TTCTTGTCGCTTCCT TCTTGTCGCTTCCTA CTTGTCGCTTCCTAT TTGTCGCTTCCTATC TGTCGCTTCCTATCA GTCGCTTCCTATCAA TCGCTTCCTATCAAA CGCTTCCTATCAAAA GCTTCCTATCAAAAT CTTCCTATCAAAATA TTCCTATCAAAATAT TCCTATCAAAATATT CCTATCAAAATATTC CTATCAAAATATTCA TATCAAAATATTCAG ATCAAAATATTCAGA TCAAAATATTCAGAG CAAAATATTCAGAGA AAAATATTCAGAGAC AAATATTCAGAGACT AATATTCAGAGACTC ATATTCAGAGACTCG TATTCAGAGACTCGA ATTCAGAGACTCGAG TTCAGAGACTCGAGC TCAGAGACTCGAGCA CAGAGACTCGAGCAC AGAGACTCGAGCACA GAGACTCGAGCACAG AGACTCGAGCACAGC GACTCGAGCACAGCA

[0122] ACTCGAGCACAGCAC CTCGAGCACAGCACC TCGAGCACAGCACCC CGAGCACAGCACCCA GAGCACAGCACCCAG AGCACAGCACCCAGA GCACAGCACCCAGAC CACAGCACCCAGACT ACAGCACCCAGACTT CAGCACCCAGACTTC AGCACCCAGACTTCA GCACCCAGACTTCAT CACCCAGACTTCATG ACCCAGACTTCATGC CCCAGACTTCATGCG CCAGACTTCATGCGC CAGACTTCATGCGCC AGACTTCATGCGCCC GACTTCATGCGCCCG ACTTCATGCGCCCGT CTTCATGCGCCCGTG TTCATGCGCCCGTGG TCATGCGCCCGTGGA CATGCGCCCGTGGAA ATGCGCCCGTGGAAT TGCGCCCGTGGAATG GCGCCCGTGGAATGC CGCCCGTGGAATGCT GCCCGTGGAATGCTC CCCGTGGAATGCTCA CCGTGGAATGCTCAC CGTGGAATGCTCACC GTGGAATGCTCACCA TGGAATGCTCACCAC GGAATGCTCACCACA GAATGCTCACCACAT AATGCTCACCACATG ATGCTCACCACATGT TGCTCACCACATGTT GCTCACCACATGTTG CTCACCACATGTTGG TCACCACATGTTGGT CACCACATGTTGGTC ACCACATGTTGGTCG CCACATGTTGGTCGA CACATGTTGGTCGAA ACATGTTGGTCGAAG CATGTTGGTCGAAGC ATGTTGGTCGAAGCG TGTTGGTCGAAGCGG GTTGGTCGAAGCGGC

[0123] TTGGTCGAAGCGGCC TGGTCGAAGCGGCCG GGTCGAAGCGGCCGA GTCGAAGCGGCCGAC TCGAAGCGGCCGACC CGAAGCGGCCGACCA GAAGCGGCCGACCAC AAGCGGCCGACCACT AGCGGCCGACCACTG GCGGCCGACCACTGA CGGCCGACCACTGAC GGCCGACCACTGACT GCCGACCACTGACTT CCGACCACTGACTTT CGACCACTGACTTTG GACCACTGACTTTGT ACCACTGACTTTGTG CCACTGACTTTGTGA CACTGACTTTGTGAC ACTGACTTTGTGACT CTGACTTT GTGACTT 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

[0124] 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 GTGCGCACAGGCTTT TGCGCACAGGCTTTA GCGCACAGGCTTTAT CGCACAGGCTTTATC GCACAGGCTTTATCG CACAGGCTTTATCGA ACAGGCTTTATCGAG CAGGCTTTATCGAGA AGGCTTTATCGAGAA GGCTTTATCGAGAAT GCTTTATCGAGAATA CTTTATCGAGAATAG TTTATCGAGAATAGG TTATCGAGAATAGGA

[0125] TATCGAGAATAGGAA ATCGAGAATAGGAAA TCGAGAATAGGAAAA CGAGAATAGGAAAAC GAGAATAGGAAAACC AGAATAGGAAAACCT GAATAGGAAAACCTT AATAGGAAAACCTTT ATAGGAAAACCTTTA TAGGAAAACCTTTAA AGGAAAACCTTTAAA GGAAAACCTTTAAAC GAAAACCTTTAAACC AAAACCTTTAAACCC AAACCTTTAAACCCC AACCTTTAAACCCCG ACCTTTAAACCCCGG CCTTTAAACCCCGGT CTTTAAACCCCGGTC TTTAAACCCCGGTCA TTAAACCCCGGTCAT TAAACCCCGGTCATC AAACCCCGGTCATCC AACCCCGGTCATCCG ACCCCGGTCATCCGG CCCCGGTCATCCGGA CCCGGTCATCCGGAC CCGGTCATCCGGACA CGGTCATCCGGACAT GGTCATCCGGACATC GTCATCCGGACATCC TCATCCGGACATCCC CATCCGGACATCCCA ATCCGGACATCCCAA TCCGGACATCCCAAC CCGGACATCCCAACG CGGACATCCCAACGC GGACATCCCAACGCA GACATCCCAACGCAT ACATCCCAACGCATG CATCCCAACGCATGC ATCCCAACGCATGCT TCCCAACGCATGCTC CCCAACGCATGCTCC CCAACGCATGCTCCT CAACGCATGCTCCTG AACGCATGCTCCTGG ACGCATGCTCCTGGA CGCATGCTCCTGGAG GCATGCTCCTGGAGC CATGCTCCTGGAGCT

[0126] ATGCTCCTGGAGCTC TGCTCCTGGAGCTCA GCTCCTGGAGCTCAC CTCCTGGAGCTCACA TCCTGGAGCTCACAG CCTGGAGCTCACAGC CTGGAGCTCACAGCC TGGAGCTCACAGCCT GGAGCTCACAGCCTT GAGCTCACAGCCTTC 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 TGAAACAAGGGCGTG GAAACAAGGGCGTGG AAACAAGGGCGTGGA AACAAGGGCGTGGAT ACAAGGGCGTGGATC CAAGGGCGTGGATCC AAGGGCGTGGATCCC AGGGCGTGGATCCCT GGGCGTGGATCCCTC GGCGTGGATCCCTCA GCGTGGATCCCTCAA CGTGGATCCCTCAAC GTGGATCCCTCAACC

[0127] TGGATCCCTCAACCA GGATCCCTCAACCAA GATCCCTCAACCAAG ATCCCTCAACCAAGA TCCCTCAACCAAGAA CCCTCAACCAAGAAG CCTCAACCAAGAAGA CTCAACCAAGAAGAA TCAACCAAGAAGAAT CAACCAAGAAGAATG AACCAAGAAGAATGT ACCAAGAAGAATGTT CCAAGAAGAATGTTT CAAGAAGAATGTTTA AAGAAGAATGTTTAT AGAAGAATGTTTATG GAAGAATGTTTATGT AAGAATGTTTATGTC AGAATGTTTATGTCT GAATGTTTATGTCTT 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

[0128] TTGGGGACTATTGGA TGGGGACTATTGGAG GGGGACTATTGGAGA GGGACTATTGGAGAA GGACTATTGGAGAAA GACTATTGGAGAAAA ACTATTGGAGAAAAT CTATTGGAGAAAATA TATTGGAGAAAATAA ATTGGAGAAAATAAG TTGGAGAAAATAAGG TGGAGAAAATAAGGT GGAGAAAATAAGGTG 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 GTTTAAAAAATATGT TTTAAAAAATATGTA TTAAAAAATATGTAT TAAAAAATATGTATC AAAAAATATGTATCT AAAAATATGTATCTA AAAATATGTATCTAA AAATATGTATCTAAG AATATGTATCTAAGA ATATGTATCTAAGAA TATGTATCTAAGAAT ATGTATCTAAGAATG TGTATCTAAGAATGT

[0129] GTATCTAAGAATGTT TATCTAAGAATGTTC ATCTAAGAATGTTCT TCTAAGAATGTTCTA CTAAGAATGTTCTAG TAAGAATGTTCTAGG AAGAATGTTCTAGGG AGAATGTTCTAGGGC GAATGTTCTAGGGCA AATGTTCTAGGGCAC ATGTTCTAGGGCACT TGTTCTAGGGCACTC GTTCTAGGGCACTCT TTCTAGGGCACTCTG TCTAGGGCACTCTGG CTAGGGCACTCTGGG TAGGGCACTCTGGGA 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 GTATTTCGGGCCCTC TATTTCGGGCCCTCC ATTTCGGGCCCTCCT TTTCGGGCCCTCCTC TTCGGGCCCTCCTCT TCGGGCCCTCCTCTT

[0130] CGGGCCCTCCTCTTC GGGCCCTCCTCTTCA GGCCCTCCTCTTCAG 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 CCAGTCGAAGGCCCA CAGTCGAAGGCCCAG AGTCGAAGGCCCAGG GTCGAAGGCCCAGGA TCGAAGGCCCAGGAT CGAAGGCCCAGGATG GAAGGCCCAGGATGG AAGGCCCAGGATGGC AGGCCCAGGATGGCT GGCCCAGGATGGCTT GCCCAGGATGGCTTT CCCAGGATGGCTTTT CCAGGATGGCTTTTG

[0131] 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

[0132] AGAGTCAGCCTCCAC GAGTCAGCCTCCACA AGTCAGCCTCCACAT GTCAGCCTCCACATT TCAGCCTCCACATTC CAGCCTCCACATTCA AGCCTCCACATTCAG GCCTCCACATTCAGA CCTCCACATTCAGAG CTCCACATTCAGAGG TCCACATTCAGAGGC CCACATTCAGAGGCA CACATTCAGAGGCAT ACATTCAGAGGCATC CATTCAGAGGCATCA ATTCAGAGGCATCAC TTCAGAGGCATCACA TCAGAGGCATCACAA CAGAGGCATCACAAG AGAGGCATCACAAGT GAGGCATCACAAGTA AGGCATCACAAGTAA GGCATCACAAGTAAT GCATCACAAGTAATG CATCACAAGTAATGG ATCACAAGTAATGGC TCACAAGTAATGGCA CACAAGTAATGGCAC ACAAGTAATGGCACA CAAGTAATGGCACAA AAGTAATGGCACAAT AGTAATGGCACAATT GTAATGGCACAATTC TAATGGCACAATTCT AATGGCACAATTCTT ATGGCACAATTCTTC TGGCACAATTCTTCG GGCACAATTCTTCGG GCACAATTCTTCGGA CACAATTCTTCGGAT ACAATTCTTCGGATG CAATTCTTCGGATGA AATTCTTCGGATGAC ATTCTTCGGATGACT TTCTTCGGATGACTG TCTTCGGATGACTGC CTTCGGATGACTGCA TTCGGATGACTGCAG TCGGATGACTGCAGA CGGATGACTGCAGAA GGATGACTGCAGAAA

[0133] GATGACTGCAGAAAA ATGACTGCAGAAAAT TGACTGCAGAAAATA GACTGCAGAAAATAG ACTGCAGAAAATAGT CTGCAGAAAATAGTG TGCAGAAAATAGTGT GCAGAAAATAGTGTT CAGAAAATAGTGTTT AGAAAATAGTGTTTT GAAAATAGTGTTTTG AAAATAGTGTTTTGT AAATAGTGTTTTGTA AATAGTGTTTTGTAG ATAGTGTTTTGTAGT TAGTGTTTTGTAGTT AGTGTTTTGTAGTTC GTGTTTTGTAGTTCA TGTTTTGTAGTTCAA GTTTTGTAGTTCAAC TTTTGTAGTTCAACA TTTGTAGTTCAACAA TTGTAGTTCAACAAC TGTAGTTCAACAACT GTAGTTCAACAACTC TAGTTCAACAACTCA AGTTCAACAACTCAA GTTCAACAACTCAAG TTCAACAACTCAAGA TCAACAACTCAAGAC CAACAACTCAAGACG AACAACTCAAGACGA ACAACTCAAGACGAA CAACTCAAGACGAAG AACTCAAGACGAAGC ACTCAAGACGAAGCT CTCAAGACGAAGCTT TCAAGACGAAGCTTA CAAGACGAAGCTTAT AAGACGAAGCTTATT AGACGAAGCTTATTT GACGAAGCTTATTTC ACGAAGCTTATTTCT CGAAGCTTATTTCTG GAAGCTTATTTCTGA AAGCTTATTTCTGAG AGCTTATTTCTGAGG GCTTATTTCTGAGGA CTTATTTCTGAGGAT TTATTTCTGAGGATA TATTTCTGAGGATAA

[0134] ATTTCTGAGGATAAG TTTCTGAGGATAAGC TTCTGAGGATAAGCT TCTGAGGATAAGCTC CTGAGGATAAGCTCT TGAGGATAAGCTCTT GAGGATAAGCTCTTT AGGATAAGCTCTTTA GGATAAGCTCTTTAA GATAAGCTCTTTAAA ATAAGCTCTTTAAAG TAAGCTCTTTAAAGG AAGCTCTTTAAAGGC AGCTCTTTAAAGGCA GCTCTTTAAAGGCAA CTCTTTAAAGGCAAA 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 ATCTTTTGTCCTCCT TCTTTTGTCCTCCTT CTTTTGTCCTCCTTA

[0135] TTTTGTCCTCCTTAG TTTGTCCTCCTTAGC TTGTCCTCCTTAGCA TGTCCTCCTTAGCAC GTCCTCCTTAGCACA TCCTCCTTAGCACAA CCTCCTTAGCACAAT CTCCTTAGCACAATG TCCTTAGCACAATGT CCTTAGCACAATGTA CTTAGCACAATGTAA TTAGCACAATGTAAA TAGCACAATGTAAAA AGCACAATGTAAAAA GCACAATGTAAAAAA CACAATGTAAAAAAG ACAATGTAAAAAAGA CAATGTAAAAAAGAA AATGTAAAAAAGAAT ATGTAAAAAAGAATA TGTAAAAAAGAATAG GTAAAAAAGAATAGT TAAAAAAGAATAGTA AAAAAAGAATAGTAA AAAAAGAATAGTAAT AAAAGAATAGTAATA AAAGAATAGTAATAT AAGAATAGTAATATC AGAATAGTAATATCA GAATAGTAATATCAG AATAGTAATATCAGA ATAGTAATATCAGAA TAGTAATATCAGAAC AGTAATATCAGAACA GTAATATCAGAACAG TAATATCAGAACAGG AATATCAGAACAGGA ATATCAGAACAGGAA TATCAGAACAGGAAG ATCAGAACAGGAAGG TCAGAACAGGAAGGA CAGAACAGGAAGGAG AGAACAGGAAGGAGG GAACAGGAAGGAGGA AACAGGAAGGAGGAA ACAGGAAGGAGGAAT CAGGAAGGAGGAATG AGGAAGGAGGAATGG GGAAGGAGGAATGGC GAAGGAGGAATGGCT AAGGAGGAATGGCTT

[0136] AGGAGGAATGGCTTG GGAGGAATGGCTTGC GAGGAATGGCTTGCT AGGAATGGCTTGCTG GGAATGGCTTGCTGG GAATGGCTTGCTGGG AATGGCTTGCTGGGG ATGGCTTGCTGGGGA TGGCTTGCTGGGGAG GGCTTGCTGGGGAGC GCTTGCTGGGGAGCC CTTGCTGGGGAGCCC TTGCTGGGGAGCCCA TGCTGGGGAGCCCAT GCTGGGGAGCCCATC CTGGGGAGCCCATCC TGGGGAGCCCATCCA GGGGAGCCCATCCAG GGGAGCCCATCCAGG GGAGCCCATCCAGGA GAGCCCATCCAGGAC AGCCCATCCAGGACA GCCCATCCAGGACAC CCCATCCAGGACACT CCATCCAGGACACTG CATCCAGGACACTGG ATCCAGGACACTGGG TCCAGGACACTGGGA CCAGGACACTGGGAG CAGGACACTGGGAGC AGGACACTGGGAGCA GGACACTGGGAGCAC GACACTGGGAGCACA ACACTGGGAGCACAT CACTGGGAGCACATA ACTGGGAGCACATAG CTGGGAGCACATAGA TGGGAGCACATAGAG GGGAGCACATAGAGA GGAGCACATAGAGAT GAGCACATAGAGATT AGCACATAGAGATTC GCACATAGAGATTCA CACATAGAGATTCAC ACATAGAGATTCACC CATAGAGATTCACCC ATAGAGATTCACCCA TAGAGATTCACCCAT AGAGATTCACCCATG GAGATTCACCCATGT AGATTCACCCATGTT

[0137] GATTCACCCATGTTT ATTCACCCATGTTTG TTCACCCATGTTTGT TCACCCATGTTTGTT CACCCATGTTTGTTG ACCCATGTTTGTTGA CCCATGTTTGTTGAA CCATGTTTGTTGAAC CATGTTTGTTGAACT ATGTTTGTTGAACTT TGTTTGTTGAACTTA GTTTGTTGAACTTAG TTTGTTGAACTTAGA TTGTTGAACTTAGAG TGTTGAACTTAGAGT GTTGAACTTAGAGTC TTGAACTTAGAGTCA TGAACTTAGAGTCAT GAACTTAGAGTCATT AACTTAGAGTCATTC ACTTAGAGTCATTCT CTTAGAGTCATTCTC TTAGAGTCATTCTCA TAGAGTCATTCTCAT AGAGTCATTCTCATG GAGTCATTCTCATGC AGTCATTCTCATGCT GTCATTCTCATGCTT TCATTCTCATGCTTT CATTCTCATGCTTTT ATTCTCATGCTTTTC TTCTCATGCTTTTCT TCTCATGCTTTTCTT CTCATGCTTTTCTTT TCATGCTTTTCTTTA CATGCTTTTCTTTAT ATGCTTTTCTTTATA TGCTTTTCTTTATAA GCTTTTCTTTATAAT CTTTTCTTTATAATT TTTTCTTTATAATTC TTTCTTTATAATTCA TTCTTTATAATTCAC TCTTTATAATTCACA CTTTATAATTCACAC TTTATAATTCACACA TTATAATTCACACAT TATAATTCACACATA ATAATTCACACATAT TAATTCACACATATA AATTCACACATATAT

[0138] ATTCACACATATATG TTCACACATATATGC TCACACATATATGCA CACACATATATGCAG ACACATATATGCAGA CACATATATGCAGAG ACATATATGCAGAGA CATATATGCAGAGAA ATATATGCAGAGAAG TATATGCAGAGAAGA ATATGCAGAGAAGAT TATGCAGAGAAGATA ATGCAGAGAAGATAT TGCAGAGAAGATATG GCAGAGAAGATATGT CAGAGAAGATATGTT AGAGAAGATATGTTC GAGAAGATATGTTCT AGAAGATATGTTCTT GAAGATATGTTCTTG AAGATATGTTCTTGT AGATATGTTCTTGTT GATATGTTCTTGTTA ATATGTTCTTGTTAA TATGTTCTTGTTAAC ATGTTCTTGTTAACA TGTTCTTGTTAACAT GTTCTTGTTAACATT TTCTTGTTAACATTG TCTTGTTAACATTGT CTTGTTAACATTGTA TTGTTAACATTGTAT TGTTAACATTGTATA GTTAACATTGTATAC TTAACATTGTATACA TAACATTGTATACAA AACATTGTATACAAC ACATTGTATACAACA CATTGTATACAACAT ATTGTATACAACATA TTGTATACAACATAG TGTATACAACATAGC GTATACAACATAGCC TATACAACATAGCCC ATACAACATAGCCCC TACAACATAGCCCCA ACAACATAGCCCCAA CAACATAGCCCCAAA AACATAGCCCCAAAT ACATAGCCCCAAATA CATAGCCCCAAATAT

[0139] ATAGCCCCAAATATA TAGCCCCAAATATAG AGCCCCAAATATAGT GCCCCAAATATAGTA CCCCAAATATAGTAA CCCAAATATAGTAAG CCAAATATAGTAAGA CAAATATAGTAAGAT AAATATAGTAAGATC AATATAGTAAGATCT ATATAGTAAGATCTA TATAGTAAGATCTAT ATAGTAAGATCTATA TAGTAAGATCTATAC AGTAAGATCTATACT GTAAGATCTATACTA TAAGATCTATACTAG AAGATCTATACTAGA AGATCTATACTAGAT GATCTATACTAGATA ATCTATACTAGATAA TCTATACTAGATAAT CTATACTAGATAATC TATACTAGATAATCC ATACTAGATAATCCT TACTAGATAATCCTA ACTAGATAATCCTAG CTAGATAATCCTAGA TAGATAATCCTAGAT AGATAATCCTAGATG GATAATCCTAGATGA ATAATCCTAGATGAA TAATCCTAGATGAAA AATCCTAGATGAAAT ATCCTAGATGAAATG TCCTAGATGAAATGT CCTAGATGAAATGTT CTAGATGAAATGTTA TAGATGAAATGTTAG AGATGAAATGTTAGA GATGAAATGTTAGAG ATGAAATGTTAGAGA TGAAATGTTAGAGAT GAAATGTTAGAGATG AAATGTTAGAGATGC AATGTTAGAGATGCT ATGTTAGAGATGCTA TGTTAGAGATGCTAT GTTAGAGATGCTATA TTAGAGATGCTATAT TAGAGATGCTATATG

[0140] AGAGATGCTATATGA GAGATGCTATATGAT AGATGCTATATGATA GATGCTATATGATAC ATGCTATATGATACA TGCTATATGATACAA GCTATATGATACAAC CTATATGATACAACT TATATGATACAACTG ATATGATACAACTGT TATGATACAACTGTG ATGATACAACTGTGG TGATACAACTGTGGC GATACAACTGTGGCC ATACAACTGTGGCCA TACAACTGTGGCCAT ACAACTGTGGCCATG CAACTGTGGCCATGA AACTGTGGCCATGAC ACTGTGGCCATGACT CTGTGGCCATGACTG TGTGGCCATGACTGA GTGGCCATGACTGAG TGGCCATGACTGAGG GGCCATGACTGAGGA GCCATGACTGAGGAA CCATGACTGAGGAAA CATGACTGAGGAAAG ATGACTGAGGAAAGG TGACTGAGGAAAGGA GACTGAGGAAAGGAG ACTGAGGAAAGGAGC CTGAGGAAAGGAGCT TGAGGAAAGGAGCTC GAGGAAAGGAGCTCA AGGAAAGGAGCTCAC GGAAAGGAGCTCACG GAAAGGAGCTCACGC AAAGGAGCTCACGCC AAGGAGCTCACGCCC AGGAGCTCACGCCCA GGAGCTCACGCCCAG GAGCTCACGCCCAGA AGCTCACGCCCAGAG GCTCACGCCCAGAGA CTCACGCCCAGAGAC TCACGCCCAGAGACT CACGCCCAGAGACTG ACGCCCAGAGACTGG CGCCCAGAGACTGGG GCCCAGAGACTGGGC

[0141] CCCAGAGACTGGGCT CCAGAGACTGGGCTG CAGAGACTGGGCTGC AGAGACTGGGCTGCT GAGACTGGGCTGCTC AGACTGGGCTGCTCT GACTGGGCTGCTCTC ACTGGGCTGCTCTCC CTGGGCTGCTCTCCC TGGGCTGCTCTCCCG GGGCTGCTCTCCCGG GGCTGCTCTCCCGGA GCTGCTCTCCCGGAG CTGCTCTCCCGGAGG TGCTCTCCCGGAGGC GCTCTCCCGGAGGCC CTCTCCCGGAGGCCA TCTCCCGGAGGCCAA CTCCCGGAGGCCAAA TCCCGGAGGCCAAAC CCCGGAGGCCAAACC CCGGAGGCCAAACCC CGGAGGCCAAACCCA GGAGGCCAAACCCAA GAGGCCAAACCCAAG AGGCCAAACCCAAGA GGCCAAACCCAAGAA GCCAAACCCAAGAAG CCAAACCCAAGAAGG CAAACCCAAGAAGGT AAACCCAAGAAGGTC AACCCAAGAAGGTCT ACCCAAGAAGGTCTG CCCAAGAAGGTCTGG CCAAGAAGGTCTGGC CAAGAAGGTCTGGCA AAGAAGGTCTGGCAA AGAAGGTCTGGCAAA GAAGGTCTGGCAAAG AAGGTCTGGCAAAGT AGGTCTGGCAAAGTC GGTCTGGCAAAGTCA GTCTGGCAAAGTCAG TCTGGCAAAGTCAGG CTGGCAAAGTCAGGC TGGCAAAGTCAGGCT GGCAAAGTCAGGCTC GCAAAGTCAGGCTCA CAAAGTCAGGCTCAG AAAGTCAGGCTCAGG AAGTCAGGCTCAGGG

[0142] AGTCAGGCTCAGGGA GTCAGGCTCAGGGAG TCAGGCTCAGGGAGA CAGGCTCAGGGAGAC AGGCTCAGGGAGACT GGCTCAGGGAGACTC 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 AGACCTCGGTGTGGA GACCTCGGTGTGGAC ACCTCGGTGTGGACA CCTCGGTGTGGACAC CTCGGTGTGGACACA TCGGTGTGGACACAC CGGTGTGGACACACG GGTGTGGACACACGC GTGTGGACACACGCT TGTGGACACACGCTG GTGGACACACGCTGC TGGACACACGCTGCA GGACACACGCTGCAT GACACACGCTGCATA ACACACGCTGCATAG CACACGCTGCATAGA ACACGCTGCATAGAG CACGCTGCATAGAGC ACGCTGCATAGAGCT CGCTGCATAGAGCTC

[0143] GCTGCATAGAGCTCT CTGCATAGAGCTCTC TGCATAGAGCTCTCC GCATAGAGCTCTCCT CATAGAGCTCTCCTT ATAGAGCTCTCCTTG TAGAGCTCTCCTTGA AGAGCTCTCCTTGAA GAGCTCTCCTTGAAA AGCTCTCCTTGAAAA GCTCTCCTTGAAAAC CTCTCCTTGAAAACA TCTCCTTGAAAACAG CTCCTTGAAAACAGA TCCTTGAAAACAGAG CCTTGAAAACAGAGG CTTGAAAACAGAGGG TTGAAAACAGAGGGG TGAAAACAGAGGGGT GAAAACAGAGGGGTC AAAACAGAGGGGTCT AAACAGAGGGGTCTC AACAGAGGGGTCTCA ACAGAGGGGTCTCAA CAGAGGGGTCTCAAG AGAGGGGTCTCAAGA GAGGGGTCTCAAGAC AGGGGTCTCAAGACA GGGGTCTCAAGACAT GGGTCTCAAGACATT GGTCTCAAGACATTC GTCTCAAGACATTCT TCTCAAGACATTCTG CTCAAGACATTCTGC TCAAGACATTCTGCC CAAGACATTCTGCCT AAGACATTCTGCCTA AGACATTCTGCCTAC GACATTCTGCCTACC ACATTCTGCCTACCT CATTCTGCCTACCTA ATTCTGCCTACCTAT TTCTGCCTACCTATT TCTGCCTACCTATTA CTGCCTACCTATTAG TGCCTACCTATTAGC GCCTACCTATTAGCT CCTACCTATTAGCTT CTACCTATTAGCTTT TACCTATTAGCTTTT ACCTATTAGCTTTTC

[0144] CCTATTAGCTTTTCT CTATTAGCTTTTCTT TATTAGCTTTTCTTT ATTAGCTTTTCTTTA TTAGCTTTTCTTTAT TAGCTTTTCTTTATT AGCTTTTCTTTATTT GCTTTTCTTTATTTT CTTTTCTTTATTTTT TTTTCTTTATTTTTT TTTCTTTATTTTTTT TTCTTTATTTTTTTA TCTTTATTTTTTTAA CTTTATTTTTTTAAC TTTATTTTTTTAACT TTATTTTTTTAACTT TATTTTTTTAACTTT ATTTTTTTAACTTTT TTTTTTTAACTTTTT TTTTTTAACTTTTTG TTTTTAACTTTTTGG TTTTAACTTTTTGGG TTTAACTTTTTGGGG TTAACTTTTTGGGGG TAACTTTTTGGGGGG AACTTTTTGGGGGGA ACTTTTTGGGGGGAA CTTTTTGGGGGGAAA TTTTTGGGGGGAAAA TTTTGGGGGGAAAAG TTTGGGGGGAAAAGT TTGGGGGGAAAAGTA TGGGGGGAAAAGTAT GGGGGGAAAAGTATT GGGGGAAAAGTATTT GGGGAAAAGTATTTT GGGAAAAGTATTTTT GGAAAAGTATTTTTG GAAAAGTATTTTTGA AAAAGTATTTTTGAG AAAGTATTTTTGAGA AAGTATTTTTGAGAA AGTATTTTTGAGAAG GTATTTTTGAGAAGT TATTTTTGAGAAGTT ATTTTTGAGAAGTTT TTTTTGAGAAGTTTG TTTTGAGAAGTTTGT TTTGAGAAGTTTGTC TTGAGAAGTTTGTCT TGAGAAGTTTGTCTT

[0145] GAGAAGTTTGTCTTG AGAAGTTTGTCTTGC GAAGTTTGTCTTGCA AAGTTTGTCTTGCAA AGTTTGTCTTGCAAT GTTTGTCTTGCAATG TTTGTCTTGCAATGT TTGTCTTGCAATGTA TGTCTTGCAATGTAT GTCTTGCAATGTATT TCTTGCAATGTATTT CTTGCAATGTATTTA TTGCAATGTATTTAT TGCAATGTATTTATA GCAATGTATTTATAA CAATGTATTTATAAA AATGTATTTATAAAT ATGTATTTATAAATA TGTATTTATAAATAG GTATTTATAAATAGT TATTTATAAATAGTA ATTTATAAATAGTAA TTTATAAATAGTAAA TTATAAATAGTAAAT TATAAATAGTAAATA ATAAATAGTAAATAA TAAATAGTAAATAAA AAATAGTAAATAAAG AATAGTAAATAAAGT ATAGTAAATAAAGTT TAGTAAATAAAGTTT AGTAAATAAAGTTTT GTAAATAAAGTTTTT TAAATAAAGTTTTTA AAATAAAGTTTTTAC AATAAAGTTTTTACC ATAAAGTTTTTACCA TAAAGTTTTTACCAT AAAGTTTTTACCATT

Example 8 Antisense oligonucleotides against IGF-I may be selected from molecules capable of interacting with one or more of the following sense oligonucleotides.

[0147] TTTTTTTTTTTTTTG TTTTTTTTTTTTTGA TTTTTTTTTTTTGAG

[0148] TTTTTTTTTTTGAGA TTTTTTTTTTGAGAA TTTTTTTTTGAGAAA

[0149] TTTTTTTTGAGAAAG TTTTTTTGAGAAAGG TTTTTTGAGAAAGGG

[0150] TTTTTGAGAAAGGGA TTTTGAGAAAGGGAA TTTGAGAAAGGGAAT TTGAGAAAGGGAATT TGAGAAAGGGAATTT GAGAAAGGGAATTTC AGAAAGGGAATTTCA GAAAGGGAATTTCAT AAAGGGAATTTCATC AAGGGAATTTCATCC AGGGAATTTCATCCC GGGAATTTCATCCCA GGAATTTCATCCCAA GAATTTCATCCCAAA AATTTCATCCCAAAT ATTTCATCCCAAATA TTTCATCCCAAATAA TTCATCCCAAATAAA TCATCCCAAATAAAA CATCCCAAATAAAAG ATCCCAAATAAAAGG TCCCAAATAAAAGGA CCCAAATAAAAGGAA CCAAATAAAAGGAAT 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

[0151] GGAGGAGGGTCCCCG GAGGAGGGTCCCCGA AGGAGGGTCCCCGAC GGAGGGTCCCCGACC GAGGGTCCCCGACCT AGGGTCCCCGACCTC GGGTCCCCGACCTCG GGTCCCCGACCTCGC GTCCCCGACCTCGCT TCCCCGACCTCGCTG CCCCGACCTCGCTGT CCCGACCTCGCTGTG CCGACCTCGCTGTGG CGACCTCGCTGTGGG GACCTCGCTGTGGGG ACCTCGCTGTGGGGG CCTCGCTGTGGGGGC CTCGCTGTGGGGGCT TCGCTGTGGGGGCTC CGCTGTGGGGGCTCC GCTGTGGGGGCTCCT 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

[0152] CTCTCGCTCTGGCCG TCTCGCTCTGGCCGA CTCGCTCTGGCCGAC TCGCTCTGGCCGACG CGCTCTGGCCGACGA GCTCTGGCCGACGAG CTCTGGCCGACGAGT TCTGGCCGACGAGTG CTGGCCGACGAGTGG TGGCCGACGAGTGGA GGCCGACGAGTGGAG GCCGACGAGTGGAGA CCGACGAGTGGAGAA CGACGAGTGGAGAAA GACGAGTGGAGAAAT ACGAGTGGAGAAATC CGAGTGGAGAAATCT GAGTGGAGAAATCTG AGTGGAGAAATCTGC GTGGAGAAATCTGCG TGGAGAAATCTGCGG GGAGAAATCTGCGGG GAGAAATCTGCGGGC AGAAATCTGCGGGCC GAAATCTGCGGGCCA 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

[0153] 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

[0154] GGCTACCTCCACATC GCTACCTCCACATCC CTACCTCCACATCCT TACCTCCACATCCTG ACCTCCACATCCTGC CCTCCACATCCTGCT CTCCACATCCTGCTC TCCACATCCTGCTCA CCACATCCTGCTCAT CACATCCTGCTCATC ACATCCTGCTCATCT CATCCTGCTCATCTC ATCCTGCTCATCTCC TCCTGCTCATCTCCA CCTGCTCATCTCCAA CTGCTCATCTCCAAG TGCTCATCTCCAAGG GCTCATCTCCAAGGC CTCATCTCCAAGGCC TCATCTCCAAGGCCG CATCTCCAAGGCCGA ATCTCCAAGGCCGAG TCTCCAAGGCCGAGG CTCCAAGGCCGAGGA TCCAAGGCCGAGGAC CCAAGGCCGAGGACT CAAGGCCGAGGACTA AAGGCCGAGGACTAC AGGCCGAGGACTACC GGCCGAGGACTACCG GCCGAGGACTACCGC CCGAGGACTACCGCA CGAGGACTACCGCAG GAGGACTACCGCAGC AGGACTACCGCAGCT GGACTACCGCAGCTA GACTACCGCAGCTAC ACTACCGCAGCTACC CTACCGCAGCTACCG TACCGCAGCTACCGC ACCGCAGCTACCGCT CCGCAGCTACCGCTT CGCAGCTACCGCTTC GCAGCTACCGCTTCC CAGCTACCGCTTCCC AGCTACCGCTTCCCC GCTACCGCTTCCCCA CTACCGCTTCCCCAA TACCGCTTCCCCAAG ACCGCTTCCCCAAGC CCGCTTCCCCAAGCT

[0155] CGCTTCCCCAAGCTC GCTTCCCCAAGCTCA CTTCCCCAAGCTCAC TTCCCCAAGCTCACG TCCCCAAGCTCACGG CCCCAAGCTCACGGT CCCAAGCTCACGGTC CCAAGCTCACGGTCA CAAGCTCACGGTCAT AAGCTCACGGTCATT AGCTCACGGTCATTA GCTCACGGTCATTAC CTCACGGTCATTACC TCACGGTCATTACCG CACGGTCATTACCGA ACGGTCATTACCGAG CGGTCATTACCGAGT GGTCATTACCGAGTA GTCATTACCGAGTAC TCATTACCGAGTACT CATTACCGAGTACTT ATTACCGAGTACTTG TTACCGAGTACTTGC TACCGAGTACTTGCT ACCGAGTACTTGCTG CCGAGTACTTGCTGC CGAGTACTTGCTGCT GAGTACTTGCTGCTG AGTACTTGCTGCTGT GTACTTGCTGCTGTT TACTTGCTGCTGTTC ACTTGCTGCTGTTCC CTTGCTGCTGTTCCG TTGCTGCTGTTCCGA TGCTGCTGTTCCGAG GCTGCTGTTCCGAGT CTGCTGTTCCGAGTG TGCTGTTCCGAGTGG GCTGTTCCGAGTGGC CTGTTCCGAGTGGCT TGTTCCGAGTGGCTG GTTCCGAGTGGCTGG TTCCGAGTGGCTGGC TCCGAGTGGCTGGCC CCGAGTGGCTGGCCT CGAGTGGCTGGCCTC GAGTGGCTGGCCTCG AGTGGCTGGCCTCGA GTGGCTGGCCTCGAG TGGCTGGCCTCGAGA GGCTGGCCTCGAGAG

[0156] 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 CCCAACCTCACGGTC CCAACCTCACGGTCA CAACCTCACGGTCAT AACCTCACGGTCATC ACCTCACGGTCATCC CCTCACGGTCATCCG CTCACGGTCATCCGC TCACGGTCATCCGCG CACGGTCATCCGCGG ACGGTCATCCGCGGC CGGTCATCCGCGGCT GGTCATCCGCGGCTG GTCATCCGCGGCTGG TCATCCGCGGCTGGA CATCCGCGGCTGGAA ATCCGCGGCTGGAAA TCCGCGGCTGGAAAC CCGCGGCTGGAAACT CGCGGCTGGAAACTC GCGGCTGGAAACTCT CGGCTGGAAACTCTT

[0157] GGCTGGAAACTCTTC GCTGGAAACTCTTCT CTGGAAACTCTTCTA TGGAAACTCTTCTAC GGAAACTCTTCTACA GAAACTCTTCTACAA AAACTCTTCTACAAC AACTCTTCTACAACT ACTCTTCTACAACTA CTCTTCTACAACTAC TCTTCTACAACTACG CTTCTACAACTACGC TTCTACAACTACGCC TCTACAACTACGCCC CTACAACTACGCCCT TACAACTACGCCCTG ACAACTACGCCCTGG CAACTACGCCCTGGT AACTACGCCCTGGTC ACTACGCCCTGGTCA CTACGCCCTGGTCAT TACGCCCTGGTCATC ACGCCCTGGTCATCT CGCCCTGGTCATCTT GCCCTGGTCATCTTC CCCTGGTCATCTTCG CCTGGTCATCTTCGA CTGGTCATCTTCGAG TGGTCATCTTCGAGA GGTCATCTTCGAGAT GTCATCTTCGAGATG TCATCTTCGAGATGA CATCTTCGAGATGAC ATCTTCGAGATGACC TCTTCGAGATGACCA CTTCGAGATGACCAA TTCGAGATGACCAAT TCGAGATGACCAATC CGAGATGACCAATCT GAGATGACCAATCTC AGATGACCAATCTCA GATGACCAATCTCAA ATGACCAATCTCAAG TGACCAATCTCAAGG GACCAATCTCAAGGA ACCAATCTCAAGGAT CCAATCTCAAGGATA CAATCTCAAGGATAT AATCTCAAGGATATT ATCTCAAGGATATTG TCTCAAGGATATTGG

[0158] CTCAAGGATATTGGG TCAAGGATATTGGGC CAAGGATATTGGGCT AAGGATATTGGGCTT AGGATATTGGGCTTT GGATATTGGGCTTTA GATATTGGGCTTTAC ATATTGGGCTTTACA TATTGGGCTTTACAA ATTGGGCTTTACAAC TTGGGCTTTACAACC TGGGCTTTACAACCT GGGCTTTACAACCTG GGCTTTACAACCTGA GCTTTACAACCTGAG CTTTACAACCTGAGG TTTACAACCTGAGGA 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 GGCCATCAGGATTGA GCCATCAGGATTGAG CCATCAGGATTGAGA CATCAGGATTGAGAA ATCAGGATTGAGAAA TCAGGATTGAGAAAA CAGGATTGAGAAAAA

[0159] 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 GTTACCTCTCCACTG TTACCTCTCCACTGT TACCTCTCCACTGTG ACCTCTCCACTGTGG CCTCTCCACTGTGGA CTCTCCACTGTGGAC TCTCCACTGTGGACT CTCCACTGTGGACTG TCCACTGTGGACTGG CCACTGTGGACTGGT CACTGTGGACTGGTC ACTGTGGACTGGTCC CTGTGGACTGGTCCC TGTGGACTGGTCCCT GTGGACTGGTCCCTG TGGACTGGTCCCTGA GGACTGGTCCCTGAT GACTGGTCCCTGATC ACTGGTCCCTGATCC CTGGTCCCTGATCCT TGGTCCCTGATCCTG GGTCCCTGATCCTGG GTCCCTGATCCTGGA TCCCTGATCCTGGAT CCCTGATCCTGGATG CCTGATCCTGGATGC

[0160] CTGATCCTGGATGCG TGATCCTGGATGCGG GATCCTGGATGCGGT ATCCTGGATGCGGTG TCCTGGATGCGGTGT CCTGGATGCGGTGTC CTGGATGCGGTGTCC TGGATGCGGTGTCCA GGATGCGGTGTCCAA GATGCGGTGTCCAAT ATGCGGTGTCCAATA TGCGGTGTCCAATAA GCGGTGTCCAATAAC CGGTGTCCAATAACT GGTGTCCAATAACTA GTGTCCAATAACTAC TGTCCAATAACTACA GTCCAATAACTACAT TCCAATAACTACATT CCAATAACTACATTG CAATAACTACATTGT AATAACTACATTGTG ATAACTACATTGTGG TAACTACATTGTGGG AACTACATTGTGGGG ACTACATTGTGGGGA CTACATTGTGGGGAA TACATTGTGGGGAAT ACATTGTGGGGAATA CATTGTGGGGAATAA ATTGTGGGGAATAAG TTGTGGGGAATAAGC TGTGGGGAATAAGCC GTGGGGAATAAGCCC TGGGGAATAAGCCCC GGGGAATAAGCCCCC GGGAATAAGCCCCCA GGAATAAGCCCCCAA GAATAAGCCCCCAAA AATAAGCCCCCAAAG ATAAGCCCCCAAAGG TAAGCCCCCAAAGGA AAGCCCCCAAAGGAA AGCCCCCAAAGGAAT GCCCCCAAAGGAATG CCCCCAAAGGAATGT CCCCAAAGGAATGTG CCCAAAGGAATGTGG CCAAAGGAATGTGGG CAAAGGAATGTGGGG AAAGGAATGTGGGGA

[0161] AAGGAATGTGGGGAC AGGAATGTGGGGACC GGAATGTGGGGACCT GAATGTGGGGACCTG AATGTGGGGACCTGT ATGTGGGGACCTGTG TGTGGGGACCTGTGT GTGGGGACCTGTGTC TGGGGACCTGTGTCC GGGGACCTGTGTCCA GGGACCTGTGTCCAG GGACCTGTGTCCAGG GACCTGTGTCCAGGG ACCTGTGTCCAGGGA CCTGTGTCCAGGGAC CTGTGTCCAGGGACC 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 GCCGATGTGTGAGAA CCGATGTGTGAGAAG CGATGTGTGAGAAGA GATGTGTGAGAAGAC ATGTGTGAGAAGACC TGTGTGAGAAGACCA GTGTGAGAAGACCAC TGTGAGAAGACCACC GTGAGAAGACCACCA TGAGAAGACCACCAT

[0162] GAGAAGACCACCATC AGAAGACCACCATCA GAAGACCACCATCAA AAGACCACCATCAAC AGACCACCATCAACA GACCACCATCAACAA ACCACCATCAACAAT CCACCATCAACAATG CACCATCAACAATGA ACCATCAACAATGAG CCATCAACAATGAGT CATCAACAATGAGTA ATCAACAATGAGTAC TCAACAATGAGTACA CAACAATGAGTACAA AACAATGAGTACAAC ACAATGAGTACAACT CAATGAGTACAACTA AATGAGTACAACTAC ATGAGTACAACTACC TGAGTACAACTACCG GAGTACAACTACCGC AGTACAACTACCGCT GTACAACTACCGCTG TACAACTACCGCTGC ACAACTACCGCTGCT CAACTACCGCTGCTG AACTACCGCTGCTGG ACTACCGCTGCTGGA CTACCGCTGCTGGAC TACCGCTGCTGGACC ACCGCTGCTGGACCA CCGCTGCTGGACCAC CGCTGCTGGACCACA GCTGCTGGACCACAA CTGCTGGACCACAAA TGCTGGACCACAAAC GCTGGACCACAAACC CTGGACCACAAACCG TGGACCACAAACCGC GGACCACAAACCGCT GACCACAAACCGCTG ACCACAAACCGCTGC CCACAAACCGCTGCC CACAAACCGCTGCCA ACAAACCGCTGCCAG CAAACCGCTGCCAGA AAACCGCTGCCAGAA AACCGCTGCCAGAAA ACCGCTGCCAGAAAA CCGCTGCCAGAAAAT

[0163] CGCTGCCAGAAAATG GCTGCCAGAAAATGT CTGCCAGAAAATGTG TGCCAGAAAATGTGC GCCAGAAAATGTGCC CCAGAAAATGTGCCC CAGAAAATGTGCCCA AGAAAATGTGCCCAA GAAAATGTGCCCAAG AAAATGTGCCCAAGC AAATGTGCCCAAGCA AATGTGCCCAAGCAC ATGTGCCCAAGCACG TGTGCCCAAGCACGT GTGCCCAAGCACGTG TGCCCAAGCACGTGT GCCCAAGCACGTGTG CCCAAGCACGTGTGG CCAAGCACGTGTGGG CAAGCACGTGTGGGA AAGCACGTGTGGGAA AGCACGTGTGGGAAG GCACGTGTGGGAAGC CACGTGTGGGAAGCG ACGTGTGGGAAGCGG CGTGTGGGAAGCGGG GTGTGGGAAGCGGGC TGTGGGAAGCGGGCG GTGGGAAGCGGGCGT TGGGAAGCGGGCGTG GGGAAGCGGGCGTGC GGAAGCGGGCGTGCA GAAGCGGGCGTGCAC AAGCGGGCGTGCACC AGCGGGCGTGCACCG GCGGGCGTGCACCGA CGGGCGTGCACCGAG GGGCGTGCACCGAGA GGCGTGCACCGAGAA GCGTGCACCGAGAAC CGTGCACCGAGAACA GTGCACCGAGAACAA TGCACCGAGAACAAT GCACCGAGAACAATG CACCGAGAACAATGA ACCGAGAACAATGAG CCGAGAACAATGAGT CGAGAACAATGAGTG GAGAACAATGAGTGC AGAACAATGAGTGCT GAACAATGAGTGCTG

[0164] AACAATGAGTGCTGC ACAATGAGTGCTGCC CAATGAGTGCTGCCA AATGAGTGCTGCCAC ATGAGTGCTGCCACC TGAGTGCTGCCACCC GAGTGCTGCCACCCC AGTGCTGCCACCCCG GTGCTGCCACCCCGA TGCTGCCACCCCGAG GCTGCCACCCCGAGT CTGCCACCCCGAGTG TGCCACCCCGAGTGC GCCACCCCGAGTGCC CCACCCCGAGTGCCT CACCCCGAGTGCCTG ACCCCGAGTGCCTGG CCCCGAGTGCCTGGG CCCGAGTGCCTGGGC CCGAGTGCCTGGGCA CGAGTGCCTGGGCAG GAGTGCCTGGGCAGC AGTGCCTGGGCAGCT GTGCCTGGGCAGCTG TGCCTGGGCAGCTGC GCCTGGGCAGCTGCA CCTGGGCAGCTGCAG CTGGGCAGCTGCAGC TGGGCAGCTGCAGCG GGGCAGCTGCAGCGC GGCAGCTGCAGCGCG GCAGCTGCAGCGCGC CAGCTGCAGCGCGCC AGCTGCAGCGCGCCT GCTGCAGCGCGCCTG CTGCAGCGCGCCTGA TGCAGCGCGCCTGAC GCAGCGCGCCTGACA CAGCGCGCCTGACAA AGCGCGCCTGACAAC GCGCGCCTGACAACG CGCGCCTGACAACGA GCGCCTGACAACGAC CGCCTGACAACGACA GCCTGACAACGACAC CCTGACAACGACACG CTGACAACGACACGG TGACAACGACACGGC GACAACGACACGGCC ACAACGACACGGCCT CAACGACACGGCCTG

[0165] AACGACACGGCCTGT ACGACACGGCCTGTG CGACACGGCCTGTGT GACACGGCCTGTGTA ACACGGCCTGTGTAG CACGGCCTGTGTAGC ACGGCCTGTGTAGCT CGGCCTGTGTAGCTT GGCCTGTGTAGCTTG GCCTGTGTAGCTTGC CCTGTGTAGCTTGCC CTGTGTAGCTTGCCG TGTGTAGCTTGCCGC GTGTAGCTTGCCGCC TGTAGCTTGCCGCCA GTAGCTTGCCGCCAC TAGCTTGCCGCCACT AGCTTGCCGCCACTA GCTTGCCGCCACTAC CTTGCCGCCACTACT TTGCCGCCACTACTA TGCCGCCACTACTAC GCCGCCACTACTACT CCGCCACTACTACTA CGCCACTACTACTAT GCCACTACTACTATG CCACTACTACTATGC CACTACTACTATGCC ACTACTACTATGCCG CTACTACTATGCCGG TACTACTATGCCGGT ACTACTATGCCGGTG CTACTATGCCGGTGT TACTATGCCGGTGTC ACTATGCCGGTGTCT CTATGCCGGTGTCTG TATGCCGGTGTCTGT ATGCCGGTGTCTGTG TGCCGGTGTCTGTGT GCCGGTGTCTGTGTG CCGGTGTCTGTGTGC CGGTGTCTGTGTGCC GGTGTCTGTGTGCCT GTGTCTGTGTGCCTG TGTCTGTGTGCCTGC GTCTGTGTGCCTGCC TCTGTGTGCCTGCCT CTGTGTGCCTGCCTG TGTGTGCCTGCCTGC GTGTGCCTGCCTGCC TGTGCCTGCCTGCCC

[0166] GTGCCTGCCTGCCCG TGCCTGCCTGCCCGC GCCTGCCTGCCCGCC CCTGCCTGCCCGCCC CTGCCTGCCCGCCCA TGCCTGCCCGCCCAA 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

[0167] GACCGTGACTTCTGC ACCGTGACTTCTGCG CCGTGACTTCTGCGC CGTGACTTCTGCGCC GTGACTTCTGCGCCA TGACTTCTGCGCCAA GACTTCTGCGCCAAC ACTTCTGCGCCAACA CTTCTGCGCCAACAT TTCTGCGCCAACATC TCTGCGCCAACATCC CTGCGCCAACATCCT TGCGCCAACATCCTC GCGCCAACATCCTCA CGCCAACATCCTCAG GCCAACATCCTCAGC CCAACATCCTCAGCG CAACATCCTCAGCGC AACATCCTCAGCGCC ACATCCTCAGCGCCG CATCCTCAGCGCCGA ATCCTCAGCGCCGAG TCCTCAGCGCCGAGA CCTCAGCGCCGAGAG CTCAGCGCCGAGAGC TCAGCGCCGAGAGCA CAGCGCCGAGAGCAG AGCGCCGAGAGCAGC GCGCCGAGAGCAGCG CGCCGAGAGCAGCGA GCCGAGAGCAGCGAC CCGAGAGCAGCGACT CGAGAGCAGCGACTC GAGAGCAGCGACTCC AGAGCAGCGACTCCG GAGCAGCGACTCCGA AGCAGCGACTCCGAG GCAGCGACTCCGAGG CAGCGACTCCGAGGG AGCGACTCCGAGGGG GCGACTCCGAGGGGT CGACTCCGAGGGGTT GACTCCGAGGGGTTT ACTCCGAGGGGTTTG CTCCGAGGGGTTTGT TCCGAGGGGTTTGTG CCGAGGGGTTTGTGA CGAGGGGTTTGTGAT GAGGGGTTTGTGATC AGGGGTTTGTGATCC GGGGTTTGTGATCCA

[0168] GGGTTTGTGATCCAC GGTTTGTGATCCACG GTTTGTGATCCACGA TTTGTGATCCACGAC TTGTGATCCACGACG TGTGATCCACGACGG GTGATCCACGACGGC TGATCCACGACGGCG GATCCACGACGGCGA ATCCACGACGGCGAG 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

[0169] ATCCGCAACGGCAGC TCCGCAACGGCAGCC CCGCAACGGCAGCCA 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 GCATCCCTTGTGAAG CATCCCTTGTGAAGG ATCCCTTGTGAAGGT TCCCTTGTGAAGGTC CCCTTGTGAAGGTCC CCTTGTGAAGGTCCT CTTGTGAAGGTCCTT TTGTGAAGGTCCTTG TGTGAAGGTCCTTGC GTGAAGGTCCTTGCC TGAAGGTCCTTGCCC GAAGGTCCTTGCCCG AAGGTCCTTGCCCGA AGGTCCTTGCCCGAA GGTCCTTGCCCGAAG GTCCTTGCCCGAAGG TCCTTGCCCGAAGGT CCTTGCCCGAAGGTC CTTGCCCGAAGGTCT TTGCCCGAAGGTCTG TGCCCGAAGGTCTGT GCCCGAAGGTCTGTG CCCGAAGGTCTGTGA

[0170] CCGAAGGTCTGTGAG CGAAGGTCTGTGAGG GAAGGTCTGTGAGGA AAGGTCTGTGAGGAA AGGTCTGTGAGGAAG GGTCTGTGAGGAAGA GTCTGTGAGGAAGAA TCTGTGAGGAAGAAA CTGTGAGGAAGAAAA TGTGAGGAAGAAAAG GTGAGGAAGAAAAGA TGAGGAAGAAAAGAA GAGGAAGAAAAGAAA AGGAAGAAAAGAAAA GGAAGAAAAGAAAAC GAAGAAAAGAAAACA AAGAAAAGAAAACAA AGAAAAGAAAACAAA GAAAAGAAAACAAAG AAAAGAAAACAAAGA AAAGAAAACAAAGAC AAGAAAACAAAGACC AGAAAACAAAGACCA GAAAACAAAGACCAT 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

[0171] TCTGCTCAGATGCTC CTGCTCAGATGCTCC TGCTCAGATGCTCCA GCTCAGATGCTCCAA CTCAGATGCTCCAAG TCAGATGCTCCAAGG CAGATGCTCCAAGGA AGATGCTCCAAGGAT GATGCTCCAAGGATG 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 GCTCATTAACATCCG CTCATTAACATCCGA TCATTAACATCCGAC CATTAACATCCGACG ATTAACATCCGACGG TTAACATCCGACGGG TAACATCCGACGGGG

[0172] 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 CTTCATGGGGCTCAT TTCATGGGGCTCATC TCATGGGGCTCATCG CATGGGGCTCATCGA ATGGGGCTCATCGAG TGGGGCTCATCGAGG GGGGCTCATCGAGGT GGGCTCATCGAGGTG GGCTCATCGAGGTGG GCTCATCGAGGTGGT

[0173] CTCATCGAGGTGGTG TCATCGAGGTGGTGA CATCGAGGTGGTGAC ATCGAGGTGGTGACG TCGAGGTGGTGACGG CGAGGTGGTGACGGG GAGGTGGTGACGGGC AGGTGGTGACGGGCT GGTGGTGACGGGCTA GTGGTGACGGGCTAC TGGTGACGGGCTACG GGTGACGGGCTACGT GTGACGGGCTACGTG TGACGGGCTACGTGA GACGGGCTACGTGAA ACGGGCTACGTGAAG CGGGCTACGTGAAGA GGGCTACGTGAAGAT GGCTACGTGAAGATC GCTACGTGAAGATCC CTACGTGAAGATCCG TACGTGAAGATCCGC ACGTGAAGATCCGCC CGTGAAGATCCGCCA GTGAAGATCCGCCAT TGAAGATCCGCCATT GAAGATCCGCCATTC AAGATCCGCCATTCT AGATCCGCCATTCTC GATCCGCCATTCTCA ATCCGCCATTCTCAT TCCGCCATTCTCATG CCGCCATTCTCATGC CGCCATTCTCATGCC GCCATTCTCATGCCT CCATTCTCATGCCTT CATTCTCATGCCTTG ATTCTCATGCCTTGG TTCTCATGCCTTGGT TCTCATGCCTTGGTC CTCATGCCTTGGTCT TCATGCCTTGGTCTC CATGCCTTGGTCTCC ATGCCTTGGTCTCCT TGCCTTGGTCTCCTT GCCTTGGTCTCCTTG CCTTGGTCTCCTTGT CTTGGTCTCCTTGTC TTGGTCTCCTTGTCC TGGTCTCCTTGTCCT GGTCTCCTTGTCCTT

[0174] GTCTCCTTGTCCTTC TCTCCTTGTCCTTCC CTCCTTGTCCTTCCT TCCTTGTCCTTCCTA CCTTGTCCTTCCTAA CTTGTCCTTCCTAAA TTGTCCTTCCTAAAA TGTCCTTCCTAAAAA GTCCTTCCTAAAAAA TCCTTCCTAAAAAAC CCTTCCTAAAAAACC CTTCCTAAAAAACCT TTCCTAAAAAACCTT TCCTAAAAAACCTTC CCTAAAAAACCTTCG CTAAAAAACCTTCGC TAAAAAACCTTCGCC AAAAAACCTTCGCCT AAAAACCTTCGCCTC AAAACCTTCGCCTCA AAACCTTCGCCTCAT AACCTTCGCCTCATC ACCTTCGCCTCATCC CCTTCGCCTCATCCT CTTCGCCTCATCCTA TTCGCCTCATCCTAG TCGCCTCATCCTAGG CGCCTCATCCTAGGA GCCTCATCCTAGGAG CCTCATCCTAGGAGA CTCATCCTAGGAGAG TCATCCTAGGAGAGG CATCCTAGGAGAGGA ATCCTAGGAGAGGAG TCCTAGGAGAGGAGC CCTAGGAGAGGAGCA CTAGGAGAGGAGCAG TAGGAGAGGAGCAGC AGGAGAGGAGCAGCT GGAGAGGAGCAGCTA GAGAGGAGCAGCTAG AGAGGAGCAGCTAGA GAGGAGCAGCTAGAA AGGAGCAGCTAGAAG GGAGCAGCTAGAAGG GAGCAGCTAGAAGGG AGCAGCTAGAAGGGA GCAGCTAGAAGGGAA CAGCTAGAAGGGAAT AGCTAGAAGGGAATT GCTAGAAGGGAATTA

[0175] CTAGAAGGGAATTAC TAGAAGGGAATTACT AGAAGGGAATTACTC GAAGGGAATTACTCC AAGGGAATTACTCCT AGGGAATTACTCCTT GGGAATTACTCCTTC GGAATTACTCCTTCT GAATTACTCCTTCTA AATTACTCCTTCTAC ATTACTCCTTCTACG TTACTCCTTCTACGT TACTCCTTCTACGTC ACTCCTTCTACGTCC CTCCTTCTACGTCCT TCCTTCTACGTCCTC CCTTCTACGTCCTCG CTTCTACGTCCTCGA TTCTACGTCCTCGAC TCTACGTCCTCGACA CTACGTCCTCGACAA TACGTCCTCGACAAC ACGTCCTCGACAACC CGTCCTCGACAACCA GTCCTCGACAACCAG TCCTCGACAACCAGA CCTCGACAACCAGAA CTCGACAACCAGAAC TCGACAACCAGAACT CGACAACCAGAACTT GACAACCAGAACTTG ACAACCAGAACTTGC CAACCAGAACTTGCA AACCAGAACTTGCAG ACCAGAACTTGCAGC CCAGAACTTGCAGCA CAGAACTTGCAGCAA AGAACTTGCAGCAAC GAACTTGCAGCAACT AACTTGCAGCAACTG ACTTGCAGCAACTGT CTTGCAGCAACTGTG TTGCAGCAACTGTGG TGCAGCAACTGTGGG GCAGCAACTGTGGGA CAGCAACTGTGGGAC AGCAACTGTGGGACT GCAACTGTGGGACTG CAACTGTGGGACTGG AACTGTGGGACTGGG ACTGTGGGACTGGGA

[0176] 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 CATCAAAGCAGGGAA ATCAAAGCAGGGAAA TCAAAGCAGGGAAAA CAAAGCAGGGAAAAT AAAGCAGGGAAAATG AAGCAGGGAAAATGT AGCAGGGAAAATGTA GCAGGGAAAATGTAC CAGGGAAAATGTACT AGGGAAAATGTACTT GGGAAAATGTACTTT GGAAAATGTACTTTG GAAAATGTACTTTGC AAAATGTACTTTGCT AAATGTACTTTGCTT AATGTACTTTGCTTT ATGTACTTTGCTTTC TGTACTTTGCTTTCA GTACTTTGCTTTCAA TACTTTGCTTTCAAT ACTTTGCTTTCAATC CTTTGCTTTCAATCC

[0177] 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 TTTACCGCATGGAGG TTACCGCATGGAGGA TACCGCATGGAGGAA ACCGCATGGAGGAAG CCGCATGGAGGAAGT CGCATGGAGGAAGTG GCATGGAGGAAGTGA CATGGAGGAAGTGAC ATGGAGGAAGTGACG TGGAGGAAGTGACGG GGAGGAAGTGACGGG GAGGAAGTGACGGGG AGGAAGTGACGGGGA GGAAGTGACGGGGAC GAAGTGACGGGGACT AAGTGACGGGGACTA AGTGACGGGGACTAA

[0178] 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 AACAACGGGGAGAGA ACAACGGGGAGAGAG CAACGGGGAGAGAGC

[0179] AACGGGGAGAGAGCC ACGGGGAGAGAGCCT CGGGGAGAGAGCCTC GGGGAGAGAGCCTCC GGGAGAGAGCCTCCT GGAGAGAGCCTCCTG GAGAGAGCCTCCTGT AGAGAGCCTCCTGTG GAGAGCCTCCTGTGA AGAGCCTCCTGTGAA GAGCCTCCTGTGAAA AGCCTCCTGTGAAAG GCCTCCTGTGAAAGT CCTCCTGTGAAAGTG CTCCTGTGAAAGTGA TCCTGTGAAAGTGAC CCTGTGAAAGTGACG CTGTGAAAGTGACGT TGTGAAAGTGACGTC 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

[0180] ACCACGTCGAAGAAT CCACGTCGAAGAATC CACGTCGAAGAATCG ACGTCGAAGAATCGC CGTCGAAGAATCGCA GTCGAAGAATCGCAT TCGAAGAATCGCATC CGAAGAATCGCATCA GAAGAATCGCATCAT AAGAATCGCATCATC AGAATCGCATCATCA GAATCGCATCATCAT AATCGCATCATCATA ATCGCATCATCATAA TCGCATCATCATAAC CGCATCATCATAACC GCATCATCATAACCT CATCATCATAACCTG ATCATCATAACCTGG TCATCATAACCTGGC CATCATAACCTGGCA ATCATAACCTGGCAC TCATAACCTGGCACC CATAACCTGGCACCG ATAACCTGGCACCGG TAACCTGGCACCGGT AACCTGGCACCGGTA ACCTGGCACCGGTAC CCTGGCACCGGTACC CTGGCACCGGTACCG TGGCACCGGTACCGG GGCACCGGTACCGGC GCACCGGTACCGGCC CACCGGTACCGGCCC ACCGGTACCGGCCCC CCGGTACCGGCCCCC CGGTACCGGCCCCCT GGTACCGGCCCCCTG GTACCGGCCCCCTGA TACCGGCCCCCTGAC ACCGGCCCCCTGACT CCGGCCCCCTGACTA CGGCCCCCTGACTAC GGCCCCCTGACTACA GCCCCCTGACTACAG CCCCCTGACTACAGG CCCCTGACTACAGGG CCCTGACTACAGGGA CCTGACTACAGGGAT CTGACTACAGGGATC TGACTACAGGGATCT

[0181] GACTACAGGGATCTC ACTACAGGGATCTCA CTACAGGGATCTCAT TACAGGGATCTCATC ACAGGGATCTCATCA CAGGGATCTCATCAG AGGGATCTCATCAGC GGGATCTCATCAGCT GGATCTCATCAGCTT 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

[0182] 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 ATGCCTGCGGCTCCA TGCCTGCGGCTCCAA GCCTGCGGCTCCAAC CCTGCGGCTCCAACA CTGCGGCTCCAACAG TGCGGCTCCAACAGC GCGGCTCCAACAGCT CGGCTCCAACAGCTG GGCTCCAACAGCTGG GCTCCAACAGCTGGA CTCCAACAGCTGGAA TCCAACAGCTGGAAC CCAACAGCTGGAACA CAACAGCTGGAACAT AACAGCTGGAACATG ACAGCTGGAACATGG CAGCTGGAACATGGT AGCTGGAACATGGTG GCTGGAACATGGTGG CTGGAACATGGTGGA TGGAACATGGTGGAC GGAACATGGTGGACG GAACATGGTGGACGT

[0183] AACATGGTGGACGTG ACATGGTGGACGTGG CATGGTGGACGTGGA ATGGTGGACGTGGAC TGGTGGACGTGGACC GGTGGACGTGGACCT GTGGACGTGGACCTC TGGACGTGGACCTCC GGACGTGGACCTCCC GACGTGGACCTCCCG ACGTGGACCTCCCGC CGTGGACCTCCCGCC GTGGACCTCCCGCCC TGGACCTCCCGCCCA GGACCTCCCGCCCAA GACCTCCCGCCCAAC ACCTCCCGCCCAACA CCTCCCGCCCAACAA CTCCCGCCCAACAAG TCCCGCCCAACAAGG CCCGCCCAACAAGGA CCGCCCAACAAGGAC CGCCCAACAAGGACG GCCCAACAAGGACGT CCCAACAAGGACGTG CCAACAAGGACGTGG CAACAAGGACGTGGA AACAAGGACGTGGAG ACAAGGACGTGGAGC CAAGGACGTGGAGCC AAGGACGTGGAGCCC AGGACGTGGAGCCCG GGACGTGGAGCCCGG GACGTGGAGCCCGGC ACGTGGAGCCCGGCA CGTGGAGCCCGGCAT GTGGAGCCCGGCATC TGGAGCCCGGCATCT GGAGCCCGGCATCTT GAGCCCGGCATCTTA AGCCCGGCATCTTAC GCCCGGCATCTTACT CCCGGCATCTTACTA CCGGCATCTTACTAC CGGCATCTTACTACA GGCATCTTACTACAT GCATCTTACTACATG CATCTTACTACATGG ATCTTACTACATGGG TCTTACTACATGGGC CTTACTACATGGGCT

[0184] TTACTACATGGGCTG TACTACATGGGCTGA ACTACATGGGCTGAA CTACATGGGCTGAAG TACATGGGCTGAAGC ACATGGGCTGAAGCC CATGGGCTGAAGCCC ATGGGCTGAAGCCCT TGGGCTGAAGCCCTG GGGCTGAAGCCCTGG GGCTGAAGCCCTGGA GCTGAAGCCCTGGAC CTGAAGCCCTGGACT TGAAGCCCTGGACTC GAAGCCCTGGACTCA AAGCCCTGGACTCAG AGCCCTGGACTCAGT GCCCTGGACTCAGTA 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 AGGCTGTGACCCTCA GGCTGTGACCCTCAC GCTGTGACCCTCACC CTGTGACCCTCACCA TGTGACCCTCACCAT

[0185] GTGACCCTCACCATG TGACCCTCACCATGG GACCCTCACCATGGT ACCCTCACCATGGTG CCCTCACCATGGTGG CCTCACCATGGTGGA CTCACCATGGTGGAG TCACCATGGTGGAGA CACCATGGTGGAGAA ACCATGGTGGAGAAC CCATGGTGGAGAACG CATGGTGGAGAACGA ATGGTGGAGAACGAC TGGTGGAGAACGACC GGTGGAGAACGACCA GTGGAGAACGACCAT TGGAGAACGACCATA 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 GTGAGATCTTGTACA TGAGATCTTGTACAT GAGATCTTGTACATT AGATCTTGTACATTC GATCTTGTACATTCG

[0186] 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 TCCTTCCATTCCCTT CCTTCCATTCCCTTG CTTCCATTCCCTTGG TTCCATTCCCTTGGA TCCATTCCCTTGGAC CCATTCCCTTGGACG CATTCCCTTGGACGT ATTCCCTTGGACGTT TTCCCTTGGACGTTC TCCCTTGGACGTTCT CCCTTGGACGTTCTT CCTTGGACGTTCTTT CTTGGACGTTCTTTC TTGGACGTTCTTTCA TGGACGTTCTTTCAG GGACGTTCTTTCAGC GACGTTCTTTCAGCA ACGTTCTTTCAGCAT CGTTCTTTCAGCATC GTTCTTTCAGCATCG TTCTTTCAGCATCGA TCTTTCAGCATCGAA

[0187] CTTTCAGCATCGAAC TTTCAGCATCGAACT TTCAGCATCGAACTC TCAGCATCGAACTCC CAGCATCGAACTCCT AGCATCGAACTCCTC GCATCGAACTCCTCT 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 CGTGAAGTGGAACCC GTGAAGTGGAACCCT TGAAGTGGAACCCTC GAAGTGGAACCCTCC AAGTGGAACCCTCCC AGTGGAACCCTCCCT GTGGAACCCTCCCTC TGGAACCCTCCCTCT GGAACCCTCCCTCTC GAACCCTCCCTCTCT AACCCTCCCTCTCTG ACCCTCCCTCTCTGC CCCTCCCTCTCTGCC CCTCCCTCTCTGCCC CTCCCTCTCTGCCCA TCCCTCTCTGCCCAA CCCTCTCTGCCCAAC CCTCTCTGCCCAACG CTCTCTGCCCAACGG

[0188] TCTCTGCCCAACGGC CTCTGCCCAACGGCA TCTGCCCAACGGCAA CTGCCCAACGGCAAC TGCCCAACGGCAACC GCCCAACGGCAACCT CCCAACGGCAACCTG CCAACGGCAACCTGA CAACGGCAACCTGAG AACGGCAACCTGAGT ACGGCAACCTGAGTT CGGCAACCTGAGTTA GGCAACCTGAGTTAC GCAACCTGAGTTACT CAACCTGAGTTACTA AACCTGAGTTACTAC ACCTGAGTTACTACA CCTGAGTTACTACAT CTGAGTTACTACATT TGAGTTACTACATTG GAGTTACTACATTGT AGTTACTACATTGTG GTTACTACATTGTGC TTACTACATTGTGCG TACTACATTGTGCGC ACTACATTGTGCGCT CTACATTGTGCGCTG TACATTGTGCGCTGG ACATTGTGCGCTGGC CATTGTGCGCTGGCA ATTGTGCGCTGGCAG TTGTGCGCTGGCAGC TGTGCGCTGGCAGCG GTGCGCTGGCAGCGG TGCGCTGGCAGCGGC GCGCTGGCAGCGGCA CGCTGGCAGCGGCAG GCTGGCAGCGGCAGC CTGGCAGCGGCAGCC TGGCAGCGGCAGCCT GGCAGCGGCAGCCTC GCAGCGGCAGCCTCA CAGCGGCAGCCTCAG AGCGGCAGCCTCAGG GCGGCAGCCTCAGGA CGGCAGCCTCAGGAC GGCAGCCTCAGGACG GCAGCCTCAGGACGG CAGCCTCAGGACGGC AGCCTCAGGACGGCT GCCTCAGGACGGCTA

[0189] CCTCAGGACGGCTAC CTCAGGACGGCTACC TCAGGACGGCTACCT CAGGACGGCTACCTT AGGACGGCTACCTTT GGACGGCTACCTTTA GACGGCTACCTTTAC ACGGCTACCTTTACC CGGCTACCTTTACCG GGCTACCTTTACCGG GCTACCTTTACCGGC CTACCTTTACCGGCA TACCTTTACCGGCAC ACCTTTACCGGCACA CCTTTACCGGCACAA CTTTACCGGCACAAT TTTACCGGCACAATT TTACCGGCACAATTA TACCGGCACAATTAC ACCGGCACAATTACT CCGGCACAATTACTG CGGCACAATTACTGC GGCACAATTACTGCT GCACAATTACTGCTC CACAATTACTGCTCC ACAATTACTGCTCCA CAATTACTGCTCCAA AATTACTGCTCCAAA ATTACTGCTCCAAAG TTACTGCTCCAAAGA TACTGCTCCAAAGAC ACTGCTCCAAAGACA CTGCTCCAAAGACAA TGCTCCAAAGACAAA GCTCCAAAGACAAAA CTCCAAAGACAAAAT TCCAAAGACAAAATC CCAAAGACAAAATCC CAAAGACAAAATCCC AAAGACAAAATCCCC AAGACAAAATCCCCA AGACAAAATCCCCAT GACAAAATCCCCATC ACAAAATCCCCATCA CAAAATCCCCATCAG AAAATCCCCATCAGG AAATCCCCATCAGGA AATCCCCATCAGGAA ATCCCCATCAGGAAG TCCCCATCAGGAAGT CCCCATCAGGAAGTA

[0190] CCCATCAGGAAGTAT CCATCAGGAAGTATG CATCAGGAAGTATGC ATCAGGAAGTATGCC TCAGGAAGTATGCCG CAGGAAGTATGCCGA AGGAAGTATGCCGAC GGAAGTATGCCGACG GAAGTATGCCGACGG AAGTATGCCGACGGC AGTATGCCGACGGCA GTATGCCGACGGCAC TATGCCGACGGCACC ATGCCGACGGCACCA TGCCGACGGCACCAT GCCGACGGCACCATC CCGACGGCACCATCG CGACGGCACCATCGA GACGGCACCATCGAC ACGGCACCATCGACA CGGCACCATCGACAT GGCACCATCGACATT GCACCATCGACATTG CACCATCGACATTGA ACCATCGACATTGAG CCATCGACATTGAGG CATCGACATTGAGGA ATCGACATTGAGGAG TCGACATTGAGGAGG CGACATTGAGGAGGT GACATTGAGGAGGTC ACATTGAGGAGGTCA CATTGAGGAGGTCAC ATTGAGGAGGTCACA TTGAGGAGGTCACAG TGAGGAGGTCACAGA GAGGAGGTCACAGAG AGGAGGTCACAGAGA GGAGGTCACAGAGAA GAGGTCACAGAGAAC AGGTCACAGAGAACC GGTCACAGAGAACCC GTCACAGAGAACCCC TCACAGAGAACCCCA CACAGAGAACCCCAA ACAGAGAACCCCAAG CAGAGAACCCCAAGA AGAGAACCCCAAGAC GAGAACCCCAAGACT AGAACCCCAAGACTG GAACCCCAAGACTGA

[0191] AACCCCAAGACTGAG ACCCCAAGACTGAGG CCCCAAGACTGAGGT CCCAAGACTGAGGTG CCAAGACTGAGGTGT CAAGACTGAGGTGTG AAGACTGAGGTGTGT AGACTGAGGTGTGTG GACTGAGGTGTGTGG ACTGAGGTGTGTGGT CTGAGGTGTGTGGTG TGAGGTGTGTGGTGG GAGGTGTGTGGTGGG AGGTGTGTGGTGGGG GGTGTGTGGTGGGGA GTGTGTGGTGGGGAG TGTGTGGTGGGGAGA GTGTGGTGGGGAGAA TGTGGTGGGGAGAAA GTGGTGGGGAGAAAG TGGTGGGGAGAAAGG GGTGGGGAGAAAGGG GTGGGGAGAAAGGGC TGGGGAGAAAGGGCC GGGGAGAAAGGGCCT GGGAGAAAGGGCCTT GGAGAAAGGGCCTTG GAGAAAGGGCCTTGC AGAAAGGGCCTTGCT GAAAGGGCCTTGCTG AAAGGGCCTTGCTGC AAGGGCCTTGCTGCG AGGGCCTTGCTGCGC GGGCCTTGCTGCGCC GGCCTTGCTGCGCCT GCCTTGCTGCGCCTG CCTTGCTGCGCCTGC CTTGCTGCGCCTGCC TTGCTGCGCCTGCCC TGCTGCGCCTGCCCC GCTGCGCCTGCCCCA CTGCGCCTGCCCCAA TGCGCCTGCCCCAAA GCGCCTGCCCCAAAA CGCCTGCCCCAAAAC GCCTGCCCCAAAACT CCTGCCCCAAAACTG CTGCCCCAAAACTGA TGCCCCAAAACTGAA GCCCCAAAACTGAAG CCCCAAAACTGAAGC

[0192] 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 CGAGAAGGAGGAGGC GAGAAGGAGGAGGCT AGAAGGAGGAGGCTG GAAGGAGGAGGCTGA AAGGAGGAGGCTGAA AGGAGGAGGCTGAAT GGAGGAGGCTGAATA GAGGAGGCTGAATAC AGGAGGCTGAATACC GGAGGCTGAATACCG GAGGCTGAATACCGC AGGCTGAATACCGCA GGCTGAATACCGCAA GCTGAATACCGCAAA CTGAATACCGCAAAG TGAATACCGCAAAGT GAATACCGCAAAGTC AATACCGCAAAGTCT ATACCGCAAAGTCTT TACCGCAAAGTCTTT ACCGCAAAGTCTTTG CCGCAAAGTCTTTGA CGCAAAGTCTTTGAG GCAAAGTCTTTGAGA CAAAGTCTTTGAGAA

[0193] AAAGTCTTTGAGAAT AAGTCTTTGAGAATT AGTCTTTGAGAATTT GTCTTTGAGAATTTC 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 TGCCCAGACCTGAAA GCCCAGACCTGAAAG CCCAGACCTGAAAGG CCAGACCTGAAAGGA CAGACCTGAAAGGAA AGACCTGAAAGGAAG GACCTGAAAGGAAGC ACCTGAAAGGAAGCG CCTGAAAGGAAGCGG CTGAAAGGAAGCGGA TGAAAGGAAGCGGAG GAAAGGAAGCGGAGA AAAGGAAGCGGAGAG AAGGAAGCGGAGAGA

[0194] AGGAAGCGGAGAGAT GGAAGCGGAGAGATG GAAGCGGAGAGATGT AAGCGGAGAGATGTC AGCGGAGAGATGTCA GCGGAGAGATGTCAT CGGAGAGATGTCATG GGAGAGATGTCATGC GAGAGATGTCATGCA AGAGATGTCATGCAA GAGATGTCATGCAAG AGATGTCATGCAAGT GATGTCATGCAAGTG ATGTCATGCAAGTGG TGTCATGCAAGTGGC 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 TGTCCAGCCGAAGCA GTCCAGCCGAAGCAG TCCAGCCGAAGCAGG CCAGCCGAAGCAGGA CAGCCGAAGCAGGAA AGCCGAAGCAGGAAC GCCGAAGCAGGAACA CCGAAGCAGGAACAC CGAAGCAGGAACACC GAAGCAGGAACACCA AAGCAGGAACACCAC

[0195] AGCAGGAACACCACG 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

[0196] CTGGAGACAGAGTAC TGGAGACAGAGTACC GGAGACAGAGTACCC GAGACAGAGTACCCT AGACAGAGTACCCTT GACAGAGTACCCTTT ACAGAGTACCCTTTC CAGAGTACCCTTTCT AGAGTACCCTTTCTT GAGTACCCTTTCTTT AGTACCCTTTCTTTG GTACCCTTTCTTTGA TACCCTTTCTTTGAG ACCCTTTCTTTGAGA CCCTTTCTTTGAGAG CCTTTCTTTGAGAGC CTTTCTTTGAGAGCA TTTCTTTGAGAGCAG TTCTTTGAGAGCAGA TCTTTGAGAGCAGAG CTTTGAGAGCAGAGT TTTGAGAGCAGAGTG TTGAGAGCAGAGTGG TGAGAGCAGAGTGGA GAGAGCAGAGTGGAT AGAGCAGAGTGGATA GAGCAGAGTGGATAA AGCAGAGTGGATAAC GCAGAGTGGATAACA CAGAGTGGATAACAA AGAGTGGATAACAAG GAGTGGATAACAAGG AGTGGATAACAAGGA GTGGATAACAAGGAG TGGATAACAAGGAGA GGATAACAAGGAGAG GATAACAAGGAGAGA ATAACAAGGAGAGAA TAACAAGGAGAGAAC AACAAGGAGAGAACT ACAAGGAGAGAACTG CAAGGAGAGAACTGT AAGGAGAGAACTGTC AGGAGAGAACTGTCA GGAGAGAACTGTCAT GAGAGAACTGTCATT AGAGAACTGTCATTT GAGAACTGTCATTTC AGAACTGTCATTTCT GAACTGTCATTTCTA AACTGTCATTTCTAA

[0197] 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 ACATTGTACCGCATC CATTGTACCGCATCG ATTGTACCGCATCGA TTGTACCGCATCGAT TGTACCGCATCGATA GTACCGCATCGATAT TACCGCATCGATATC ACCGCATCGATATCC CCGCATCGATATCCA CGCATCGATATCCAC GCATCGATATCCACA CATCGATATCCACAG ATCGATATCCACAGC TCGATATCCACAGCT CGATATCCACAGCTG GATATCCACAGCTGC ATATCCACAGCTGCA TATCCACAGCTGCAA ATCCACAGCTGCAAC TCCACAGCTGCAACC CCACAGCTGCAACCA CACAGCTGCAACCAC ACAGCTGCAACCACG CAGCTGCAACCACGA

[0198] AGCTGCAACCACGAG GCTGCAACCACGAGG CTGCAACCACGAGGC TGCAACCACGAGGCT GCAACCACGAGGCTG CAACCACGAGGCTGA AACCACGAGGCTGAG ACCACGAGGCTGAGA CCACGAGGCTGAGAA CACGAGGCTGAGAAG ACGAGGCTGAGAAGC CGAGGCTGAGAAGCT GAGGCTGAGAAGCTG AGGCTGAGAAGCTGG GGCTGAGAAGCTGGG GCTGAGAAGCTGGGC CTGAGAAGCTGGGCT TGAGAAGCTGGGCTG GAGAAGCTGGGCTGC AGAAGCTGGGCTGCA GAAGCTGGGCTGCAG AAGCTGGGCTGCAGC AGCTGGGCTGCAGCG GCTGGGCTGCAGCGC CTGGGCTGCAGCGCC TGGGCTGCAGCGCCT GGGCTGCAGCGCCTC GGCTGCAGCGCCTCC GCTGCAGCGCCTCCA CTGCAGCGCCTCCAA TGCAGCGCCTCCAAC GCAGCGCCTCCAACT CAGCGCCTCCAACTT AGCGCCTCCAACTTC GCGCCTCCAACTTCG CGCCTCCAACTTCGT GCCTCCAACTTCGTC CCTCCAACTTCGTCT CTCCAACTTCGTCTT TCCAACTTCGTCTTT CCAACTTCGTCTTTG CAACTTCGTCTTTGC AACTTCGTCTTTGCA ACTTCGTCTTTGCAA CTTCGTCTTTGCAAG TTCGTCTTTGCAAGG TCGTCTTTGCAAGGA CGTCTTTGCAAGGAC GTCTTTGCAAGGACT TCTTTGCAAGGACTA CTTTGCAAGGACTAT

[0199] TTTGCAAGGACTATG TTGCAAGGACTATGC TGCAAGGACTATGCC GCAAGGACTATGCCC CAAGGACTATGCCCG AAGGACTATGCCCGC AGGACTATGCCCGCA GGACTATGCCCGCAG GACTATGCCCGCAGA ACTATGCCCGCAGAA CTATGCCCGCAGAAG TATGCCCGCAGAAGG ATGCCCGCAGAAGGA TGCCCGCAGAAGGAG GCCCGCAGAAGGAGC CCCGCAGAAGGAGCA CCGCAGAAGGAGCAG CGCAGAAGGAGCAGA 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

[0200] ACCTGGGAGCCAAGG CCTGGGAGCCAAGGC CTGGGAGCCAAGGCC TGGGAGCCAAGGCCT GGGAGCCAAGGCCTG GGAGCCAAGGCCTGA GAGCCAAGGCCTGAA AGCCAAGGCCTGAAA GCCAAGGCCTGAAAA CCAAGGCCTGAAAAC CAAGGCCTGAAAACT AAGGCCTGAAAACTC AGGCCTGAAAACTCC GGCCTGAAAACTCCA GCCTGAAAACTCCAT CCTGAAAACTCCATC CTGAAAACTCCATCT TGAAAACTCCATCTT GAAAACTCCATCTTT AAAACTCCATCTTTT AAACTCCATCTTTTT AACTCCATCTTTTTA ACTCCATCTTTTTAA CTCCATCTTTTTAAA TCCATCTTTTTAAAG CCATCTTTTTAAAGT CATCTTTTTAAAGTG ATCTTTTTAAAGTGG TCTTTTTAAAGTGGC CTTTTTAAAGTGGCC TTTTTAAAGTGGCCG TTTTAAAGTGGCCGG TTTAAAGTGGCCGGA TTAAAGTGGCCGGAA TAAAGTGGCCGGAAC AAAGTGGCCGGAACC AAGTGGCCGGAACCT AGTGGCCGGAACCTG GTGGCCGGAACCTGA TGGCCGGAACCTGAG GGCCGGAACCTGAGA GCCGGAACCTGAGAA CCGGAACCTGAGAAT CGGAACCTGAGAATC GGAACCTGAGAATCC GAACCTGAGAATCCC AACCTGAGAATCCCA ACCTGAGAATCCCAA CCTGAGAATCCCAAT CTGAGAATCCCAATG TGAGAATCCCAATGG

[0201] GAGAATCCCAATGGA AGAATCCCAATGGAT GAATCCCAATGGATT AATCCCAATGGATTG ATCCCAATGGATTGA TCCCAATGGATTGAT CCCAATGGATTGATT CCAATGGATTGATTC CAATGGATTGATTCT AATGGATTGATTCTA ATGGATTGATTCTAA TGGATTGATTCTAAT GGATTGATTCTAATG GATTGATTCTAATGT ATTGATTCTAATGTA TTGATTCTAATGTAT 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

[0202] 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 AGACAGGAATACAGG GACAGGAATACAGGA ACAGGAATACAGGAA CAGGAATACAGGAAG AGGAATACAGGAAGT GGAATACAGGAAGTA GAATACAGGAAGTAT AATACAGGAAGTATG ATACAGGAAGTATGG TACAGGAAGTATGGA ACAGGAAGTATGGAG CAGGAAGTATGGAGG AGGAAGTATGGAGGG GGAAGTATGGAGGGG GAAGTATGGAGGGGC AAGTATGGAGGGGCC AGTATGGAGGGGCCA GTATGGAGGGGCCAA TATGGAGGGGCCAAG ATGGAGGGGCCAAGC TGGAGGGGCCAAGCT GGAGGGGCCAAGCTA GAGGGGCCAAGCTAA AGGGGCCAAGCTAAA

[0203] GGGGCCAAGCTAAAC GGGCCAAGCTAAACC GGCCAAGCTAAACCG GCCAAGCTAAACCGG CCAAGCTAAACCGGC CAAGCTAAACCGGCT AAGCTAAACCGGCTA AGCTAAACCGGCTAA GCTAAACCGGCTAAA CTAAACCGGCTAAAC TAAACCGGCTAAACC AAACCGGCTAAACCC AACCGGCTAAACCCG ACCGGCTAAACCCGG CCGGCTAAACCCGGG CGGCTAAACCCGGGG GGCTAAACCCGGGGA GCTAAACCCGGGGAA CTAAACCCGGGGAAC TAAACCCGGGGAACT AAACCCGGGGAACTA AACCCGGGGAACTAC ACCCGGGGAACTACA CCCGGGGAACTACAC CCGGGGAACTACACA CGGGGAACTACACAG GGGGAACTACACAGC GGGAACTACACAGCC GGAACTACACAGCCC GAACTACACAGCCCG AACTACACAGCCCGG ACTACACAGCCCGGA CTACACAGCCCGGAT TACACAGCCCGGATT ACACAGCCCGGATTC CACAGCCCGGATTCA ACAGCCCGGATTCAG CAGCCCGGATTCAGG AGCCCGGATTCAGGC GCCCGGATTCAGGCC CCCGGATTCAGGCCA CCGGATTCAGGCCAC CGGATTCAGGCCACA GGATTCAGGCCACAT GATTCAGGCCACATC ATTCAGGCCACATCT TTCAGGCCACATCTC TCAGGCCACATCTCT CAGGCCACATCTCTC AGGCCACATCTCTCT GGCCACATCTCTCTC

[0204] GCCACATCTCTCTCT CCACATCTCTCTCTG CACATCTCTCTCTGG ACATCTCTCTCTGGG CATCTCTCTCTGGGA ATCTCTCTCTGGGAA 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 ATCCTGTGTTCTTCT TCCTGTGTTCTTCTA CCTGTGTTCTTCTAT CTGTGTTCTTCTATG TGTGTTCTTCTATGT GTGTTCTTCTATGTC TGTTCTTCTATGTCC GTTCTTCTATGTCCA TTCTTCTATGTCCAG TCTTCTATGTCCAGG CTTCTATGTCCAGGC TTCTATGTCCAGGCC TCTATGTCCAGGCCA CTATGTCCAGGCCAA TATGTCCAGGCCAAA ATGTCCAGGCCAAAA TGTCCAGGCCAAAAC

[0205] GTCCAGGCCAAAACA TCCAGGCCAAAACAG 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 CTGATCATCGCTCTG TGATCATCGCTCTGC GATCATCGCTCTGCC ATCATCGCTCTGCCC TCATCGCTCTGCCCG CATCGCTCTGCCCGT ATCGCTCTGCCCGTC TCGCTCTGCCCGTCG CGCTCTGCCCGTCGC GCTCTGCCCGTCGCT CTCTGCCCGTCGCTG TCTGCCCGTCGCTGT CTGCCCGTCGCTGTC TGCCCGTCGCTGTCC GCCCGTCGCTGTCCT

[0206] 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

[0207] TTCCATAGAAAGAGA TCCATAGAAAGAGAA CCATAGAAAGAGAAA CATAGAAAGAGAAAT ATAGAAAGAGAAATA TAGAAAGAGAAATAA AGAAAGAGAAATAAC GAAAGAGAAATAACA AAAGAGAAATAACAG AAGAGAAATAACAGC AGAGAAATAACAGCA GAGAAATAACAGCAG AGAAATAACAGCAGG GAAATAACAGCAGGC AAATAACAGCAGGCT AATAACAGCAGGCTG ATAACAGCAGGCTGG TAACAGCAGGCTGGG AACAGCAGGCTGGGG ACAGCAGGCTGGGGA CAGCAGGCTGGGGAA AGCAGGCTGGGGAAT GCAGGCTGGGGAATG CAGGCTGGGGAATGG AGGCTGGGGAATGGA GGCTGGGGAATGGAG GCTGGGGAATGGAGT CTGGGGAATGGAGTG TGGGGAATGGAGTGC GGGGAATGGAGTGCT GGGAATGGAGTGCTG GGAATGGAGTGCTGT GAATGGAGTGCTGTA AATGGAGTGCTGTAT ATGGAGTGCTGTATG TGGAGTGCTGTATGC GGAGTGCTGTATGCC GAGTGCTGTATGCCT AGTGCTGTATGCCTC GTGCTGTATGCCTCT TGCTGTATGCCTCTG GCTGTATGCCTCTGT CTGTATGCCTCTGTG TGTATGCCTCTGTGA GTATGCCTCTGTGAA TATGCCTCTGTGAAC ATGCCTCTGTGAACC TGCCTCTGTGAACCC GCCTCTGTGAACCCG CCTCTGTGAACCCGG CTCTGTGAACCCGGA

[0208] 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

[0209] 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 GGGCAGGGGTCGTTT GGCAGGGGTCGTTTG GCAGGGGTCGTTTGG CAGGGGTCGTTTGGG AGGGGTCGTTTGGGA GGGGTCGTTTGGGAT GGGTCGTTTGGGATG GGTCGTTTGGGATGG GTCGTTTGGGATGGT

[0210] TCGTTTGGGATGGTC CGTTTGGGATGGTCT GTTTGGGATGGTCTA TTTGGGATGGTCTAT TTGGGATGGTCTATG TGGGATGGTCTATGA GGGATGGTCTATGAA GGATGGTCTATGAAG GATGGTCTATGAAGG ATGGTCTATGAAGGA TGGTCTATGAAGGAG GGTCTATGAAGGAGT GTCTATGAAGGAGTT TCTATGAAGGAGTTG CTATGAAGGAGTTGC TATGAAGGAGTTGCC ATGAAGGAGTTGCCA TGAAGGAGTTGCCAA GAAGGAGTTGCCAAG AAGGAGTTGCCAAGG AGGAGTTGCCAAGGG GGAGTTGCCAAGGGT GAGTTGCCAAGGGTG AGTTGCCAAGGGTGT GTTGCCAAGGGTGTG TTGCCAAGGGTGTGG TGCCAAGGGTGTGGT GCCAAGGGTGTGGTG CCAAGGGTGTGGTGA CAAGGGTGTGGTGAA AAGGGTGTGGTGAAA AGGGTGTGGTGAAAG GGGTGTGGTGAAAGA GGTGTGGTGAAAGAT GTGTGGTGAAAGATG TGTGGTGAAAGATGA GTGGTGAAAGATGAA TGGTGAAAGATGAAC GGTGAAAGATGAACC GTGAAAGATGAACCT TGAAAGATGAACCTG GAAAGATGAACCTGA AAAGATGAACCTGAA AAGATGAACCTGAAA AGATGAACCTGAAAC GATGAACCTGAAACC ATGAACCTGAAACCA TGAACCTGAAACCAG GAACCTGAAACCAGA AACCTGAAACCAGAG ACCTGAAACCAGAGT

[0211] CCTGAAACCAGAGTG CTGAAACCAGAGTGG TGAAACCAGAGTGGC GAAACCAGAGTGGCC AAACCAGAGTGGCCA AACCAGAGTGGCCAT ACCAGAGTGGCCATT CCAGAGTGGCCATTA CAGAGTGGCCATTAA AGAGTGGCCATTAAA GAGTGGCCATTAAAA AGTGGCCATTAAAAC 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

[0212] GAGAGGATTGAGTTT AGAGGATTGAGTTTC GAGGATTGAGTTTCT AGGATTGAGTTTCTC GGATTGAGTTTCTCA GATTGAGTTTCTCAA ATTGAGTTTCTCAAC TTGAGTTTCTCAACG TGAGTTTCTCAACGA GAGTTTCTCAACGAA AGTTTCTCAACGAAG 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 TTCAATTGTCACCAT TCAATTGTCACCATG CAATTGTCACCATGT AATTGTCACCATGTG ATTGTCACCATGTGG TTGTCACCATGTGGT TGTCACCATGTGGTG GTCACCATGTGGTGC TCACCATGTGGTGCG

[0213] 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 TGGTCATCATGGAAC GGTCATCATGGAACT

[0214] GTCATCATGGAACTG TCATCATGGAACTGA CATCATGGAACTGAT ATCATGGAACTGATG TCATGGAACTGATGA CATGGAACTGATGAC ATGGAACTGATGACA TGGAACTGATGACAC GGAACTGATGACACG GAACTGATGACACGG AACTGATGACACGGG ACTGATGACACGGGG CTGATGACACGGGGC TGATGACACGGGGCG GATGACACGGGGCGA ATGACACGGGGCGAT TGACACGGGGCGATC GACACGGGGCGATCT ACACGGGGCGATCTC CACGGGGCGATCTCA ACGGGGCGATCTCAA CGGGGCGATCTCAAA GGGGCGATCTCAAAA GGGCGATCTCAAAAG GGCGATCTCAAAAGT GCGATCTCAAAAGTT CGATCTCAAAAGTTA GATCTCAAAAGTTAT ATCTCAAAAGTTATC TCTCAAAAGTTATCT CTCAAAAGTTATCTC TCAAAAGTTATCTCC CAAAAGTTATCTCCG AAAAGTTATCTCCGG AAAGTTATCTCCGGT AAGTTATCTCCGGTC AGTTATCTCCGGTCT GTTATCTCCGGTCTC TTATCTCCGGTCTCT TATCTCCGGTCTCTG ATCTCCGGTCTCTGA TCTCCGGTCTCTGAG CTCCGGTCTCTGAGG TCCGGTCTCTGAGGC CCGGTCTCTGAGGCC CGGTCTCTGAGGCCA GGTCTCTGAGGCCAG GTCTCTGAGGCCAGA TCTCTGAGGCCAGAA CTCTGAGGCCAGAAA TCTGAGGCCAGAAAT

[0215] CTGAGGCCAGAAATG TGAGGCCAGAAATGG GAGGCCAGAAATGGA AGGCCAGAAATGGAG GGCCAGAAATGGAGA GCCAGAAATGGAGAA CCAGAAATGGAGAAT CAGAAATGGAGAATA AGAAATGGAGAATAA GAAATGGAGAATAAT AAATGGAGAATAATC AATGGAGAATAATCC ATGGAGAATAATCCA TGGAGAATAATCCAG GGAGAATAATCCAGT GAGAATAATCCAGTC AGAATAATCCAGTCC GAATAATCCAGTCCT AATAATCCAGTCCTA ATAATCCAGTCCTAG TAATCCAGTCCTAGC AATCCAGTCCTAGCA ATCCAGTCCTAGCAC 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

[0216] AAGATGATTCAGATG AGATGATTCAGATGG GATGATTCAGATGGC ATGATTCAGATGGCC TGATTCAGATGGCCG GATTCAGATGGCCGG ATTCAGATGGCCGGA TTCAGATGGCCGGAG TCAGATGGCCGGAGA CAGATGGCCGGAGAG AGATGGCCGGAGAGA GATGGCCGGAGAGAT ATGGCCGGAGAGATT TGGCCGGAGAGATTG GGCCGGAGAGATTGC GCCGGAGAGATTGCA CCGGAGAGATTGCAG CGGAGAGATTGCAGA GGAGAGATTGCAGAC GAGAGATTGCAGACG AGAGATTGCAGACGG GAGATTGCAGACGGC AGATTGCAGACGGCA GATTGCAGACGGCAT 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

[0217] GCCAATAAGTTCGTC CCAATAAGTTCGTCC CAATAAGTTCGTCCA AATAAGTTCGTCCAC ATAAGTTCGTCCACA TAAGTTCGTCCACAG AAGTTCGTCCACAGA AGTTCGTCCACAGAG GTTCGTCCACAGAGA TTCGTCCACAGAGAC TCGTCCACAGAGACC CGTCCACAGAGACCT GTCCACAGAGACCTT TCCACAGAGACCTTG CCACAGAGACCTTGC CACAGAGACCTTGCT ACAGAGACCTTGCTG CAGAGACCTTGCTGC AGAGACCTTGCTGCC GAGACCTTGCTGCCC AGACCTTGCTGCCCG GACCTTGCTGCCCGG ACCTTGCTGCCCGGA CCTTGCTGCCCGGAA 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

[0218] GAAGATTTCACAGTC AAGATTTCACAGTCA AGATTTCACAGTCAA GATTTCACAGTCAAA ATTTCACAGTCAAAA 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 TATGACGCGAGATAT ATGACGCGAGATATC TGACGCGAGATATCT GACGCGAGATATCTA ACGCGAGATATCTAT CGCGAGATATCTATG GCGAGATATCTATGA CGAGATATCTATGAG GAGATATCTATGAGA AGATATCTATGAGAC GATATCTATGAGACA ATATCTATGAGACAG TATCTATGAGACAGA ATCTATGAGACAGAC TCTATGAGACAGACT CTATGAGACAGACTA TATGAGACAGACTAT ATGAGACAGACTATT TGAGACAGACTATTA

[0219] GAGACAGACTATTAC AGACAGACTATTACC GACAGACTATTACCG ACAGACTATTACCGG CAGACTATTACCGGA AGACTATTACCGGAA GACTATTACCGGAAA ACTATTACCGGAAAG CTATTACCGGAAAGG TATTACCGGAAAGGA ATTACCGGAAAGGAG TTACCGGAAAGGAGG TACCGGAAAGGAGGC ACCGGAAAGGAGGCA CCGGAAAGGAGGCAA CGGAAAGGAGGCAAA GGAAAGGAGGCAAAG GAAAGGAGGCAAAGG AAAGGAGGCAAAGGG AAGGAGGCAAAGGGC AGGAGGCAAAGGGCT GGAGGCAAAGGGCTG GAGGCAAAGGGCTGC AGGCAAAGGGCTGCT GGCAAAGGGCTGCTG GCAAAGGGCTGCTGC CAAAGGGCTGCTGCC AAAGGGCTGCTGCCC AAGGGCTGCTGCCCG AGGGCTGCTGCCCGT GGGCTGCTGCCCGTG GGCTGCTGCCCGTGC GCTGCTGCCCGTGCG CTGCTGCCCGTGCGC TGCTGCCCGTGCGCT GCTGCCCGTGCGCTG CTGCCCGTGCGCTGG TGCCCGTGCGCTGGA GCCCGTGCGCTGGAT CCCGTGCGCTGGATG CCGTGCGCTGGATGT CGTGCGCTGGATGTC GTGCGCTGGATGTCT TGCGCTGGATGTCTC GCGCTGGATGTCTCC CGCTGGATGTCTCCT GCTGGATGTCTCCTG CTGGATGTCTCCTGA TGGATGTCTCCTGAG GGATGTCTCCTGAGT GATGTCTCCTGAGTC

[0220] ATGTCTCCTGAGTCC TGTCTCCTGAGTCCC GTCTCCTGAGTCCCT TCTCCTGAGTCCCTC CTCCTGAGTCCCTCA TCCTGAGTCCCTCAA CCTGAGTCCCTCAAG CTGAGTCCCTCAAGG TGAGTCCCTCAAGGA GAGTCCCTCAAGGAT AGTCCCTCAAGGATG GTCCCTCAAGGATGG TCCCTCAAGGATGGA CCCTCAAGGATGGAG CCTCAAGGATGGAGT CTCAAGGATGGAGTC TCAAGGATGGAGTCT CAAGGATGGAGTCTT AAGGATGGAGTCTTC AGGATGGAGTCTTCA GGATGGAGTCTTCAC GATGGAGTCTTCACC ATGGAGTCTTCACCA TGGAGTCTTCACCAC GGAGTCTTCACCACT GAGTCTTCACCACTT AGTCTTCACCACTTA GTCTTCACCACTTAC TCTTCACCACTTACT CTTCACCACTTACTC TTCACCACTTACTCG TCACCACTTACTCGG CACCACTTACTCGGA ACCACTTACTCGGAC CCACTTACTCGGACG CACTTACTCGGACGT ACTTACTCGGACGTC CTTACTCGGACGTCT TTACTCGGACGTCTG TACTCGGACGTCTGG ACTCGGACGTCTGGT CTCGGACGTCTGGTC TCGGACGTCTGGTCC CGGACGTCTGGTCCT GGACGTCTGGTCCTT GACGTCTGGTCCTTC ACGTCTGGTCCTTCG CGTCTGGTCCTTCGG GTCTGGTCCTTCGGG TCTGGTCCTTCGGGG CTGGTCCTTCGGGGT

[0221] 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

[0222] 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 GTCATGGAGGGCGGC TCATGGAGGGCGGCC CATGGAGGGCGGCCT ATGGAGGGCGGCCTT TGGAGGGCGGCCTTC GGAGGGCGGCCTTCT GAGGGCGGCCTTCTG AGGGCGGCCTTCTGG GGGCGGCCTTCTGGA GGCGGCCTTCTGGAC GCGGCCTTCTGGACA CGGCCTTCTGGACAA GGCCTTCTGGACAAG GCCTTCTGGACAAGC CCTTCTGGACAAGCC

[0223] 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 GACATGCTGTTTGAA ACATGCTGTTTGAAC CATGCTGTTTGAACT ATGCTGTTTGAACTG TGCTGTTTGAACTGA GCTGTTTGAACTGAT CTGTTTGAACTGATG TGTTTGAACTGATGC GTTTGAACTGATGCG TTTGAACTGATGCGC TTGAACTGATGCGCA TGAACTGATGCGCAT GAACTGATGCGCATG AACTGATGCGCATGT ACTGATGCGCATGTG CTGATGCGCATGTGC TGATGCGCATGTGCT GATGCGCATGTGCTG ATGCGCATGTGCTGG TGCGCATGTGCTGGC GCGCATGTGCTGGCA CGCATGTGCTGGCAG GCATGTGCTGGCAGT CATGTGCTGGCAGTA

[0224] ATGTGCTGGCAGTAT TGTGCTGGCAGTATA GTGCTGGCAGTATAA TGCTGGCAGTATAAC GCTGGCAGTATAACC CTGGCAGTATAACCC TGGCAGTATAACCCC GGCAGTATAACCCCA GCAGTATAACCCCAA CAGTATAACCCCAAG AGTATAACCCCAAGA GTATAACCCCAAGAT TATAACCCCAAGATG ATAACCCCAAGATGA TAACCCCAAGATGAG AACCCCAAGATGAGG 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 GATCATCAGCAGCAT ATCATCAGCAGCATC TCATCAGCAGCATCA CATCAGCAGCATCAA ATCAGCAGCATCAAA TCAGCAGCATCAAAG CAGCAGCATCAAAGA

[0225] AGCAGCATCAAAGAG GCAGCATCAAAGAGG CAGCATCAAAGAGGA AGCATCAAAGAGGAG GCATCAAAGAGGAGA CATCAAAGAGGAGAT ATCAAAGAGGAGATG TCAAAGAGGAGATGG CAAAGAGGAGATGGA AAAGAGGAGATGGAG AAGAGGAGATGGAGC AGAGGAGATGGAGCC GAGGAGATGGAGCCT AGGAGATGGAGCCTG GGAGATGGAGCCTGG GAGATGGAGCCTGGC AGATGGAGCCTGGCT GATGGAGCCTGGCTT ATGGAGCCTGGCTTC TGGAGCCTGGCTTCC GGAGCCTGGCTTCCG GAGCCTGGCTTCCGG AGCCTGGCTTCCGGG GCCTGGCTTCCGGGA CCTGGCTTCCGGGAG CTGGCTTCCGGGAGG TGGCTTCCGGGAGGT GGCTTCCGGGAGGTC GCTTCCGGGAGGTCT CTTCCGGGAGGTCTC TTCCGGGAGGTCTCC TCCGGGAGGTCTCCT CCGGGAGGTCTCCTT CGGGAGGTCTCCTTC GGGAGGTCTCCTTCT GGAGGTCTCCTTCTA GAGGTCTCCTTCTAC AGGTCTCCTTCTACT GGTCTCCTTCTACTA GTCTCCTTCTACTAC TCTCCTTCTACTACA CTCCTTCTACTACAG TCCTTCTACTACAGC CCTTCTACTACAGCG CTTCTACTACAGCGA TTCTACTACAGCGAG TCTACTACAGCGAGG CTACTACAGCGAGGA TACTACAGCGAGGAG ACTACAGCGAGGAGA CTACAGCGAGGAGAA

[0226] TACAGCGAGGAGAAC ACAGCGAGGAGAACA 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

[0227] GAGAACATGGAGAGC AGAACATGGAGAGCG GAACATGGAGAGCGT AACATGGAGAGCGTC ACATGGAGAGCGTCC CATGGAGAGCGTCCC ATGGAGAGCGTCCCC TGGAGAGCGTCCCCC GGAGAGCGTCCCCCT GAGAGCGTCCCCCTG AGAGCGTCCCCCTGG GAGCGTCCCCCTGGA AGCGTCCCCCTGGAC GCGTCCCCCTGGACC CGTCCCCCTGGACCC GTCCCCCTGGACCCC TCCCCCTGGACCCCT CCCCCTGGACCCCTC CCCCTGGACCCCTCG CCCTGGACCCCTCGG CCTGGACCCCTCGGC CTGGACCCCTCGGCC TGGACCCCTCGGCCT 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

[0228] 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 AGGCCGAGAACGGCC GGCCGAGAACGGCCC GCCGAGAACGGCCCC CCGAGAACGGCCCCG CGAGAACGGCCCCGG GAGAACGGCCCCGGC AGAACGGCCCCGGCC GAACGGCCCCGGCCC AACGGCCCCGGCCCT ACGGCCCCGGCCCTG CGGCCCCGGCCCTGG GGCCCCGGCCCTGGG GCCCCGGCCCTGGGG CCCCGGCCCTGGGGT CCCGGCCCTGGGGTG CCGGCCCTGGGGTGC CGGCCCTGGGGTGCT GGCCCTGGGGTGCTG GCCCTGGGGTGCTGG CCCTGGGGTGCTGGT CCTGGGGTGCTGGTC CTGGGGTGCTGGTCC TGGGGTGCTGGTCCT

[0229] GGGGTGCTGGTCCTC GGGTGCTGGTCCTCC GGTGCTGGTCCTCCG GTGCTGGTCCTCCGC TGCTGGTCCTCCGCG GCTGGTCCTCCGCGC CTGGTCCTCCGCGCC TGGTCCTCCGCGCCA GGTCCTCCGCGCCAG GTCCTCCGCGCCAGC TCCTCCGCGCCAGCT CCTCCGCGCCAGCTT CTCCGCGCCAGCTTC TCCGCGCCAGCTTCG CCGCGCCAGCTTCGA CGCGCCAGCTTCGAC GCGCCAGCTTCGACG CGCCAGCTTCGACGA GCCAGCTTCGACGAG CCAGCTTCGACGAGA CAGCTTCGACGAGAG AGCTTCGACGAGAGA GCTTCGACGAGAGAC CTTCGACGAGAGACA TTCGACGAGAGACAG TCGACGAGAGACAGC CGACGAGAGACAGCC GACGAGAGACAGCCT ACGAGAGACAGCCTT CGAGAGACAGCCTTA GAGAGACAGCCTTAC AGAGACAGCCTTACG GAGACAGCCTTACGC AGACAGCCTTACGCC GACAGCCTTACGCCC ACAGCCTTACGCCCA CAGCCTTACGCCCAC AGCCTTACGCCCACA GCCTTACGCCCACAT CCTTACGCCCACATG CTTACGCCCACATGA TTACGCCCACATGAA TACGCCCACATGAAC ACGCCCACATGAACG CGCCCACATGAACGG GCCCACATGAACGGG CCCACATGAACGGGG CCACATGAACGGGGG CACATGAACGGGGGC ACATGAACGGGGGCC CATGAACGGGGGCCG

[0230] ATGAACGGGGGCCGC TGAACGGGGGCCGCA GAACGGGGGCCGCAA AACGGGGGCCGCAAG ACGGGGGCCGCAAGA CGGGGGCCGCAAGAA GGGGGCCGCAAGAAC GGGGCCGCAAGAACG GGGCCGCAAGAACGA GGCCGCAAGAACGAG GCCGCAAGAACGAGC CCGCAAGAACGAGCG CGCAAGAACGAGCGG GCAAGAACGAGCGGG CAAGAACGAGCGGGC AAGAACGAGCGGGCC AGAACGAGCGGGCCT GAACGAGCGGGCCTT AACGAGCGGGCCTTG ACGAGCGGGCCTTGC CGAGCGGGCCTTGCC GAGCGGGCCTTGCCG AGCGGGCCTTGCCGC GCGGGCCTTGCCGCT CGGGCCTTGCCGCTG GGGCCTTGCCGCTGC GGCCTTGCCGCTGCC GCCTTGCCGCTGCCC CCTTGCCGCTGCCCC CTTGCCGCTGCCCCA TTGCCGCTGCCCCAG TGCCGCTGCCCCAGT GCCGCTGCCCCAGTC CCGCTGCCCCAGTCT CGCTGCCCCAGTCTT GCTGCCCCAGTCTTC CTGCCCCAGTCTTCG TGCCCCAGTCTTCGA GCCCCAGTCTTCGAC CCCCAGTCTTCGACC CCCAGTCTTCGACCT CCAGTCTTCGACCTG CAGTCTTCGACCTGC AGTCTTCGACCTGCT GTCTTCGACCTGCTG TCTTCGACCTGCTGA CTTCGACCTGCTGAT TTCGACCTGCTGATC TCGACCTGCTGATCC CGACCTGCTGATCCT GACCTGCTGATCCTT

[0231] ACCTGCTGATCCTTG CCTGCTGATCCTTGG CTGCTGATCCTTGGA TGCTGATCCTTGGAT GCTGATCCTTGGATC CTGATCCTTGGATCC TGATCCTTGGATCCT GATCCTTGGATCCTG ATCCTTGGATCCTGA TCCTTGGATCCTGAA CCTTGGATCCTGAAT CTTGGATCCTGAATC TTGGATCCTGAATCT TGGATCCTGAATCTG GGATCCTGAATCTGT GATCCTGAATCTGTG ATCCTGAATCTGTGC TCCTGAATCTGTGCA CCTGAATCTGTGCAA CTGAATCTGTGCAAA TGAATCTGTGCAAAC GAATCTGTGCAAACA AATCTGTGCAAACAG 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

[0232] GCGCAGCGGGGTGGG CGCAGCGGGGTGGGG GCAGCGGGGTGGGGG CAGCGGGGTGGGGGG AGCGGGGTGGGGGGG GCGGGGTGGGGGGGG CGGGGTGGGGGGGGA GGGGTGGGGGGGGAG GGGTGGGGGGGGAGA GGTGGGGGGGGAGAG GTGGGGGGGGAGAGA TGGGGGGGGAGAGAG GGGGGGGGAGAGAGA GGGGGGGAGAGAGAG GGGGGGAGAGAGAGT GGGGGAGAGAGAGTT GGGGAGAGAGAGTTT GGGAGAGAGAGTTTT GGAGAGAGAGTTTTA GAGAGAGAGTTTTAA AGAGAGAGTTTTAAC GAGAGAGTTTTAACA AGAGAGTTTTAACAA GAGAGTTTTAACAAT AGAGTTTTAACAATC GAGTTTTAACAATCC AGTTTTAACAATCCA GTTTTAACAATCCAT TTTTAACAATCCATT TTTAACAATCCATTC TTAACAATCCATTCA TAACAATCCATTCAC AACAATCCATTCACA ACAATCCATTCACAA CAATCCATTCACAAG AATCCATTCACAAGC ATCCATTCACAAGCC TCCATTCACAAGCCT CCATTCACAAGCCTC CATTCACAAGCCTCC ATTCACAAGCCTCCT TTCACAAGCCTCCTG TCACAAGCCTCCTGT CACAAGCCTCCTGTA ACAAGCCTCCTGTAC CAAGCCTCCTGTACC AAGCCTCCTGTACCT AGCCTCCTGTACCTC GCCTCCTGTACCTCA CCTCCTGTACCTCAG CTCCTGTACCTCAGT

[0233] TCCTGTACCTCAGTG CCTGTACCTCAGTGG CTGTACCTCAGTGGA TGTACCTCAGTGGAT GTACCTCAGTGGATC TACCTCAGTGGATCT ACCTCAGTGGATCTT CCTCAGTGGATCTTC CTCAGTGGATCTTCA TCAGTGGATCTTCAG CAGTGGATCTTCAGT AGTGGATCTTCAGTT GTGGATCTTCAGTTC TGGATCTTCAGTTCT GGATCTTCAGTTCTG GATCTTCAGTTCTGC ATCTTCAGTTCTGCC TCTTCAGTTCTGCCC CTTCAGTTCTGCCCT TTCAGTTCTGCCCTT TCAGTTCTGCCCTTG CAGTTCTGCCCTTGC AGTTCTGCCCTTGCT GTTCTGCCCTTGCTG TTCTGCCCTTGCTGC TCTGCCCTTGCTGCC CTGCCCTTGCTGCCC TGCCCTTGCTGCCCG GCCCTTGCTGCCCGC CCCTTGCTGCCCGCG CCTTGCTGCCCGCGG CTTGCTGCCCGCGGG TTGCTGCCCGCGGGA TGCTGCCCGCGGGAG GCTGCCCGCGGGAGA CTGCCCGCGGGAGAC TGCCCGCGGGAGACA GCCCGCGGGAGACAG CCCGCGGGAGACAGC CCGCGGGAGACAGCT CGCGGGAGACAGCTT GCGGGAGACAGCTTC CGGGAGACAGCTTCT GGGAGACAGCTTCTC GGAGACAGCTTCTCT GAGACAGCTTCTCTG AGACAGCTTCTCTGC GACAGCTTCTCTGCA ACAGCTTCTCTGCAG CAGCTTCTCTGCAGT AGCTTCTCTGCAGTA

[0234] GCTTCTCTGCAGTAA CTTCTCTGCAGTAAA TTCTCTGCAGTAAAA TCTCTGCAGTAAAAC CTCTGCAGTAAAACA TCTGCAGTAAAACAC CTGCAGTAAAACACA TGCAGTAAAACACAT GCAGTAAAACACATT CAGTAAAACACATTT AGTAAAACACATTTG GTAAAACACATTTGG TAAAACACATTTGGG AAAACACATTTGGGA AAACACATTTGGGAT AACACATTTGGGATG ACACATTTGGGATGT CACATTTGGGATGTT ACATTTGGGATGTTC CATTTGGGATGTTCC ATTTGGGATGTTCCT TTTGGGATGTTCCTT TTGGGATGTTCCTTT TGGGATGTTCCTTTT GGGATGTTCCTTTTT GGATGTTCCTTTTTT GATGTTCCTTTTTTC ATGTTCCTTTTTTCA TGTTCCTTTTTTCAA GTTCCTTTTTTCAAT TTCCTTTTTTCAATA TCCTTTTTTCAATAT CCTTTTTTCAATATG CTTTTTTCAATATGC TTTTTTCAATATGCA TTTTTCAATATGCAA TTTTCAATATGCAAG TTTCAATATGCAAGC TTCAATATGCAAGCA TCAATATGCAAGCAG CAATATGCAAGCAGC AATATGCAAGCAGCT ATATGCAAGCAGCTT TATGCAAGCAGCTTT ATGCAAGCAGCTTTT TGCAAGCAGCTTTTT GCAAGCAGCTTTTTA CAAGCAGCTTTTTAT AAGCAGCTTTTTATT AGCAGCTTTTTATTC GCAGCTTTTTATTCC

[0235] CAGCTTTTTATTCCC AGCTTTTTATTCCCT GCTTTTTATTCCCTG CTTTTTATTCCCTGC TTTTTATTCCCTGCC TTTTATTCCCTGCCC TTTATTCCCTGCCCA TTATTCCCTGCCCAA TATTCCCTGCCCAAA ATTCCCTGCCCAAAC TTCCCTGCCCAAACC TCCCTGCCCAAACCC CCCTGCCCAAACCCT CCTGCCCAAACCCTT CTGCCCAAACCCTTA TGCCCAAACCCTTAA GCCCAAACCCTTAAC CCCAAACCCTTAACT CCAAACCCTTAACTG CAAACCCTTAACTGA AAACCCTTAACTGAC AACCCTTAACTGACA ACCCTTAACTGACAT CCCTTAACTGACATG CCTTAACTGACATGG CTTAACTGACATGGG TTAACTGACATGGGC TAACTGACATGGGCC AACTGACATGGGCCT ACTGACATGGGCCTT CTGACATGGGCCTTT TGACATGGGCCTTTA GACATGGGCCTTTAA ACATGGGCCTTTAAG CATGGGCCTTTAAGA ATGGGCCTTTAAGAA TGGGCCTTTAAGAAC GGGCCTTTAAGAACC GGCCTTTAAGAACCT GCCTTTAAGAACCTT CCTTTAAGAACCTTA CTTTAAGAACCTTAA TTTAAGAACCTTAAT TTAAGAACCTTAATG TAAGAACCTTAATGA AAGAACCTTAATGAC AGAACCTTAATGACA GAACCTTAATGACAA AACCTTAATGACAAC ACCTTAATGACAACA CCTTAATGACAACAC

[0236] CTTAATGACAACACT TTAATGACAACACTT TAATGACAACACTTA AATGACAACACTTAA ATGACAACACTTAAT TGACAACACTTAATA GACAACACTTAATAG ACAACACTTAATAGC CAACACTTAATAGCA AACACTTAATAGCAA ACACTTAATAGCAAC CACTTAATAGCAACA ACTTAATAGCAACAG CTTAATAGCAACAGA TTAATAGCAACAGAG TAATAGCAACAGAGC AATAGCAACAGAGCA ATAGCAACAGAGCAC TAGCAACAGAGCACT AGCAACAGAGCACTT GCAACAGAGCACTTG CAACAGAGCACTTGA AACAGAGCACTTGAG ACAGAGCACTTGAGA CAGAGCACTTGAGAA AGAGCACTTGAGAAC GAGCACTTGAGAACC AGCACTTGAGAACCA GCACTTGAGAACCAG CACTTGAGAACCAGT ACTTGAGAACCAGTC CTTGAGAACCAGTCT TTGAGAACCAGTCTC TGAGAACCAGTCTCC GAGAACCAGTCTCCT AGAACCAGTCTCCTC GAACCAGTCTCCTCA AACCAGTCTCCTCAC ACCAGTCTCCTCACT CCAGTCTCCTCACTC CAGTCTCCTCACTCT AGTCTCCTCACTCTG GTCTCCTCACTCTGT TCTCCTCACTCTGTC CTCCTCACTCTGTCC TCCTCACTCTGTCCC CCTCACTCTGTCCCT CTCACTCTGTCCCTG TCACTCTGTCCCTGT CACTCTGTCCCTGTC ACTCTGTCCCTGTCC

[0237] CTCTGTCCCTGTCCT TCTGTCCCTGTCCTT CTGTCCCTGTCCTTC TGTCCCTGTCCTTCC GTCCCTGTCCTTCCC TCCCTGTCCTTCCCT CCCTGTCCTTCCCTG CCTGTCCTTCCCTGT CTGTCCTTCCCTGTT 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 TCCTCTCTGCTTCAT CCTCTCTGCTTCATA CTCTCTGCTTCATAA TCTCTGCTTCATAAC CTCTGCTTCATAACG TCTGCTTCATAACGG CTGCTTCATAACGGA TGCTTCATAACGGAA GCTTCATAACGGAAA CTTCATAACGGAAAA TTCATAACGGAAAAA TCATAACGGAAAAAT CATAACGGAAAAATA ATAACGGAAAAATAA TAACGGAAAAATAAT

[0238] AACGGAAAAATAATT ACGGAAAAATAATTG CGGAAAAATAATTGC GGAAAAATAATTGCC GAAAAATAATTGCCA AAAAATAATTGCCAC AAAATAATTGCCACA AAATAATTGCCACAA AATAATTGCCACAAG ATAATTGCCACAAGT TAATTGCCACAAGTC AATTGCCACAAGTCC 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 CCTTTTTATCAGTTT CTTTTTATCAGTTTG TTTTTATCAGTTTGA TTTTATCAGTTTGAG TTTATCAGTTTGAGG TTATCAGTTTGAGGA TATCAGTTTGAGGAA ATCAGTTTGAGGAAG TCAGTTTGAGGAAGT CAGTTTGAGGAAGTG AGTTTGAGGAAGTGG GTTTGAGGAAGTGGC TTTGAGGAAGTGGCT TTGAGGAAGTGGCTG

[0239] TGAGGAAGTGGCTGT GAGGAAGTGGCTGTC AGGAAGTGGCTGTCC GGAAGTGGCTGTCCC GAAGTGGCTGTCCCT AAGTGGCTGTCCCTG AGTGGCTGTCCCTGT 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

[0240] TGACACCGTGGGTCA GACACCGTGGGTCAT ACACCGTGGGTCATT CACCGTGGGTCATTA ACCGTGGGTCATTAC CCGTGGGTCATTACA CGTGGGTCATTACAA GTGGGTCATTACAAA TGGGTCATTACAAAA GGGTCATTACAAAAA GGTCATTACAAAAAA GTCATTACAAAAAAA TCATTACAAAAAAAC CATTACAAAAAAACA ATTACAAAAAAACAC TTACAAAAAAACACG TACAAAAAAACACGT ACAAAAAAACACGTG 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 CTTTATCTTTCACCT TTTATCTTTCACCTT

[0241] 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 GTTCATCCAAGGCTG TTCATCCAAGGCTGT TCATCCAAGGCTGTT CATCCAAGGCTGTTA ATCCAAGGCTGTTAC TCCAAGGCTGTTACC

[0242] CCAAGGCTGTTACCA CAAGGCTGTTACCAT AAGGCTGTTACCATT AGGCTGTTACCATTT 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 GCCAAAATCCTGAAC CCAAAATCCTGAACT CAAAATCCTGAACTT AAAATCCTGAACTTT AAATCCTGAACTTTC AATCCTGAACTTTCT ATCCTGAACTTTCTC TCCTGAACTTTCTCC CCTGAACTTTCTCCC CTGAACTTTCTCCCT TGAACTTTCTCCCTC GAACTTTCTCCCTCA AACTTTCTCCCTCAT ACTTTCTCCCTCATC CTTTCTCCCTCATCG TTTCTCCCTCATCGG

[0243] TTCTCCCTCATCGGC TCTCCCTCATCGGCC CTCCCTCATCGGCCC TCCCTCATCGGCCCG CCCTCATCGGCCCGG CCTCATCGGCCCGGC CTCATCGGCCCGGCG TCATCGGCCCGGCGC CATCGGCCCGGCGCT ATCGGCCCGGCGCTG TCGGCCCGGCGCTGA CGGCCCGGCGCTGAT GGCCCGGCGCTGATT GCCCGGCGCTGATTC CCCGGCGCTGATTCC CCGGCGCTGATTCCT CGGCGCTGATTCCTC GGCGCTGATTCCTCG GCGCTGATTCCTCGT CGCTGATTCCTCGTG GCTGATTCCTCGTGT CTGATTCCTCGTGTC TGATTCCTCGTGTCC GATTCCTCGTGTCCG ATTCCTCGTGTCCGG TTCCTCGTGTCCGGA TCCTCGTGTCCGGAG CCTCGTGTCCGGAGG CTCGTGTCCGGAGGC TCGTGTCCGGAGGCA CGTGTCCGGAGGCAT GTGTCCGGAGGCATG TGTCCGGAGGCATGG GTCCGGAGGCATGGG TCCGGAGGCATGGGT CCGGAGGCATGGGTG CGGAGGCATGGGTGA GGAGGCATGGGTGAG GAGGCATGGGTGAGC AGGCATGGGTGAGCA GGCATGGGTGAGCAT GCATGGGTGAGCATG CATGGGTGAGCATGG ATGGGTGAGCATGGC TGGGTGAGCATGGCA GGGTGAGCATGGCAG GGTGAGCATGGCAGC GTGAGCATGGCAGCT TGAGCATGGCAGCTG GAGCATGGCAGCTGG AGCATGGCAGCTGGT

[0244] 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

[0245] CCATCCGACTGCCCC CATCCGACTGCCCCT ATCCGACTGCCCCTG TCCGACTGCCCCTGC CCGACTGCCCCTGCT CGACTGCCCCTGCTG GACTGCCCCTGCTGT ACTGCCCCTGCTGTG CTGCCCCTGCTGTGC TGCCCCTGCTGTGCT GCCCCTGCTGTGCTG CCCCTGCTGTGCTGC CCCTGCTGTGCTGCT CCTGCTGTGCTGCTC CTGCTGTGCTGCTCA TGCTGTGCTGCTCAA GCTGTGCTGCTCAAG CTGTGCTGCTCAAGG TGTGCTGCTCAAGGC GTGCTGCTCAAGGCC TGCTGCTCAAGGCCA GCTGCTCAAGGCCAC CTGCTCAAGGCCACA TGCTCAAGGCCACAG GCTCAAGGCCACAGG CTCAAGGCCACAGGC TCAAGGCCACAGGCA CAAGGCCACAGGCAC AAGGCCACAGGCACA AGGCCACAGGCACAC GGCCACAGGCACACA GCCACAGGCACACAG CCACAGGCACACAGG CACAGGCACACAGGT ACAGGCACACAGGTC CAGGCACACAGGTCT AGGCACACAGGTCTC GGCACACAGGTCTCA GCACACAGGTCTCAT CACACAGGTCTCATT ACACAGGTCTCATTG CACAGGTCTCATTGC ACAGGTCTCATTGCT CAGGTCTCATTGCTT AGGTCTCATTGCTTC GGTCTCATTGCTTCT GTCTCATTGCTTCTG TCTCATTGCTTCTGA CTCATTGCTTCTGAC TCATTGCTTCTGACT CATTGCTTCTGACTA

[0246] 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 GGGGAACTGGACACA GGGAACTGGACACAA GGAACTGGACACAAT GAACTGGACACAATA AACTGGACACAATAG ACTGGACACAATAGG CTGGACACAATAGGT TGGACACAATAGGTC GGACACAATAGGTCT GACACAATAGGTCTT ACACAATAGGTCTTT CACAATAGGTCTTTC ACAATAGGTCTTTCT CAATAGGTCTTTCTC AATAGGTCTTTCTCT ATAGGTCTTTCTCTC TAGGTCTTTCTCTCA AGGTCTTTCTCTCAG GGTCTTTCTCTCAGT GTCTTTCTCTCAGTG TCTTTCTCTCAGTGA CTTTCTCTCAGTGAA TTTCTCTCAGTGAAG TTCTCTCAGTGAAGG TCTCTCAGTGAAGGT

[0247] CTCTCAGTGAAGGTG TCTCAGTGAAGGTGG CTCAGTGAAGGTGGG TCAGTGAAGGTGGGG CAGTGAAGGTGGGGA AGTGAAGGTGGGGAG GTGAAGGTGGGGAGA TGAAGGTGGGGAGAA GAAGGTGGGGAGAAG AAGGTGGGGAGAAGC AGGTGGGGAGAAGCT GGTGGGGAGAAGCTG GTGGGGAGAAGCTGA TGGGGAGAAGCTGAA GGGGAGAAGCTGAAC GGGAGAAGCTGAACC GGAGAAGCTGAACCG GAGAAGCTGAACCGG AGAAGCTGAACCGGC

Example 9 HaCaT cells near confluence were treated with phosphorothioate oligonucleotide IGFR. AS (antisense: 5'-ATCTCTCCGCTT
CCTTTC-3 '(SEQ ID NO: 10), reference 13) and IGFR. S (sense control: 5'-GAAAGGAAGCGGAGAGAT-3 '(SEQ ID NO: 1
1) and the cited document 13), and processed as described above. IGF-I binding to the cell monolayer was then measured as ¹²⁵ I-IGF-I.

Example 10 The experimental results are shown in FIGS. 7 and 8.

HaCaT cells were first plated in DMEM containing 10% v / v serum and then AS oligo experiments were performed in complete “keratinocyte-SFM” (Gibco) to eliminate the effects of exogenous IGFBPs. did. Oligos were synthesized as phosphorothioate (nuclease resistant) derivatives (Bresatech, South Australia),
It was as follows. Antisense: AS2,5'-GCGCCCGCTGCATGACGCCCTG
CAAC-3 ′ (IGFBP-3, start codon), control group: AS2NS, 5′-CGGAGATGGCCGCATGCCAGCGC
AGG-3 ', AS4,5'-AGGCGGCTGACGGCACTA-3',
AS4NS, 5'-GACAGCGTCGGAGCCGATC-3 ', IGFRA
S, 5'-ATCTCTCCGCTTTCCTTTC-3 ', IGFRS, 5'-
GAAAGGAAGCGGAGAGAT-3 '.

The oligos for IGFBP-3 were based on the published sequence of Splat et al. [12]. AS oligos were added to HaCaT monolayers in 0.5 ml medium in 24 well plates at the indicated concentrations and addition frequency. IGFBP-3 is
It was measured in cell-conditioned medium using a modified dot blot assay from the Western ligand blotting of Hossenlop et al. [11]. In this case, 100 μL of conditioned medium was applied to the nitrocellulose filter using a vacuum dot blot apparatus. Three
After drying the membrane at 7 ° C, the relative amount of IGFBP was determined by ¹²⁵ I-IGF-I binding, autoradiography and computerized image densitometry. Triplicate wells (except for FIG. 7, where duplicate wells were measured as shown) were analyzed and corrected for changes in cell number per well. Relative cell numbers per well were measured using the amide black dye method, which develops specifically on monolayers of cultured HaCaT cells. The difference in cell number after treatment was less than 10%. Oligos for the IGF receptor were quantified by incubating the amount of receptor in intact HaCaT monolayers with ¹²⁵ I-IGF-I (30,000 cpm / well) overnight at 4 ° C.

Example 11 Ribozyme experiments are generally carried out as described in International Patent Application No. WO 89/05852 and Hazelhoff and Gerach [8]. Ribozymes are constructed with a hybridizing region that is a nucleotide sequence that is complementary to at least a portion of the target RNA, the RNA encoding IGFBP-2 in this experiment. Ribozyme activity can be measured, for example, on the basis of Northern blots or using animal models such as the nude mouse model (15,16) or the "flaky skin" mouse model (17,18).

Example 12 The method described in Example 11 is used to screen for ribozymes that inhibit IGFBP-3 production. The activity of the ribozyme is measured as in Example 11.

Example 13 The method described in Example 11 is used to screen for ribozymes that inhibit IGF-1 production. The activity of the ribozyme is measured as in Example 11.

Example 14 The method described in Example 11 is used to screen for ribozymes that inhibit IGF-1 production. The activity of the ribozyme is measured as in Example 11.

Example 15 Twenty-one antisense oligonucleotides and four random oligonucleotides targeting the mRNA sequence that gives rise to the IGF-I receptor were synthesized. The antisense oligonucleotides are C5-propynyl-dU, dC15 mer phosphorothioate oligodeoxyribonucleotides. In these oligonucleotides, the phosphorothioate backbone replaces the phosphodiester backbone of naturally occurring DNA. Regarding the mRNA structure of the IGF-I receptor,
The positions of the antisense oligonucleotides specific to these 21 sequences are shown in FIG.

Example 16 An experiment was conducted to determine the uptake of the antisense oligonucleotide of Example 15 into keratinocytes. HaCaT, which is a cell of a differentiated human keratinocyte cell line, was labeled with a fluorescently labeled oligonucleotide (R451, randomized sequence oligonucleotide, 30 nM) and cytofectin GS.
10% (w / v) containing V (2 μg / ml, Glen Research, 44901 Falcon Place, Stirling, VA20166, Catalog No. 70-3815-78)
) Modified Dulbecco's modified Eagle medium (DMEM) supplemented with fetal calf serum (FCS)
) For 24 hours. Next, the cells were transferred to a medium containing no oligonucleotide, and fluorescence microscope images and phase contrast images of the cells were obtained. FIG. 10 shows fluorescence microscopy images (panel A) and phase contrast images (panel B) of uptake of fluorescently labeled oligonucleotides in the majority of HaCaT monolayer cells. The degree of uptake obtained with the cationic lipid cytofectin was much higher than that obtained with the next best lipid tested, Tfx-50.

A further experiment was conducted over 5 days to assess the uptake and toxicity associated with the use of cytofectin GSV. Confluent HaCaT keratinocytes were incubated in DMEM containing fluorescently labeled oligonucleotide R451 (30 nM or 100 nM) and cytofectin GSV (2 μg / ml or 5 μg / ml) for 120 h and observed by fluorescence microscopy. Stained with triptan blue and counted. The graph in Figure 11 shows uptake (panel A) and toxicity (panel B). The percentage of cells containing the oligonucleotide remained high for 120 hours. The combination of 30 nM oligonucleotide and 2 μg / ml GSV showed optimal uptake and minimal toxicity.

Example 17 The 21 oligonucleotides of Example 15 were then screened for their ability to inhibit IGF-I receptor mRNA levels in HaCaT cells according to the teachings herein. HaCaT cells were grown in DMEM supplemented with 10% (v / v) FCS to 90% confluence. Cytofectin GSV (2 μg / ml) was added to the antisense oligonucleotide (30 nM) and added to the cells in the presence of serum. The HaCaT keratinocyte is an oligonucleotide / GSV complex or a randomized sequence oligonucleotide (R451, R
766), treated with liposomes alone (GSV) or left untreated (UT
). Double treatment was performed. Repeated additions of oligonucleotide / GSV complex were made at 24, 48 and 76 hours after the first addition. Total RNA was isolated 96 hours after the first addition according to the RNA Sol B protocol (Biotech Laboratories, 6023 South Loop East, Hauston, Tex. 77033).

The levels of IGF-I receptor mRNA and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) mRNA were compared to those of ribonuclease (R
(Nase) protection assay. The RNase protection assay kit, the in vitro transcription kit, and the DNA templates for the IGF-I receptor and GAPDH are available from Ambion (Woodward Street, Houston, 78744, Texas).
130). The amount of IGF-I receptor mRNA in any given sample was expressed as the amount of IGF-I receptor mRNA relative to the amount of GAPDH mRNA. Each oligonucleotide was tested in at least two separate experiments.

FIG. 12 shows a representative result of the screening process. Panel A shows electrophoretic analysis of IGF-I receptor and GAPDH mRNA fragments after RNase protection.
Molecular weight markers are shown on the far right. The full length probe is shown at the left end and the G-probe is I
Refers to the GF-I receptor probe. The GAPDH protected fragment (G) is found at 316 bases and the IGF-I protected fragment (I) is found at 276 bases. Display E in panel B provides a graph showing the relative levels of IGF-I receptor mRNA after each treatment.

The results obtained from the above screening assay are summarized in FIG. This graph was treated with oligonucleotides complementary to human IGF-I receptor mRNA (26-86), four randomized sequence oligonucleotides (R1, R4, R7, R9), liposomes alone (GSV). The relative levels of IGF-I receptor mRNA after or without treatment (UT) are shown. Asterisks indicate significant differences in relative IGF-I receptor mRNA when compared to GSV treated cells (n = 4-10, p <0.
05).

As demonstrated in FIG. 13, treatment with 18 of 21 oligonucleotides resulted in a significant difference in the levels of IGF-I receptor mRNA compared to GSV treated cells. Three of the antisense oligonucleotides tested in the screening assay showed that up to 35% of GSV-treated cells were IGF-I receptor mR.
Reduce NA. These antisense oligonucleotides have the following sequences shown in the 5'to 3'direction. # 27 UCCGGAGCCAGACUU # 64 CACAGUUGCUGCAAG # 78 UCUCCGCUUCCUCUUC

As further demonstrated in FIG. 13, six of the antisense oligonucleotides tested in the screening assay were found to be 35% to 50% of GSV treated cells.
IGF-I receptor mRNA is reduced until. These antisense oligonucleotides have the following sequences shown in the 5'to 3'direction. # 28 AGCCCCCACAGCGAGG # 32 GCCUGUGGAGAUGAGC # 40 UAACAGAGGUCAGCCA # 42 GGAUCAGGGACCAGU # 46 CGGCAAGCUACACAG # 50 GGCAGGCAGGCACAC

Example 19 Targeting the Genetic Sequence Encoding the IGF0I Receptor and IGF-I Receptor m
Another experiment was performed demonstrating that antisense oligonucleotides that reduce the level of RNA also inhibit the level of IGF-I receptor on the surface of treated cultured keratinocytes. HaCaT cells were grown to confluence in 24-well plates in DMEM with 10% (v / v) FCS. Oligonucleotide and cytofectin GSV were mixed in serum-free DMEM, incubated for 10 minutes at room temperature, then diluted 10-fold with medium and added onto the cells. 30 nM cells
Randomized sequences or antisense oligonucleotides and 2 μM / ml GSV, or GSV alone in DMEM containing 10% (v / v) FCS for 72 hours, changing solutions every 24 hours. This was followed by 48 hours incubation with oligonucleotide / GSV in serum-free DMEM solution. All incubations were done at 37 ° C. Cells were washed twice with 1 ml cold PBS.
Serum-free DMEM containing 10 ⁻¹⁰ M ¹²⁵ I-IGF-I in the presence or absence of 10 ⁻¹¹ M to 10 ⁻⁷ M of the IGF-I analog des (1-3) IGF-I. Was added. Incubate cells at 4 ° C for 17 hours with gentle shaking, then 1 ml
Wash three times with cold PBS, 250 μL 0.5 M NaOH / 0.1% (v / v) Triton X-
Lysis was carried out in 100 at room temperature for 4 hours. As shown in FIG. 14, treatment of HaCaT keratinocytes with oligonucleotides reduces the level of cell surface IGF-I receptor to 30% of that in untreated keratinocytes or liposomes alone or keratinocytes treated with the random oligonucleotide R766. did. As shown in FIG. 15, treatment with oligonucleotide # 27 also significantly reduced cell surface IGF-I receptor levels compared to treatment with untreated keratinocytes or liposomes alone or the random oligonucleotide R451. As demonstrated in Example 17, oligonucleotides # 64 and # 27 were found in GSV-treated cells.
Reduces IGF-I receptor mRNA levels in cultured keratinocytes by less than 35%. Thus, the ability of oligonucleotides to reduce IGF-I receptor mRNA levels correlates with the ability to reduce cell surface IGF-I receptor levels.

The above examples demonstrate that antisense oligonucleotides targeting the IGF-I receptor can be delivered to human keratinocytes in vitro and inhibit IGF-I receptor mRNA levels in human keratinocytes in vitro. We demonstrate that inhibition of mRNA levels correlates with decreased levels of cell surface IGF-I receptors.

Example 19 Further experiments demonstrated the efficacy of antisense oligonucleotides targeting the IGF-I receptor in an in vivo model of psoriasis. The animal model of psoriasis is a xenograft model of human psoriatic skin. The skin used in this model contains a true pathology. In this model, the reduction in epidermal thickness of psoriatic explants in response to treatment has a positive correlation with treatment efficacy. Both normal and psoriatic human skin have been reported by Baker et al. (1992) Brit. J. Dermatol. 126: 105 and Nanny et al. (1992) J. I.
Transplanted in thymic (nude) mice according to the method of nvest. Dermatol, 92: 296.
Translocation was successfully achieved as shown in FIG. FIG. 16 shows a hematoxylin and eosin (H & E) stained section of a 49 day old human psoriatic skin explant compared to the histology of a preexplant skin explant (panel A) (panel B). The histological features of psoriasis present in pre-transplant sections (eg, parakeratosis, epidermal thickening, and prominent interpapillary elevation) are present in explants more than 7 weeks after transplantation.

Using this model, oligonucleotide uptake was measured in vivo on epidermal keratinocytes after intradermal injection. Fluorescently labeled oligonucleotide (R451
, 50 μL, 10 μM injection) was intradermally injected into psoriasis and normal skin explants on thymic mice. Then live confocal microscopy and fixed section fluorescence microscopy were used. Using both techniques, the oligonucleotide was found to be localized in the nucleus of more than 90% of basal keratinocytes. FIG. 17 shows nuclear localization of oligonucleotides in psoriatic skin cells using conventional fluorescence microscopy of excised and sectioned explants after 24 hours.

After establishing oligonucleotide uptake in the in vivo model, the IG
A few preliminary experiments were performed to determine a strategy for treatment of transplanted mice with antisense oligonucleotides targeting the genetic sequence encoding the FI receptor. This treatment plan was determined as follows.

[0270]

[Table 1]

Oligonucleotide # 27 (ODN # 27) was GS when measured as above.
IGF-I receptor mRNA was reduced in vitro to less than 35% of V-treated cells. Oligonucleotide # 50 (ODN # 50) is 35% of GSV treated cells
Reduced IGF-I receptor mRNA in vitro by between 50% and 50%. Oligonucleotide # 74 (ODN # 74) was added to IGF-I receptor mRNA in vitro.
Did not inhibit. In this in vivo model, each mouse underwent two transfers. Random oligonucleotides or vehicles were injected subcutaneously in one explant and served as controls. The second explant was injected with the targeted oligonucleotide.
Each explant received injections every other day during the treatment period.

The histology of typical explants obtained from each treatment type is shown in FIG.
(D) and (a) to (d) of FIG. Each sheet shows three images of H & E stained sections: pre-transplantation histology, control treated explants, and explants treated with targeted oligonucleotides. 18A to 18D are shown at 100 × magnification, and FIGS. 19A to 19D are shown at 400 × magnification. The entire epidermal section of each explant was evaluated using MCID analysis software. Results pooled from all treated explants are shown in FIG.

As shown in Figures 18 (a)-(d) and Figure 19 (a)-(d), the vehicle-treated (control) explants were slightly thinner than the pre-transplant sections. It was The degree of regression (ie less than 10%) in these experiments is not significant. Since a similar slight thinning of the epidermis compared to pre-transplantation also occurred in preliminary experiments where psoriatic explants were not injected,
The vehicle itself is unlikely to have any effect. The histological features of psoriasis present in pre-transplant skin samples (hyperpapillary bulge, parakeratosis, epidermal thickening) were also present in these explants.

Transplants treated with this random oligonucleotide had varying epidermal thickness after 20 days of treatment. The explants were either as thick as the pre-transplant histology or were slightly thinner. Transplants treated with random oligonucleotides were in each case significantly thicker than their targeting oligonucleotide-treated pairs.

As shown in FIG. 20, explants treated with this targeting oligonucleotide were
It was significantly thinner than the section before transplantation and showed no keratokeratosis or hypertrophy of the interpapillary ridge. Antisense oligonucleotides (# 27 and # 50) that are effective in reducing IGF-I receptor mRNA levels in vitro have been tested for in vitro IGF-I receptor m
Epidermal thinning was greater than that of the oligonucleotide (# 74), which did not inhibit RNA. Thus, there is a direct correlation between the ability of oligonucleotides targeting the IGF-I receptor to inhibit IGF-I receptor mRNA levels in vitro and the efficacy of the oligonucleotide as an anti-psoriatic agent in an in vivo model. I have a relationship.

Example 20 In another experiment, treatment of psoriatic explants with an oligonucleotide targeting the genetic sequence encoding the IGF-I receptor was shown to inhibit growth. Pre-transplant explants from psoriasis patients, control explants treated with R4541, and explants treated with oligonucleotide # 27 were obtained as described in Example 19. Antibodies to the cell cycle-specific nuclear antigen Ki67 were used to detect actively dividing cells by immunohistochemistry, which assessed proliferation. This αKi67 antibody (DAKO, Grostrap, Denmark) serves as a proliferation marker by recognizing the Ki67 antigen transiently expressed in the nucleus of proliferating cells during the late G1, S, M, and G2 phases of the cycle. Become. Pre-transplant and transplant sections were immunohistochemically treated by standard methods with αKi67, peroxidase-conjugated anti-rabbit secondary antibody, and chromogenic peroxidase substrate (according to manufacturer's instructions). .

The results of this experiment are shown in Figure 21 as immunohistochemical sections at 100x magnification. Figure 2
The top panel of 1 shows a pre-transplant section obtained from a psoriasis patient. The epidermis is thicker than normal epidermis and the nucleus is evident in the stratum corneum. Ki67 positive cells appearing as brown dots are evident in the basal and suprabasal layers, indicating actively proliferating cells. Control (R450 treated) explants in the lower panel of Figure 21 also show evidence of proliferation, containing Ki67-positive cells appearing as keratinization and brown stained nuclei. The middle panel of Figure 21 shows an explant treated with oligonucleotide # 27. The explants exhibit significantly reduced proliferation, lack of invagination, and substantial loss of Ki67 positive cells as evidenced by normal (thin) epidermis.

These results indicate that treatment of human psoriasis explants with an oligonucleotide targeting the mRNA encoding the IGF-I receptor results in inhibition of epidermal proliferation.

Example 21 A topical formulation of a complex of cytofectin GSV water-soluble formulation or methylcellulose gel formulation with an oligonucleotide was prepared and evaluated for in vivo uptake of the oligonucleotide by keratinocytes. As taught herein, the topical formulation included an oligonucleotide complexed with an aqueous solution of cytofectin GSV or a methylcellulose carrier. Localization of the oligonucleotide R451 to the keratinocyte nucleus and cytoplasm in normal human skin explants on nude mice was observed using both water-soluble and methylcellulose gel formulations. FIG. 22 shows the nuclear and cytoplasmic oligonucleotides of keratinocytes in normal human skin explants after topical application of fluorescently labeled oligonucleotides (10 μMR451) complexed with cytofectin GSV (10 μg / ml). 3 shows an image obtained from a confocal microscope demonstrating the localization of A. FIG. 23
Shows images obtained from confocal microscopy demonstrating that local application of the same oligonucleotide / GSV concentration in 3% (v / v) methylcellulose gels results in similar uptake in the target keratinocyte population. While the infiltration of the oligonucleotide into the living epidermis was observed using a water soluble formulation of the oligonucleotide / GSV complex, application of the oligonucleotide formulation complexed with other cationic lipids resulted in As a result, the localization of the oligonucleotide in the stratum corneum occurred.

Example 22 Thirteen antisense oligonucleotides targeting IGFBP-3 were synthesized. This antisense oligonucleotide is C5-propynyl-dU, dC15
Is a phosphorothioate oligodeoxyribonucleotide. FIG. 24 attached hereto is a conceptual diagram showing the position of 13 oligonucleotides compared to the IGFBP-3 mRNA structure.

These oligonucleotides were screened for their ability to inhibit IGFBP-3 mRNA levels in HaCaT cells according to the teachings herein. HaCaT cells are 90% in DMEM supplemented with 10% (v / v) FCS
After being grown to the confluence of the above, the plate was placed in a complete keratinocyte serum-free medium (KSFM, Gibco) containing a defined amount of EGF for 24 hours. Oligonucleotides (30 nM or 100 nM) were complexed with GSV cytofectin (2 μg / ml) and added to cells in complete KSFM to remove the EGF after allowing the oligonucleotide to enter the nucleus. Repeated additions were made at 3 hours (in serum-free DMEM releasing the EGF inhibition of IGFBP-3 mRNA) and again after 24 hours. HaCaT cells are also randomized sequence oligonucleotides (R12
1, R451, R766 and R961), treated with liposomes alone (GSV) or left untreated (UT). Total RNA was isolated as described in Example 17 24 hours after the final treatment. Total RNA (15 μg) was analyzed for IGFBP-3 mRNA and GADPH mRNA by Northern analysis and phosphorimager quantification. IGFBP-3 mRNA is IGFBP relative to GAPDH mRNA amount
-3 expressed as mRNA level.

25 (a)-(d) provide graphs showing the results of this screening step. In these graphs, R1 and R12 refer to R121, and R4, R4 (
0) and R45 refer to R451, R7, R7 (0) and R76 refer to R766, and R9 and R96 refer to R961. These values were normalized to GSV treated cells and the data pooled and analyzed statistically by ANOVA before
A Domet test was performed to compare V-treated cells with each treatment. This pooled data is presented as a bar graph in Figure 26. As has been demonstrated, treatment of HaCaT cells with 8 of the 12 targeted oligonucleotides tested at 30 nM concentration resulted in a statistically significant reduction in IGFBP-3 mRNA levels compared to cells treated with GSV. Occurred. Treatment with nine of the thirteen targeted oligonucleotides tested at 100 nM concentration resulted in a statistically significant reduction in IGFBP-3 mRNA levels compared to cells treated with GSV.

These experiments show that antisense oligonucleotides targeting the genetic sequence encoding IGFBP-3 were IGFB in human keratinocytes in vitro.
It has been demonstrated that P-3 mRNA levels can be inhibited.

Example 23 The IGF-I Receptor is a Potent Mitotic Signal Molecule of Keratinocytes and the Human Receptor Induces Distinct Intracellular Signals That Prevent Apoptosis (19).
It is proposed by the present invention that inactivation of the IGF-I receptor in epidermal keratinocytes achieves three important outcomes with subsequent UV treatment of lesions. (I) It has been suggested that acute epidermal hyperplasia after UV increases the risk of oncogenic transformation of keratinocytes [22]. Reducing IGF-I receptor expression in the epidermis appears to reduce the incidence of epidermal hyperplasia after UV exposure and generally promote normalization of the lesion and reduced risk of carcinogenesis. .. (Ii) Inhibition of the anti-apoptotic effect of IGF-I receptor enhances reversal of epidermal thickening and promotes normalization of differentiation. Topical or injected IGF-I receptor antisense as an adjunct therapy increases epidermal layer apoptosis, thereby enhancing the reduction in epidermal thickening observed with UV treatment. (Iii) When cells damage DNA, keratinocytes appear to survive, that is, escape from apoptosis. Such mutations can occur within the tumor suppressor region. Consequently, antisense therapy screens rarely mutated keratinocytes, resulting in a reduced incidence of basal cell carcinoma and scaling.

Therefore, antisense treatments, particularly antisense treatments for IGF-I receptors, are useful in combination with UV treatments in the treatment of epidermal hyperplasia.

Example 24 HaCaT cells were treated with antisense oligonucleotides against IGF-I receptor mRNA. The level of IGF-I receptor mRNA was then monitored.
Essentially, confluent HaCaT cells were treated with 2 μg / ml of GSV lipid alone (GSV) or 30 nM oligonucleotide (#) specific for the IGF-I receptor.
26 to # 86) or random sequence oligonucleotides (R121, R451
And R766) and treated with the lipid complexed every 24 hours for 4 days. FIG. 27 (a) is a photographic representation showing a typical RNase protection assay gel showing IGF-I receptor (IGFR) mRNA and GAPDH mRNA in untreated or treated HaCaT cells. Figure 27 (b) shows untreated cells (UT, vertical stripes).
Ha after treatment with IGF-I receptor-specific oligonucleotides (black solid), random sequence oligonucleotides (horizontal stripes) or GSV alone (hidden lines) compared to
Densitometric quantification of IGF-I receptor mRNA in CaT cells.

Example 25 In this example, the reduction of total cellular IGF-I receptor protein after antisense oligonucleotide treatment was monitored. Confluent Ha
CaT cells were complexed with 2 μg / ml GSV lipid alone (GSV) or 30 nM AONS (# 27, # 50 and # 64) specific for the IGF-I receptor or R451, a random sequence oligonucleotide. The treated lipids were treated every 24 hours for 4 days. Whole cell proteins were isolated and after SDSPAGE, human IGF
-IGF- by Western blotting using an antibody specific for the -I receptor
The I receptor was analyzed. FIG. 28 (a) shows the IGF with an estimated size of 110 kD.
Figure 3 shows duplicate processed cell extracts containing -I receptor. FIG. 28 (b) shows IGF-I.
Densitometric quantification of receptor proteins.

Example 26 Decrease in the number of IGF-I receptors was measured on the keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells were tested for IGF-I receptor specific AON # 27, # 50, # 64, random sequence oligonucleotides (R
451) or treated with GSV lipid alone every 24 hours for 4 days. ¹²⁵ I-IGF-I and de, an analogue specific to the receptor
A competitive binding assay using s (1-3) IGF-I was performed. The results are shown in Fig. 29.

Example 27 In this example, the anti-apoptotic effect of IGF-I receptors on keratinocyte cells was tested by following the decrease in keratinocyte number following antisense oligonucleotide treatment. Initially, 40% confluence of HaCaT cells
AON # 64 specific for the IGF-I receptor, control sequences R451 and 6414
Or treated with GSV lipid alone every 24 hours for 2 days. Cell number was measured in culture wells using a dye binding assay. The result is shown in FIG. This result clearly confirms that the IGF-I receptor exhibits an anti-apoptotic effect. By lowering IGF-I receptor levels using antisense oligonucleotide treatment, the anti-apoptotic effect is blocked, resulting in a decrease in keratinocyte cell number due to apoptosis. Results are shown in FIG.

Example 28 This example demonstrates the reversal of epidermal hyperplasia in human psoriatic skin explants on nude mice after intradermal injection of antisense oligonucleotides. Transplanted psoriatic lesions were injected histologically after injection every 2 days for 20 days with AON specific for the IGF-I receptor, PBS with random sequence oligonucleotides, or PBS alone. The result is shown in FIG. In Figure 31 (a), donor A explants treated with AON # 50 showed epidermal thinning compared to pre-transplant and control (PBS) treated explants, Grafts from donors treated with AON # 27 showed epidermal thinning compared to pre-transplant grafts and control (R451) treated transplants. Figure 31
In (b) the average epidermal cross-sectional area across the entire width of the explant as measured by digital image analysis is shown. The results show that epidermal hyperplasia is reversed after intradermal injection of antisense oligonucleotides.

Example 29 Figure 32 shows that reversal of epidermal hyperplasia correlates with a decrease in IGF-I receptor mRNA in transplanted psoriatic lesions treated with antisense oligonucleotides. FIG. 32 (a) shows IGF-I receptor-specific oligonucleotide # 27 (AON) immunostained with an antibody against Ki67 to identify psoriatic lesions and proliferating cells before and after transplantation. # 27) or the random sequence (R451). Proliferating cells are indicated by dark brown nuclei (arrows). 32 (
b) shows the same pre-transplantation and post-oligonucleotide treatment foci as in FIG. 32 (a) but subjected to in situ hybridization with a ³⁵ S-labeled cRNA probe complementary to human IGF-I receptor mRNA. . IGF-I receptor mRNA
Is present by silver particles, which is almost abolished in the epidermis of lesions treated with oligonucleotide # 27 (AON # 27) specific for the IGF-I receptor. This experiment shows that reversal of epidermal hyperplasia correlates with a decrease in IGF-I receptor mRNA in transplanted psoriatic lesions treated with antisense oligonucleotides.

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

Example 31 Treatment of Figure 34 with oligonucleotides. HaCaT cell monolayers were grown to 90% confluence in DMEM with 10% fetal bovine serum and 2 μg / ml GSV lipid alone (GSV) or 30 nM oligonucleotide complexed with the lipid were used. For 24 days every 24 hours. Cells, 50 mM Hepes, 150 m
M NaCl, 10% v / v glycerol, 1 v / v Triton X-100 and 100 μg / m
After lysing for 30 minutes on ice in a buffer containing 1 aprotinin, 30 μg of the lysate was loaded on a 7% w / v denaturing polyacrylamide gel, and then transferred onto an immobilon-P membrane. The membrane was then incubated with anti-IGF-I receptor antibody C20 (Santa Cruz Biotechnology, Inc., Santa Cruz, Calif.) For 1 hour at room temperature and developed using the Vistra ECF Western Blotting Kit (Amersham). . The results shown in Figure 34 confirm that the IGF-I receptor protein is reduced in HaCaT keratinocytes after treatment with the oligonucleotide.

Example 32 This example shows a reduction in HaCaT keratinocyte cell numbers after treatment with oligonucleotides. The result is shown in FIG. HaCaT cell monolayers were grown to 40% confluence in DMEM containing 10% fetal bovine serum and grown to 2 μg / m 2.
1 GSV lipid alone (GSV) or the lipid complexed with 15 nM oligonucleotide was treated every 24 hours for 3 days. Cell numbers were then measured every 24 hours using the Amido Black dye binding assay [32]. The result is that the IGF-
HaC after oligonucleotide treatment by reducing the anti-apoptotic effect of I receptor
It shows that the number of aT keratinocytes is decreased.

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 this invention includes all such variations and modifications. The present invention includes all or all of the steps, features, compositions and compounds referred to or shown herein, individually or collectively, and any or all of any two or more of the steps or features. Also includes combinations.

References 1. Sarah, V, Physiological Reviews 70: 591-614, 1990. 2. Letchler, MM and Brown, AL, Growth Regulation 2 : 55-68, 1992.
3. Clemmons, DR, Growth Regn 2 : 80, 1992. 4. Oaks, SR, KM, Haines, MJ, Waters, AC, Herrington and
GA, Werther, J. Clin Endocrinol Metab 73 : 1368-1373, 1992. 5. Camacho-Havner, C et al., J Biol Chem 267 : 11949-11956, 1992.

6. Nealy, KE et al., J Inv Derm 96: 104, 1991. 7. Zo POP, Aurelian, L, Chang, E and Miller, PS, Nonionic oligonucleotide analogues (Matagen ™) as an anticodon agent in double- and triple-strand formation in "Antisense Strategy", Annal of the New York
Academy of Science 660 : 159-177 (Edited by Baserga R and Denhardt DT), 1993.
8. Haseloff and Gerach, L, Nature 334 : 586-591, 1988. 9. Boukamp, P, Petrcebska, RT, Breitkreuz, D, Hornang, J, Markham, A, Fusenig, NE, J Cell Biol 106 : 761-771, 1988.
Ten. Reinwald and Green, Cell 6 : 331-344, 1975.

11. Hossenlop, P, Seulin, D, Segovia-Quinson, B, Hardwin, S, Binoux, M, Anal Biochem 154 : 138-143, 1986. 12. Splat, SK, Tatsuno, GP, Yamanaka, MK, Ark, BC, Detmer,
J, Muscaren Haz, D, Flynn, J, Talkington-Belser, C, Spencer, EM, Growth Factors 3 : 63-72, 1990. 13. Pietrtskovsky, Z, Cell, C, Ramers, R, Alrich, A and Baserga, R, Mol. Cell. Biol. 12: 3883-3889, 1992. 14. Schulz, J, Detlav, S, Frice, U, Harms, U, Sebel, H
, Deller, W, Fusenig, NE, Frusen, A and Baume, M, J. Immunol. Meth.
. 167 : 1-13, 1994. 15. Baker, BS, Brent, L, Valdi Marson, H, Pauls, AV, Al-
Imara, L, Vulker, M and Fry, L, Brit. J. Dermatol 126 : 105-110,
1992.

16. Nanny, LB et al., J. Invest. Dermatol 98: 296-301, 1992. 17. Sandberg, JP et al., Immunol. Investigations 22: 389-401, 1993.
18. Sandberg, JP et al., J. Invest. Dermatol 102 : 781-788, 1994. 19. Oconol et al., Mol Cell Biol 17: 427-435, 1997. 20. Kuhn et al., Int J Cancer 80 : 431-438, 1999.

21. Resnikov et al., Cancer Res 55 : 3739-3741, 1995. twenty two. Ortit et al., Am J Pathol 156 : 201-207, 2000. twenty three. Fuller et al., Tetrahedrin Lett 34 : 1003-1006, 1992. twenty four. Gennaro (eds.), Remington's Pharmaceutical Sciences, 18th Edition, Mac Publishing, Easton, Pennsylvania, USA, 1990. twenty five. Flanagan et al., Nat Biotechnol 14 : 1139-1145, 1996.

26. Flanagan et al., Nucleic Acids Res 24: 2936-2941, 1996. 27. Flanagan et al., Mol Cell Biochem 172: 213-225, 1997. 28. Guchierets et al., Biochemistry 36 : 743-748, 1997. 29. Mouls et al., Biochemistry 34 : 5044-5053, 1995. 30. Wagner et al., Science 260 : 1510-1513, 1993.

31. Wagner et al., Nature 372: 333-335, 1994. 32. Schultz et al., J Immunol Meth 167: 1-13, 1994.

[Sequence list]

[Brief description of drawings]

FIG. 1 is a diagram showing the nucleotide sequence of IGFBP-2. Locus HSIGFBP2 1433 base pairs RNA PRI 1990 1
31st definition Human mRNA for insulin-like growth factor binding protein (IGFBP-2)
Deposited X16302 Keywords Insulin-like growth factor binding protein. Origin Human Organism Name Homo sapiens Eukaryote, Animalia, Metazoa, Chordata, Subvertebrate, Mammalia,
Beast subclass, Orthodox subclass, Primates, Subrhinoidea, Hymenoptera, Human superfamily. Reference 1 (1-1433 bases) Author Vinkert, See. , Landwer, Jay. , Mary, Jay. Elle. , Schwander, Jay. And Heinrich, Gee. . Title: Novel insulin-like growth factor binding protein (IGFBP-2) cDNA
Cloning, sequence analysis and expression of A Publication name EMBO J. 8, 2497-2502 (1989) Standard Fully automatic comment NCBI gi: 33009 Sequence features Position / property Origin 1. ． 1433 / organism name = "Homo sapiens" / developmental stage = "fetus" / tissue type = "liver" Other characteristics 1416. ． 1420 / Note = "potential polyadenylation signal" poly A site 1433 / Note = "polyadenylation site" CDS 118. ． 1104 / Note = "Polypeptide precursor, (-39 to 289 amino acids), NCBI gi: 33010." / Codon start point = 1 / Translation = "MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARAE
VLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCAELVREPGCGCCSVCARLEGEACGVYTPRCGQGL
RCYPHPGSELPLQALVMGEGTCEKRRDAEYGASPEQVADNGDDHSEGGLVENHVDSTMNMLGGGGSAGRKPL
KSGMKELAVFREKVTEQHRQMGKGGKHHLGLEEPKKLRPPPARTPCQQELDQVLERISTMRLPDERGPLEHL
YSLHIPNCDKHGLYNLKQCKMSLNGQRGECWCVNPNTGKLIQGAPTIRGDPECHLFYNEQQEACGVHTQRMQ
(<400> 21) CDS 118. ． 234 / Note = "Signal peptide, (-39 to -1 amino acid), NCBI gi: 33011." / Codon start point = 1 / Translation = "MLPRVGCPALPLPPPPLLPLLPLLLLLLGASGGGGGARA
(<400> 22) CDS 235. ． 1101 / Note = "Mature IGFBP-2, (1-289 amino acids), NCBI gi: 33012." / Codon start point = 1 / Translation = "EVLFRCPPCTPERLAACGPPPVAPPAAVAAVAGGARMPCA
ELVREPGCGCCSVCARLEGEACGVYTPRCGQGLRCYPHPGSELPLQALVMGEGTCEKRRDAEYGASPEQVAD
NGDDHSEGGLVENHVDSTMNMLGGGGSAGRKPLKSGMKELAVFREKVTEQHRQMGKGGKHHLGLEEPKKLRP
PPARTPCQQELDQVLERISTMRLPDERGPLEHLYSLHIPNCDKHGLYNLKQCKMSLNGQRGECWCVNPNTGK
LIQGAPTIRGDPECHLFYNEQQEACGVHTQRMQ ”(<400> 23) Adenine with 239 bases 466 Cytosine 501 Guanine 22
7 Thymine Source HSIGFBP2 Sequence length: 1433 May 11, 1994 10:06 Sequence type: N Test: 6232. ．

[Figure 1 (i)]   FIG. 1 (i) is a part of FIG.

[Figure 1 (ii)]   FIG. 1 (ii) is a part of FIG.

FIG. 2 is a diagram showing the nucleotide sequence of IGFBP-3. Locus HUMGFIBPA 2474 base pair ss-mRNA PRI 1
June 15, 990 Definition Human growth hormone-dependent insulin-like growth factor binding protein mRNA
, Full length cds. Deposited M31159 Keywords Insulin-like growth factor binding protein. Origin human plasma, cDNA to mRNA, clone BP-53. Organism name Homo sapiens Eukaryote, Animalia, Metazoa, Chordata, Subvertebrate, Mammalia,
Beast subclass, Orthodox subclass, Primates, Subrhinoidea, Hymenoptera, Human superfamily. Reference 1 (1 to 2474 bases) Author Wood, W. Eye. , Cassians, Gee. , Hansel, W. Gee. , Winslow, Gee. A. , Spencer, S. A. Helmis, Earl. , Martin, Jay. Elle. And Baxter, Earl. C. . Title Cloning and expression of growth hormone-dependent insulin-like growth factor binding protein Publication name Mol. Endocrinol. 2, 1176-1185 (1988) Standard fully automatic comment NCBI gi: 183115 Sequence features Position / property mRNA <1. ． 2474 / Points to be noted = "GFIBP mRNA" CDS 110. ． 985 / gene = “IGFBP1” / attention point = “insulin-like growth factor binding protein, N
CBI gi: 183116. ] / Codon start point = 1 / Translation = “MQRARPTLWAAALTLLVLLRGPPVARAGASSGGLGPVVRC
EPCDARALAQCAPPPAVCAELVREPGCGCCLTCALSEGQPCGIYTERCGSGLRCQPSPDEARPLQALLDGRG
LCVNASAVSRLRAYLLPAPPAPGNASESEEDRSAGSVESPSVSSTHRVSDPKFHPLHSKIIIIKKGHAKDSQ
RYKVDYESQSTDTQNFSSESKRETEYGPCRREMEDTLNHLKFLNVLSPRGVHIPNCDKKGFYKKKQCRPSKG
RKRGFCWCVDKYGQPLPGYTTKGKEDVHCYSMQSK "(<400> 24) Origin 1. ． 2474 / organism name = "Homo sapiens" Number of bases 597 adenine 646 cytosine 651 guanine 58
Source of 0 thymines. Length of HUMGFIBPA sequence: 2474 May 11, 1994, 10:00.
0 min Array type: N Test: 9946. ．

[Figure 2 (i)]   FIG. 2 (i) is a part of FIG.

[Figure 2 (ii)]   FIG. 2 (ii) is a part of FIG.

[Fig. 2 (iii)]   FIG. 2 (iii) is a part of FIG.

[Fig. 2 (iv)]   FIG. 2 (iv) is a part of FIG.

FIG. 3 is a diagram showing the nucleotide sequence of the IGF-1 receptor. Loci HSIGFIRR 4989 base pair RNA PRI 1991 3
Mon 28th Definition Human mRNA deposit of insulin-like growth factor I receptor X04434 M24599 Keywords Glycoprotein, insulin receptor, insulin-like growth factor I receptor, membrane glycoprotein, receptor, tyrosine kinase. Origin Human Organism Name Homo sapiens Eukaryote, Animalia, Metazoa, Chordata, Subvertebrate, Mammalia,
Beast subclass, Orthodox subclass, Primates, Subrhinoidea, Hymenoptera, Human superfamily. Reference 1 (1 to 4989 bases) Author Ulrich, E. , Gray, A .. , Tam, A. W. , Young-Feng, Tee. , Tsubokawa, M. , Corinth, C. , Hansel, W. , Bon, Tee. Elle. , Kasria, S. , Chen, E. , Jacobs, S. Frankie, You. , Ramachandran, Jay. And Fujita Yamaguchi, Yi. . Title Primary structure of insulin-like growth factor I receptor: Comparison with insulin receptor suggests that structural determinants define functional specificity Publication name EMBO J. 5, 2503-2512 ( 1986) Standard fully automatic comment NCBI gi: 33058 Sequence features Position / property Origin 1. ． 4989 / organism name = "Homo sapiens" / tissue type = "placenta" / clone library = "(lambda) gt10" / clone = "(lambda) IGF-1-R.85, (lambda) IGF-1" -R.76 "signal peptide 32. ． 121 mature peptide 122. ． 4132 / Note = "IGF-I receptor" and other features 122. ． 2251 / Notes = "alpha-subunit (1 to 710 amino acids)" Other characteristics 182. ． 190 / Note = “potential N-linked glycosylation site (21
~ 23 amino acids) "Other characteristics 335. ． 343 / Note = "potential N-linked glycosylation site (72
~ 74 amino acids) "Other characteristics 434. ． 442 / Note = “potential N-linked glycosylation site (10
5 to 107 amino acids) "Other features 761. ． 769 / Note = “potential N-linked glycosylation site (21
4 to 216 amino acids) "Other characteristics 971. ． 979 / Note = “potential N-linked glycosylation site (28
4 to 286 amino acids) "Other characteristics 1280. ． 1288 / Note = "potential N-linked glycosylation site (38
7-389 amino acids) "Other characteristics 1343. ． 1351 / Note = "potential N-linked glycosylation site (40
8 to 410 amino acids) "Other characteristics 1631. ． 1639 / Note = "potential N-linked glycosylation site (50
4 to 506 amino acids) "Other characteristics 1850. ． 1858 / Note = "potential N-linked glycosylation site (57
7-579 amino acids) "Other characteristics 1895. ． 1903 / Note = "potential N-linked glycosylation site (59
2 to 594 amino acids) ”Other characteristics 1949. ． 1957 / Note = "potential N-linked glycosylation site (61
0-612 amino acids) "Other characteristics 2240. ． 2251 / Note = "putative proreceptor processing site (707
~ 710 amino acids) "Other characteristics 2252. ． 4132 / Note = "Beta-subunit (711-1337
Amino acid) ”Other characteristics 2270. ． 2278 / Note = "potential N-linked glycosylation site (71
7-719 amino acids) "Other characteristics 2297. ． 2305 / Note = “Potential N-linked glycosylation site (72
6 to 728 amino acids) ”Other characteristics 2321. ． 2329 / Note = "Potential N-linked glycosylation site (73
4 to 736 amino acids) "Other characteristics 2729. ． 2737 / Note = "potential N-linked glycosylation site (87
0-872 amino acids) "Other characteristics 2768. ． 2776 / Note = "potential N-linked glycosylation site (88
3-885 amino acids) "Other characteristics 2837. ． 2908 / Notes = "Transmembrane region (906 to 929 amino acids)" Other characteristics 2918. ． 2926 / Note = "Potential N-linked glycosylation site (93
3 to 935 amino acids) "Other characteristics 3047. ． 3049 / Note = "Potential ATP binding site (976 amino acids)
Other features 3053. ． 3055 / Note = "Potential ATP binding site (978 amino acids)
Other features 3062. ． 3064 / Note = "Potential ATP binding site (981 amino acids)
Other features 3128. ． 3130 / Note = "Potential ATP binding site (1003 amino acids)" CDS 32. ． 4132 / Product = “IGF-I receptor” / Points to note = “When the translation of frame 1, code 0 is attempted, it stops at position 50.” Base number 1216 adenine 1371 cytosine 1320 guanine 1082 Source of thymine: Length of HSIGFIRR sequence: 4989 May 11, 1994 12:10.
Sequence type: N test: 133. ．

[Figure 3 (i)]   FIG. 3 (i) is a part of FIG.

[Figure 3 (ii)]   FIG. 3 (ii) is a part of FIG.

[Fig. 3 (iii)]   FIG. 3 (iii) is a part of FIG.

[Fig. 3 (iv)]   FIG. 3 (iv) is a part of FIG.

[Fig. 3 (v)]   FIG. 3 (v) is a part of FIG. 3.

[Figure 3 (vi)]   FIG. 3 (vi) is a part of FIG.

[Figure 3 (vii)]   FIG. 3 (vii) is a part of FIG.

FIG. 4A shows 0.5 μM and 5 μM phosphorothioate oligonucleotides (
3 is a photograph of a Western ligand blot of HaCaT culture medium showing IGFBP-3 secreted during 24 hours after 7 days of treatment with BP3AS2, BP3AS3 and BP3S). * No oligonucleotide added.

FIG. 4B is a scan imaging densitometry graph of a Western Ligand Blot (FIG. 4A). This is the IG after phosphorothioate oligonucleotide treatment.
FIG. 3 shows the relative intensities of FBP-3 and 24 kDa IGFBP-4 bands. * No oligonucleotide added.

FIG. 5A: 0.5 μM phosphorothioate oligonucleotide BP3AS2.
Shows IGFBP-3 secreted during 24 hours after 7 days of treatment with
3 is a photograph of a Western ligand blot of HaCaT culture medium. Compared to some control oligonucleotides at 0.5 μM. (A) Oligonucleotide B
P3AS2NS, (b) oligonucleotide BP3AS4, (c) oligonucleotide BP3AS4NS, and no oligonucleotide added (no treatment).

FIG. 5B is a scan imaging densitometry graph of a Western Ligand Blot (FIG. 5A). As in FIG. 5A, the relative intensity of the IGFBP-3 band after phosphorothioate oligonucleotide treatment is shown. Then, the relative intensity of the IGFBP-3 band is expressed as a percentage of the average relative intensity of the band from the culture medium of cells not treated with the oligonucleotide.

FIG. 6 shows antisense oligonucleotides against the IGF-I receptor,
5 is a graph showing inhibition of IGF-I binding. IGFR. AS is antisense and IGFR. S is sense.

FIG. 7 is a graph showing inhibition of IGFBP-3 production in the medium after the first antisense oligonucleotide treatment by treatment once daily for 2 days.

FIG. 8: I determined by relative concentration of IGFBP-3 in culture medium
FIG. 7 is a graph showing optimization of GFBP-3 antisense oligonucleotide concentration.

FIG. 9 is a diagram showing the map of IGF-1 receptor mRNA and the position of the target ODN.

FIG. 10 is a photograph showing lipid-mediated uptake of oligonucleotides in keratinocytes. HaCaT keratinocytes were labeled with fluorescently labeled ODN
(R451, 30 nM) and cytofectin GSV (2 μg / mL) (1
Incubated in 0% v / v FCS-supplemented DMEM) medium for 24 hours. Then, the cells were transferred to an ODN-free medium to obtain a fluorescence microscope image (a) and a phase contrast microscope image (b) of the cells.

FIG. 11 is a graph showing ODN / lipid complex uptake (A) and toxicity (B) in keratinocytes. Confluent HaCaT keratinocytes,
Incubated in DMEM containing fluorescently labeled ODN (R451) and liposomes for> 120 hours, examined by fluorescence microscopy and trypan blue staining and counted.

FIG. 12: HaCaT cells treated with ODN (30 nM) (2 μg / mL G
3 is a graph showing IGF-1 receptor mRNA in SV). HaCaT keratinocytes, C-5 propynyl complexed with cytofectin GSV, d
It was treated with U, dC.ODN for 96 hours. Human IGF-I receptor mRNA (27,
32, 74 and 78), an ODN complementary to two randomized sequences (R45
1 and R766) or liposomes alone (GSV) or left untreated (UT). Total RNA was isolated and then analyzed for IGF-I receptor mRNA levels and GAPDH mRNA levels by RNase protection and PhosphorImager quantification. (A) IGF-I receptor mRNA fragment and GAPD after RNase protection treatment
Electrophoretic analysis of H mRNA fragments. Molecular weight markers are shown on the right hand side. The total length of the probe is shown on the left hand side (G-probe and I-probe). The GAPDH protected fragment (G) was found at the position of 316 bases, and the IGF-I receptor protected fragment (
I) is found at the 276 base position. (B) shows the relative levels of IGF-I receptor mRNA following each treatment.

FIG. 13: HaCaT cells treated with ODN (30 nM) (2 μg / mL G
3 is a graph showing IGF-1 receptor mRNA in SV). IGF-I receptor O
A summary of DN screening data. HaCaT keratinocytes were complexed with cytofectin GSV to form C-5 propynyl, dU, dC.ODN.
Treated for 96 hours. Total RNA was isolated and then analyzed for IGF-I receptor mRNA levels and GAPDH mRNA levels by RNase protection and phosphorimager quantification. An ODN complementary to human IGF-I receptor mRNA,
IGF-I after treatment with four randomized sequence ODNs and liposomes alone
The relative levels of receptor mRNA are shown. (26-86 = IGF-I receptor ODN,
R1, R4, R7 and R9 = randomized ODN (R1 = R121, R4 = R451
, R7 = R766, R9 = R961), GSV = liposome alone, UT = untreated). * Indicates that the difference between the relative amount of IGF-I receptor mRNA and the GSV-treated cells is significant (n = 4-10, p <0.05).

FIG. 14 is a graph showing the effect of antisense oligonucleotides on IGF-1 receptor levels on the surface of keratinocytes. 24-hole plate, 1
HaCaT cells were cultured to confluence in DMEM containing 0% v / v FCS. Oligodeoxynucleotide (ODN) and cytofectin GS
Vs (GSV, Glen Research) were mixed together in serum-free DMEM, incubated at room temperature for 10 minutes, then diluted 10-fold with medium and plated on the cells.
Cells were treated with 30 nM random sequence or antisense ODN and 2 μg / mL G
DM with 10% v / v FCS for 72 hours with SV or with GSV alone
Incubated in EM, changing solution every 24 hours. Then serum-free D
Incubated for 48 hours with ODN / GSV in MEM. All incubations were performed at 37 ° C. Wells were washed twice with 1 mL cold PBS.
Des (1-3) IGF-I, which is an IGF-I analog of 10 ⁻¹⁰ M to ^{10 −7} M
-Free DM containing 10 ⁻¹⁰ M ¹²⁵ I-IGF-I with or without
EM was added. The cells were incubated at 4 ° C. for 17 hours with gentle shaking, then washed 3 times with 1 mL cold PBS and 250 μL 0.5 M NaOH.
/0.1% v / v Triton X-100 at room temperature for 4 hours. Specific binding of solubilized cell extracts was measured using a gamma counter.

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

FIG. 16 is a photograph showing H & E stained sections of (A) psoriatic skin biopsy before transplantation and (B) psoriatic skin graft after 49 days using skin from the same donor for transplantation. is there.

FIG. 17 is a photograph showing oligonucleotide uptake after intradermal injection into psoriatic skin grafts on nude mice. Intracutaneous ODN (R45
1, 50 μL, 10 μM) was injected. The graft was peeled off, sectioned 24 hours later, and observed by confocal microscopy.

FIG. 18 (a) shows that donor JH before transplantation, donor J treated with 50 μL PBS.
3 is a photograph of donor JH treated with H and 50 μL, 10 μM # 50.

FIG. 18 (b) shows donor LB before transplantation, donor L treated with 50 μL PBS.
B, and 50 μL of donor LB treated with 10 μM # 74.

FIG. 18 (c) shows donor PW (50 μL, 10 μM) R451 treated with pre-transplant donor PW, and donor L treated (50 μL, 10 μM) # 74.
It is a photograph of B.

FIG. 18 (d): Donor GM before transplantation, donor GB treated with (451 μL, 10 μM) R451, and donor G treated with (50 μL, 10 μM) # 27.
It is a photograph of M.

FIG. 19 (a) shows that donor JH before transplantation, donor J treated with 50 μL PBS.
3 is a photograph of donor JH treated with H and 50 μL, 10 μM # 50.

FIG. 19 (b) shows donor LB before transplantation, donor L treated with 50 μL PBS.
B, and 50 μL of donor LB treated with 10 μM # 74.

FIG. 19 (c) is a photograph of donor PW before transplantation, 50 μL, 10 μM r451-treated donor PW, and 50 μL, 10 μM # 74-treated donor PW.

FIG. 19 (d) is a photograph of donor GM before transplantation, 50 μL, donor GM treated with 10 μM R451, and donor treated with 50 μL, 10 μM # 27.

FIG. 20 is a photograph showing inhibition of psoriasis after (quantitative) treatment with oligonucleotides. Oligonucleotides (50 μL, 10 μM) were injected every other day for 20 days, which served as a control. Peel the skin, measure the thickness of the skin, and (
The exact thickness of each implant was measured using computer software (for MCID analysis). N = 3 to 4 for each measurement. * Indicates that the difference from the value before transplantation is significant (ANOVA, p <0.05).

FIG. 21   FIG. 21 is a photograph showing immunobiological binding of αhKi-67.

FIG. 22 is a photograph showing penetration of oligonucleotides into human skin after topical treatment. After mixing with cytofectin GSV (10 μg / mL), fluorescently labeled oligonucleotides (10 μM R451) were applied topically and observed using confocal microscopy.

FIG. 23 is a photograph showing oligonucleotide penetration into human skin after application of topical gel formation. Fluorescently labeled oligonucleotide (10 μM R451) and cytofectin GSV (10 μg / mL) were complexed and applied topically after mixing with 3% methylcellulose gel. Images were acquired using a confocal microscope.

FIG. 24   FIG. 24 shows IGFBP-3 mRNA.

FIG. 25 (a) is a diagram showing IGFBP-3 mRNA levels in AON (100 nM) -treated HaCaT cells (2 μg / mL GSV).

FIG. 25 (b) is a diagram showing IGFBP-3 mRNA levels in AON (100 nm) -treated HaCaT cells (2 μg / mL GSV).

25 (c) FIG. 25 (c) shows AON (30 nM) -treated HaCaT cells (2 μg / mL G).
It is a figure which shows the mRNA of IGFBP-3 in SV).

25 (d) FIG. 25 (d) shows AON (30 nM) -treated HaCaT cells (2 μg / mL G).
It is a figure which shows the mRNA of IGFBP-3 in SV).

FIG. 26 (a) is a diagram showing IGFBP-3 mRNA levels in ODN (30 nM) -treated HaCaT cells (2 μg / mL). HaCaT keratinocytes complexed with cytofectin GSV C-5 propynyl, dU, dC
-Treat with ODN for 51 hours. Total RNA was isolated and then IGFBP-3 mR
NA levels and GAPDH mRNA levels were analyzed by Northern analysis and phosphorimager quantification. O complementary to human IGFBP-3 mRNA
Relative levels of IGFBP-3 mRNA after treatment of cells with DN, ODN of four randomized sequences, and liposomes alone. (1 to 24 = IGFBP-3
ODN, and R1, R4, R7 and R9 = randomized ODN (R1 = R121
, R4 = R451, R7 = R766, R9 = R961), GS = liposomes alone, UT = no treatment. ) * Indicates that the difference between the relative amount of IGFBP-3 mRNA and the GSV-treated cells is significant (n = 5 to 8, p <0.01). ** is I
It shows that the difference between the relative amount of GFBP-3 mRNA and the GSV-treated cells is significant (n = 5 to 8, p <0.05).

FIG. 26 (b) is a diagram showing mRNA of IGFBP-3 in ODN (100 nM) -treated HaCaT cells (2 μg / mL GSV). HaCaT keratinocytes complexed with cytofectin GSV, C-5 propynyl, dU
, DC.ODN for 51 hours. Total RNA was isolated and then IGFBP-3
And GAPDH mRNA levels were analyzed by Northern analysis and phosphorimager quantification. The relative levels of ODN complementary to human IGFBP-3 mRNA, ODNs of four randomized sequences, and IGFBP-3 mRNA after treatment with liposomes alone are shown. (1-24 = ODF of IGFBP-3, and R1, R4, R7 and R9 = randomized ODN (R1-R121,
R4 = R451, R7 = R766, R9-R961), GS = liposomes alone,
UT = no treatment. ) * Indicates that the difference between the relative amount of IGFBP-3 mRNA and the GSV-treated cells is significant (n = 6-8, p <0.01).

FIG. 27 (a) FIG. 27 shows I in HaCaT cells after treatment with antisense oligonucleotides.
It is a figure which shows the decrease of GF-I receptor mRNA. Confluent HaCaT cells for 4 days with 2 μg / mL GSV lipid alone (GSV) every 24 hours,
Or 30 nM IGF-I receptor-specific oligonucleotide (# 26 to # 86)
, Or random sequence oligonucleotides (R121, R451 and R766). Total RNA was isolated and then analyzed for IGF-I receptor mRNA and GAPDH mRNA by RNase protection analysis. (A) Untreated HaCa
IGF-I receptor (IGFR) mRN in T cells or treated HaCaT cells
1 is a representative RNase protection assay gel showing A and GAPDH mRNA. In this example, the decrease in band intensity of IGFR compared to GAPDH is
It is seen with N # 27 and # 78, but with # 32 and # 74 and the control (R4 and R7 are random oligonucleotides R451 and R76, respectively).
6 and G is a GSV lipid and UT is untreated).

FIG. 27 (b): (b) IGF-I receptor-specific oligonucleotides (black), random sequence oligonucleotides (horizontal stripes) or GSV compared to untreated cells (UT, vertical stripes).
IGF-I receptor mR in HaCaT cells after treatment alone (shadow)
Densitometer quantification of NA (normalized to GAPDH mRNA). Each oligonucleotide was analyzed in duplicate in at least two independent experiments.
The results are shown as mean ± SEM. A one-way ANOVA followed by a Chukey test (▲) was performed. The ▴ indicates that there is a significant difference between IGF-I receptor-specific AON-treated cells and all control treatments (p <0.05). # 27 and # 32 (n = 6), # 28 and # 68 (n = 3), R766 (n = 9), R4
N = 4 except for 51, GSV and no treatment (n = 10).

FIG. 28 (a) shows that cytoplasmic IG after treatment with antisense oligonucleotides.
It is a figure which shows the decrease of the total amount of FI receptor protein. Confluent HaC
aT cells were treated with 2 μg / mL GSV lipid alone (GS) every 24 hours for 4 days.
V), or 30 nM IGF-I receptor-specific AON (# 27, # 50 and # 6).
4) or with the random sequence oligonucleotide R451. All cytoplasmic proteins were isolated and then analyzed for IGF-I receptor by SDS-PAGE followed by Western blotting with human IGF-I receptor-specific antibodies. (A) IGF-I receptor is shown at the expected size of 110 kD in cell extracts treated twice.

FIG. 28 (b). (B) Densitometer quantification of IGF-I receptor protein. The results of four different experiments, each performed in duplicate, are shown as the mean ± SEM.
A one-way ANOVA followed by Dunnett's tests were performed. * Is GSV
Shown to be significantly different from treated cells (p <0.01). GSV is GSV
Lipid alone, UT untreated, R451 random sequence oligonucleotide, 64, 5
0 and 27 are IGF-I receptor-specific AON.

FIG. 29. Reduction of total number of IGF-I receptors on keratinocyte cell surface after antisense oligonucleotide treatment. HaCaT cells, IG
FI receptor-specific AONs # 27 (-▲-), # 50 (-x-), # 64
(--- ■ ---), random sequence oligonucleotide R451 (-○-), or GS
V-lipid alone (-□-) was transfected every 24 hours for 4 days (
Untreated cells are-*-). ¹²⁵ I-IGF-I and the receptor-specific analog d
A competitive binding assay using es (1-3) IFG-I was performed (inset). The entered values are mean ± standard error. These averages were then submitted for Scatchard analysis.

FIG. 30 is a diagram showing a decrease in the number of keratinocyte cells after treatment with an antisense oligonucleotide. 40% confluence of HaCaT cells at the start
GF-I receptor-specific AON # 64, control sequences R451 and 6416, or G
SV lipids alone were transfected every 24 hours for 2 days (UT is untreated cells). Cell numbers were determined in culture wells using a dye binding assay (experimental protocol). Results are shown as mean ± SD. A one-way ANOVA followed by a Chukey test was performed. ▲ indicates that there is a significant difference between AON # 64 treated cells and all control treatments (p <0.001).

FIG. 31 (a) shows the reversal of epidermal hyperplasia in human psoriatic skin grafts on nude mice after intradermal injection with antisense oligonucleotides. Transplanted psoriatic lesions were injected with IGF-I receptor-specific AON, random sequence oligonucleotides in PBS, or PBS alone every 2 days for 20 days and then analyzed histologically. . (A) Donor A graft treated with AON # 50
It shows that the epidermis is thinner compared to the pre-transplanted and control (PBS) treated implants, the donor B-graft treated with AON # 27 was It shows that the epidermis is thinner compared to the control (R451) treated graft. E is the epidermis, the scale bar is 400 mm, and all the photographs have the same magnification.

Figure 31 (b) (b) The average epidermal cross-sectional area across the entire width of the implant was determined by digital image analysis. The results are shown as mean ± SEM. Shaded bars are control treatments, R451, random oligonucleotide sequence treatments, filled bars are treatments with oligonucleotides that inhibited IGF-I receptor expression in vitro. * Indicates significant difference from vehicle treated implants (p <
0.01, n = 5-7). ++ indicates that the difference from the graft treated with the random sequence (R451) is significant (p <0.01, n = 5-7).

FIG. 31 (c): (c) Parakeratosis (arrow) was not present in grafts treated with IGF-I receptor AON (AON # 50), but not in previously grafted grafts or It was maintained in control (PBS) treated implants. The scale bar is 100 mm.

FIG. 32 (a) shows that the reversal phenomenon of epidermal hyperplasia is correlated with the decrease of IGF-I receptor mRNA in the transplanted psoriatic lesion treated with antisense oligonucleotide. Is. (A) Psoriatic lesions before transplantation, and by transplantation, IGF-I receptor-specific oligonucleotide # 27 (AON # 27) or random sequence (R45
The lesion of psoriasis after the treatment in 1) was immunostained with an antibody against Ki67 to identify proliferating cells. Proliferating cells are indicated by dark brown nuclei (arrows). The scale bar is 250 mm and all pictures have the same magnification.

FIG. 32 (b). (B) Lesions before transplantation and after oligonucleotide treatment (same as the lesions in (a)) were subjected to in situ hybridization. Here, human IGF
A ³⁵ S-labeled cRNA probe complementary to the -I receptor mRNA was used. IGF-
The presence of I receptor mRNA was indicated by silver staining (black specks). This spot is
Almost disappeared in the epidermis of the lesion treated with IGF-I receptor-specific oligonucleotide # 27 (AON # 27). The basal layer of the epidermis along with the dermis base are indicated by arrows. The scale bar is 50 μm.

FIG. 33 shows the reduction of IGF-I receptor mRNA in HaCaT keratinocytes after oligonucleotide treatment. HaCaT monolayer cells grown to 90% confluence in DMEM medium containing 10% v / v fetal bovine serum were complexed with 2 μg / mL GSV lipid alone (GSV) or 30 nM oligonucleotide for 2 days. The treated GSV lipid was used for treatment every 24 hours. To isolate total RNA and analyze for IGF-I receptor mRNA and GAPDH mRNA, a commercially available ribonuclease protection assay kit (RPAII,
(Ambicon, Austin, TX) was used. Band intensity was quantified using ImageQuant software (Molecular Dynamics, Sunnyvale, CA).

FIG. 34 shows the reduction of IGF-I receptor protein in HaCaT keratinocytes after oligonucleotide treatment. HaCaT monolayer cells grown to 90% confluence in DMEM containing 10% v / v fetal bovine serum were complexed with 2 μg / mL GSV lipid alone (GSV) or 30 nM oligonucleotide for 4 days. Treated with GSV lipids every 24 hours. 50 mM Hepes, 150 mM NaCl, 10% v / v glycerol, 1
Lyse cells on ice for 30 minutes in a buffer containing% v / v Triton X-100 and 100 μg / mL aprotinin, then add 30 μg lysate to 7%.
It was loaded on a w / v denaturing polyacrylamide gel and then transferred onto an Immobilon-P membrane (Millipore, Bedford, Mass.). The membrane was anti-IGF-I receptor antibody C20 (Santa Cruz Biotechnology, Santa Cruz, Calif., 150 mM NaCl, 10 mM Tris-HCl, pH 7.4, 25 ng / 0.1% v / v Tween 20). mL) and incubated for 1 hour at room temperature and developed using the Vistra ECF Western Blotting Kit (Amersham, Buckinghamshire, England). Image Quant Software (Molecular Dynamics, Inc.)
Sunnyvale, CA).

FIG. 35 is a diagram showing a decrease in the number of HaCaT keratinocyte cells after oligonucleotide treatment. 40 in DMEM medium containing 10% fetal bovine serum
HaCaT monolayer cells grown to% confluence were 2 μg /
Treatments were performed every 24 hours with mL of GSV lipid alone (GSV) or GSV lipid complexed with 15 nM oligonucleotide. Cell counts were measured every 24 hours using the Amido Black dye binding assay [32].

[Procedure for Amendment] Submission for translation of Article 34 Amendment of Patent Cooperation Treaty

[Submission date] September 27, 2001 (2001.9.27)

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be amended] Claims

[Correction method] Change

[Contents of correction]

[Claims]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 9/10 101 A61P 9/10 101 13/12 13/12 17/00 17/00 17/02 17 / 02 17/06 17/06 17/12 17/12 29/00 29/00 35/00 35/00 43/00 111 43/00 111 C12N 15/09 ZNA C12N 15/00 ZNAA (81) Designated country EP ( AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR , LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Werther, George, Arthur Australia, Victoria 3124, Camberwell, Bellett Street 65 (72) ) Inventor Edmondson, Su Fanny, Route Australia, Victoria 3150, Glen Waverley, Cunnarda Avenue No. 2 F term (reference) 4B024 AA01 BA56 CA04 HA17 4C084 AA13 NA14 ZA36 ZA45 ZA66 ZA81 ZA89 ZA91 ZB11 ZB21 ZB26 ZC02 ZC41 MA01A04A04A01A02A. ZA36 ZA45 ZA66 ZA81 ZA89 ZA91 ZB11 ZB21 ZB26 ZC02 ZC41

Claims (44)

[Claims] 1. A method of ameliorating the effects of a medical disorder, such as proliferative and / or inflammatory skin disorders in a mammal, which is proliferating and / or inflamed or proliferative skin. And / or cells capable of inflaming skin or cells otherwise involved in the medical disorder can inhibit cell proliferation and / or inflammation and / or other medical disorders mediated by growth factors or otherwise A method comprising contacting with an effective amount of a nucleic acid molecule or a chemical analogue thereof that can be reduced by. 2. Cell proliferation and / or inflammation and / or other medical disorders
Insulin-like growth factor I (IGF-I), keratinocyte growth factor (KGF),
Transforming growth factor-α (TGF-α), tumor necrosis factor-α (TNF
α), interleukin (IL) -1 (IL-1), IL-4, IL-6, IL
8. The method of claim 1, which is mediated by at least one of -8 and / or basal fibroblast growth factor (bFGF). 3. Cell proliferation and / or inflammation or other medical disorder is IGF-.
The method of claim 2, wherein the method is mediated by I. 4. The cell growth and / or IGF-I mediated cell proliferation and / or the nucleic acid molecule.
Or the method of claim 1 which inhibits or otherwise reduces inflammation or other medical disorders. 5. The proliferative or inflammatory skin disorder is psoriasis of the skin, ichthyosis, pityriasis rubra pilaris, seborrhoea, keloid, keratosis, tumor formation, scleroderma, warts, benign proliferation. The method according to claim 1, wherein the method is cancer. 6. The method of claim 5, wherein the skin condition is psoriasis. 7. The other medical disorder is a neovascularization state of the retina, brain or skin, a growth factor mediated malignancy, other sclerosis, renal disease or hyperproliferation of the vascular inner wall or any other. The method according to claim 1, which is a hypervascularization state such as hyperplasia. 8. The method according to claim 1 or claim 4 or claim 7, wherein the mammal is a human. 9. The method of claim 1 or claim 4 or claim 7 wherein said nucleic acid molecule is one that inhibits, reduces or otherwise interferes with the interaction of IGF-I with its receptor. 10. The nucleic acid molecule is IGF-I, IGF-I receptor or I.
The method according to claim 9, which is an antisense molecule capable of reducing the expression of a gene encoding a GF binding protein (IGFBP). 11. The nucleic acid molecule is IGFBP-2, -3, -4, -5 or-
11. An antisense molecule capable of reducing the expression of the gene encoding 6.
The method described. 12. The method according to claim 11, wherein the nucleic acid molecule is an antisense molecule capable of reducing the expression of a gene encoding IGFBP-2 or IGFBP-3. 13. The antisense molecule is at least about 15 nucleotides in length and interacts with at least one of the sequences selected from the list set forth in Example 6 or Example 7 or Example 8. The method according to claim 10 or 12, which is capable. 14. The antisense molecule has the following nucleotide sequence: 5'-ATCTCTCCGCTTCCTTTC-3 '(<400> 10) 13. The method of claim 12, comprising: 15. The antisense molecule has the following sequence: 5'-UCCGGAGCCAGACUU-3 '(<400> 12) 5'-CACAGUUGCUGCAAG-3 '(<400> 13) 5'-UCUCCGCUUCCUUUC-3 '(<400> 14) 5'-AGCCCCCCACAGCGAG-3 '(<400> 15) 5'-GCCUUGGAGAUGAGC-3 '(<400> 16) 5'-UAACAGAGGUCAGCA-3 '(<400> 17) 5'-GGAUCAGGGGACCAGU-3 '(<400> 18) 5'-CGGCAAGCUACACAG-3 '(<400> 19) 5'-GGCAGGGCAGGCACAC-3 '(<400> 20) 13. The method of claim 12, selected from: 16. The antisense molecule comprises SEQ ID NO: 12 and SEQ ID NO: 13.
Alternatively, the method according to claim 15, which is that shown in SEQ ID NO: 14. 17. The method of claim 15, wherein the antisense molecule is that of SEQ ID NO: 12. 18. A nucleic acid molecule comprising at least about 10 nucleotides capable of hybridising to a complementary form of SEQ ID NO: 12 to SEQ ID NO: 20, forming a heteroduplex or otherwise interacting. 19. A nucleic acid molecule comprising at least about 15 nucleotides capable of hybridising to a complementary form of <400> 12 to <400> 14, forming a heteroduplex or otherwise interacting. 20. Proliferating skin or proliferative skin or cells otherwise associated with said medical disorder and inhibiting or otherwise inhibiting IGF-I mediated cell proliferation or other medical disorders. A method of ameliorating the effects of psoriasis or other medical disorders comprising contacting with one or more effective amounts of a nucleic acid molecule or a chemical analogue thereof that can be reduced by IGF-I. A method comprising a polynucleotide capable of interacting with mRNA directed by a gene, an IGF-I receptor gene or a gene encoding IGFBP. 21. The method of claim 20, wherein the IGFBP is IGFBP-2 or IGFBP-3. 22. The method of claim 20 or 21, wherein the mammal is a human. 23. The method of claim 22, wherein the nucleic acid molecule is capable of interacting with a nucleotide sequence selected from the list of <400> 12 to <400> 14. 24. The method of claim 23, wherein the nucleic acid molecule comprises a nucleotide sequence selected from the sequences <400> 12 to <400> 14. 25. A composition comprising a nucleic acid molecule capable of inhibiting or otherwise reducing IGF-I mediated cell proliferation or other medical disorders, wherein the composition comprises one or more pharmaceutically acceptable carriers. And / or a composition further comprising a diluent. 26. The nucleic acid molecule is IGF-I, IGF-I receptor or IGF.
26. The composition according to claim 25, which is an antisense molecule against a gene encoding BP. 27. The composition of claim 26, wherein the nucleic acid molecule is selected from the sequences <400> 12 to <400> 20. 28. The composition according to claim 26, which is selected from the sequences <400> 12 to <400> 14. 29. A method of ameliorating the effects of proliferative and / or inflammatory skin disorders such as psoriasis, which comprises proliferating and / or inflamed skin or proliferative and / or inflamed skin. , Contacting with an effective amount of a nucleic acid molecule or a chemical analog thereof capable of inhibiting or otherwise reducing cell proliferation and / or inflammation mediated by UV irradiation and IGF-I. 30. The proliferative or inflammatory skin disorder is psoriasis, ichthyosis, pityriasis rubra pilaris, seborrhea, keloid, keratosis, neoplasia,
30. The method according to claim 29, which includes scleroderma of the skin, warts, benign growth of skin and cancer. 31. The method of claim 30, wherein the proliferative or inflammatory skin disorder is psoriasis.
The method described. 32. The method of claim 29 or claim 30 or claim 31, wherein the nucleic acid molecule is one that inhibits, reduces or otherwise interferes with the interaction of IGF-I with its receptor. 33. The nucleic acid molecule is IGF-I, IGF-I receptor or IGF.
33. The method according to claim 32, which is an antisense molecule capable of reducing the expression of a gene encoding a binding protein (IGFBP). 34. The nucleic acid molecule is IGFBP-2, -3, -4, -5 or-
34. An antisense molecule capable of reducing the expression of the gene encoding 6.
The method described. 35. The method according to claim 34, wherein the nucleic acid molecule is an antisense molecule capable of reducing the expression of a gene encoding IGFBP-2 or IGFBP-3. 36. The method according to claim 33, wherein the nucleic acid molecule is an antisense molecule capable of reducing the expression of the gene encoding the IGF-I receptor. 37. The antisense molecule is at least about 15 nucleotides in length and is capable of interacting with at least one of the sequences selected from the list set forth in Example 6 or Example 7 or Example 8. 37. The method according to any one of claims 29 to 36, which is 38. The antisense molecule has the following nucleotide sequence:   5'-ATCTCTCCGCTTCCTTTC-3 '(<400> 10) 38. The method of claim 37, including 39. The antisense molecule has the following sequence:             UCCGAGGCCAGACUU (<400> 12)             CACAGUUGCUGCAAG (<400> 13)             UCUCCGCUUCCUUUC (<400> 14)             AGCCCCCACACGCGAG (<400> 15)             GCCUUGGAGAUGAGC (<400> 16)             UAACAGAGGUCAGCA (<400> 17)             GGAUCAGGGACCAGU (<400> 18)             CGGCAAGCUACACAG (<400> 19)             GGCAGGCAGGCACAC (<400> 20) 38. The method of claim 37, which is selected from: 40. The antisense molecule is <400> 12, <400> 13.
40. The method according to claim 39, which is the one described in <400> 14. 41. The method of claim 40, wherein said antisense molecule is as described in <400> 12. 42. The method according to claim 39, wherein the UV irradiation is carried out simultaneously with or after contact with the nucleic acid molecule or a chemical analogue thereof. 43. Use of an antisense molecule directed to a gene encoding an IGF-I receptor or its mRNA as an adjunct therapy in combination with UV irradiation to reduce proliferation and / or inflammation of keratinocyte cells. . 44. The use according to claim 43 in the treatment of psoriasis.