Lewin Benjamin (ed.) Genes IX

jfrd

@

Binding

to the

Response

Etement

Is Activated

by Ligand-Binding

r

Binding

of tigand

to the

C-terminal

domain increases

the affinitv

of the DNA-

binding

domain for its

speciiic

target site

in

DNA.

Steroid Receptors

Recognize

Response

Etements

by a CombinatoriaI

Code

o

A steroid response

etement

consists of

two

short half

sites that

may be

pa[indrom'ic

or directly repeated.

r

There

are onty

two types

of half sites.

o

A receptor

recognizes

its

response

etement

by the

orientation

and spacing

of the hatf

sites.

.

The

sequence

of the hatf

sjte is recognized

by the first zinc

finger.

o

The

second zinc

finger is

responsibte for

dimerization, which

determines

the dis-

tance between

the subunits.

o

Subunit

separation in

the receptor

deter-

mines

the recognition

of

spacing

in

the

response

e[ement,

.

Some steroid receptors

function

as homo-

dimers,

whereas

others form heterodimers.

o

Homodimers

recognize

patindromic

response

etements;

heterodimers

recog-

nize response

etements with

directty

repeated

hatf

sites.

Homeodomains

Bind

Retated Tarqets

in DNA

r

The

homeodomain

is a DNA-bindinq

domain of 60

amino acids

that hasihree

cr-

he[ices.

r

The

C-terminaI

a-hetix-3 is 17

amino acids

and

binds

in

the major

groove

of

DNA.

o

The N-terminal

arm

of the homeodomain

projects

into

the minor

groove

of

DNA.

bind

inverted repeats in DNA.

Summary

r

Proteins

containing

homeodomains may

be

either activators or

reDressors

of

tra nscri

ption.

Hetix-Loop-Helix Proteins Interact

by

Com bi natoriaI Association

o

Helix-toop-helix

proteins

have a motif of

40 to 50 amino acids

that comprises

two amphipathic

q-helices

of 15 to

L6 residues

separated

by a Loop.

o

The hetices are resDonsibte

for

dimer

formation.

.

bHLH

proteins

have a basic sequence adja-

cent to the

HLH motif that

is

responsible

for

binding to

DNA.

r

Ctass A bHLH

proteins

are ubiquitously

expressed. Ctass

B

bHLH

proteins

are

tissue-soecific.

.

A class B

protein

usuatty

forms

a

het-

erodimer with a class

A

orotein.

r

HLH

proteins

that lack the basic

region

prevent

a bHLH

partner

in

a

heterodimer

from

binding

to DNA.

o

HLH

proteins

form

combinatoriaI

associa-

tions that may be changed

during devet-

opment by the

addition or

removal

of

specific

proteins.

Leucine Zippers

Are Involved in Dimer

Formation

The

leucine

zipper

is

an amphipathic

helix

that dimerizes.

The zipper

is

adjacent

to a basic

region

that binds

DNA.

Dimerization

forms the bZIP motif

in

which

the two

basic regions symmetricatly

Introduction

r

Eukaryotic

gene

expression is

usualty

controlted at

the [eve[

of

initiation

of

transcriotion.

The

phenotypic

differences

that distinguish

the

various kinds

of cells in

a higher

eukaryote are

Iargely

due to differences in

the expression

of

genes

that code for

proteins,

that is,

those tran-

scribed by RNA

polymerase

II. In

principle,

the

expression

of these

genes

might

be regulated

at

any one of several

stages. We

can distinguish

(at

least) five

potential

control

points,

which

[orm

the following

series:

Activation

of

gene

structure

J

Initiation

of transcrintion

Processing the transcript

Transport

to

cytoplasm

Translation

it

-**o

As we see in

FIGURE 25.1,

gene

expression

in

eukaryotes is largely controlled

at the initiation

of transcription. For most

genes,

this

is

the

major

control

point

in their expression.

It involves

changes in the structure

of chromatin at

the

promoter (see

Section

30.11,

PromoterActiva-

tion Involves

an Ordered

Series

of Events),

accompanied by the binding

of the basal

tran-

scription apparatus

(including

RNA

poly-

merase II) to the

promoter.

(Regulation

at

subsequent stages of transcription

is rare in

eukaryotic

cells.

Premature

termination

occurs

at

some

genes

and is counteracted

by a

kinase,

P-TEFb, but otherwise

antitermination

does

not

seem to be employed.)

25.1

Introduction 641

Control of transcription initiation: used

for

most

genes

Local structure of the

gene

is

changed

General transcription apparatus

binds to

promoter

RNA

is modified and

processed:

can control expression of alternative

products

lrom

gene

Finally, the translation

of an mRNA in the

cytoplasm can be specifically

controlled. While

employment

of this

mechanism is

uncommon

adult somatic cells,

it does occur in some embry-

onic situations.

This can involve localization of

the mRNA to specific sites

where it is expressed

and/or the blocking of

initiation of translation

by specific

protein factors.

Regulation of tissue-specific

gene

transcrip-

tion lies at the

heart of eukaryotic differentia-

tion.

A regulatory transcription factor serves to

provide

common control of

a large number

of

target

genes,

and we seek to answer two

ques-

tions about this

mode of regulation: How does

the transcription

factor identify its

group

of tar-

get genes,

and how is the activity of the tran-

scription factor

itself regulated in response to

intrinsic or extrinsic signals?

There Are

Several

Types

of

Transcri

ption

Factors

The

basa[ apparatus

determines the startpoint for

transcription.

Activators determine

the frequency

of

transcri

ption.

o

Activators work by making

protein-protein

contacts

with

the basal

factors.

e

Activators may work via coactivators.

.

Some components of

the transcriptional

apparatus

work

by changing

chromatin structure.

Initiation of

transcription involves

many

protein-protein

interactions

among transcrip

-

tion factors bound at the

promoter

or at an

enhancer, as well as with RNA

polymerase.

We

can divide the factors required for transcrip-

tion into several classes, which are described

in the following 1is1.

;jdiifil J:,;.:

summarizes

their

properties.

.

Basal factors, together

with RNA

poly-

merase,

bind

at the

startpoint and TAIA

box

(see

Section 24.10, The Basal

Appa-

ratus Assembles at the Promoter).

.

Activators are transcription

factors that

recognize

specific short consensus

elements. They

bind to sites in the

promoter

or

in

enhancers

(see

Sec-

tion 24.11, Short Sequence

Elements

Bind Activators). They

act by increas-

ing the efficiency with

which the

basal

apparatus

binds to the

promoter.

They

therefore increase the frecuencv

of tran-

mRNA is exported from nucleus to cytoplasm:

not regulated

mRNA

is translated:

regulated in

amphibian development

i:i=,::iii ;::.

-i

Gene expression is controtled

principal.l"y

at

the

initiation

of transcriotion. It is rare for the subse-

quent

stages of

gene

expression to be used to determine

whether

a

gene

is

expressed, aLthough controI of

process-

ing

may be used to determine which form

of a

gene

is rep-

resented

in mRNA.

The

primary

transcript is modified

by cap-

ping

at the 5'end,

and

in

general

also is modi-

fied

by

polyadenylation

at the 3' end.

Introns

must be excised from

the transcripts of inter-

rupted

genes.

The mature RNA must be

exported from the nucleus

to the cytoplasm.

Regulation

of

gene

expression

by selection of

sequences

at the level of nuclear RNA might

involve

any or all of these stages,

but the one

for which

we have most

evidence concerns

changes in splicing;

some

genes

are expressed

by means

of alternative splicing

patterns

whose

regulation

controls the type

of

protein product

(see

Section 26.12, Alternative

Splicing Involves

Differential

Use of Splice Junctions).

CHAPTER 25 Activating

Transcription

scription,

and

are required

for

a

pro-

moter to function

at an adequate

level.

Some activators

act

constitutively

(they

are

ubiquitous),

whereas

others have

a

regulatory

role

and

are synthesized

or

activated

at specific

times

or in specific

tissues.

These

factors

are therefore

responsible

for

the control

of transcrip-

tion

patterns

in time

and

space. The

sequences

that

they bind

are called

response

elements.

Members

of another group

of factors

necessary

for

efficient

transcription

do

not

themselves

bind DNA.

Coactiva-

tors

provide

a connection

between

acti-

vators and

the basal

apparatus

(see

Section 25.5,

Aclivators

Interact

with

the Basal Apparatus).

They work

by

protein-protein

interactions,

forming

bridges between

activators

and the

basal

transcription

apparatus.

Some coactivators

and

other regulators

act to make

changes in

chromatin

(see

Section 30.7,

Acetylases

Are Associated

with Activators).

The

diversity

of elements

from which

a

functional

promoter

may

be constructed,

and

the variations

in their

locations

relative to

the

startpoint,

argues

that the

activators have

an

ability to interact

with one

another by

protein-protein

interactions

in

multiple

ways.

There

appear to be no

constraints

on the

poten-

tial

relationships

between

the elements. The

modular nature

of the

promoter

is illustrated

by experiments

in which

equivalent

regions of

different

promoters

have

been exchanged.

Hybrid

promoters,

for

example,

between the

thymidine kinase

and

p-globin

genes,

work

well.

This

suggests that the main

purpose

of the ele-

ments is

to bring the

activators

they bind into

the vicinity of the initiation

complex, where

protein-protein

interactions

determine the

effi-

ciency

of the initiation

reaction.

The

organization of RNA

polymerase

II

pro-

moters

contrasts with

that of

bacterial

promot-

ers,

where all the transcription

factors

must

interact

directly with

RNA

polymerase.

In the

eukaryotic

system, only the

basal factors inter-

act directly with the

enzyme. Activators

may

interact with

the basal factors,

or they may inter-

act

with coactivators that in

tum interact

with the

basal

factors.

The construction

of the

apparatus

through layers

of

interactions

explains the flex-

ibility with which

elements may

be arranged and

the distance over which

thev can

be disnersed.

Enhancer

RNA

polymerase

and basal factors

bind

at

promoter

Activators

bind at

promoter

Activators

bind to distal

sites in

promoter

or

to enhancers

Coactivators

connect

activators to

basal

factors

Coactivators/

regulators

act

on local

structure

of

gene

i

!*liit[:

'l:1."]

Factors involved in

gene

expression

include

RNA

polymerase

and the

basaI apparatus,

activators that

bind

directLy to

DNA

at

the

promoter

or at

enhancers, coac-

tjvators

that bind to

both activators

and the basal appa-

ratus, and requlators that act on

chromatin structure.

Independent

Domains

Bind DNA and

Activate

Transcription

r

DNA-binding activity and

transcription-activation

are carried

by

independent

domains of an

activator.

r

The role

of the

DNA-binding domain

is

to bring

the

tra

nscri

ption

-activation

doma'i

n i nto the vici

nity

of the oromoter.

Activators

and other

regulatory

proteins require

two types

of

ability:

o

They recognize specific

target

sequences

located

in

enhancers,

promoters,

or

25.3 Independent

Domains

Bind DNA and

Activate Transcription

other regulatory elements that affect

a

particular

target

gene.

.

Having

bound

to DNA, an activator

exercises

its function by binding to other

components of the transcription

ap-

paratus.

Can we characterize

domains in the acti-

vator

that are

responsible for these activities?

Often an activator

has

separate domains

that

bind DNA and activate transcription. Each

domain behaves as a separate

module

that

func-

tions independently when

it is linked

to

a

domain of the other type. The

geometry

of the

overall transcription

complex

must allow the

activating domain to contact the basal appara-

tus irrespective

of the exact

location

and orien-

tation of the DNA-bindine domain.

Upstream

promoter

elements may be an

appreciable distance

from the

startpoint,

and in

many

cases

may be oriented

in

either direction.

Enhancers may be even

farther

away and

always

show orientation

independence. This organi-

zation has implications

for both the DNA and

proteins.

The DNA

may

be

looped

or condensed

in

some

way

to allow the formation of the tran-

scription complex.

In addition, the domains of

the activator may be connected

in

a

flexi-

ble way, as

illustrated diagrammatically in

ilESi.Jftf 85.3. The main

point

here is that the

DNA-binding and activating domains are

inde-

pendent,

and are connected in a way that allows

the activating domain to

interact

with the basal

apparatus

irrespective of the orientation and

exact location of the

DNA-binding

domain.

Binding to DNA is necessary for activating

transcription, but

does activation depend on

the

p

articul ar

DNA-binding

domain?

FIfri.lRil E$.,{,

illustrates an experiment to

answer this

question.

The activator

Ga14

has

a DNA-binding domain that recognizes a UAS

and an

activating domain that stimulates initi-

ation at the target

promoter.

The

bacterial

repressor LexA

has

an N-terminal

DNA-

binding domain

that recognizes a specific oper-

ator. When LexA binds to this operator, it

represses

the adjacent

promoter.

In

a

"swap"

experiment, the

DNA-binding domain

of

LexA

can be substituted

for the DNA-binding

domain

of Gal4. The hybrid

gene

can then be introduced

Connecting domain

DNA-binding

domain

if*LJfr{

I5"3 DNA-binding

and activating

functions in a

transcription factor may comprise independent domains

of the

protein.

Gal4

activator

Gal4 DNA-binding

Binding

and

transcription

@

No

binding

I

LexA

DNA-binding

No

binding

Binding and

transcription

i:Ifil.Jft{ fh.r"i The

abitity of Gat4 to activate transcription is independent

of

its

specificity for

binding DNA. When

the Gal.4

DNA-binding

domain

is

reptaced bythe LexA DNA-binding domain,

the hybrid

protein

can activate transcription when a LexA

operator

is

ptaced

near

a

promoter.

CHAPTER 25 Activating

Transcription

644

into

yeast

together

with

a target gene

that con-

tains either

the U1S

or a LexA

operator.

An authentic

Gal4

protein

can

activate a

target

gene

only if it has

a

rJ

AS. The LexA

repres-

sor

by

itself

of course

lacks

the ability

to activate

either

sort of target.

The

LexA-Gal4

hybrid

can

no longer

activate

a

gene

with a

UAS, but it

can

now

activate

a

gene

that

has a

LexA

operatorl

This

result fits

the modular

view of tran-

scription activators.

The

DNA-binding

domain

serves to bring

the

protein

into

the right

Io-

cation. Precisely

how

or

where it is

bound to

DNA

is irrelevant,

but

once it

is there,

the

transcription-activating

domain

can

play

its

role.

According

to this view

it

does not matter

whether the transcription-activating

domain is

brought to

the vicinity

of the

promoter

by recog-

nition of a

U,4S via the DNA-binding

domain

of

Gal4

or by recognition

of a LexA

operator via

the LexA specificity

module.

The

ability of

the

two types

of module

to function

in hybrid

pro-

teins

suggests that

each

domain of

the

protein

folds

independently

into an

active

structure that

is

not influenced

by the rest

of the

protein.

The

idea that

activators

have independent

domains

that bind DNA

and

that activate

tran-

scription is reinforced

by the ability

of rhe rar

protein

of HIV to stimulate

initiation

without

binding DNA

at all. The

tat

prorein

binds

to a

region

of secondary

structure

in the RNA

prod-

uct; the

part

of the RNA

required

for tat action

is

called rhe tar

sequence.

A model for

the role

of the taI-tar interaction

in

stimulating

tran-

scription is shown in

i:,r-'iJil!,:

tiij.lr.

The /ar

sequence is located

just

downstream

of the

startpoint, so that

when

tat binds to /ar,

it is

brought into

the vicinity

of the initiation

complex. This is

sufficient

to ensure

that its acti-

vation domain is in

close

enough

proximity

to

the initiation

complex. The

activation

domain

interacts

with one

or more of

the transcription

factors

bound

at the complex

in the

same way

as an

activator.

(Of

course,

the first transcript

must be made

in the

absence

of tat in order to

provide

the binding

site.)

An

extreme demonstration

of the indepen-

dence

of the localizing

and activating

domains

is indicated

by

some constructs

in which

tat was

engineered

so that the

activating

domain was

connected to a DNA-binding

domain instead

of

to the

usual /ar-binding

sequence.

When an

appropriate target

site was

placed

into the

pro-

moter, the tat

activating-domain

could

activate

transcription. This

suggests that

we should think

of

the

DNA-binding (or

in this

case the RNA-

binding) domain

as

providing

a

"tethering"

func-

tion,

whose main

purpose

is to ensure that the acti-

vating

domain

is

in

the

vicinity of the initiation

complex.

The

notion of tethering is a more specific

example of the

general

idea that initiation

requires

a

high

concentration

of transcription

factors

in the

vicinity

of the

promoter.

This

may

be achieved

when

activators bind to enhancers

in

the

general

vicinity, when they bind to

upstream

promoter

components, or, in an

extreme

case, when

they bind by tethering to

the RNA

product.

The

common

requirement of

all

these situations is flexibility

in

the exact

three-dimensional

arrangement

of DNA and

proteins.

The

principle

of independent domains

is common in

transcriptional

activators.

We might view the

function

of the

DNA-

binding domain as bringing the activating

domain

into thevicinity 0f the rtarryoint.This explains why

the

exact locations of

DNA-binding sites can

varv

within the oromoter.

The Two Hybrid

Assay

Detects Protei

n- Protei n

Interactions

r

The

two

hybrid

assay

works by requiring an

interaction

between two

oroteins,

where one

has

a

DNA-binding

domain

and the other has a

transcriotion-activation domai

n.

i:r.tii.ilil

,lli"::i

Theactivatingdomainofthetatproteinof

HlVcanstimutatetranscrip-

tion

if it is

tethered

in the vicinity by binding

to the RNA

product

of a

of transcription.

Actjvation is independent

of the means of tethering,

as shown by the

substitution of a DNA-bindinq

domain

for

the

RNA-bindinq domain.

25.4 lhe Two Hybrid

Assay Detects

Protein-Protein Interactions

The model of domain independence

is the basis

for an extremely useful assay

for

detecting

protein

interactions. In effect, we

replace the

connecting domain

in Figure 25.3 wiLh'

a

protein-protein

interaction.

The

principle

is

illustrated in

i:ii.r-:i.t:

'.i1.t-:.

We fuse one of

the

proteins

to

be

tested to a DNA-binding domain.

We fuse

the other

protein

to a transcription-

activating domain.

(This

is

done by

linking the

appropriate coding sequences

in each case and

making synthetic

proteins

by expressing each

hybrid

gene.)

I{

the two

proteins

that

are being

tested can

interact

with one another, the two

hybrid

pro-

teins will interact. This is reflected in the

name

of the technique: the two hybrid assay.

The

protein

wirh the DNA-binding domain binds to

a

reporter

gene

that

has a

simple

promoter

con-

taining its

target site.

It

cannot,

however, acti-

vate the

gene

by itself. Activation occurs only

if the second hybrid binds to the first hybrid to

bring the activation domain to the

promoter.

Any reporter

gene

can be used where the

prod-

uct

is readily

assayed, and this

technique has

i

i,.,,,ii1rr i:;.i. The

two-hybrid technique

tests

the

abil.ity

of two

proteins

to interact

by

incorporating

them

into

hybrid

proteins

where

one

has

a DNA-binding domain and

the other has a transcription-activating

domain.

CHAPTER 25 Activating

Transcription

given

rise to several automated

procedures

for

rapidly testing

protein-protein

interactions.

The effectiveness of the technique

dramat-

ically illustrates

the modular nature of

proteins.

Even when fused to another

protein,

the

DNA-

binding domain

can bind to DNA and the

transcription-activating

domain can activate

transcription. Correspondingly,

the interaction

ability

of the two

proteins

being tested

is not

inhibited by the attachment

of the DNA-

binding or transcription-activating

domains.

(Of

course, there are some

exceptions for which

these

simple rules do

not apply and interfer-

ence

between the domains of the

hybrid

pro-

tein

prevents

the technique from working.)

The

power

of this assay is that it requires

only that the two

proteins

being tested

can

inter-

act

with each other.

They need

not have any-

thing

to do with transcription. As a result of

the

independence of the DNA-binding and

transcription-activating domains, all we

require

is that they are

brought together. This will hap-

pen

so

long as the two

proteins

being tested can

interact

in

the

environment of the nucleus.

Activators Interact

with

the

BasaI Apparatus

The

principte

that

governs

the functjon of a[[

activators

is that a DNA-binding domain

determines specificity

for

the target

promoter

or ennancer.

The DNA-binding domain

is responsible for

localizing a transcription-activating domain

jn

the

proximity

of the basaI apparatus.

An

activator

that works directty has a DNA-binding

domain and an activating domain.

An act'ivator that does

not have

an activating

domain may work by binding a coactivator that

has an activating domain.

Several

factors in

the basal apparatus are targets

with which

activators

or coactivators interact.

RNA

polymerase

may be associated wjth various

atternative sets of transcriotion factors in the form

of a holoenzyme complex.

An

activator

may

work directly when it con-

sists of a DNA-binding domain linked to a tran-

scription-activating domain, as illustrated in

Figure

25.3.

ln other cases, the activator does

not itself have a transcription-activating

domain,

but binds another

protein-a

coactivator-that

has the transcription-activating

domain.

liirti!{[

l1ii. ,'" shows the action of

such an activa-

tor. We may regard coactivators as transcrip-

tion

factors

whose specificity is conferred by the

The

players

Proteinl Protein2

fused

to fused to

DNA-binding

domain activation domain

The reporting

system

Protein-bindingsrte Reportergene

=\'ffi*.ffi

I

Y

CAT or other reporter

product

Noninteracting

proteins:

no

expression

I nteracting

proteins

activate expression

646

L'9

snlplpddv

lespg

aql

qlm

lleralul

srolp^ltlv

g.gz

.€rrl1

bu!

-llpluol

Aq

lo

0IIII

Jo

slvj

aql Eurlreluor Aq uorlerlruL

1o

sa6e1s

lua.laJJtp

le

lloM

feu

srolenrlry

t"tji: rtl*ili*g*

gllgl

slceluoc

role^tlcv

'snle.lPddP

lPsPq

aql sllel

-uor

lpqlrolp^qlpol

p

purq

r\eLu rolerrq:e

uV

e1.*rl

i]tr**i:l

sI

luaurelJ

c5yp

lseaz(

p

ueqM

'aldruexa

ro4

'slueruJla

]o

suortpurqruoJ

Mau

Jo

Sullslsuol

sJeloruord

Surlrnrlsuor

dq paqsrldruoJJe

uaeq

aneq z(ltTtlesJa^ q)ns

Jo

suorleJlsn11r

Sur>Ilrts

eluos

'uolleluroJ

s1r Jlelnurls

ol JIqp aq

.{eru

xalduror

uortellrul

Ipspq

erll

;o

a8uer urqlrM

lq8norq

sr uor8ar

Surle,Lrlre

JSoqM sJolelrlJe

,{uy

'arnleu

ur

leraua8

dlanqelar

arp

pJle^rl)e

sl

lI

qJrqM

z(q

sluazra

Jr{l

lpqt

stsaSSns

'tuasard

slueurele

relnrrlred

Jql

ot uene JJueJalJrpur

sll

pue

'slualuale

yo

luaruaSueJJpJr

Jql 0l JJlOru

-ord

1

aseraruLlod

yNU

ue

Jo

JtuJIIrseJ JqJ

'JolelrlJp

JrprJp

up

;o

etuaserd aql

dq parelnulrs

sr

rpql

dals Surtrrurl-aler e JroJ

-eJJql

sr raloruord

slqt

lp

xelduol

eql olq

gIIdJ

yo

,{lqruassy

'gIIdJ

ol

,{lDarrp purq

ue) rolel

-lDe

9 14n

Jql

leql

pue

'srole^rlre

prrp

g

I dA

Jo

71eC

Jo

aruasard

aql

,{q

palelnurts

sr ratoruord

SnJIAouJpe

ue

tP

xelduoJ

uollelllul up ol

gIIdJ

;o

Sutpurq

teql

,lror{s

zJlt^ ut

sluarurradxg

'xa1d

-ruoJ

uopellrut

1eseq

aq1 uroI

ot

gIIdI

yo

.dtlgqe

aqt

Suouequa Lq

uorpunJ

sJolelrDp JIpIJV

';lloru

8ut

-pulq-VNO

p

ot

pe>lurl

uor8ar Surlenrpe

914n

aql

Jo

asn apeu uauo

a^eq suorl)unJ JolenrlJP

JrprJe JZrJepeJpqJ 01 sluerurJJdxg

('uralord

[re

-rperurJtul

ue erl snlereddB uorldrnsue;1

aql

qlIM

speJelul

lnq

'ureruop

Eurpurq-yN(

p

aleq

JIJSIT

tou

sJop

9IdA)

'snrn

xaldrurs

sad-raq aqt;o

uratord

9 I dA

eql ,{.q

parrrer

sr ad[t

slqt

Jo

Jolpn

-rtJp

JAT1JJJJa Lpelnrrged

raqtouv,,'sJolelrtJe

)rpr)p,, se uoudrJJsap reql 01 asu SurArB

'sa8req;

enrlp8au a1dr11nru eleq

tu)t

pup

71eC

srol

-elrtf,p

1sea,{

aql

Jo

sureuop Supezrlne aq1

'ralourord

aql

Jo

Jsn sasPeJJur

.{qa:aqt

pup

'uorlpprur

Jo

ssaJord

aql spaads

srql

lxaldruor

uortdrnsueJl

Ieseq

aql sezrlrq

-e1s

uorpPJJlur 3q1

'esp)

Jeqlra

u1

'xaldruo;

xoq

VJyJ-CIII4J

aql

punoJe

sJotelrl)e raqlo

1o

3ur

-purq

aql slsrssp ro xoq

VJVJ

rqlol

(IIdJ

Jo

3ul

-purq

slsrsse Jaqlra

uortJerJtur aql

lpql

aurnsse

J14

'sdVJ

aldrllnru

qllm

Deretur

sraqlo lsdvJ

Ienprnrput

qrpl

dpo

tJerelur

sJotp^rDe aruos

'sJole^rlJe

lueJaJJrp

qu1!t

1JeJJlul 1eql

sJJeJJns

apnord,{.eru

qIIdJ

uI sdvJ

lueJeJJrq

'sJolplrlJe

.{q

palelnrults

JJp

tpqt

uoltdlJJsuprt

Jo

sIJAJI

raq8q eql roJ

pa:rnbar

are

qIIdJ

Jo

sdVJ

eql

seJJJqM

'uorldrnsueJl

la^al-leseq

uoddns

uel

auole

dgJ

z(qm

surcldxa srqJ

'sJolpnrlJe

01 snl

-eredde

Ieseq

Jr{1 ruoJJ uorlJauuoJ Jqt apmord

01 sr s{vJ eql

Jo

JIor rolpru e

'lJeJ

uI

's{VJ

IpJe

-^as

Jo

auo

^up

lJeluoJ

,{eru

qlqazr

'sJolpnrlJp

ro1

1a8rel

uoruruoJ

lsoru

eql ae,r{eur

qIrgl

'snleredde

Ipseq

aqt;o

dlqruasse

aqt

eJuenlJur 01 sr sJolelrlJe Jql

Jo

lra;;a

roleru

eql

'Jpeu

sr

lJeluo)

e

q)ns

uJqM uorlenlls

Jql selPJl

-snlll

S'$ff

jHfisij

'ftyVZ

arn8rg aas) snleredde

Ieseq

Jql;o,{lqruasse

yo

sa8els d1:ea ur aledolt

-red

srope; esaql

Jo IIV

'YII{J

Jo

'gIIdJ '(ndJ

r{llM srnJJo .{1prrd,fu

tnq

'srolJeJ

Ieseq

lpra^es

Jo

auo z(ue

qlr,u

Jperu Jq l(eru snleredde

pseq

eqt

qrlm

tletuoJ

'snleredde

Ieseq

eqt

Jo

^lq

-Luesse

aloruord

lpql

sJolJpJ uopdrnsuerl

pra

-ua8

qluzr.

stf,etuoJ uralord-uralord Suqeru dq

s>lJom ureruop Surle.ulre-uorldrnsuerl

V

'slrunqns

urJloJo

alorl

-Fru

olur

paprlrp

Jo

llunqns

uralord

arups aql ur

luasard

eJe sureruop snorJpl aqt Jaqlaqu

Jo

eAIl

-radsarrr

'uorlplrlJe

ro; alqrsuodsal eJe suorl)p

-Jelur

eurps aq1-'(L'SZ arn8rg

pue

f'SZ

arn8rg

aredruor)

slrunqns uralo:d ueemlJq Supurq

lualP^oJuou

eAIoAur suorlJJuuoJ Jql

'JoleA

-ltlpoJ

e

q8norql

s>lroM rolelrl)e ue uaq6

'ureruop

Surpurq-y1trq

rr{t ot

parrauuor

d1lua1

-Pno)

ureruop uorle^rl)e uP sPq

,{lDarrp

snlBr

-edde

pseq

Jql speluoJ

lpr{l

Jolp^ltJp uV'erues

aql sl lusruPqrrtu

Jq1 ,(1tuaral;rp

pazrueSro

are sluauoduroJ ureloJd aqr

q8noqrly

'rolelrlJpoJ

rr;neds e arrnbar deru role.r.

-rpe

JelnJrued

v

'VN(

ol

,{pralp;o

peJtsur

sJol

-re;

uorldr.rrsuerl Surpurq-vNq 01

purq

o1 d111qe

uorldulsuerl

6urlp^!]lv

gZ

UlIdVHl

srql JoJ elqrspJJ

tl

sI

'suleloJd

gtr<

Jo

stslsuoJ

leql

snleredde a3re1

Lrarr e

la8

a.,tzr-srolelllJe

-oJ

pue

'sJotplrtJe

'aseraru.dlod

VNU

'sJo1

-JeJ

Ipspq-uortdrnsuerl

lueIJIJJe

ro;

pattnbar

sluauodruoJ eq1

IIe

dn

ppe

eM

urq6

'ralouord

aqt

te

aseraru,{1od

VNU

}o

uolteJluJ)uot

aAIDJJJJ

Jql

aseJnur

ol sr

tJJJJa

elos sll

teql

stsaSSns

srql

'uorldrnsueJt

ul

JSeJrJur

due

arnpord

or

palpy

rolenrlJp aq1 ^ltuJlrlJJns

pJSeeJlul

sem

eseJaur

-,{1od

ypg

Jo

uorleJlueJuoJ

aqt uaq6'uo1tel

-l]Je

JoJ

lunoJJe

ueJ

luJrulInJJJJ lPql

peMoqs

tsea.{

ur JSe) Juo

ut slepou JSJqI

Jo

lset

V

',{ruaog;a

s1r sasPeJ)uI

q)lqm

'arudzua

Jql

Jo

uolteruJoJuoJ

aql ur

'aldruexa

ro;

'xaldtuo)

IPuoIl

-drnsuert

aql ur a8ueqf, aruos

sJJnpq

tl

leql

asoddns ol sl

IJporu

eAlleuJal{p

uf o

'ralouord

eql ot esPrau[1od

y51g

;o

Surpurq

Jql aspaJJur ol sl

1IJJJJ

JIos

str

leql

san8re

lJporu

luerullnJf,al

JVJ .

:lapolu

;o

sad,{1

leraua8

o.ral aut8erul

upJ eM

Zuoll

-drnsuerl

elplnrurls JolplrlJe

up seop

.ryroH

'lseaL

ur slJeluoJ

IpruJou

slr selquJsJr

teqt

snterpdde

uottdtns

-uerl

uerleruueru Jql

Jo

arnleJJ

aruos azruSo

-f,JJ

tsnur

ulatord

TlpD

aql

'salorfuelna;aq8tq

pue

lseaL

ueJMleq

pe^rasuoJ

uaeq eleq ol JroJ

-JJJql

sruJJS rJloruord

aql Jlp^tDe

01 sJsn

TleO

SUPJLU Je^eleqM

'llJr

palnlln)

uPllPrurueru

e

ul

Tlec

.riq

palenrpe

eq ue)

auaS srql

'aua3

trlo

-Lrelna

raq8rq

p

Jo

reloruoJd

aql reau

pauJSuI

819

aqr Aq

parsaSSns

st uorDBrJtul slql

Io

aruetrodtut

aq1

'sn1e;edde

leseq

Jqt

Jo

stueuodruor raqto

qlpu

SurlrerJtur tuorJ

tl luJAJld

01

dgI

ot spurq

teql

reurporJlrq e

'I

dVUC/ I

r(I/Zf

N

rossardar

1eqo13

eql sr ese) euo

'umou4

are saldruexa

JluOS

lnq'arer

r(1anr1e1ar

are uoudlJrsueJl

>lJolq

ol srossardar

IerJaDeq

?u\te-suau a>lrl uorDunJ

leql

sulJloJd roleln8ar lJrnl)nrls ulleluoJql

Suouangur

Jo Ia^JI

eql

te

peqsrldruole

L11era

-ua8

sr salodre>1na ur uorldrrlsuerl;o uorssardag

'srelouord

rgLrads o1 6uLpurq

fiq

pe

1eq1

srosseldar aie araql

lnq

'arnlln.lls

urlpuolql

6uLlrege

fiq

panarqre

r\11ensn sr uorssaldag

o

srossajdau erv

suralojd

6urpurg-ralouord auos

@

-rrporuru,n"-o,u,

1:T?",1*,iiiil#;i:il

-oJqJ

Jo

eJntf,nJls Suqelndrueru Lq >Fo,u sJeqlo

1nq

'snleredde

leseq

aqt ro aserarudlod

y51g

V1IM

Sutperalut .dq ,{lDarrp uortdtrlsuert eJua

-nlJur

sJolJel uorldursuerl

eruos

'uorle8uola

suels JserJruLlod e uaq.tr

pesealeJ,{1qeqo:d

sr

t1

'ase:aur[1od

VNU

eql o1 sluauodtuor ueartsdn

ruorl slJaJJe Surssardar ro

Surlearlre rJqlrJ

lnu

-suert

ue)

11

'aseraru.{.1od

VXU

Jo

(q13)

ureuop

IeuruJet-)

eq1

qtrM

stJerJtur

U

uJqM a8ueqr

puorleuJoJuol

e sao8rapun JolerpapsauaB

rrloL,re4na raq8rq

tsoru

Jo

uortdrnsuert

eql

ro;

parrnbar

are saxaldruor

snoSoloruog

'sauaB

lsBar(

lsoru

Jo

uorldtDsupJl

roJ Lressarau sr Jolp

-rpew'sJole^Ipe

Jo

S]JJJJJ

Jql JlprpJru or,{tr[qe

str Lq

parsaSSns

se,u

erupu ar{J

'(g

aseraru.dlod

VNU

ul suollptnru

;o

srossarddns se

parJrtuJpr

LlleurSrro

ara^,u saua8 rraql

Jo

Lueru asneraq

peueu

os) no1

gyg

aruos Surpnpur

'uorldursuerl

>lJolq suo4elnru

qJrqM

ur seuaS

IpJJ^es Jo

slJn

-pord

sapnpul JotprpeW'Jotplpaur

pa11er

xald

-luo)

llunqns-02

e

qlIM pJlelf,osse

aseraurr(1od

VNU

Jo

stslsuo)

(sluauodruoJ

Ieuorlrppe

tno

-qlptt

uopdtnsueJl Suuertrur

yo

alqeder Suraq se

paulyap)

tsea,{

ur

,,xalduror

aur,{zuao1oq,,

tuau

-rruord

tsoru

JqJ

'sJoDeJ

uortdrnsuerl snorJel

qllM

pelerJosse

sr arudzuJ

Jqt

qJrqM

ur

punoJ

uJJq JAeq aseraurdlod

y51U

Io

stuJoJ

IeraAaS

'{'rii:

;iijili,:j:i

uI

pelPI]Snlll

sB

'srole^r]f,eof,

pup

sJolp^rlJp JaqunJ

qll,!1. pJIq

-ruasseard

aseraur,{1od

vNU

Jo

Surlsrsuor xald

-ruor

a8rel

L:a.r

e Lq

paurot

aq ,{.eru uaql

tnq

taloruord aqt

le

astrrzrdals

alquJSSe Aeru srotrey

IPSeq

puP

'srole^rpPof,

'sJolPArDe

eluos

zJalou

-ord

aqt

1e

dals-dq-dals

JIqruJSSp ol snlBredde

's.loJPnrllP

fueu 6uru reluor

auAzueoloq e sp

slsrxo aserauAlod

VNU $.'jf, $+.9{j5:j

6V9

srolp^r.llv

Aq

pazru6orau

alv

sluaual3

asuodsaS

1.g7

sJteJlsnllr

saua8

lroqs

tpaq

eqt

Jo IonuoJ

aqJ

'svNuru

Jo

uorlelsupll

Jr{l ul

sa8ueqr sJsnpf,

pue

'sauaE

>IJoqs

leeq

aql

Jo

uortdrnsuerl

uo

surnl

'saua8

eruos

Jo

uorldrrtsuert

JJo

suJnl

arnleradrual

ur

JsealJur

uy

:uorssJrdxa

aua8

]o

sloJluoJ

a1drl1nru

sJAIo^ur

pue

saloLrelna

pue

sa1o.,{relord

;o

JBUPJ JprM

p

ol uoru

-Luo)

sr srql

'asuodsal

>lJoqs

leeq

aqt .{q

paprrr

-ord

sr roDe;

a13urs

e

, q pa11oDuof,

aJe saueS

z(ueru qrrqaa.

ur uorlpnlrs

e;o

alduexe uv

_

'passJJoxa

Jq

ol sr aua8

aql

uJqM

JunuJJlap suorlrpuoJ

JqI

'suolllpuo)

uIelJJJ

JJpun .{.luo

anrlre sr ro

elqelrele

JerIlrJ

sr uralord

Jql

tpql

sr

slolelr]f,p

enrlle,{1anr1n1r1suo)

uoJJ JJuJreJ}rp

aqJ'uorl

-dtnsuert

alertrur

ot aseraruLlod

VNU

Molle ol

parmbar

sr

luJruJIJ

asuodsar

Jql

ol JolplrlJe ue

;o

Surpurg

'aldnur:d

leraua8

eues eqt.{q uorl

-JunJ

stueuala

asuodsal

IIe

tpqt

Junsse JM

'JJJuequJ

ue

ur

punoJ

sMug e

seeJJqM

'Jelou

-ord

e ur

punoJ

sl

gSH

ue ,{11ensn :JJqlo

eq1

upql

JJrltpJ

euo

ur

punoJ

,{11elrdz(1

JJp slueur

-JIa

Jo

sadu(l aruos

'sre)uequJ

ur ro

slJlour

-ord

ur

pJtpJol

aq.{eu

stuJruele

asuodsag

'sardor

a1drl1nu

are JJeql

seurrleruos

1nq

'asuodsar

LrolelnBar

Jqt JaJuoJ

ol

IUJIJIJJns

sr ,{1ensn

luarualJ

a13urs e

Jo

JJuJ

-sard

aq1

'tl

Jo

ueartsdn

dq

ggg>

,{11ensn

are

lnq'luloduPts

eqt

uoJJ sJJuptsrp

paxrJ

te

luasard

lou

JJp

slueruJlJ

Jql

'srJloruord

u1

'aruanbas

sns

-uJSuoJ

Jql

Jo

Jprs

Jeqlre uo

J)uelsrp

lJorls

p

JoJ

spuJtxJ

rolJey

aqr.dq

punoq

uor8a; JqJ'leJrluepr

dFressarau

lou

lnq'peleleJ

Llasop are saua8

lueJJJJrp

ur

punol

stuJruJIJ

asuodsar

Jql

Jo

sardot lsaruanbas

snsuasuo)

uoqs

ureluo) slueru

-a1a

asuodsag

'(1uarua1a

asuodsar

urnras)

gUS

aqr

pue'(1uatua1a

asuodsar

pIoJIUoJ

-ornp)

trUD

rql

'(1uarua1a

asuodsar >IJoqs

lpeq)

gSH

eql

eJe saldruexa ltuJLuJIJ

asuodsar

p

pJIIpJ

sr JollpJ

e qJns

ot

puodsar

tll JuJS e

sasneJ

leql

luJuele

uv

'.t)lqNila

ua '{q

panuSont

s!

ru41

ruawtala

(ntua4ua

n)

nlotuotd a anuls far1l

leql

sI

loJluof,

uoruuroJ

repun sauaS;o sdnor8

Sutztratlerer{J

tuoJJ sa8rarua

leql

aldourrd

aq1

'suorleurquol

utpilal

ur to Alluapuadapur

uoqdursuerl

ele^rltp l\eu

urnl ur

qlrqM

'sluouralo

asuodset

Aueu

eneq fieu telouord

y

lolPA!1rP

rgoads

e r{q

pezru6oral

sr

}uaulela

asuodsar

qre3

'slaluPuua

ro sralouro.rd

ur

palerol

aq Aeu

sluauale asuodsag

'uorldrnsuerl

aua8 ol

luelalaJJr

uJAJ

.ro iossardar

p

tole^rl)p

ue aq.deru

1I

:pJrunsse

Jq

louueJ

lueruJle

raloruord uMou>l

e ol

8ul

-pulq

ul uralord e

Jo

uorl)unJ aqt

leqr turod

aqt

e>leru osp stlnsJr

asaql'snohqo sr ralourord

aql

le

Suueqrul ruoJJ eseJeru,{1od

y111g

Suuuanard

ur rossardar

lprraDeq

p

Jo

paJJe

Jqt

qrlM

^3o

-leue

aqJ

'pelquasse

Suraq uror; xaldruor

uorl

-drnsuerl

e sluanard ralourord Jql ruoJJ

JoDeJ

Supurq-1yy) eqt

Jo

uorsnlJxJ eql

'Jnssrl

Jruo

-.drqrua

uI'sa)uJnbJs Jarrrepo

pue

'sexoqJW)

'xoq

VJVJ

eql

le

sJope; uorldrnsuerl ,{q

punoq

sr raloruord

Jql

'susel

u1

'uorssardxa

aua8

ro;

saruanbasuoJ Jql sJleJtsnfir

ij

i'

ii

i1 :ii,.i ir* {:!

'wa41

6utztu6nat wott

to1

-o^tpo

atltr 6u4ua^ard f.qata4l'sJxoq

JyV)

eql 01

spulq

'(dql)

ularord

luaurareldstp-JyV)

rql

pJIIp)

'urJlord:aqloue

sanssrl lruoz(Jqrua

Jr{l uI

'xoq

Jvy)

Jqt ol

pulq

ueJ rrurroJ

aql

,{1uo

rnq

'sJnssrl

rruo,{rqua uorJ

oslp

pup

Jnssrl srlsal

ruorJ

patJeJtxa

eq upf, sJolf,pJ Surpurq-1yy3

'urqf,Jn

pJS

e ur srsauaSolerurads Surrnp zlpo

passa:dxa

\lr-q1(Ze'VZ

arn8r4 aas)

g3g

auolsrq

ro;

aua8 e

Jo

Jaloruord aqt ur

punoJ

eJp

tuaur

-elJ

srql;o sardor olAl'uoueln8ar ro;

ta8Jel

p

sr

aruanb a s

rYY )

aqr'ffi

ijlllli:i::H;"1,

"o

Surlrqrqur ur JIoJ Jlrl)e ue eleq z(e,lr

srql ur

>lJoM

leql

srossardag

'lsead

ur rossarda:

eq1 JoJ

apoJ

teql

saua8 aql ur suouelnru

1nu

yo,{r1pqta1

'ul.lol

louuPl

xalouoJ

e^qlP

uP

os

'6urpurq

uorJ.lolleJ 6uLpurq-1yy3 eq1 sluanard oArqtua

ur. rollpJ

lueuereldsrp

lVVl

aqt

yo

6urpurg

'srlsal

ur

.lalourojo

8zH

urql.ln eas aql ur sluau0l0

lera^es Jo

u0rl

-ru6orar

sanlo,ruL

xaldtuoc

uorldulsue:l

V

il;

i.'i,i

ri,tJillti::

sroJP^tllv

Aq

pazru6olau

eJV

slueulall

esuodsau

uoqdulsuprl

6urlp^ltlv

9z

ulldvHl

'Molaq

polPrrpur

ale uaqJ

pulq

lPLll

sutolold

pue

'deu

aql

a^oqP uMoqs arP sJuauala lalouo.ld

'prolr.ilorornl6

ol asuodsor loJ

luauale

uP sPq

.laluequa

uP

luorllnpur

lelau

r0J sluauala sPq .lalour0rd

aql

'laluPqua

pue

leloul0.l0 sl! tlloq

ut sluau

-ola

loleln6ol surpluol auab urouorqlollplaur

ueunq

p

Jo

uotbai

fuoleqnEat aql

t i.'{i

$:{i!1}5i

099

-Fru

]o

uorsnlrur Jql

^q

pJlarqJe

sr uorDnpur

Jo

1a,r,a1

ralear8 e

1p1aru

Lneaq ot

puodsar

o1 ,{1gqe

aqt sJaJuoJ

AUW

auo;o

aruasa:d eqJ'sluauelJ

JJloruoJd se uort)unJ

qJIqM'seJuanbes

(AUW)

tuJruele

asuodsar

letaru

a1dr11nru aqt

z(q

peJJeJ

-uoJ

sr slplJru ol asuodsar

J^rlJnpur

JqI

'sa8ueqr

leuorldrnsue,rl

Jo

sJUJS

e raSSrrt sJJlsJ

Ioqroqd

qrrq,t,r

Lq

sueaur

(a1os

aqr,{.pessarau

tou tnq)

auo sr uorDear 3ur

-pulq

slqJ

'guJ

eqt

qllM

Idy

Jo

uorl)Pralur rql

z(q

pateparu

sr asuodsar slqt

pue

'(srorunl

saloru

-ord

leqt lua8e

ue)

y41

sp

qrns

sratsa

Ioqroqd

ol

asuodsar

p

srJJuoJ

iIUJ

JqJ

:uou)unJ

puo)as

p

spq

osp Surpurq

Idy

'Jolp^rtJp

ue sr

Idy

qJrqm

roJ

'uorssardxa

Jnrlnlrlsuo) roJ

tusrueqf,au

aql

Jo

ued

sr uorDerJlul slqt

jIdV

rope; roy atrs Surpurq

e seq

AUJ

eqJ

'07AS

snrr^ rqt;o sleadar dq

74

Jqt

pup

urJuorqtollplau

Jo

ilfg

Juo Surpnpur

'sraJupque

IeJJAJs

ur

luasard

sr

teqt

aruanbas sns

-uesuo)

e sl

(HUJ)

tuJrxelJ

asuodsar

y41

aql

'JeJuPquJ

07AS

Jql

purq

lpql

suratord lq

punoq

JJe

pue

'sJJJueque

rJqlo ur

punoJ

Jsoqt ot

pJtelar

saluanbas

uretuoJ

f,aql

'rralJa

Jo

ssol

tnoqtrM

JJJqM

-asle

peloru

eq ueJ Laqt

'turodlrpts

Jqt

Jeau

pJte)ol q8noqrly'sreJueque

;o

uortdrnsap

leru

-JoJ

Jqt

tlJ

q)IqM

'(Efg)

stuerurlr

Ir^rl

Ipseq

oul Jqt ate uorssardxa

Jo IJ^JI Iespq

Jqt JoJ

pepeau

oslv

'lurod1.rpts

Jqt ot JSoIJ dpre; suorl

-rsod

lensn

JrJql

te

pJle)ol

eJp sJxoq

)1;

pue

VIVI

JqI'uo1ldrnsuerl JleArDe ueJ

teqt

sluJur

-JIJ

Jo

,i.1rsuap q8rq

aqf

sr deru srqt

Jo

JJnteJJ

roferu

V'.i::'i;r: .{*,=*-*l:j

uI

pazrJeur[rns

st aua8

IW

ue.rol ratoruord Jql

Jo

uortpzrue8ro aq1

'slueurJle

rfuoteln8ar

;o

spuDI

luaJJJJrp

IeJe^es

saurqruoJ uorSa,r

lorluoJ

eql

'splo)IuorornlS

.dq ro

(runuuper

se

qrns)

suor

Ieleru

Lneaq r(q uorssardxe

Jo

sle^al ratear8

ot

peJnpur

sl

lnq

'lJ^al

Ipspq

p

te

passardxa

sr

aua8 aql

'lla)

aql ruorJ

ll

Sur.loruat

pue

Ipteru

aql Surpurq

z(q

slelaru

,{,teaq

Jo

suollertuetuoJ

ssJJXe

tsure8e

IIJJ

Jqt

stralord utalord

urauolt{l

-ollelJru

aqJ

'slrnJJrJ

luJlJJlIp

,(ueu ,{q

patel

-n8ar

aq.,{eru aua8 a18uts

e Moq

Jo

aldruexa ue

saprao.rd auaS

(tw)

ulauolqtolletalrr

JqI

'uratord

aqt

Sutte.lrDe

loJ Jlqlsuodsar

st

uorlef,rlrporu srql

1pa>lJoqs-lPJq

ere sllJ) uJq^l.

patelfuoqdsoqd

saruoraq

4JSH

tsee

'saruanbas

g5g

SururetuoJ

VNC

uo

uralted

tulrdtool

etups eql Moqs

pue

Telrurs readde

rsea.d

pue z(g

tlnJJ

Jo

suralord

dJSH

JqJ

'sulqJrn

eJS

ro slpru

-rueru

se

luplslp

se sat:ads ul

pJtpAIlJe

Jq

ueJ

nlsadoualaw

'(

ruorJ

aua8

4roqs

teaq

p

leqt

3ut

-IIJls

sl

1l

pue

'uounlo^J

uI

pJ^resuoJ

uaaq

e^eq

dJSH

pue

iISH

aqt

qrog

'stuJluale

asuodsar

luarefpe

ot

.{la.trleradoor sputq

;IISH

ar{J

'ASH

aqt;o satdor

a1dr11nru urctuo)

filso6oua1aw

alttldosotq

yo

saueB

>l)oqs

tprq

eql

IIV

'ratouord

sll

tp

J)uJnbas

1a3:el

ate

-rrdo.rdde

eqt suretuoJ

leql

saua8

0Z-

lo

dnorS

rr;nads

aql

le

uorldtJJsuprl

elelllul ot sueJru

e

sapnord eJoJeJJqt

ropeJ srqt

Jo

uoltpllDp

eqJ

'(S1SH)

rope; uorldrrJsueJt

>lloqs

leaq

totel

-rDe

luapuadJpur

uP Lq

pazruS0rar

sr

pue

lurod

-lJPlS

Jql 01 JArlelal

suOrlrSOd SnOIJPA

lP

pJlP)OI

sr

1r lnq'(ASU)

aruanbas

snsuJsuor

uoruuro)

p

ssassod osle saua8

>lJoqs

teaq

aql

'satozfuelna

u1

'(uouertrul

Iortuo)

.ri.eyq srotre4

eu8rg

Jo

uortntrlsqns

'9I 'I

I

uoItJJS

aas) saua8

lloqs

lpJq

Jo

s.raloruo.rd aql ol

uoruuor aruanbas

g

1-

anrleuJalle ue azruSolar

o1 arudzuaoloq espleur

-.{1od

y1qg

slrarrp

lpqt

pazlsaqlu,{s sr Jot)e}

eur8rs

,vlau e

'errJl)eq

uI

'lorluoJ

Jo

seporu JIlo

-/.-rapa

pue

rrlorfuelord

uae.ttlaq seruJJJlJIp

Jql

]uauralo

asuodsol

Vdl_

=

fUL

luaurole

osuoosol

lelaLu

=

3gy1

luauala

asuodsel

proctpococn16

=

399

luoulela lo^al lPseq

=

fl8

rdv

zdv

trry{

zdv

rsn

l.?ig?Sid

0urputq

utalor6

00r- 0zr- 0?r-

091- 0Br- 002-

0zz-

jvz-

092-

=fi ffi

'E

*o+i

i'e

3tB f ul/\

sluor..uala esuodsog

Lewin Benjamin (ed.) Genes IX

Подождите немного. Документ загружается.