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THIMEROSAL-CONTAINING VACCINES UNDER REVIEW: THIMEROSAL-CONTAINING VACCINES AND NEURODEVELOPMENTAL DISORDERS 27 The Immunization Safety Review committee examined the hypothesized causal relationship between exposure to thimerosal-containing vaccines and neurodevelopmental disorders (NDDs), specifically autism, ADHD, and speech or language delay. Thimerosal contains 49.6% mercury by weight. At high doses, mercury and mercuric compounds including thimerosal, its metabolite ethylmercury, and methylmercury are well-established nephro- and neuro- toxicants (AT SDR, 1999, EPA, 1997, NRC, 2000~. The data regarding the tox- icity of low doses of thimerosal and ethylmercury are very limited, and only delayed hypersensitivity reactions have been demonstrated. Prenatal exposure to low doses of methylmercury, however, has been associated with subtle neurode- velopmental abnormalities (EPA, 1997~. Thimerosal in Vaccines Thimerosal, also known as thiomersal, has been used as a preservative in some vaccines and other biological and pharmaceutical products since the 1930s. FDA regulations require the use of preservatives in multi-dose vials of vaccines to prevent fungal and bacterial contamination (General Biologics Products Stan- dards, 2000~. Until 1999, thimerosal was present in over 30 vaccines licensed and marketed in the United States, including some of the vaccines administered to infants for protection against diphtheria, tetanus, pertussis, Haemophilus influen- zue type b (Hib), and hepatitis B (see Table 2, Figure 1, and Appendix C). Prior to 1991, the only thimerosal-containing vaccine that was recommended for all infants was the whole-cell pertussis vaccine (DTP).~ In 1991, Hib and hepatitis B vaccines were also recommended for all infants (CDC, 1991a, CDC, l991b).2 Inactivated polio vaccine (IPV) and live viral vaccines, such as measles-mumps- rubella (MMR), varicella, and oral polio vaccine (OPV) do not contain, and have never contained, thimerosal (AAP, 1999, FDA, 2001~. The potential significance of the thimerosal content of these vaccines was identified through a FDA risk assessment that was called for by the FDA Mod- ernization Act of 1997 (FDAMA) (Ball et al., 2001~. Specifically, FDAMA re- quired that FDA compile a list of drugs and foods that contain intentionally in- troduced mercury compounds, and provide a quantitative and qualitative analysis of the mercury compounds in the list (Section 413(a) Pub L. 105-115~. ~ Acellular pertussis vaccines (DTaP) replaced whole-cell pertussis (DTP) vaccines on the rec- ommended schedule in the 1990s. Infanrix, the f~rst thimerosal-free DTaP vaccine (produced by Glaxo-Smith Kline) was licensed in 1997 (CDC, 1997). 2 Only one Hib vaccine that was given to children 6 months or younger contained thimerosal (Appendix C; AAP, 1999).

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28 IMMUNIZATION SAFETYREVIEW TABLE 2 Estimated Exposure to Mercury from Vaccines ~ U.S. Infants in 1999 and in 2001. (< 6 Months) Vaccines 1999 Maximum Mercury Dose (pa) 75.0 37.5 75.0 o [12.5] 2001 Maximum Mercury Dose (pa) o o o o [12.5] 3 doses of DTaP 3 doses of Hep B 3 doses of HIB 3 doses of IPV [1 dose of influenza] *(selected populations) TOTAL 187.5 [200] [12e5] Estimated Exposure to Mercury from Vaccines in U.S. Infants in 1999 and in 2001. (< 2 Years) Vaccines 1999 Maximum Mercury Dose (pa) 100 37.5 100 o [37.5] 2001 Maximum Mercury Dose (pa) o o o o [37.5] 4 doses of DTaP 3 doses of Hep B 4 doses of HIP 3 doses of IPV [3 doses of influenza] *(selected populations) TOTAL SOURCE: AAP, 1999, FDA 2001. 237.5 12751 [37.5] . _ _ In December 1998 and April 1999, FDA requested information from U.S. vac- cine manufacturers about the thitnerosal content of their vaccines. As a result of their review, FDA scientists determined that under the rec- ommended childhood i..~.~,ni~ation schedule (see Figure 1), infants could re- ceive a cumulative dose of mercury from vaccines as high as 187.5 fig during the first 6 months of life, depending on the specific vaccines and administration schedule used. A 2-year-old could receive as much as 237.5 fig of mercury. Some high-nsk children may also receive the influenza vaccine, increasing He maximum cumulative dose to approximately 200 fig in the first 6 months and 275 fig in the first 2 years of life (see Table 2~. The maximum cumulative doses of mercury from vaccines in the first six months and two years of life were then compared to estimated cumulative limits for mercury exposure based on guidelines of the Environmental Protection

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30 IMMUNIZATION SAFETY RE VIE W Agency (EPA), the Agency for Toxic Substance and Disease Registry (ATSDR), the FDA, and the World Health Organization (WHO). This compari- son found that six-month-olds could have received cumulative doses of mercury that exceeded the EPA limits calculated for each body-weight category, and the ATSDR limits for the lowest-weight infants who also received the influenza vaccine (see Table 3~. These estimated exposure levels were a source of con- cern, but they did not constitute direct evidence of harm, and no other evidence of harm other than delayed-type hypersensitivity reactions was found at the time of the FDA review. FDA then sent a letter to vaccine manufacturers on July 1, 1999, requesting their plans to remove thimerosal from U.S.-licensed vaccines, or an explanation for its continued use. Also in July 1999, a joint statement was issued by the American Academy of Pediatrics (AAP) and the U.S. Public Health Service (PHS), and consented to by the American Academy of Family Physicians (AAFP), recommending the removal of thimerosal from vaccines as soon as possible (CDC, 1 999a). The AAP-PHS statement also recommended one temporary change in the immunization schedule: deferring the first hepatitis B vaccination from birth until two to six months of age for children born to low-risk mothers (i.e., hepatitis B- surface-antigen-negative). However, with the rapid development of single-antigen, thimerosal-free hepatitis B vaccine, which was approved in August 1999, the Ad- visory Committee on Immunization Practices (ACIP) recommended in September 1999 that the birth dose of hepatitis B vaccine be resumed (CDC, l999c). Substantial progress has been made in removing thimerosal from childhood vaccines in the United States. At this time, vaccines currently manufactured or marketed that are on the recommended immunization schedule and given to children six years of age or younger contain no thimerosal as a preservative or contain only trace amounts (<0.5 ,ug Hg per dose) of thimerosal left over from the manufacturing process (CDC, 2000b). Some amounts of previously pro- duced lots of vaccines that still contain thimerosal as a preservative, however, also remain available at present, although the amounts are unknown because it is considered proprietary information by the manufacturers. In addition, thimerosal is used as a preservative in other vaccines, such as influenza, that are given to adults and certain high-risk children. For these children, the typical cumulative dose of mercury from the influenza vaccine is 12.5,ug at six months and 37.5,ug by two years old. Some children are administered the diphtheria-tetanus toxoids vaccine without a pertussis component (DT), which contains 25 ,ug mercury.

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THIMEROSAL-CONTAINING VACCINES TABLE 3 Calculated Exposure Limits for Mercury, Using Various Agency Guidelines for Exposure to Methylmercury, in Infants < 6 Months of Age by Percentile Body Weight Percentile Body Weight 31 Agency EPA ATSDR FDA WHO 5th 50th 95th . ~,.,.~ ~.~.,.,~ ~ ~ ~ ................................................................................................................................. ,........................................................... ............ , i E .~ 2.2.2.2.2 2 6 6 ~ ~ ~ ret -e 259,ug 305 ,ug 354 ,ug 7,ug 319,ug 425 ,ug . . Calculate Exposure Limit = dose/kg body weight/week x average weight x 26 weeks x 0.932 (mercury molecular weight/methylmercury molecular weight); e.g., EPA calculated exposure limit = 0.7 ug/kg body weight/week x 26 weeks x (2.36kg + 5.25 kg)/2 x 0.932 = 65,ug. Assumes average of 5th, 50th, and 95th % weight for females at birth (2.36 kg, 3.23 kg, 3.81 kg) and 6 months (5.25 kg, 7.21 kg, 8.73 kg) = 3.81 kg, 5.22 kg, 6.27 kg. Fe- males were selected because their smaller body weight makes them more susceptible than males. Recommended limits on methylmercury exposure: EPA: 0.1 ,ug/kg body weight/day; ATSDR: 0.3 ,ug/kg/ body weight/day; FDA: 0.4 ,ug/kg body weight/day; WHO 3.3 ,ug/kg body weight/week. For calculations, daily limits multiplied by 7 to obtain weekly limits. NOTE: Areas were shaded by the TOM, not by the original authors of the table. SOURCE: Ball et al., 2001. Repnnted with permission Mom Pediatrics 107: 1150, Table 1, Copynght 2001. Neurodevelopmental Disorders In its assessment of possible neurodevelopmental effects from exposure to thimerosal in vaccines, the committee decided to focus on a few clinically de- fined diagnoses of NDDs rather than on markers of subclinical differences, such as psychometric test scores, that may or may not correlate well with differences in diagnosis. The specific NDDs considered by the committee were autism, at- tention deficit/hyperactivity disorder (ADHD), and speech or language delay. The committee selected these outcomes based on two factors. First, published reports (Grandjean et al., 1997, NRC, 2000) have associated deficits in language, atten- tion, and memory with prenatal exposure to methylmercury. Also, unpublished epidemiological data (Verstraeten, 2001) show weak associations between diag- noses of ADHD and speech or language delay and exposure to thimerosal- containing vaccines. Second, some parents and members of the medical and sci- entific communities have expressed concern that exposure to thimerosal in vac- cines may cause autism. Complicating these hypotheses, however, is the fact that NDDs often are recognized and diagnosed only when children are old enough to have already received most of the recommended vaccinations.

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32 Autism IMMUNIZATION SAFETY RE VIE W Autism is a complex and severe developmental disorder characterized by impairments of social interaction, impairments in verbal and nonverbal commu- nication, and restricted or repetitive and stereotyped patterns of behaviors and interests (APA, 1994, Filipek et al., 1999~. Over time, research has identified subtle differences in the onset and progression of autistic symptoms. The term "autistic spectrum disorders" (ASD), synonymous with "pervasive develop- mental disorders" (PDD), refers to a continuum of related cognitive and neuro- behavioral disorders that reflects the heterogeneity of these symptoms. ASD encompasses the more narrowly defined "autistic disorder" as well as childhood disintegrative disorder, Asperger's syndrome, Rett's syndrome, and pervasive developmental disorder not otherwise specified (PDD-NOS, or atypical autism). Box 1 lists diagnostic criteria for autistic disorder. Research has established a strong genetic component in the etiology of autism, but other factors, including infectious, neurological, metabolic, immuno- logical, and environmental insults, may play important roles. Although the con- sensus of most scientific experts is that most cases of autism are caused by early prenatal exposures such as valproic acid (Moore et al., 2000) or thalidomide (Stromland et al., 1994), or are linked to early developmental genes (Ingram et al., 2000, Persico et al., 2001, Wassink et al., 2001), significant gaps still remain in our understanding of the risk factors and etiological mechanisms of ASD. There is considerable uncertainty about the prevalence of autistic disorder and other ASDs. Two large reviews of epidemiological studies conducted out- side the United States conclude that the best conservative estimate of prevalence of autistic disorder is approximately 10 per 10,000 (Fombonne, 2001b, Gillberg and Wing, 1999~. This estimate does not include other categories of ASD. A recent study conducted in Britain suggests that the prevalence of autistic disor- der may be higher than previously thought, this study estimated the prevalence of autistic disorder to be 16.8 per 10,000, and the prevalence of ASD to be 62.6 per 10,000 (Chakrabarti and Fombonne, 2001~. Information about the preva- lence of autism in the United States is limited, reflecting a lack of epidemiologi- cal research on autism in this country. Attention Deficit/Hyperactivity Disorder (ADHDJ Attention deficit/hyperactivity disorder (ADHD) is a behavioral disorder characterized by persistent patterns of inattention and/or hyperactivity. (In this report, the terms ADHD and Attention Deficit Disorder (ADD) are used inter- changeably. ADHD is the term used in the Diagnostic and Statistical Manual (DSM-IV), while ADD refers to a specific ICD-9 code (314.0) that can include hyperactivity symptoms. Such patterns must be present before a child is seven

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34 IMMUNIZATION SAFETY RE VIE W years old, and must cause significant interference and impairment in at least two areas of life such as home and school, or home and work (APA, 1994~. Standard diagnostic criteria for ADHD are listed in Box 2. There is currently no clinical test for diagnosing ADHD. Rather, diagnosis depends on careful observation and evaluation of the child in multiple settings. Psychometric tests, such as the Con- tinuous Performance Test (CPT), a standard measure of attention, are often used, however, there is no relation between CPT scores alone and a diagnosis of ADHD. The most commonly cited prevalence rate suggests that 3-5% of school-age children are affected by ADHD, making it the most commonly diagnosed behav- ioral childhood disorder (NIH, 1998~. Boys are diagnosed with ADHD more often than girls, although the exact ratio is unclear. Three- to nine-fold differences be- tween the sexes are reported (Eme and Kavanaugh, 1995), and sex differences are also seen in the prevalence of subtypes of ADHD (Wolraich et al., 1996b). How- ever, prevalence of the disorder is still debated. Wolraich and colleagues (1996a) reported an increase in prevalence to 12.4% as a result of a change in diagnostic criteria in 1995. A recent review also found that prevalence varied, depending on which DSM criteria were used in evaluation (Brown et al., 2001~. Speech or Language Delay Medical diagnostic codes (ICD-9) for speech or language delay correspond with three communication disorders described in DSM-IV, namely expressive language disorder, mixed receptive-expressive language disorder, and phonological disorder (see Box 3~. Expressive language disorder is characterized by a significant impairment in vocabulary, difficulty forming sentences of de- velopmentally appropriate length, and misuse of verb tense (APA, 1994~. Mixed receptive-expressive language disorder has similar features, with additional dif- ficulties comprehending words and sentences. Phonological disorder is charac- terized by difficulties in forming age-appropriate speech sounds. Close clinical observation and standardized tests of language and intelli- gence are used to diagnose speech or language delay. For expressive language disorders, a child's scores are lower on tests of expressive language than they are for receptive language and intelligence. For mixed receptive-expressive lan- guage disorder, a child will score lower on tests of receptive and expressive lan- guage than on tests of nonverbal intellectual capacity (APA, 1994~. These com- munication disorders can also be diagnosed when a child's speech development and language skills are significantly behind those of other children of the same age (Leung and Kao, 1999~. Estimates of the prevalence of speech or language delay vary, largely be- cause of differences in terminology and diagnostic criteria used by practitioners, the subjective nature of parent and practitioner observations (Leung and Kao, 1999), and the age at which the child was evaluated. For example, 9-17% of two-year olds were reported to have a language delay, but prevalence was 1-3%

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THIMEROSAL-CONTAINING VACCINES 35 by age 5 (Whitehurst and Fischel, 1994~. A recent review (Leung and Kao, 1999) reported speech delay for 3-10% of all children, which is consistent with additional rates reported in the literature (Boyle et al., 1994, Shriberg et al., 1999, Silva et al., 1983~. The researchers also noted that speech delay affects boys three to four times more often than girls (Leung and Kao, 1999~. Other researchers reported a median prevalence of speech or language delay of 6% for children aged 0-7 years, and that this prevalence had remained constant over the past 30 years (Law et al., 2000~. ...................................................... ................ ..................................................... .......................................................................................................................... ~ 1""~ ~-IX-'-' -or mom ~ off me Io-~-l-ow-l-n-g~ sym--plo-m-s~ of I-n-allen-~-lo-n~ eaves p-em-l-steu~ . ... ............................................................................................................................ ....... ............. .... ............. ... ^ . ................. ....................... . . ~;.^ ~ - . . - ~^ An- ~ - . . ~m ~ .^ ~ ~ I .^ ~^ ^~ ~^ .~ ~~' .~m.~ arm. ~ `atl : A:::::::::::: ::::::: :~: ::::::::: ::: :~:~: :: A::::::: : :: : :::1: . :::1:~:::: Aid::: A::: :~ :G~:I:::GG::::::: : :1 At: ::::::1:~:::::::1::1:::1:~: ~:~ :~:~: :1: V:G::::::~:1:::1:~ ::::::::1:l:::l:~:: l =:l:~: G:1:::1:: .:::::: VV :1:: ''''''''''''''''''''''''''''M'.''~ I'M I''I'''I'= I I'O' 'LV'''~ I V'~'''~'E Vet O'''= VL='I'I'tI~'I'I''''i~'''U'= L I I='''VI''''I'I'I'" ~=''~='I'= I'=~O''-'I'I'I'I ~' :::::::::::::::::::::::::::::::::::::::::::::::::::::::::~::::::::I:~:::::^T:TD:n =~=I::l\~::::f:11~1~= -.~-.-.T=f1:::::r~t' "vIr-=n=^l le oT'ml llI::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: .:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.:.':.:!.:~.:.:!.~. .:.-.~.:!.:~. ~.:!.:.':.:.:~. .~.~.':2' ,,:':':'~:!'~'~':' .~.-.:~ ~ ""'' """""""""""" 'i' ""' o'' ""'' 'o e' ""'o' "'t' 'e""'' ''1'' ' '" ' """so' ' '' o" 'a""" ' ""' ' ' ' '' a' ' i' 'it' 'i" " '' '1" 'i' ''' ' """""' . . . -. . . ...... -. - - - -. - - -. - -. - . h,.,"a."""v."""e."'.,,.,p""e."'.""'~,""*' t' Dot of '' t-- ............................................................................................................................. ~ ~~ ^tt~-n- - -tl-~-~^t~ - -ten- - -a ~ are- - as- -bent - -^ r - -- - ~-~-rm ~ - - In - -~=t~ ~ v B ~ - I ! e ! ~L~ V V I Hi ~ I ! ~ ~ ~ ~~ ~ l l ~ ~ L ~ ~ - ~ ~ ~ ! ~ i ! ~ t ~ ! ~ .~. . :~:::::::::::::::: ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~ ~~ IT-- ~:~ ~:~:~ :~:~T:~ ~~ ::--:. ~~:~ ~:r:~ ~~ :~r-~-~-r~ ~~ l:~Tl:~-~-~ ~~ -l: I. 'a 'it ~'1-'t,~'l-'-l'~ 1'=,M,'V'=-~ ~-~='L~ l'l-'-I'~ ~-~=l-'~-l'-'l-'I'~ '~-l'~ 'I'l-'-l'~ ~'L'~-'-~='l~ ='~-LU-='Ll-~'~-'-l'O'~ l'~-'-l'~

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36 IMMUNIZATION SAFETY RE VIE W ':':':':':':':':':':':':':':':':':':':':':':':':':':':':'' ':':':':' ~ I' 'I ':':':' I:':,':' :' ':':':' j ':':' 'I ':':'' ' :;'j ... . . . . * . ':':':': :' :':':' 1''i' .;. ; ; ' :':':';:t':':'*' :':':';:' ':':': :~ :: A: -: .~:I':'I:':':'I:':U:'E:':I=':':'~ J:VU' :'-'V:l~ :~: '1:1':'1:'I' ~'O':,:'=A~=I:V-'=: 'V: ~-l:-:l~ At- U'~: I-~:l-:-l:~:':':I':I':'I:':':'YV': ':'1:1'~ :':1':':':1 ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~ a-p-pm-p-rl-a en ---in at -o- Descent ~~ or am . ~~ maw ~-e~ I - , ~ """""""""""""""""""""" """""""""""'' e" """b'l"''d' """ ' 't""' ' $' ' '' ""'b' by'' """ '''' $ti' ''''""'h'' ' ' ""'b' ' ''""'' ' 'm" I t d ~ ............. ............................................... ................... ~ . j At ,.,.,.,.j, . * . ........ ... 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THIMEROSAL-CONTAINING VACCINES 37 B:-: -: :~ ~ : ~ .~. \-/1~ :-~-:~:-:-: :~ ~1 ~ ~1-~-:-:' ! : :-:-~-: :~ :~ --:-: :-:-:~-~-~:1-:-1:~:~-~: -:-: :- :: :~:-.- -:~:-:~:~ -my ~:~:^ :~ ~-:~:-~ ~ . A::- ~ : _ :~ :V:I' - ' :':V':':': - : ':'E: =' 1= - : ':':'-'~': :: ':'1:':':~'1:':': ' ='1:':1'~:~:~=':':' :G' =:'V:':.:I:' :':'1:':~'.: ':':1':':':'=:1':'1:~ :':':~':':1:'~:': =':1:':':':':':':' ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ::::::::::::::::::: :::::::::::::: A:::::::::::Ti: :::::::::::::::::::::::::::::::::::::::::i -:: ::::: :::::::::: ::::: ::::::::::::::::::::: ::::::::: i:: ............................................................................................................................ ............................................................................................................................. 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E Eage---E ESo~er as well as ~l~E~ El~ un~e slan~lng.wo Es sen e-n-~es~ o-r~ s-pe ~ ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: B - _ , - ~ `.. . - `.. e~ ~-l~lcu-l~l-es~ witn~ e e-~lve~ a E ~""'~Xp~SS'iVe""'l'an E'Ua0'e""'S'Ia'E '~~l'0a'E {Iy""'l'nte~"""""" ..... tere wit'.acaEeml.~ u ab-oEal--a- nie m- Et"o- It'-- o lal--- E 'E "'El atl''E'*"""""""""" ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~ """"""""""~""""""""""~'E lte'~l'a""a'E e""'E 'ot""'m'et"'lo'("'a""'E e'E a$1Ye""'~0V0'i'O'p' Ee'n'ta'l"""U'lSOE 0'e'E """"""""""""""""""""""""""""""""""""" ::::::::::::::::::: ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::-:::::::::::::::::::::::::::::: ~ . D. It M E tal ~ ta'datio' a s E E t E E E E --tl it E jE E ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: EentaI OOn 1" atl """1$""" Ee eE t tMe EaE E'' -a- -e~ ~---~l-- - Eltl s~ a~ I'E ~ e- - - s-s~ ~ tn~ ,,,,,,,,, ,,, ,,,,, r ~ ~ ~ A~ ~-a-i-l-u-- e~ `o~ u-s-e~ d-ev.-elo-p n-ental-lv~ expe ie E~ s-pee-c-h~ s-ou-n-d-s~ i-ha-t~ a- e~ ap~ ....................................................................... - ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ....................... - , .................................... - - - i t t a . ~ I E t t ~ I ~ E~ ~ t ............................................................................................................................ , j , , ~ s-en-tallo-n~ o-~ o-~-a-n-l-zal-l-on~ s-u-cn~ as~ D Et~ n-ol~ l-l-m-l~ec~ t ::::::: :: ::.: : : :.:.:~::::: :.::::: :.:~ : : : : : : : : :.:.:.: : : : : :.:.:.: : :1.:.:.: ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ......................... - - - - - - -. - - ........... - ,,,,,, ~ t tE L ~ /D t t t, t~ ~ E 1$ 1 ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: .............. -. -. -. - - -. - -. - - - - -. -. -. -. - - - - - .......... ~ C~ If---M- t -I---R ~ d- ti~ b '' '' t '' ""'' """'$' ''' ' '' """~- i' t'"'."'' '""" ''' 'i"' ' '"""""" ............................................................................................................................ :::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ~ m t | ~ j tj i r t t' Ph jff; ~ ~|t; j P f th ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ....................... -. -. - - - - -. - - - - - - ::::::::::::~::I=:I:::I:~:I:.t!::::~:~:~.-~.-.I=T=r1 lAIIT~ Tm=~" nr~rl'=mO ...... ~,~,~.,,, ~,.,.,.~.~,,~.~.~ ,.,,.r,~ ,,.,.,.~,,.,,.~.~,.,.,~,,.,.~,~,,.~,, ~ ~e-prl-n~ Itn permlsslon ~mn ~ ~-n-e~ u- agnost/~ ~ ~-~~f~ Man-- a~ or~n~f~ .............................................................................................................................. ~ msomem-,~ ~-ou-~n~ ~-lil-~-n~ ~-pyElg-nl~ l ~Y~ nmerican ~syonlairlc ~ssoolallon. ............................................................................................................................ ::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::::: ........................................................................................................................................................................................................................................................