Androgens in Human Evolution
A New Explanation of Human Evolution
James Michael Howard
Fayetteville, Arkansas, U.S.A.
Human evolution consists of chronological changes in gene regulation of a
continuous and relatively stable genome, activated by hormones, the
production of which are intermittently affected by endogenous and exogenous
forces. Periodic variations in the gonadal androgen, testosterone, and the
adrenal androgen, dehydroepiandrosterone (DHEA), significantly participated
in all hominid transformations. The hominid characteristics of early
Australopithecines are primarily a result of increased testosterone. The
first significant cold of the early Pleistocene resulted in an increase in
DHEA that simultaneously produced Homo and the robust Australopithecines.
Subsequent Pleistocene climatic changes and differential reproduction
produced changes in DHEA and testosterone ratios that caused extinction of
the robust Australopithecines and further changes in Homo. Changes in
testosterone and DHEA produce allometric and behavioral changes that are
identifiable and vigorous in modern populations.
Keywords: androgen, breasts, dehydroepiandrosterone, estradiol, estrogen,
Pleistocene, testosterone, thermogenesis
Humans and chimpanzees differ in hormones that produce significant effects
on anatomy, physiology, and behavior. Human males and females produce more
testosterone than chimpanzee males and females, respectively (Winter et al.,
1980). Chimpanzee and human females produce similar levels of estradiol
(Winter et al., 1980) and progesterone (Hobson et al., 1976). I suggest
early differences in testosterone levels started species divergence and
promoted hominid evolution.
Estradiol and testosterone support different functions in females.
Estradiol stimulates genital displays that advertise ovulation in monkeys
(Wilson, 1977), gibbons (Nadler et al., 1993), chimpanzees (Ozasa & Gould,
1982) and gorillas (Nadler, 1980), but not women. Estradiol and
testosterone both peak near ovulation in female orangutans, gorillas,
chimpanzees and humans. Estradiol and testosterone act synergistically to
maximize reproduction. Estradiol prepares the sexual apparatus for coitus
and impregnation; testosterone stimulates sexual activity.
While it is a general trend in Western societies to blame psychosocial
factors for diminished sexuality in women, diminished sexual drive and
other aspects of sexual dysfunction, in androgen-deficit women, are
primarily improved by testosterone therapy (Davis, 1996; Kaplan & Owett,
1993). In postmenopausal women, combined estrogen-androgen therapy
significantly improves sexual desire, satisfaction and frequency, whereas
estrogen alone, or estrogen-progestin therapies do not, leading to the
conclusions that androgens play a pivotal role in sexual function and
estrogens are not a significant factor determining levels of sexual drive
and enjoyment (Sarrel et al., 1998). Because estrogens prepare female
genitalia for coitus, it is best to treat sexual dysfunction in women with
testosterone and estradiol (Davis et al., 1995). Nevertheless, libido is
primarily an effect of testosterone. In sexually functional women,
testosterone treatment produces a statistically significant increase in
genital responsiveness and subjective reports of genital sensations and
sexual lust (Tuiten et al., 2000). Supplementary testosterone not only
corrects deficiencies in sexual desire, it intensifies normal sex drive.
Estradiol levels in women and chimpanzees are optimal. Therefore,
increasing testosterone to estradiol ratios in hominids increases sexuality
proportionately. As testosterone increases, so does the sexual activity of
the female. This increases male attendance and reproduction. These females
have an advantage in representation in future generations.
Increasing the testosterone to estradiol ratio reduces the effects of
estradiol. Human female fetal external genitalia contain AR (androgen
receptors) and ER (estrogen receptors), while male external genitalia lack
ER (Kalloo et al., 1993). The AR in the female external genitalia were
strikingly similar to that in the male. In women, increased testosterone
competes with the effects of estradiol on external genitalia. As the
testosterone to estradiol ratio increases, the labial display decreases.
This is why humans do not produce a labial display. (Adrenal androgens
stimulate male and female pubic hair just prior to puberty and probably act
through the common AR in both sexes.) The primary sexual signal of female
chimpanzees is the labial display. In women the primary display of sexual
maturity is the breast. Chimpanzee mothers and small breasted women produce
ample nutrition for nursing offspring. I suggest the increased size of the
human breast is a sexual signal. Breasts are estradiol-dependent
structures. Breast enlargement is a signal of maturing estradiol levels,
and may also be a signal of maturing testosterone levels and, therefore, of
increased sexual arousal.
Fat tissues capture steroid hormones, including testosterone. Testosterone
is aromatized to estradiol in fat tissues. While breast fat is not as
active as axillary fat in converting testosterone into estradiol, results
indicate a possible role of adipose tissue as a significant extra-gonadal
source of estrogens" (Nimrod & Ryan, 1975). This increased level of
estradiol in the breast could increase breast size. Aromatization of
testosterone occurs in normal female breast tissue and in gynecomastia in
men. Breast tissue from five out of six men with gynecomastia aromatized
testosterone into estradiol (Perel et al., 1981). (Gynecomastia is true
breast development in men, vis-à-vis pseudogynecomastia caused by fat
deposits.) Conversion of testosterone into estradiol in human breast fat
augments breast development and size. Testosterone and estrogen both
inhibit human hair production, in vitro (Kondo et al., 1990). Increasing
testosterone levels in hominids reduced hair production in both sexes. The
combined effects of testosterone and estradiol further reduce hair growth in
women. This increases the prominence of the breast. The female human
breast is a signal of mature estrogen and testosterone production. The
female human breast is largest among primates due to increased testosterone.
The pubic bones of male mice are shorter and thicker than those of female
mice. Neonatal testosterone treatment of female mice produces pubic bones
shorter and thicker than those of age-matched females and Pubes in male
mice castrated at the day of birth were thinner than those of intact males.
(Iguchi et al., 1989). Androgens directly affect bone growth in women
(Gasperino, 1995). Testosterone is involved in bone growth and produces
changes in the female pelvis. Increasing testosterone in hominid females
would change growth and development of the pelvis with time. Essentially
all tissues produce androgen receptors, therefore growth and development of
all tissues in emerging hominids were affected by testosterone. The muscles
that control upright walking increased in strength as a result of increased
testosterone. The large size of the gluteus maximus is one of the most
characteristic features of the muscular system in man, connected as it is
with the power he has of maintaining the trunk in the erect posture. (Gray,
The brain also enlarged as a response to the effects of increasing
testosterone. The brain produces androgen receptors throughout.
Testosterone exposure of the male human brain, in utero, results in
increased head circumference of male brains at birth (Liebermen L.S., 1982).
Androgen treatment of female monkeys increased performance to male levels,
on an object discrimination task. Both male and female performance levels
were adversely affected by lesions in the orbital prefrontal cortex,
indicating that gonadal hormones may play an inductive role in the
differentiation of higher cortical function in nonhuman primates. (Clark &
The single phenomenon of increasing testosterone produced the hominid
characteristics of Australopithecus. The single phenomenon of increased
testosterone production participated in every hominid characteristic,
simultaneously. Testosterone increased female sexual activity, reduced
female genital display, reduced hair growth, increased breast size, changed
pelvic growth, and produced increases in brain size. These combined changes
accelerated the advent of upright, bipedal locomotion and larger brains.
(Male and female pubic hair is visually different. It may be that pubic
hair was the first appreciable change in sexual display as body hair and the
labial display digressed in Australopithecus.)
The canine teeth of Australopithecus were smaller, and less projecting
than contemporary primates. However, in living monkeys, testosterone
increases large canine teeth. The canines are larger in males and prenatal
exposure of females to testosterone increases the size of their canines
(Zingeser & Phoenix, 1978). This appears to present a quandary for this
explanation of human evolution. Humans produce more testosterone, yet the
canine teeth are small.
In hominids the effects of testosterone, on brain size, teeth, and other
tissues, are due to changes in availability of DHEA. I suggest DHEA is
involved in growth and maintenance of all tissues, especially the brain, and
is paramount in the formation of the robust Australopithecines and Homo.
DHEA is proven to positively affect growth and function of many tissues,
including the brain. Dehydroepiandrosterone and its sulphate ester are
neuroactive and are both imported into the brain from the circulation and
produced in the nervous system. These neurosteroids have neurotrophic and
excitatory effects. (Baulieu, 1999). (The enlargement of neural tissue
during primitive evolution may be due to increased absorption and production
of DHEA.) Testosterone evolved after DHEA; testosterone is a conversion
product of androstenedione, which is a direct conversion product of DHEA.
Therefore growth before testosterone relied on DHEA. Testosterone evolved
because its molecular structure affected DNA in an advantageous manner. My
principal hypothesis is DHEA optimizes transcription and replication of DNA.
Therefore, a subordinate hypothesis suggests the advantage of testosterone
is that it directs DHEA use for genes that are targets of testosterone
action. Testosterone increases the rate of DHEA use. (Males produce more
testosterone, therefore, in males, testosterone-target-tissues are larger,
e.g., muscle, bone, etc., or grow at different rates, producing different
structures from the same beginning tissues, e.g., genitalia, or differences
in final brain function, e.g. male-female differences in the brain.
Testosterone is not the male hormone, males simply produce more.)
That testosterone affects levels of DHEA is supported by reductions of DHEA
during increased levels of testosterone in some nonhuman primates. The
following references support a pattern of decline of DHEA levels when
testosterone levels increase. In the crab-eating monkey, DHA [DHEA] levels
were high during the first months, decreased at about 1 year, remained
stable during infancy and prepuberty and then declined again during puberty.
At about 5 years, the values were 28% of those in neonates. (Meusy-Dessolle
& Dang, 1985). By contrast the serum prolactin and dehydroepiandrosterone
levels showed an inverse pattern achieving their highest levels in spring,
during the period of reduced testicular function. (Wickings & Nieschlag,
1980). Serum testosterone levels rose during male development; however,
there was a progressive decrease in dehydroepiandrosterone sulfate levels
indicating the absence of adrenarche. (Crawford et al., 1997). The decline
in DHEA when testosterone is increased in these examples could indicate that
DHEA is being utilized in tissues, therefore reducing measurable levels in
In the Australopithecines, as in the primates above, a limited amount of
DHEA was directed toward one tissue at the expense of another. As
testosterone increased in Australopithecus, the brain increased use of DHEA.
When testosterone increased use of DHEA for the brain, the available DHEA
for growth and development of canine teeth was reduced. (The brain may be
the paramount tissue in vertebrate evolution because it is able to capture
DHEA better than other tissues.) The brain increased slightly and the
canines decreased slightly. Brain tissue simply takes more of the supply of
DHEA; canines do not grow as large in response. (Measurable levels of DHEA
are very high in monkeys, much lower in humans, with chimpanzees levels very
similar to humans. I suggest this is an indication of relative use of DHEA
by the respective brains.)
The cold periods of the Pleistocene epoch directly caused changes in hominid
evolution. Homo and the robust Australopithecines are the results of the
first, large cold increase around 2.5 mya. A common phenomenon occurred in
both. This particular cold selected for individuals that produced more
DHEA. Increased DHEA is an advantage during cold. DHEA treatment in rats
affected body weight, body composition and utilization of dietary energy by
both impairing fat synthesis and promoting fat-free tissue deposition and
resting heat production. (Tagliaferro et al., 1986). This effect of DHEA
is due to increased thermogenesis (Bobyleva et al., 1993). Individuals who
produce more DHEA derive more heat from the same nutrition. As cold
decreased available nutrition, individuals that could derive more benefit
from sparse nutrition had a survival advantage. The ratio of DHEA to
testosterone in hominids started to change at this time. (Increased DHEA
may have been involved in early mammalian evolution. That is, increased
ability to make DHEA may have been the reason mammals survived events that
caused extinction of the dinosaurs.)
The Australopithecines remained relatively unchanged during the upper
Pliocene. The change from A. afarensis to A. africanus was probably due to
increasing testosterone. A noticeable change occurred in the
Australopithecines during the first cold of the early Pleistocene. The
robust Australopithecines appeared, i.e., robustus and boisei. Robustus and
boisei differed from afarensis and africanus mainly in teeth size and facial
size, little in body size. Pronounced sexual dimorphism continued in the
Australopithecines, including the robust types. That is, the survival
strategy of these groups continued to mainly depend on increased
testosterone in males. The levels of testosterone did not increase much, so
brain size did not increase much. The cold selected for individuals of
higher DHEA in this group. Therefore, increased availability of DHEA
increased effects on testosterone-target-tissues. Teeth and facial
structures are testosterone-target-tissues. The available DHEA, not used in
thermogenesis, caused increased size in the teeth and facial structures.
The testosterone levels of the males did not change significantly, so their
brain size did not change significantly.
Homo differs from Australopithecus mainly in a small increase in brain size
at the time of separation of the two. I suggest separation of Homo from
Australopithecus occurred as a result of increased testosterone in Homo
females. It is in Homo that the true effects of increased testosterone
began to increase rapidly. The breast would increase in Homo and increase
selection pressure for those changes that produce more efficient bipedal
locomotion. As testosterone increased in Homo females, brain size continued
to increase over that of Australopithecus. When this increase in
testosterone first began in Homo, there should be transitional forms with
larger brains, but which continued to exhibit small bodies and sexual
dimorphism, such as Homo rudolfensis and Homo habilis. H. rudolfensis and
habilis developed contemporaneously with A. robustus and boisei.
As testosterone and DHEA increased during this time period, increases in
growth continued in the brain and began to affect growth of the body. Homo
began to increase in overall size. The effects of these two hormones
increased as the climate began to warm. (There is no selection pressure to
reduce testosterone and DHEA levels by relative warmth.) Reduced use of
DHEA for thermogenesis increased availability for body and brain growth.
Homo ergaster and H. erectus emerged at this time. It is the increase in
females of higher testosterone that produced Homo. It is first identifiable
in Homo erectus/ergaster. Sexual dimorphism declined in Homo erectus as a
result of increased female size, not a decline in male size. This increase
in testosterone in both sexes, and the increase in DHEA, would increase bone
growth and length.
Treatment of rats with DHEA increases bone mineral density. Treatment with
DHEA caused a 4-fold stimulation of serum alkaline phosphatase, a marker of
bone formation, while the urinary excretion of hydroxyproline, a marker of
bone resorption, was decreased by DHEA treatment. (Martel et al., 1998).
DHEA treatment of postmenopausal women stimulates increases in serum
osteocalcin, another marker of bone formation (Labrie, 1997). Adrenarche is
the beginning of the measurable increase of DHEA in humans that begins
around five- or six-years-of-age and increases rapidly until about age
twenty. Adrenarche continues for years prior to puberty. A significant
amount of bone growth occurs prior to the growth spurt of puberty.
Premature adrenarche produces an acceleration of bone age that was greater
in males, and the appearance of premature pubic hair in 93.8% of both sexes
(Likitmaskul et al., 1995). The testosterone conversion product,
dihydrotestosterone (DHT), produces no qualitative differences in bone
growth, only a more rapid increase in bone growth in vitro. DHEA and DHT
both stimulated cell proliferation and differentiated functions, but the
gonadal androgen DHT was significantly more potent than DHEA. (Kasperk et
al., 1997). Years of bone growth due to DHEA occurs prior to puberty;
testosterone rapidly increases and finalizes body growth at puberty during
the growth spurt. Testosterone and estradiol rapidly increase the final
development of bone. A direct connection of increased bone formation in
individuals of higher testosterone exists. Serum testosterone, estradiol
and bone density are higher in black women than white women (Perry et al.,
1996). Testosterone is significantly higher in black college students than
white college students (Ross et al., 1986). Black males and females
consistently exhibit greater mean levels of areal and volumetric bone
mineral density at all skeletal sites than Asians, Hispanics, and whites
(Bachrach et al., 1999). Increased testosterone increases bone growth. As
testosterone and DHEA increased in Homo, growth in size and length of bones
Homo erectus existed during a time of relative warmth. This climate change
means that its DHEA could be used for purposes other than thermogenesis.
The brain of H. erectus doubled that of Australopithecus. There was less
sexual dimorphism in H. erectus than in the Australopithecines, but still
more than that of later hominids. Musculoskeletal development was very
robust, another consequence of additional DHEA for growth, not used by the
brain or for thermogenesis. The anterior teeth were larger and the molar
teeth smaller than those of Australopithecus. The decrease in posterior
teeth results from an increase in development of anterior parts of the
brain. Brain forming later, during the time of formation of posterior
teeth, reduces available DHEA for those teeth, therefore, they are smaller.
Again, the brain takes DHEA at the expense of other tissues.
The return of cold later in the Pleistocene returned selection for increased
DHEA. Neandertal habitat was characterized by relative containment. The
cold and containment increased DHEA and testosterone in Neandertal.
Neandertal continued to increase in brain size. The teeth and facial
structures and brain development of Neandertal are exaggerated due to
increased testosterone and DHEA. The large teeth and brains indicate there
was plenty of DHEA for sharing between various tissues. However, this large
brain was increased in posterior regions, not in anterior areas. This would
be consistent with early puberty.
High testosterone and high DHEA could cause early puberty. Increased
androgen receptors in the brains of individuals of higher testosterone
increase use of DHEA for brain growth during childhood. This accelerates
the onset of puberty, because the brain structures that control puberty
mature early. This shortens the time to hypothalamic stimulation of
testosterone production by the gonads. As testosterone-target-tissues grow
and begin to increase use of DHEA, competition for available DHEA increases.
Therefore, early puberty reduces available DHEA for growth of anterior parts
of the cerebrum. Large bodies and early puberty reduce final (anterior)
brain development. That is, early puberty reduces the time of basic growth
and development of the brain that occurs under the influence of DHEA.
Effects of low testosterone on craniofacial growth and statural height have
been demonstrated in boys with delayed puberty. These results show that
statural height and craniofacial dimensions are low in boys with delayed
puberty. Low doses of testosterone accelerate statural and craniofacial
growth, particularly in the delayed components, thus leading towards a
normalization of facial dimensions. (Verdonck et al., 1999). Osteoporosis
in vertebrae, the diaphysis of the radius, and neck of the femur in male
leprosy patients were significantly correlated with [reduced] FT [free
testosterone] in all three regions of the skeleton. (Ishikama et al.,
1999). Assuming sufficient DHEA is available, too much testosterone
increases bone size and prognathism; too little has the opposite effect.
Continued cycling of cold during the upper Pleistocene and changes in
containment areas selected for hominids with different ratios of DHEA and
testosterone. Some combination of testosterone and DHEA occurred that
favored increased use of DHEA for brain growth. A change in the ratio of
DHEA and testosterone can slow the onset of puberty and increase anterior
brain size. Producing less DHEA reduces the effects of testosterone.
Reduced containment (testosterone) or reduced nutrition will slow the pace
of puberty. (Increased nutrition should favor those with early puberty.)
The percentage of high testosterone individuals would decrease and average
size of the forebrain would increase. This began in H. antecessor and H.
heidelbergensis. Delayed puberty and increased brain size produced Homo
sapiens. Increased brain growth in H. sapiens occurred in the anterior
portion of the brain, the prefrontal lobes. This produces the high
Another shift downward in testosterone levels in a population could occur
rapidly. Testosterone compromises the immune system. The effects are
especially dangerous when trauma is involved. Male gender is associated
with a dramatically increased risk of major infections following trauma .
This effect is most significant following injuries of moderate severity and
persists in all age groups. (Offner et al., 1999). Castration before
soft-tissue trauma and hemorrhagic shock maintains normal immune function in
male mice, but sham-castrated male mice show significant immunodepression.
The maintenance of immune function by androgen deficiency does not seem to
be related to changes in the release of corticosterone. We conclude that
male sex steroids are involved in the immunodepression observed in after
trauma-hemorrhage. Thus, the use of testosterone-blocking agents following
trauma-hemorrhage should prevent the depression of immune functions and
decrease the susceptibility to sepsis under those conditions. (Wiehmann et
al., 1996). These negative effects of testosterone on immunity could
increase the probability of infectious epidemics that could radically change
the percentage of individuals of higher testosterone in a population. This
is very possibly the mechanism involved in extinctions of the robust
Australopithecines and various Homo populations.
Once a population is reduced in high testosterone individuals, a stable
population could exist for some time. However, due to the influence of
testosterone on reproduction, most populations will regain their high levels
of testosterone in time. Every positive increase in nutrition would
increase the probability of increasing the percentage of high testosterone
individuals. Therefore, a cycling of high testosterone populations should
occur. This may have occurred at the end of the Upper Paleolithic, through
the Neolithic, when body size in males and females clearly declined (Frayer,
1984). A reduction in body size indicates that individuals of high
testosterone levels in the population died. Body size then increased into
the Middle Ages during which epidemics occurred with some frequency.
Increased availability of food increases the rate of these cycles, but does
not cause them. People of high testosterone simply reproduce faster when
more food is available.
Homo sapiens exhibit a constellation of characteristics that separate
sapiens from other hominids. Postcranial skeleton, teeth, and craniofacial
size are all reduced coincidentally with changes in brain growth, that is,
increases in size in the frontal areas. Earlier, I suggested that canines
are reduced in size in Australopithecus because the brain is using DHEA for
growth at the expense of these teeth. The part of the brain that increased
in Australopithecus reduced growth of front teeth. These are increases
mainly in the posterior parts of the brain. Posterior growth of the brain
retards growth of anterior teeth because they occur concurrently. Many
hominids exhibit increased posterior brain size and reduced anterior teeth.
The increase in brain growth of Homo sapiens includes the posterior and the
anterior parts of the cerebrum. Therefore, in Homo sapiens, both the
anterior and posterior teeth compete for DHEA during times of brain growth.
This is why the entire dentition is reduced in Homo sapiens.
There are two dentitions in humans. DHEA levels are very high at birth,
then decline to very low levels within a year and remain low for some time.
Around age five to six, DHEA levels increase rapidly (adrenarche) and peak
around age twenty, at levels about half as much as that of the levels at
birth. The brain is using so much DHEA for growth and development during
early childhood that measurable levels of DHEA are very low. From age
twenty, DHEA levels begin to decline, reaching very low levels in old age.
The high levels of DHEA at birth stimulate growth of deciduous teeth. This
period of high levels of DHEA declines rapidly to very low levels in the
first year. This decline of DHEA of early childhood is so low that it does
not support continued maintenance of the deciduous teeth, and they are lost.
The permanent dentition occurs as a result of increasing DHEA beginning at
adrenarche. Adrenarche begins as the brain begins to finalize growth.
These teeth are supported until DHEA begins to decline in old age, unless
something interferes with DHEA. This explains human dentition. This
implies that teeth are very sensitive to DHEA levels. With the simple
assumption that the bone of the mandible is less sensitive to reduced DHEA,
the reduction of the size of the anterior teeth produces the chin.
Australopithecus and Homo evolved as consequence of differential gene
regulation, in continuous, relatively comparable genomes, resulting mainly
from chronological differences in production of the androgenic hormones,
testosterone and dehydroepiandrosterone (DHEA). The cold periods of the
Pleistocene epoch selected for individuals of higher DHEA, which interacted
with levels of testosterone that varied according to behavioral advantages.
The two principal events of hominid evolution are 1) increased testosterone
in females, that stimulated increased testosterone in males, and 2) the
amplification of testosterone-directed characteristics by increased DHEA.
The effects of these events resulted in bipedal, upright locomotion, breasts
as sexual displays, larger brains, and the effects of increased use of DHEA
by larger brains throughout the body.
Individuals who produce large amounts of testosterone are vulnerable to
infections. Moreover, high testosterone individuals may act as carriers of
infectious agents. Testosterone and puberty are directly connected to
establishment and maintenance of the carrier state of an infectious virus
in horses (McCollum et al., 1994; Holyoak et al., 1993). This may have
caused past epidemics, when populations were composed of high percentages of
high testosterone individuals in dense populations. The end result would be
a new population reduced in the testosterone to DHEA ratio. This may have
produced the first population of Homo sapiens and, thereafter, periodically
reduced the percentages of individuals of high testosterone in later
Increased amounts of DHEA for relatively lengthy, slower development of the
brain results in larger brains in the remaining population. These types of
events increase during times of higher population density due to increased
nutrition. This phenomenon is identifiable as the decline in body size that
occurred from the upper Paleolithic through the Neolithic periods. That is,
increased food increases reproduction rates and concentrates high
testosterone individuals into population centers. When testosterone reaches
supra-optimal levels, infection rates increase. Body size increased in the
Middle Ages, which frequently included epidemics. Learning disabilities are
significantly associated with high testosterone levels (Kirkpatrick et
al., 1993). The Renaissance followed the Middle Ages. Populations will
periodically cycle through times of increased and reduced percentages of
high testosterone individuals. Civilizations evolve in this manner. I
suggest the increase in percentage of individuals of higher testosterone
produces the secular trend, in populations. The secular trend is real,
identifiable, and vigorous in the U.S.A., at this time (Freedman et al.,
This is a new explanation of human evolution. It accounts for all aspects
of human evolution, including the formation and declines of Australopithecus
and Homo, formation and declines of civilization, and is identifiable in
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