Review

Eur Urol 2001;40:601608

Dopamine and Male Sexual Function
Fax +41 61 306 12 34
E-Mail karger
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2001 S. Karger AG, Basel
03022838/01/04060601 $17.50/0
Accessible online at:
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Franois Giuliano
Department of Urology, CHU de Bictre
78, rue du Gnral-Leclerc
F94270 Le Kremlin-Bictre Cedex (France)
Tel. +33 1 45213698, Fax +33 1 45212170, E-Mail giuliano@cyber-sante.org
Franois Giuliano
a
, Julien Allard
b
a
Groupe de Recherche en Urologie, UPRES, EA 1602, Medical University of Paris South, Le Kremlin-Bictre, et
b
PELVIPHARM Laboratories, Domaine INRA, Bures-sur-Yvette, France
Abstract
The use of the D1/D2 dopamine receptor agonist apomorphine for the treatment of erectile dys-
function provides strong support in favor of a participation of the dopaminergic system in the
control of sexual function. However, the exact involvement of dopamine in the control of sexu-
al motivation and genital arousal in males is unknown. Experimental data in male rats suggest-
ed an implication of dopamine in sexual motivation as well as in copulatory performance. Spe-
cific tests allowing assessment of sexual motivation showed that the release of dopamine at the
level of the nucleus accumbens (innervated by the mesolimbic dopaminergic pathway) and the
medial preoptic area of the hypothalamus (innervated by the dopaminergic incertohypothala-
mic pathway) positively regulated the anticipatory/motivational phase of copulatory behavior.
A permissive role of dopamine released at the level of the median preoptic area of the hy-
pothalamus in the display of copulatory behavior has also been demonstrated. It is noteworthy
that these participations of the dopaminergic system are not specific for sexual behavior but
rather reflect the involvement of dopamine in the regulation of cognitive, integrative and re-
ward processes. Because of its role in the control of locomotor activity, the integrity of the ni-
grostriatal dopaminergic pathway is also essential for the display of copulatory behavior.
Somehow more specific to sexual function, it is likely that dopamine can trigger penile erection
by acting on oxytocinergic neurons located in the paraventricular nucleus of the hypothalamus,
and perhaps on the proerectile sacral parasympathetic nucleus within the spinal cord. In con-
clusion, central dopamine is a key neurotransmitter in the control of sexual function.
Key Words
Erectile dysfunction Apomorphine D1/D2 dopamine receptor agonist Sexual function
European
Urology
Copyright 2001 S. Karger AG, Basel
Introduction
Sexual function, which includes a complex set of behav-
ioral and physiological processes, is under the control of the
central nervous system, which therefore constitutes a key
pharmacological target for the treatment of sexual dysfunc-
tions [1]. Within the central nervous system, the master or-
gan is the brain, which sends both activatory and inhibitory
projections on the spinal centers driving the sexual organs
[2]. Dopamine (DA) is one candidate neurotransmitter
constitute the only robust argument supporting the implica-
tion of DAin the control of penile erection in humans. The
notion that DA participates actively in the control of male
sexual function is, however, supported by numerous phar-
macological studies in male rats [for an extensive review
see, 17]. In the following are reviewed data suggesting that
DA can influence sexual behavior at different levels, from
motivation to performance.
DA Synthesis, Metabolism and Receptors
The catecholamine family is made up of DA, together
with norepinephrine and epinephrine. With serotonin and
histamine, they represent the main amines within the central
nervous system. DAis synthesized from tyrosine in a 2-step
reaction first involving tyrosine hydroxylase (generating L-
DOPA) and second DOPA decarboxylase, generating DA.
Conversion of tyrosine to L-DOPA and L-DOPA to DA oc-
curs in the cytosol; DA is then taken up into storage vesi-
cles. After release in the synaptic cleft, DAis actively taken
up from the extracellular space by specific transporters. In
humans, the catabolic inactivation of DAis ensured princi-
pally (but not exclusively) by monoamine oxidase (MAO)
A (as opposed to B) and catechol-o-methyl transferase [for
a comprehensive review see, 18]. The alternative pathways
for DAmetabolism are presented in figure 1.
602 Eur Urol 2001;40:601608
Giuliano/Allard
among others for the control of sexual functions at the level
of the central nervous system [3, 4].
Historically, the prosexual effect of DA in humans was
first suggested by the observation of increased sexual activ-
ity in patients with Parkinsons disease treated with DAag-
onists, although the incidence of such symptoms were very
rare [5, 6]. Several reports confirmed the ability of 3,4-di-
hydroxy-L-phenylalanine (L-DOPA, the precursor of DA)
to induce erections [79]. The ergot alkaloid bromocriptine,
a preferential D2 DAreceptor agonist, restored sexual func-
tion in cases where hyperprolactinemia was a component of
the disease [1012]. Hyperprolactinemia was frequently as-
sociated with typical neuroleptic medication, as a conse-
quence of the ability of these neuroleptics to block DA D2
receptors in the anterior pituitary, and correlated to erectile
dysfunction [13]. Whether the reversal of sexual dysfunc-
tion secondary to bromocriptine treatment is directly related
to the lowering of serum prolactin levels or to the correction
of hypothalamic dopaminergic regulation or to a combina-
tion of both mechanisms has not yet been established [14].
Subcutaneous injections of low doses of the semisynthetic
catecholic alkaloid apomorphine, a D1/D2 receptor
dopaminergic agonist (0.250.75 mg s.c.), elicited penile
erections in healthy subjects without sexual stimulation
[15]. Later, double-blind placebo-controlled studies showed
that higher doses of apomorphine (24 mg) delivered sub-
lingually could induce penile erections in men with erectile
dysfunctions [16]. The proerectile effects of apomorphine
Fig. 1. Alternative pathways of dopamine
metabolism. COMT = Catechol O-methyl-
transferase; MAO = monoamine oxidase; AD
= aldehyde dehydrogenase; AR = aldehyde
reductase (alcohol dehydrogenase); DOPAC
= 3,4-dihydroxyphenylacetic acid. Repro-
duced from Sourkes [19].
Five DA receptors have been cloned. D1-like receptors
(D1 and D5) are positively coupled to adenylate cyclase,
and D2-like receptor (D2, D3 and D4) are negatively or not
coupled to this enzyme. The main outcomes concerning
molecular biology and location of dopaminergic receptor
subtypes are given in table 1.
DA is implicated in a wide range of physiological func-
tions. For example, in Parkinsons disease, which is charac-
terized by a degeneration of the nigrostriatal DAtract, there
is a dramatic loss in the control of motor activity [for review
see, 19]. On the other hand, neuroleptics, which are often
effective in blocking hallucinations and delusions in schi-
zophrenia share the common property of DA antagonists
[for review see, 20]. Thus, DAis involved in the control of
motor activity in the striatum and also in cognitive, emo-
tional and reward processes in limbic areas. In this line, it
has been proposed that DA neurons do not have specific
functions but rather regulate and enable integrative func-
tions in the neuronal system onto which they project [21].
Figure 2 represents a schematic diagram of the dopaminer-
gic tracts in the rat brain discussed in this report.
Control of Penile Erection ex copula by DA
Ex copula refers to experiments performed in absence of
sexual partner. In males, experiments ex copula underline
the ability of a given compound to induce genital arousal
(i.e. penile erection) without sexual stimuli. This is fairly in-
teresting if one considers that in mating experiments, the
sexual motivation of the male rat, and hence its level of sex-
ual arousal, is dependent on the receptive and proceptive
behavior of the female, which is a variable parameter.
PVN and Penile Erection
The paraventricular nucleus of the hypothalamus (PVN)
is innervated by DA neurons that belong to the incertohy-
pothalamic system, which is part of the intrinsic DA inner-
vation of the hypothalamus [22, 23]. The incertohypothala-
mic system is constituted by the A13 cell group in the
rostral region of the medial zona incerta and the A14 cell
group in the rostral periventricular nucleus.
Injection of doses of apomorphine as low as 5 ng in the
PVN can induce penile erections in the freely moving rat
without the presence of a female [24]. Similar responses are
obtained when the selective D2 agonist LY171555 is inject-
ed in place of apomorphine, but not with the D1 agonist,
Dopamine and Male Sexual Function Eur Urol 2001;40:601608
603
Table 1. Characteristics of dopaminergic receptors from molecular biology
D1-like D2-like
D1 D5/D1b D2 (short)/(long)
a
D3 D4
Amino acids 446 (h, r) 477 (h) 414/443 (h) 400 (h) 387 (h)
475 (r) 415/444 (r) 446 (r) 368 (r)
Pharmacological SCH23390 (0.35) SCH23390 (0.30) Spiperone (0.05) Spiperone (0.61) Spiperone (0.05)
characteristics Dopamine (2340) Dopamine (288) Raclopride (1.8) Raclopride (3.5) Raclopride (237)
K
d
, nM Clozapine (56) Clozapine (180) Clozapine (9)
Dopamine (1705) Dopamine (27) Dopamine (450)
Homology, %
With D1 receptor 100 82 44 44 42
with D2 (short) 44 49 100 76 54
Receptor localization Caudate/putamen Hippocampus Caudate/putamen Nucleus accumbens Frontal cortex
Nucleus accumens Hypothalamus Nucleus accumbens Olfactory tubercle Midbrain, amygdala
Olfactory tubercle Olfactory tubercle Islands of Calleja medulla (all low
b
)
Frontal cortex Cerebral cortex (low
b
) Cerebral cortex (low
b
) Cardiovascular system
Retina
Adapted from Civelli [59]. h = Human; r = rat; K
d
= dissociation constant, obtained with human or rat recombinant receptors.
a
Two isoforms have been cloned: K
d
refers to the long isoform.
b
Refers to the level of expression of the corresponding mRNAwithin the structure considered in rats.
SKF38393 [24]. Erections induced by apomorphine injec-
tions in the PVN are abolished by systemic pretreatment
with the central D1 antagonist, SCH23390, and the D2
antagonist, sulpiride [24]. In anesthetized rats, penile erec-
tions induced by peripheral delivery of apomorphine are
antagonized by a preceding injection in the PVN of
SCH23390 or sulpiride [25]. These results strongly suggest
that activation of the dopaminergic receptors in the PVN is
responsible for the proerectile effect of apomorphine. Apo-
morphine injection in other hypothalamic structures, such
as the ventromedial and dorsomedial nucleus, the preoptic
area or the nucleus accumbens, did not induce penile erec-
tion [24]. The prosexual effects of apomorphine are likely
restricted to the central nervous system. In conscious rats,
apomorphine-induced erections are abolished by transec-
tion of the cavernous nerves [26]. They are inhibited by the
central DA antagonist, haloperidol, whereas they are unaf-
fected by the peripheral DA antagonist, domperidone [27].
Lastly, intracavernous injection of apomorphine failed to
elicit penile erection [25].
Altogether, activation of neurons in the PVN can be con-
sidered as a sine qua non condition for the proerectile effect
of apomorphine to occur, and this effect is mediated by DA
D1 and D2 receptors. The measurement of some DArelease
within the PVN concomitant to penile erection during cop-
ulation would be a definite argument for the physiological
implication of DA/PVN in the induction of penile erection.
Measurement of catecholamine turnover in the PVN has
been shown to be feasible in rats [28], but it has not yet been
performed before, during or after copulation. However, the
preceding data demonstrate that activation of dopamine re-
ceptors in the PVN can trigger penile erection.
Spinal Cord and Penile Erection
Whereas the brain is the master organ in sexual function,
sexual response is eventually controlled by spinal autonom-
ic nuclei [3]. Penile erection is caused by a change in the ac-
tivity of efferent autonomic pathways to the erectile tissues,
i.e. a shift from an overall predominant sympathetic to
parasympathetic outflow. The cell bodies of these autonom-
ic neurons are located in the spinal cord at the thoracolum-
bar level for the sympathetic nuclei and at the sacral level
for the parasympathetic nuclei (SPN).
The existence of DAprojections from the A11 cell group
to the spinal cord as well as an intrinsic DA innervation
within the spinal cord raises the possibility of an additional
direct action of apomorphine at the spinal level [29, 30]. Im-
munocytochemical studies revealed that DA fibers and ter-
minals exist in virtually all laminae throughout the spinal
cord [31, 32]. Furthermore, studies using ligand-binding
techniques have shown the presence of D1 and D2 receptors
in the spinal cord [33]. In male rats, D2 receptors identified
with immunochemistry and in situ hybridization have been
located in the parasympathetic nucleus of the lumbosacral
spinal cord, which contains the cellular bodies of the
proerectile autonomic neurons innervating the penis [34].
604 Eur Urol 2001;40:601608
Giuliano/Allard
Fig. 2. Main dopaminergic pathways in-
volved in the control of sexual function. The
nigrostriatal DA tract originates in the zona
compacta of the substantia nigra (A9 cell
group) and projects to the striatum. It is
mainly involved in the control of movement.
Cognitive and reward processes are sub-
served in part by the mesocortical/mesolim-
bic DA projections. Mesolimbic projections
originate in the ventral tegmental area (A10
cell group) and notably target the nucleus ac-
cumbens and forebrain. The incertohypotha-
lamic pathway is part of the intrinsic
dopaminergic innervation of the hypothala-
mus: the A13 and A14 cell groups project to
the paraventricular nucleus of the hypothala-
mus and the median preoptic area, both struc-
tures involved in regulating sexual function.
The A11 cell group projects to the spinal
cord, and may also play a role in the control
of sexual function. Adapted from Weiner and
Molinoff [18].
D2 receptors have also been found to be particularly abun-
dant in the dorsomedian and the dorsolateral nucleus which
innervate the bulbospongiosus and ischiocavernosus striat-
ed muscles involved in penile rigidity in the rat [34].
In agreement with these anatomical findings, apomor-
phine delivered at the lumbosacral level with an intrathecal
catheter elicited erectile activity in anesthetized rats [35].
Apomorphine delivered systemically displayed proerectile
activity in both anesthetized and conscious spinalized rats
[36, 37]. In conscious rats, reflexive erections are depressed
by peripheral injection of the nonspecific DAagonist RDS-
127 in normal and spinalized rats, and by intrathecal injec-
tion of apomorphine at the lumbosacral level [38, 39].
Moreover, intrathecal infusion of the dopaminergic agonist,
lisuride, decreased the number of intromissions and ejacula-
tion latency in copula, consistent with a prosexual effect of
dopamine at the level of the spinal cord [40]. The negative
effect of DA agonist on reflexive erections is probably due
to an inhibition of the sensory afferens from the penis with-
in the spinal circuitry. In contrast, the induction of penile
erection by apomorphine delivery within the spinal cord is
caused by a direct action on the SPN, independent of the in-
hibition of sensory afferens. Such results suggest the exis-
tence of a DA spinal component in the control of penile
erection.
Control of Sexual Motivation and
Performance by DA
A brief outline of some aspects of rat sexual behavior is
necessary for the understanding of the present report [for re-
view see, 41]. In classical copulation tests, or mating exper-
iments, a male rat is placed together with a receptive female.
The male rat performs a succession of mounts without and
with intromission before performing a mount with intromis-
sion and ejaculation. At the same time, the female displays
characteristic behaviors, such as a lordotic posture during
mounts (a reflexive behavior hormonally induced) and se-
quences of running away from the male with a characteris-
tic gait (hopping and darting). For the male, the latency of
the first intromission can be considered as a parameter re-
flecting the motivation of the rate to copulate. In agreement
with the observations in humans, systemically delivered DA
agonists, such as apomorphine, bromocriptine, pergolide or
lisuride, as well as L-DOPA, facilitate copulation in male
rats in the presence of receptive female rats (decreasing the
intromission latency), and lower the ejaculatory threshold
(decreasing the intromission number and ejaculation laten-
cy) [17].
Mesocortical Pathway
The nucleus accumbens is innervated by the mesocorti-
cal/mesolimbic pathway. The mesocortical/mesolimbic
pathway is constituted by DA cell bodies that lie medial to
the substantia nigra (ventral tegmental area, A10 cell
group). They provide a diffuse innervation to the forebrain,
including frontal and cingulate cortex, septum, nucleus ac-
cumbens and olfactory tubercle. The mesocorticolimbic
dopamine tract is considered to be a substrate for motivation
and reward as well as for locomotor behavior [21].
In mating experiments, injection of apomorphine in the
nucleus accumbens decreased the latency to begin copulat-
ing, whereas injection of apomorphine in the striatum was
without effect [42]. Conversely, injection of apomorphine
in the ventral tegmental area increased intromission latency,
likely by inhibiting the mesolimbic DA pathway through
stimulations of autoreceptors, and thus decreasing DA
transmission at the level of the nucleus accumbens [43].
Specific tests have been developed to discriminate ap-
petitive from consumatory components of sexual behavior,
such as the bilevel chambers. In this test, the male rate chas-
es the female from one level to another after each intromis-
sion. The number of level changes in a fixed time before the
introduction of the females is considered a measure of the
anticipatory phase (or appetitive phase) of sexual activity.
That bilateral infusions of haloperidol into the nucleus ac-
cumbens reduced the number of level changes without af-
fecting consummatory measures of copulation is evidence
that DA positively regulates the appetitive phase of sexual
behavior in male rats [44]. Injection of the D2 antagonist,
raclopride, in the nucleus accumbens was found to have no
effect on mount and intromission latencies when injected in
mating experiments in the presence of fully receptive fe-
males. However, when females were treated with flu-
penthixol, eliminating proceptive behavior, raclopride great-
ly increased the mount and intromission latencies when
injected in the nucleus accumbens [45, 46]. This demon-
strates (1) that the appetitive behavior of the male rat relies
upon female behavior, which can overcome the specific an-
tagonistic effect of a given drug on the anticipatory behav-
ior of the male rat, and (2) the importance of the dopamin-
ergic innervation of the nucleus accumbens in the display of
appetitive responses to sexual incentive stimuli.
The extracellular DA concentration was increased in the
nucleus accumbens when an estrous female was presented
behind a barrier, as well as during copulation [47]. Control
experiments indicate that neither novelty nor locomotor ac-
tivity can account for the increased extracellular DA con-
centrations observed in the nucleus accumbens of male rats
during the presentation of a sexually receptive female and
Dopamine and Male Sexual Function Eur Urol 2001;40:601608
605
during copulation [47]. Exposure to a nonestrous female
did not elicit DA release in the nucleus accumbens in the
male rat [48]. Thus, DA plays a positive role in the antici-
patory phase in male rats at the level of the nucleus accum-
bens.
Incertohypothalamic Pathway
The median preoptic area (MPOA) is innervated by the
incertohypothalamic pathway, originating from the A14 cell
group. First, it is noteworthy that destruction of the MPOA
destroys male copulatory behavior but neither the occur-
rence of spontaneous erection or penile erection upon penile
reflex [49]. In mating experiments, injection of apomor-
phine in the MPOA displayed clear prosexual effects [42].
Injections of DAantagonist (cis-flupenthixol) had the oppo-
site effect (increased intromission and ejaculation latency,
decreased number of rats which copulated and ejaculated)
and prevented the effects of apomorphine injected in this
area [50]. The selective D2 agonist, LY163502, and the se-
lective D1 antagonist, SCH23390, increased mount and in-
tromission latency when injected in the MPOA, suggesting
an opposite role for the D1 and D2 DA receptor in the
MPOAon sexual desire [51].
In the bilevel chamber paradigm, infusion of haloperidol
in the MPOAreproduced all the effects of systemic admin-
istration, i.e. decrease in the anticipatory/preparatory and
consummatory phase of copulatory behavior [44]. Instru-
mental measures of sexual motivation were also achieved
by training males to work for an estrous female presented in
an operant chamber under a second-order schedule of rein-
forcement. MPOAlesions abolished mounts, intromissions,
and ejaculations but did not disrupt instrumental responses,
investigation of the female, or abortive mounting attempts.
These data indicate a preponderant role of DAin the MPOA
in the performance of sexual behavior, although a role in
sexual motivation cannot be completely ruled out. The ma-
jor efferent projections of the MPOA are to hypothalamic,
midbrain, and brain stem nuclei that regulate autonomic or
somatomotor patterns and motivational state [52]. It has
been postulated that the MPOAremoves the tonic inhibition
on these patterns and thereby allows sensory stimuli to elic-
it a motor response.
The stimulatory role of DAin the MPOAin physiologi-
cal conditions has been confirmed as DAand 3,4-dihydrox-
yphenylacetic acid (DOPAC) were shown to be increased
during the precopulatory phase and during copulation, and
declined after ejaculation [53]. Note that the increase in DA
level in the MPOA during the precopulatory phase under-
lines a potential role in the anticipatory phase, in addition to
its well-established role on performance. Thus, DA partici-
pates at the level of the MPOAin the control of sexual per-
formance, and to a lesser extent in the control of sexual mo-
tivation.
Nigrostriatal Pathway
The nigrostriatal pathway is the major DA tract within
the brain. It originates in the zona compacta of the substan-
tia nigra (A9 cell group) and sends axons that provide a
dense innervation to the caudate nucleus and putamen of the
striatum (nearly 80% of all the DA in the brain is found in
the corpus striatum). The nigrostriatal system plays a key
role in the initiation and control of movement, as empha-
sized in Parkinsons disease.
Apomorphine injected in the striatum was without effect
on copulation in male rats [42]. In the bilevel chamber
paradigm, high doses of systemic haloperidol delayed or
abolished level changing and the initiation of copulation
likely because of impaired motor performance [44]. Bilater-
al infusions of haloperidol into the striatum only increased
the number of ejaculations in the bilevel chamber paradigm,
perhaps because the striatum is a rather big structure
which needs a considerable amount of drugs to be fully af-
fected [44].
DAis released in the dorsal striatum only after the male
begins to copulate, suggesting that DAlevels in the striatum
primarily reflect motor activation rather than motivational
aspects of copulation [47]. Nevertheless, forced locomotion
on a rotating drum, exposure to a novel chamber, and expo-
sure to sex odors did not increase DA significantly in the
striatum, although both DOPAC and homovanillic acid, the
major metabolites of DA, increased significantly [47]. This
experiment points to a specific sexual involvement of DA
release within the striatum during copulation.
In Humans
As mentioned above, the only direct argument support-
ing the involvement of the DA system in human sexual
function comes from the clinical use of apomorphine. One
cannot exclude that apomorphine acts at sites other than DA
receptors and the use of one compound is far from sufficient
to establish a pharmacological identity for a given physio-
logical response. As a consequence, it is worth stating that
the DAtheory of the control of sexual function in humans
is almost exclusively inferred from the results obtained in
rodents [4]. Nonhuman primate studies showed that apo-
morphine and LY163502 were capable of facilitating the
sexual behavior of male rhesus monkeys only in the pres-
ence of a receptive female they could at least see and smell
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References
[54, 55]. Interestingly, no facilitator effect was seen in the
absence of females.
Magnetic resonance imaging gave some insight into the
brain structures involved in sexual arousal induced by apo-
morphine. In a study of 6 patients with a history of psy-
chogenic erectile dysfunction, it was shown that the inferior
temporal regions on the right, superior prefrontal cortex and
posterior parietal regions bilaterally, and the thalamus, were
specifically activated upon sublingual administration of
apomorphine [56]. In comparison, visually evoked sexual
arousal (without drug treatment) was characterized by: bi-
lateral activation of the inferior temporal cortex, a visual as-
sociation area; activation of the right insula and right inferi-
or frontal cortex, which are two paralimbic areas relating
highly processed sensory information with motivational
state, and activation of the left anterior cingulate cortex, an-
other paralimbic area known to control autonomic and
neuorendocrine functions [57]. More precise data are re-
quired to make a comparison in order to determine to which
extent apomorphine activates brain structures which are
kept silent in drug-free sexual arousal.
It has been demonstrated in rats that the DAsystem was
involved in all steps of the control of the sexual function,
from the appetitive to the consummatory phase. It is likely
that this is also the case in humans. Thus, the prosexual ac-
tion of apomorphine might be much more complex that the
simple triggering of penile erection. Nevertheless, in a clin-
ical trial with sublingual apomorphine, there was no effect
on sexual desire according to the IIEF questionnaire [58].
Conclusions
In male rats, DAis involved in the appetitive/anticipato-
ry phase of sexual behavior in the nucleus accumbens and in
the consumatory phase in the MPOAand the striatum. Such
results illustrate the general role of DAin emotion and cog-
nitive function in the limbic area and in the control of move-
ment in the striatum, respectively. DA is also likely in-
volved in the specific control of erectile responses at the
level of the PVN and possibly in the lumbosacral spinal
cord. These experimental data suggest that DAis a key neu-
rotransmitter in the control of sexual functions, potentially
involved in both sexual motivation and control of sexual
performance.
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