Curr Neurol Neurosci Rep (2016) 16:74
DOI 10.1007/s11910-016-0673-2
AUTONOMIC DYSFUNCTION (LH WEIMER, SECTION EDITOR)
Pure Autonomic Failure
Pariwat Thaisetthawatkul 1
# Springer Science+Business Media New York 2016
Abstract Pure autonomic failure (PAF) is a rare sporadic
neurodegenerative autonomic disorder characterized by
slowly progressive pan autonomic failure without other
features of neurologic dysfunctions. The main clinical
symptoms result from neurogenic orthostatic hypotension
and urinary and gastrointestinal autonomic dysfunctions.
Autonomic failure in PAF is caused by neuronal degeneration
of pre- and postganglionic sympathetic and parasympathetic
neurons in the thoracic spinal cord and paravertebral autonom-
ic ganglia. The presence of Lewy bodies and α-synuclein
deposits in these neural structures suggests that PAF is one
of Lewy body synucleinopathies, examples of which include
multiple system atrophy, Parkinson disease, and Lewy body
disease. There is currently no specific treatment to stop pro-
gression in PAF. Management of autonomic symptoms is the
mainstay of treatment and includes management of orthostatic
hypotension and supine hypertension. The prognosis for sur-
vival of PAF is better than for the other synucleinopathies.
Keywords Pure autonomic failure . Synucleinopathy .
Neurogenic orthostatic hypotension . Lewy body . α-synuclein
This article is part of the Topical Collection on Autonomic Dysfunction
* Pariwat Thaisetthawatkul
pthaiset@unmc.edu
1
Department of Neurological Sciences, University of Nebraska
Medical Center, 988435 Nebraska Medical Center,
Omaha, NE 68198-8435, USA
Introduction
Pure autonomic failure (PAF) is a rare sporadic neurodegen-
erative disease characterized by progressive idiopathic auto-
nomic failure without other neurologic abnormalities. It was
first described by Bradbury and Eggleston in a report of 3
cases in 1925 [1]. The findings in the report characterized
typical clinical description of sympathetic and parasympathet-
ic autonomic failures known today: dizziness, lightheadedness
on standing up, recurrent attacks of syncope, orthostatic hy-
potension without changing in heart rate, absence of sweat,
supine hypertension, nocturnal diuresis, and blood pressure
responses to leg stocking and abdominal binding. PAF results
from lesions in the peripheral autonomic nervous system in
contrast to multiple system atrophy where the lesions are lo-
cated centrally but which can have similar autonomic presen-
tations earlier in the course of illness [2]. The involvement of
the peripheral autonomic system is shown in pathologic de-
scriptions of PAF where neuronal degeneration is observed in
preganglionic neurons in the intermediolateral column of the
thoracic spinal cord [3] and in paravertebral ganglia [4] and
significant decrease in norepinephrine synthesis and release
from sympathetic nerve terminals in this disorder [5].
Subsequent postmortem studies showing Lewy bodies in
sympathetic ganglia, substantia nigra, locus ceruleus, and the
posterior horn of lumbar spinal cord as well as nerves in the
epicardial fat, the adrenal gland, and the urinary bladder sug-
gest that PAF is one of neurodegenerative Lewy body diseases
[6, 7]. More recent pathologic studies showed accumulation of
α-synuclein immunoreactivity in association with Lewy bod-
ies in pre-and postganglionic sympathetic and parasympathet-
ic lesions in patients with PAF [8, 9]. These pathologic studies
strongly suggest that PAF is a synucleinopathy with limited
involvement to the autonomic nervous system while the other
synucleinopathies such as Parkinson disease (PD), Lewy body
74 Page 2 of 7
disease, and multiple system atrophy (MSA) have variable
autonomic involvement, as well as manifestations of motor
or cognitive abnormalities caused by lesions in the central
nervous system.
Symptoms and Signs
The original description of PAF by Bradbury and Eggleston
revealed typical symptoms of PAF patients [1]. Patients with
PAF present predominantly with symptoms related to ortho-
static hypotension caused by severe sympathetic failure (neu-
rogenic orthostatic hypotension). Orthostatic hypotension is
defined by reduction of systolic blood pressure at least by 20
mm Hg or diastolic blood pressure of 10 mm Hg within 3
minutes of assuming an upright position. The onset is usually
insidious and starts around middle age. The majority of pa-
tients with PAF describe their symptoms as dizziness,
lightheadedness, and giddiness [10]. Symptoms of visual dis-
turbance including visual blurring, change in colors, white-out
or grey-out, enhanced brightness, or tunnel vision are frequent
[10]. Often they have recurrent syncope while standing up.
Another frequent postural symptom is a Bcoat-hanger^ head-
ache or suboccipital pain in the distribution of the neck or
shoulder regions, which comes on while a patient assumes
an upright position. This headache is believed to arise from
decreased perfusion to the neck muscles when standing up,
and it disappears when the patient lies down [11].
Precipitating factors of orthostatic hypotension are commonly
heat, exercise, and large meals (postprandial hypotension).
Raise in body temperature such as from taking a warm bath
can cause cutaneous vasodilatation. A supine exercise can
induce supine hypotension and worsening orthostatic hypo-
tension in patients with PAF [12]. Postprandial hypotension
happens within 10 minutes after eating and could last up to 45
minutes in PAF patients [13]. It can cause supine hypotension
and worsening orthostatic hypotension because of splanchnic
vasodilatation caused by release of gut polypeptides [13].
Straining during defecation can also precipitate syncope.
The role of cerebral autoregulation in keeping cerebral blood
flow during orthostatic hypotension is uncertain. A few stud-
ies have shown conflicting results [14–16]. This could be due
to different methods used in the study of cerebral blood flow.
Supine hypertension is a frequent occurrence in PAF seen in
up to 56% in 1 study [17]. It is usually asymptomatic but is an
important cause of nocturnal diuresis that can worsen ortho-
static symptoms in the morning. It can cause important detri-
mental effect on cardiac myocardium causing left ventricular
hypertrophy [18] and kidney causing renal impairment [19].
Higher incidence of cerebral white matter changes in neuro-
imaging studies suggesting cerebrovascular lesions has been
observed in patients with PAF with supine hypertension [20].
The cause of supine hypertension in PAF is unclear but a study
Curr Neurol Neurosci Rep (2016) 16:74
using trimetraphan as a ganglion blocker showed that in MSA
supine hypertension could be from residual sympathetic activ-
ity. In MSA, there was significant reduction in supine blood
pressure after infusion with trimetraphan but the response to
trimethaphan in PAF was more variable [21]. Urinary bladder
symptoms have been observed in PAF. Frequent urinary
symptoms are nocturnal frequency, feeling of urgency, and
urinary hesitation [22]. Urodynamic study showed detrusor
hyperreflexia in most patients. Erectile dysfunction is very
commonly seen in male patients with PAF. Chronic constipa-
tion can be seen as a gastrointestinal symptom in PAF. A case
of intestinal pseudo-obstruction has been reported in PAF
[23]. Decreased sweat is variably seen but a case of PAF with
cold induced sweating has been reported [24]. REM sleep
behavior disorder, a paroxysmal movement or verbalization
during REM sleep without losing motor tone, has been rarely
observed in PAF [25]. Other nonspecific symptoms such as
weakness, fatigue, and lack of energy are also common [10].
Physical examination is usually unremarkable apart from or-
thostatic hypotension without compensatory change in the
heart rate. Neurologic examination is usually normal and
should not show pyramidal signs, Parkinsonism, cerebellar
ataxia, or other abnormal movement, which would otherwise
suggest other synucleinopathies. Abnormal pupils can be seen
in 67% of patients with PAF, most commonly bilateral
Horner’s syndrome [26]. Olfactory dysfunction, a common
feature seen in synucleinopathies, has been observed in PAF
[27]. Olfactory dysfunction in PAF is less severe than in PD
where hyposmia is a very common symptom [28]. Olfactory
dysfunction in PD is attributed to frequent and early involve-
ment of olfactory bulb with α-synuclein deposit [29], but sim-
ilar pathologic explanation in PAF is lacking. Unlike Lewy
body disease where cognitive dysfunction occurs early and is
a prominent clinical manifestation, PAF, in general, does not
have cognitive dysfunction. Detailed neuropsychological
tests, however, reveal deficits of attention and executive func-
tioning, possibly related to cerebral hypoperfusion from sys-
temic hypotension [30].
Pathology
The pathologic changes in PAF are predominantly widespread
neuronal degeneration in preganglionic sympathetic
intermediolateral column and paravertebral ganglia [31]
resulting in loss of peripheral adrenergic innervation [32].
Typical Lewy bodies seen in PD are present in sympathetic
ganglia, distal sympathetic nerves, substantia nigra, and locus
ceruleus in PAF patients [6, 7]. α-Synuclein, a 140 -amino acid
protein, is a major component of Lewy body and Lewy
neurites that are defining neuropathologic features of PD and
Lewy body dementia [33]. Immunoreactivity of α synuclein
has been observed in Lewy bodies in substantia nigra, locus
Curr Neurol Neurosci Rep (2016) 16:74
ceruleus, thoracolumbar and sacral spinal cord, and sympathet-
ic ganglia [9]. Strongest immunoreactivity was observed in the
halos than the cores of the Lewy bodies [8]. This makes PAF a
restricted Lewy body synucleinopathy [34]. Recent studies on
cutaneous autonomic nerves have recently shown that α-
synuclein immunoreactivity detected in skin biopsy samples
are potential biomarkers for PAF. Deposits of phosphorylated
α-synuclein can be demonstrated in skin autonomic nerve fi-
bers in PAF patients through skin biopsy samples from thighs
and legs [35•]. Of note is that phosphorylated α-synuclein
immunoreactivity was detected in all thigh skin samples from
patients with PAF, whereas all the control consisting of ac-
quired autonomic neuropathy had no immunoreactivity.
Phosphorylated α-synuclein immunoreactivity was detected
in sympathetic and parasympathetic nerve fibers alike but not
in epidermal nerve fibers or dermal plexus [35•]. α-Synuclein
immunoreactivity was also observed in the autonomic nerves
of patients with PD [36, 37]. α-Synuclein can also be detected
ante-mortem in colonic tissue acquired during colonic dissec-
tion and suggests that enteric α-synuclein pathology can be
useful as a biomarker for PAF [38]. A study of unmyelinated
nerve fibers in sural nerve biopsy of PAF patients showed that
mean unmyelinated nerve fiber density was significantly lower
than normal control [39] confirming peripheral autonomic in-
volvement in PAF. Similar results were observed with a study
on cutaneous autonomic innervation in patients with PAF
showing severe postganglionic denervation in both sympathet-
ic and cholinergic fibers compared with MSA where cutaneous
autonomic innervation was preserved [40]. This study sug-
gested that the determination of cutaneous autonomic innerva-
tion can be useful in differentiating PAF, a peripheral autonom-
ic disorder, from MSA, a central autonomic disorder.
Diagnosis
The diagnosis of PAF is based on compatible clinical features
of insidious, progressive pan autonomic failure, most impor-
tantly orthostatic hypotension, without the other neurologic ab-
normalities, particularly Parkinsonism, cognitive impairment,
cerebellar ataxia, or tremors. The presence of these abnormal
movements suggest the other forms of synucleinopathies such
as MSA (Parkinsonism, cerebellar ataxia, or tremor), PD with
autonomic failure (Parkinsonism), or Lewy body dementia
(cognitive impairment and Parkinsonism). All these
synucleinopathies have autonomic insufficiency as a common
clinical feature. Major disorders that can cause chronic auto-
nomic failure, such as diabetes mellitus, or subacute autonomic
neuropathy, such as paraneoplastic autonomic neuropathy, am-
yloid neuropathy, or autoimmune autonomic neuropathy need
to be excluded. MSA is an important differential diagnosis.
MSA can present with progressive autonomic failure first with-
out abnormal movement. It is recommended that the diagnosis
Page 3 of 7 74
of PAF can be secured if a patient has autonomic symptoms for
at least 5 years without other neurologic abnormalities [2]. To
demonstrate autonomic failure, one needs standardized and
quantitative autonomic function tests. An autonomic reflex
screening (ARS) test has served this purpose [41]. ARS is non-
invasive, quantitative, standardized assessment of autonomic
functions that have well-developed normative data acquired
from a large number of normal subjects. ARS consists of 3
main portions: quantitative sudomotor axon reflex test
(QSART), cardio-vagal tests, and adrenergic tests. These mo-
dalities can be assessed separately and independently. QSART
assesses the integrity of the postganglionic sympathetic
sudomotor functions by iontophoresed acetylcholine diffusing
through the skin and stimulating distal sweat nerves. The acti-
vation of sudomotor nerves produces sweat output from the
sweat glands. The sweat output is collected, quantitated, and
compared with normative data. Cardio-vagal function is
assessed through heart rate response to deep breathing
(HRDB) and Valsalva ratio (VR). These tests require noninva-
sive beat-to-beat blood pressure monitoring by Finometer tech-
nique, continuous electrocardiogram monitoring and respirato-
ry monitoring. HRDB is performed by a subject taking deep
breathing in cycles while lying in supine position. The maxi-
mum difference between the highest and the lowest heart rate is
obtained and compared with normative data. The test is usually
repeated a few times to ensure reproducibility. VR is obtained
by a subject maintaining a column of mercury at 40 mm Hg for
15 seconds by blowing into a bugle (Valsalva maneuver). VR is
derived from maximum HR divided by minimum HR that fol-
lows within 30 seconds during Valsalva maneuver. VR is then
compared with normative data. Valsalva maneuver also as-
sesses adrenergic function from beat-to-beat blood pressure
tracing during the maneuver. Apart from Valsalva maneuver,
adrenergic function can be assessed by a head-up tilt test
(HUTT). HUTT is performed by tilting a subject from supine
position to a 70° upright position for 5–10 minutes. Adrenergic
function can be assessed by maintenance of blood pressure and
changes in the heart rate during HUTT. In PAF, there is evi-
dence of pan autonomic failure in ARS [42]. QSART usually
shows diffuse and severe sweat loss or decrease indicating
postganglionic sudomotor impairment. HRDB and VR are usu-
ally reduced indicating cardio-vagal impairment. Valsalva ma-
neuver usually reveals blunt or loss of late phase II, loss or blunt
phase IV, and prolonged recovery time in beat-to-beat blood
pressure tracing indicating adrenergic dysfunction. Frequently,
orthostatic hypotension is seen immediately during HUTT
without compensatory tachycardia. Unfortunately, results ob-
tained from ARS do not differentiate autonomic failure of
PAF from the other causes. MSA, a central autonomic disorder,
can also cause abnormalities in QSART attributable to
transsynaptic defect [42]. The assessment of plasma catechol-
amine when a patient is in supine and upright position can help
differentiate a peripheral from central autonomic disorder [5].
74 Page 4 of 7
In supine position, patients with PAF usually have very low
plasma norepinephrine consistent with decreased spillover of
norepinephrine because of degeneration of distal sympathetic
nerves, whereas patients with MSA usually have normal nor-
epinephrine level. In upright position, there is usually no
change in norepinephrine level in both PAF and MSA com-
pared with supine position consistent with autonomic failure
with decreased net sympathetic activity. However, these find-
ings are not always reliable as there can be decreased clearance
of norepinephrine during an upright position causing some ris-
ing in the level [43]. Sympathetic denervation of the heart has
been shown in PAF by measuring norepinephrine spillover in
the heart and the kidneys [44]. Cardiac spillover of norepineph-
rine and its precursor is significantly reduced compared with
normal control. Recent development of cardiac sympathetic
neuroimaging has helped visualizing noradrenergic innervation
of the heart, which represents sympathetic postganglionic
nerves [45]. Two types of scans are commonly used for this
purpose: 123I -metaiodobenylguanidine (123I-MIBG) myocardi-
al single-photon emission computed tomography and 6-[18F]
fluorodopamine positron emission tomography scan.
Decreased cardiac sympathetic innervation has been shown in
PAF in both 123I -metaiodobenylguanidine single-photon emis-
sion computed tomography scan [46] and 6-[ 1 8 F]
fluorodopamine positron emission tomography scan [47] of
the myocardium. Similar findings are observed consistently in
patients with PD [47, 48]. In MSA, however, cardiac sympa-
thetic innervation assessed by these methods is usually normal
[45, 49]. Decreased sympathetic cardiac innervation in PAF
and PD has been confirmed in a postmortem study [50].
Brain magnetic resonance imaging can be helpful in diag-
nosis of MSA showing T2 signal hyperintensity in the pons
in a cruciform manner (Bhot cross bun^ sign), T2
hypointensity in the putamen with rim T1 hypetrintensity
on FLAIR sequence, and cerebellar and pontine atrophy
[51•], whereas brain MRI in PAF is generally unremark-
able. Measurement of vasopressin release in response to
hypotensive episode showed significant increase in the lev-
el in patients with PAF, whereas patients with MSA
showed no significant change compared with baseline [52].
Management
Currently, there is no treatment to slow the progression of or
cure this neurodegenerative disease. Management is focused
mainly on the autonomic symptoms that a patient has, partic-
ularly symptoms related to orthostatic hypotension. The aim is
to prevent injury from syncope and fall, to lessen the frequen-
cy of syncopal episodes, and to improve quality of life [53•].
Initial assessment is important as nonneurogenic causes of
orthostatic hypotension can co-exist with PAF and needs man-
agement separately. These include hypovolemia, cardiac
Curr Neurol Neurosci Rep (2016) 16:74
failure, and venous pooling [54•]. Medications that can exac-
erbate orthostatic hypotension should be identified and
discontinued or the dose adjusted. These medications include
diuretics, alpha-adrenergic antagonists, calcium channel
blockers, nitrates, levodopa and dopaminergic drugs for PD,
antipsychotics, and antidepressants. The patient should be
taught physical counter maneuvers to cope with impending
presyncopal symptoms. These include cross-leg maneuver,
squatting, bending forward, and tensing their legs or thighs
[53•]. Wearing an abdominal binder can help reducing ortho-
static hypotension [55] as wearing compression stockings
[56]. Most importantly, a patient should be encouraged to
drink adequate water intake (at least 2–2.5 L/d) and take salt
intake at last 5–10 g/d [56]. Water and salt intake can be
monitored in an individual by obtaining 24-hour urine sodi-
um. In general, a 24-hour urine sodium above 170 mmoL/d is
considered adequate [54•]. Because heat and large meals can
exacerbate symptoms of orthostatic hypotension, avoidance
of heat and large meals is preferable. In summer time, a patient
with PAF should be encouraged to stay indoors, particularly in
the afternoon and use an air-conditioner to dissipate heat. If
one has to go outdoors, one should drink 2 8-oz cups of water
before heading out. Rapid water drinking can induce hypo-
osmolality in the portal vein and in turn triggers vasoconstric-
tion [53•]. A patient with supine hypertension should be
instructed to raise the head up about 4–6 inches when sleeping
at night to ameliorate high blood pressure and nocturnal di-
uresis. Pharmacotherapy of neurogenic orthostatic hypoten-
sion is required if above measures fails to prevent syncope
or falls in patients with orthostatic hypotension. There are
currently 3 commonly used medications: midodrine,
pyridostigmine, and fludrocortisone. Midodrine is an α-1 ad-
renergic agonist that reacts directly on the arterioles and ve-
nous capacitance vessels causing vasoconstriction [57].
Midodrine is also a Food and Drug Administration (FDA)-
approved medication for neurogenic orthostatic hypotension
based on consistent results seen in 3 double-blind, placebo-
controlled clinical trials [58–60]. The dose varies from 2.5 mg
to 10 mg 3 times daily. Major side effects include hyperten-
sion, headache, and paresthesia. Because its half-life is about 4
hours, the last daily dose of midodrine should be taken in the
midafternoon time to minimize its effect on supine hyperten-
sion at night. Pyridostigmine is a cholinesterase inhibitor. It
works by inhibiting degradation of acetylcholine at the auto-
nomic ganglia thereby enhancing ganglionic transmission in
both sympathetic and parasympathetic systems. Because sym-
pathetic transmission at the autonomic ganglia is low on su-
pine position, pyridostigmine shows promise as a medication
to treat orthostatic hypotension without causing supine hyper-
tension as usually seen in the other medications as an effect of
nonspecific raising of the blood pressure. The dose is 30–60
mg 3 times daily. However, the effect of pyridostigmine on
orthostatic blood pressure is only moderate even though there
Curr Neurol Neurosci Rep (2016) 16:74
is improvement in symptoms [61]. A subsequent study of
pyridostigmine alone and in combination with midodrine in
orthostatic hypotension showed that orthostatic blood pres-
sure improved significantly with pyridostigmine alone com-
parable to a combination of pyridostigmine and midodrine
without worsening supine hypertension [62]. Major side ef-
fects include abdominal cramps and increased tear and saliva.
Fludrocortisone is a synthetic mineralocorticoid with almost
no corticosteroid effect. It works by increasing reabsorption of
sodium at the kidney tubules, causes volume expansion, and
raises blood pressure. The dose is usually 0.1-0.2 mg/d. The
major concern on using fludocortisone is that it can potentially
aggravate supine hypertension [63]. Droxidopa recently
emerges as a new medication to treat orthostatic hypotension.
It is recently approved by FDA for neurogenic orthostatic
hypotension associated with primary autonomic failure (PD
and autonomic failure, PAF, MSA) [64••]. It is synthetic ami-
no acid precursor that is converted to norepinephrine by dopa
decarboxylase [65]. A randomized placebo-controlled clinical
trial showed that droxidopa with dose range from 100 to 600
mg 3 times daily can increase standing blood pressure, im-
prove quality of life, and is well tolerated in patients with
neurogenic orthostatic hypotension [66]. Major adverse ef-
fects include hypertension, headache, and nausea.
Atomoxetine is a selective norepinephrine reuptake inhibitor.
It is FDA-approved for the treatment of attention deficit hy-
peractivity disorder [67]. In neurogenic orthostatic hypoten-
sion, atomoxetine has been shown to be most helpful in in-
creasing orthostatic blood pressure in a central autonomic dis-
order such as MSA, whereas the effect on a peripheral auto-
nomic disorder such as PAF is not significant [68]. The role of
atomoxetine is, therefore, in treating orthostatic hypotension
refractory to more common medications in a central autonom-
ic disorder [64]. In a patient with PAF who has orthostatic
hypotension and anemia, subcutaneous recombinant erythro-
poietin 4000 U biweekly can help correct anemia and increase
standing blood pressure [69]. However, supine hypertension is
usually seen following the use of recombinant erythropoietin
because of increased red cell mass and, hence, blood volume
[70]. Side effects include thrombocytosis, flu-like symptoms,
and occasionally, seizures [53•]. Postprandial hypotension
can be attenuated by octreotide or acarbose, but their ther-
apeutic effects are mostly marginal; the treatment of this
condition remains suboptimal [71, 72]. Supine hyperten-
sion can be ameliorated by sleeping with head up about
4–6 inches, and vasoactive medications such as midodrine
should not be given beyond 4–5 pm. If supine hypertension
remains significant, medications such as hydralazine, ni-
fedipine, amlodipine, angiotensin converting enzyme in-
hibitors, or nitrates can be given at night [56].
Management of urinary bladder, and gastrointestinal and
sexual dysfunction requires consultation to specialists in
each entity to exclude the other causes.
Page 5 of 7 74
Prognosis
Even though the presence of cardiovascular autonomic failure,
which is a common feature in PAF, has been considered to play
a negative prognostic role in the synucleinopathy [73], PAF
has a much better prognosis for survival compared with the
other synucelinopathies in a prospective cohort study [74•].
Survival in PAF is comparable to PD without orthostatic hy-
potension and is much better than MSA. Probability of 10-year
survival in PAF is 87%, whereas in MSA, a 10-year survival
rate is about 33%–39% depending on the MSA type [74•]. The
major causes of death in PAF in a retrospective study are in-
fection and cancer while infection, cardiac cause, and stroke
are the main causes of death in MSA [75]. A patient with PAF
has 70% less risk than a patient with MSA for cardiac death.
Conclusions
PAF is a sporadic neurodegenerative disorder that presents
with autonomic symptoms, most importantly neurogenic or-
thostatic hypotension, without other neurologic abnormalities.
PAF is a synucleinopathy. The diagnosis requires quantitated
and standardized autonomic testing showing pan autonomic
failure. Secondary causes of autonomic failure and the other
forms of synucleinopathy, particularly MSA, need to be ex-
cluded because of a better prognosis for survival in PAF.
Neurogenic orthostatic hypotension is the major cause of mor-
bidity associated with PAF. Management of PAF focuses
mainly on management of neurogenic orthostatic hypoten-
sion. New researches show that subcutaneous deposit of α-
synuclein may be a potential biomarker of this disease entity.
Compliance with Ethical Standards
Conflict of Interest Pariwat Thaisetthawatkul declares no conflict of
interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
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