Download Voltage-Gated Na+ Channels in the CNS

Voltage-Gated Na+ Channels in the CNS
Ronit Cherki, Ph.D., Director, Electrophysiology Group
Voltage-gated Na+ channels are membrane proteins that are essential for the generation
and propagation of action potentials in excitable tissues, such as brain, muscle, and
heart following membrane depolarization. These channels are heteromultimeric protein
complexes consisting of one α and one or two β subunits. Alomone Labs offers an
extensive list of primary polyclonal antibodies as well as modulators related to this
family. The use of Alomone Labs antibodies in fluorescence immunocytochemistry and
western blot analyses demonstrates membrane expression of the different subtypes of
voltage-gated Na+ channels and allow to monitor the developmental and physiological
changes as described and presented in the article below.
Introduction
There are nine recognized members of the
voltage-gated Na+ channel family (VGSC; Nav1.1Nav1.9). Of these, Nav1.1, Nav1.2, Nav1.3 and
Nav1.6 are highly (but not exclusively) expressed
in the central nervous system (CNS), whereas
Nav1.7, Nav1.8 and Nav1.9 demonstrate a more
restricted expression pattern in autonomic
and sensory neurons of the peripheral nervous
system (PNS). Nav1.4 and Nav1.5 represent the
predominant skeletal muscle and cardiac Na+
channels, respectively. The Nav1.6 subtype is
also highly expressed in the peripheral nervous
system where it is enriched at the nodes of
Ranvier of myelinated axons and contributes to
saltatory conduction4,18.
The expression of the different subtypes of
voltage-gated Na+ channels is variable within
different types of neurons, or within different
parts of the membrane of a single neuron. The
subtype composition, density and distribution
of voltage-gated Na+ channels determine
the property of the various types of neurons
or the specific areas of each neuron26. Also,
expression and distribution of the different
members of the voltage-gated Na+ channel
family at the subcellular level, differs during the
development19.
The expression of voltage-gated Na+ channels
10
is a dynamic process, and alterations in the
physiological state as well as injury induce
changes in their expression, which can alter
neuronal behavior.
Figure 1. Nav1.6 Appears at AISs during
Maturation in Cultured Cells.
A
Localization and Distribution of
Voltage-Gated Na+ Channels
A study of the normal distribution of voltagegated Na+ channels using immunohistochemistry
and immunolabelling analyses showed that
Nav1.3 (using Anti-Nav1.3 antibody (#ASC004)), and other voltage-gated Na+ channels are
expressed in the human optic nerve1.
B
The distribution of voltage-gated Na+ channels
in spiral ganglion neurons (SGN) was examined
using RT-PCR and immunohistochemistry
analyses. The use of Anti-Nav1.1 (#ASC-001),
Anti-Nav1.6 (#ASC-009), and Anti-Nav1.7 (#ASC008) antibodies demonstrated that the respective
channels are localized in SGN cell bodies and in
axonal processes11.
CG cells were labeled with Anti-Nav1.6 antibody (#ASC-
A study compared voltage-gated Na­­­­­­+­ channels
in cerebellar Purkinje cells from mormyrid
fish and rat using immunohistochemical and
electrophysiological methods. Results show
that Nav1.1, Nav1.2, and Nav1.6 channels are
present in comparable densities and locations
in the mormyrid and rat cerebellum, using their
009) at DIV 8 (A) or DIV 12 (B). Right columns show
immunoreactivity for Nav1.6 when the primary antibody was
preincubated with the immunizing peptide. At DIV 8, Nav1.6
staining was diffusely distributed and rarely concentrated
at the AIS whereas accumulation was detected in most AISs
at DIV 12.
Adapted from reference 22 with permission of Blackwell
Publishing Ltd.
Modulator No.24 Summer 2010 www.alomone.com
respective Alomone Labs antibodies, and also
share the same set of Na+ conductance8.
Figure 2. Polarized Distribution of Na+ Channel Subtypes.
aA
b
B
AnkG
AnkG
Merge
Normalized
fluorescence intensity
Nav1.2
0.8
Nav1.2
0.8
AnkG
Merge
Merge
Nav1.6
Pan-Nav
Nav1.2
Nav1.6
0.8
0.6
0.6
0.6
0.4
0.4
0.4
0.2
0.2
(n = 55)
Soma 10
20
30
40
Axon initial segments (AISs) and nodes of Ranvier
contain high densities of voltage-gated Na+
channels. AISs are a structurally and functionally
specialized region of the axon believed to be
critical for the generation of action potentials (AP).
The high density of voltage-gated Na+ channels at
AISs20 lowers the threshold for AP initiation and
gives rise to a fast, regenerative inward current
during the rising phase of the depolarization. The
nodes of Ranvier ensure efficient AP conduction.
c
C
Soma 10
20
Pan-Nav
0.2
(n = 55)
30
40
Morphologically differentiated cerebellar granule
(CG) cells express Nav1.2 and Nav1.6, though both
subunits appear to be differentially regulated.
Immunocytochemical analysis, using Alomone
Labs antibodies showed that Nav1.2 is localized
at most AISs of CG cells from 8 days in vitro
(DIV 8 to DIV 15). At DIV 8, Nav1.6 was found
uniformly throughout the somata, dendrites and
axons with occasional clustering in a subset of
AISs. Accumulation of Nav1.6 at most AISs was
evident by DIV 13–14 (Figure 1), suggesting it is
developmentally regulated at AISs22.
Soma 10
(n = 43)
20
30
40
Distance from soma (µm)
A) Antibody staining for AnkG (red) and Nav1.2 with Anti-Nav1.2 antibody (#ASC-002), (green) in the rat
prefrontal cortex. Note that the proximal AIS has strong staining for Nav1.2. B) Double staining for AnkG
and Nav1.6 with Anti-Nav1.6 antibody (#ASC-009), (green). Note that the distal region of the AIS is heavily
stained. C) Double staining for AnkG and Nav with Anti-Pan Nav antibody (#ASC-003), (green). Plots of the
averaged (± s.e.m.) fluorescence intensity as a function of distance from the soma at the AIS are shown.
Images are projections of confocal z stacks. Scale bars 10 µm. Error bars represent s.e.m.
Adapted from reference 13 with permission of Macmillan Publishers Ltd.
Figure 3. Nav1.6 and Ankyrin-G Are Targeted to AISs of Cerebellar
Purkinje Neurons by Postnatal Day 9.
Sections of P9 rat cerebellum were
double labeled with antibodies against
ankyrin-G (green), and Nav1.6 using
Anti-Nav1.6 antibody (#ASC-009), (red).
Arrowheads indicate Purkinje cell initial
segments. Scale Bars, 10 µm.
Adapted from reference 14 with
Nodes of Ranvier in myelinated axons in the CNS
are ideal places to examine how certain subtypes
of voltage-gated Na+ channels are inserted into a
specific region of a neuron. During development,
Nav1.2 first appears in the predicted nodes during
myelination, and Nav1.6 replaces it in the mature
nodes25,26. These characteristic localizations
are influenced by myelination. Examination of
the influence of the paranodal junction on the
switching of Na+ channel subunits was done
using the sulfatide-deficient mouse model (this
mutant displays disruption of paranodal axoglial
junctions). The initial switching of Nav1.2 to
Nav1.6 in the optic nerve was observed using
Anti-Nav1.6 antibody. However, the number of
Nav1.2-positive clusters was significantly higher
than in wild-type mice suggesting that paranodal
junction formation may be necessary for complete
replacement of nodal Nav1.2 to Nav1.6 during
development as well as maintenance of Nav1.6
clusters at the nodes26.
Nav1.2 and Nav1.6 are selectively targeted to the
proximal and distal AISs, respectively (in the rat
prefrontal cortex)13, in AISs of CA1 hippocampal
pyramidal neurons23 and in mature Purkinje
neuron initial segments14. Nav1.6 channels
accumulate at the distal AIS to determine the
lowest threshold for AP initiation. On the other
hand Nav1.2 channels are highly clustered at the
proximal AIS guaranteeing that the AP initiated
at the distal AIS will not back-propagate into
the soma as shown in immunohistochemical
studies in rat prefrontal cortex using Anti-Nav1.2
and Nav1.6 as well as Anti-Pan Nav (#ASC-003)
antibodies13 (Figure 2).
permission of Rockefeller University
Press.
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In different types of neurons the expression
11
Figure 4. Nav1.6 Is Expressed along Extensive
Regions of Most β-APP Immunopositive
Axons.
% of β-APP positive axons that express
diffusely distributed Na channels
A
80
60
40
20
0
Nav1.6
Nav1.6/
Nav1.2
Nav1.2
B
of various Na+ and K+ channel subunits varies
along the proximo-distal axis of AIS. This precise
arrangement is likely to contribute to the diversity
of firing properties observed among central
neurons20. Using an antigen retrieval method,
Anti-Nav1.6 was used to monitor the distribution
of Nav1.6 which was found to be expressed
in AISs of different neurons in the neocortex,
hippocampus, main olfactory bulb (MOB) and
cerebellum along with other channel subunits20.
Another direction of research was done to
investigate the mechanism for targeting and
restricting voltage-gated Na+ channels to
excitable membranes. It was proposed that one
or more proteins colocalize with Na+ channels
including βIV spectrin, ankyrin-G (ankyrin-3),
and the L1 cell adhesion molecule (L1 CAM)14,15.
Immunohistochemistry studies showed that
ankyrin-G and IV spectrin appear at AIS by P2,
whereas L1 CAM and Nav1.6 (using Alomone Labs’
antibody) are not fully assembled at continuous
high density along AISs until P9. Furthermore,
Nav1.6 and L1 CAM are not clustered in adult
Purkinje neuron initial segments of mice lacking
cerebellar ankyrin-G. These results support
the conclusion that ankyrin-G coordinates the
physiological assembly of voltage-gated Na+
channels, in AISs14. Similarities were found
in the clustering of ankyrin-G, defining early
developmental intermediates in the nodes of
Ranvier formation in the mouse optic nerve14
(Figure 3).
Contactin (also known as F3, F11 in various
species) is a glycosyl-phosphatidylinositol (GPI)anchored protein, expressed in neurons and glia.
In the CNS, there is a high level of colocalization
of contactin and voltage-gated Na­+ channels at
the nodes of Ranvier, both during development
and in the adult. A combination of biochemical,
electrophysiological, and immunolocalization
experiments (in optic nerves of rat, using Anti-Pan
Nav antibody) all pointed to a specific association
of contactin with voltage-gated Na+ channels
and concluded that contactin may influence the
functional expression and distribution of Na+
channels in neurons16.
In another study, in order to understand the
mechanisms and sequences responsible for
targeting and localizing Nav1.2 to unmyelinated
axons, chimeras between Nav1.2 and Nav1.6
were generated (Nav1.6 does not localize at
unmyelinated axons). Results suggest that the
451 amino acids of Nav1.2 C-terminal are likely
required for its interaction with neuron-specific
factors in order to direct it to axons as tested
using Anti-Nav1.219.
Figure 5. Immunofluorescent Photomicrographs of Neonatal Rat Spinal Cord Sections.
A) Histogram demonstrating the percentage of
β-APP-positive axons that are Nav1.6-positive,
Nav1.6/Nav1.2-positive (i.e., co-express both Nav1.6
and Nav1.2), or Nav1.2-positive in EAE. B) Digital
images of a representative field demonstrating
axonal profiles in EAE spinal cord immunostained
for β-APP (blue; top panel), Nav1.6 and Nav1.2 using
Anti-Nav1.6 (#ASC-009), (red; middle panel) and
Neonatal rat spinal cord sections were labeled with ChAT (green, A), a marker for spinal motor neuron and Nav1.6 using Anti-
Anti-Nav1.2 antibodies (#ASC-002), (green; bottom
Nav1.6 antibody (#ASC-009), (red, B). The merged image (C) confirms that Nav1.6 is expressed in motor neurons. Arrows
panel) respectively. Arrows point to β-APP-positive
indicate the spinal motor neurons in the ventral horn of spinal cord showing Nav1.6 labeling co-localised to ChAT positive
and Nav1.6-positive axons that do not display Nav1.2
neurons. Absence of staining in the negative control (D) confirms specificity of staining. Scale bars, 75 µm (A–D). Note a
immunostaining.
decreased Nav1.6 expression in rat pups injected with ALS-CSF (H), when compared to those injected with nonALS-CSF (G),
Adapted from reference 5 with permission of Oxford
sham control (F) and normal control (E).
University Press.
Adapted from reference 12 with permission of Elsevier.
12
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Neuronal Disorders Involving
Voltage-Gated Na+ Channels
Multiple Sclerosis/Myelination
The optic nerve axon is a CNS tract commonly
affected in multiple sclerosis (MS). Numerous
studies investigating the organization of Na+
channels along the axons of the optic nerve, were
carried in experimental allergic encephalomyelitis
(EAE) mice, a model of MS. Immunocytochemical
analysis using Anti-Nav1.2 and Anti-Nav1.6
antibodies, demonstrated a significant switch
from Nav1.6 to Nav1.2 expression in the optic
nerve in EAE. In addition, there was a reduction
in frequency of Nav1.6-positive nodes and
increased frequency of Nav1.2-positive nodes.
These findings suggest that electrogenesis in EAE
may revert to a stage similar to that observed in
immature retinal ganglion cells in which Nav1.2
channels support conduction of action potentials
along axons6.
The expression of Nav1.2 and Nav1.6, Na+/
Ca2+ exchanger (NCX) and β-amyloid precursor
protein (β-APP a marker of axonal injury), were
examined in the spinal cord dorsal columns of
mice with (EAE)5 and in postmortem cervical
spinal cord and optic nerve tissue, from patients
with disabling secondary progressive MS7. Using
triple labeled fluorescent immunohistochemistry,
it was shown that Nav1.6 and NCX are colocalized
with β-APP in acute MS lesions. The results
demonstrate the molecular identities of the Na+
channels expressed along demyelinated and
degenerating axons in MS and suggest that the
coexpression of Nav1.6 and NCX is associated
with axonal degeneration in MS5,7. Furthermore,
there was a significant increase in the number
of demyelinated axons demonstrating diffused
Nav1.6 and Nav1.2 channels in EAE using AntiNav1.2 and Anti-Nav1.6 antibodies5 (Figure 4).
Demyelination can be repaired by remyelination
in both humans and rodents, and even within
the CNS. Congenitally dysmyelinated spinal
cord axons can undergo remyelination, by
transplanting adult neural precursor cells
(aNPCs) from the brain of transgenic mice into
the spinal cords of adult Shiverer (shi/shi ) mice,
which lack compact CNS myelin. Six weeks
after transplantation, the transplanted aNPCs
expressed oligodendrocyte markers, and formed
compact myelin10. Anti-Nav1.6 and Anti-Nav1.2
were both used to show that Na+ channels are
not affected by dysmyelination. Specifically,
the lack of immunoreactivity is as expected and
that of Nav1.6 remains clustered at the nodes
of Ranvier10. Similarly, glial cells, from olfactory
ensheathing cells were transplanted into the
demyelinated spinal cord and subsequently
formed a compact myelin. Immunocytochemical
analysis in remyelinated axons, with antibodies
purchased from Alomone Labs, showed that
Nav1.6 was clustered at nodes of Ranvier, whereas
Kv1.2 was aggregated in juxtaparanodal regions,
recapitulating the distribution of these channels
within mature nodes of uninjured axons. These
findings indicate that, in addition to forming
myelin, glial cell transplantion provides an
environment that supports the development and
maturation of nodes of Ranvier and the restoration
of impulse conduction in central demyelinated
axons24.
Cerebro spinal fluid (CSF) from patients with
Amyotrophic Lateral Sclerosis (ALS) evokes a
change in ion channel expression in newborn rat
spinal motor both in vivo and in vitro. Following
exposure of CSF from ALS patients, cultures
and spinal cord sections were processed for
immunostaining of Nav1.6 using Anti-Nav1.6.
A decrease in the expression of Nav1.6 in
motor neurons in the ALS-CSF treated group
was observed; thereby indicating that altered
expression of Nav1.6 may interfere with the
electrical activity of motor neurons, and thereby
leads to the degeneration of neurons12 (Figure 5).
Figure 6. Down-Regulation of Nav1.1 following Focal Ischemia.
A
B
sham
2h
6h
24h
48h
time point post-MCAo
Nav1.1 immunoreactive cells (dark brown) with Anti-Nav1.1 antibody (#ASC-001) counterstained with cresyl violet (light purple) from striatal brain regions of sham animals and at
2, 6, 24 and 48 h post-MCAo. A) Contralateral; B) Ipsilateral. Sham images taken 24 h following sham surgery. Scale bars, 50 µm.
Adapted from reference 28 with permission of Elsevier.
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13
Ischemia and Nerve Injury
Alterations in the expression, molecular
composition, and localization of voltage-gated
Na+­­­­­­­ channels play major roles in a broad range of
neurological disorders. Alteration of Na+­­­­­­­ channel
function has been reported to occur in a variety
of neuropathological states including axonal
degeneration, epilepsy and brain injury. Changes
in voltage-gated Na+ channel activity can play
a role in reorganization, recovery, or possibly
excitotoxic damage following injury.
Prolonged hypoxemia in fetal llama brain caused
a significant decrease in the expression of
Nav1.1 and less so for Nav1.2 channels detected
with Anti-Nav1.1 and Nav1.2 respectively9.
The decrease in their expression was not
accompanied by cell death suggesting that the
fetal llama brain responded to hypoxemia with an
adaptive hypometabolism as opposed to a more
degenerative effect.
In order to gain further insight into the
molecular events underlying brain injury, male
rats were subjected to ischemic brain injury.
Immunoreactive analysis of brain tissue, using
Anti-Nav1.1 revealed a qualitative decrease in
protein levels of Nav1.1 throughout the ischemic
regions, beginning at the early stage of injury (6
h) with dramatic losses at later stages (24 and 48
h)28, (Figure 6).
in genes that affect voltage-gated Na+ channel
expression pathways, ultimately predisposing
neurons toward repetitive firing and network
hyperexcitability. Because voltage-gated Na+
channels can underlie neuronal bursting, it
was asked whether there are differences in the
expression of voltage-gated Na+ channels in
the rodent model of absence epilepsy (WAG/
Rij ) cortex compared to non-epileptic controls.
Immunocytochemistry analysis showed that
protein levels of Nav1.1 and Nav1.6 were upregulated in layer II–IV in the cortical neurons17,
using Alomone Labs specific antibodies (Figure
7). This region of the cortex approximately
matches the electrophysiologically determined
region of seizure onset17. Early treatment with
ethosuximide blocks changes in the expression
of Nav1.1 and Nav1.6, normally associated with
epilepsy in this model, leading to the suppression
of seizures even after therapy was discontinued.
These findings suggest that early treatment
during the development provides a new strategy
for preventing epilepsy2.
Kindling is a form of abnormal activity-dependent
facilitation that can be initiated, developed, and
expressed in wild-type mice. Voltage-gated Na+
channel expression by immunocytochemistry was
verified using Alomone Labs-related antibodies.
It was found that kindling is associated with
increased expression of Nav1.6, which occurs
selectively in hippocampal CA3 neurons, while no
changes regarding the expression of Nav1.1 and
Nav1.2 was observed. These results suggest an
important role for altered expression of voltagegated Na+ channels in the abnormally enhanced
excitability seen in epilepsy and other chronic
disorders of the nervous system3.
Figure 7. Voltage-Gated Na+ Channels in Layers II-IV Neurons of WAG/Rij
and Wistar Rat Cortex.
Voltage-gated Na+ channel proteolysis occurs in
an early event following ischemia and traumatic
brain injury. A recent study showed that activated
calpain causes voltage-gated Na+ channel
proteolysis. Using Anti-Pan Nav and Anti-Nav1.2, it
was shown that calpain-mediated voltage-gated
Na+ channel cleavage may play an important
pathophysiological role in recovery or demise
after injury27.
Neurogenesis in the neocortex following ischemia
has been for long a controversial issue. Using
retrovirus-mediated labeling of neocortical layer 1
proliferating cells with membrane-targeted green
fluorescent protein (GFP), it was found that the
neocortical layer is a source of adult neurogenesis
under ischemic conditions. In addition, it was
found that a large number of the GFP-positive cells
express voltage-gated Na+ channels, which are
essential for the production of action potentials,
of which 98 of 162 GFP-positive cells were Nav1.6positive (using Anti-Nav1.6), strongly suggesting
that biogenesis not only occurs at the expression
level but also at the functional level21.
Epilepsy
CNS plasticity is essential for normal function, but
can also reinforce abnormal network behavior,
leading to epilepsy and other disorders. Certain
types of epilepsy can result from direct voltagegated Na+ channel gene mutations or changes
14
Immunostaining in control rats (no *) versus WAG/Rij rats (*) using Anti-Nav1.1 (#ASC-001), (A, A*), Anti-Nav1.2
(#ASC-002), (B, B*), and Anti-Nav1.6 antibody antibodies (#ASC-009), (C, C*). The control and epileptic images
were digitally contrast-enhanced using identical parameters to qualitatively illustrate the up-regulation of the
Na+ channels. D) Optical intensity quantification from unenhanced images of individual neurons in layers II-IV
shows increased staining with Anti-Nav1.1 and Anti-Nav1.6 antibodies in the epileptic animals (V) compared to
controls (V), indicating up-regulated Na+ channel expression.
Adapted from reference 17 with permission of Elsevier.
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Phrixotoxin-3 Inhibits the Na+ Current of NaV1.2 Channel Expressed in Xenopus oocytes.
Superimposed traces of Nav1.2 currents before
(black) and during (green) application of 300 nM
Phrixotoxin-3 (#P-720). Currents were elicited from
a holding potential of -100 mV and test pulses of 35
ms to +60 mV were delivered every 5 sec.
Experimental procedure and figure processed at
Alomone Labs Ltd.
Expression of Nav1.1 in Rat DRG.
A
B
C
Immunocytochemical staining of paraformaldehyde-fixed and permeabilized rat dorsal root ganglion (DRG) cells using Anti-Nav1.1 antibody (#ASC-001), (1:200)
followed by goat anti-rabbit-AlexaFluor-555 secondary antibody. Hoechst 33342 was used as the counterstain (blue).
Experimental procedure and figure processed at Alomone Labs Ltd.
References
20. Lorincz, A. and Nusser, Z. (2008) J. Neurosci. 28, 14329.
21. Ohira, K. et al. (2010) Nat. Neurosci. 13, 173.
1. Barron, M.J. et al. (2004) Br. J. Ophthalmol. 88, 286.
22. Osorio, N. et al. (2005) J. Physiol. 569, 801.
2. Blumenfeld, H. et al. (2008) Epilepsia 49, 400.
23. Royeck, M. et al. (2008) J. Neurophysiol. 100, 2361.
3. Blumenfeld, H. et al. (2009) Epilepsia 50, 44.
24. Sasaki, M. et al. (2006) J. Neurosci. 26, 1803.
4. Caldwell, J.H. et al. (2000) Proc. Natl. Acad. Sci. U.S.A. 97, 5616.
25. Southwood, C. et al. (2004) J. Neurosci. 24, 11215.
5. Craner, M.J. et al. (2004) Brain 127, 294.
26. Suzuki, A. et al. (2004) Glia 46, 274.
6. Craner, M.J. et al. (2003) Brain 126, 1552.
27. von Reyn, C.R. et al. (2009) J. Neurosci. 29, 10350.
7. Craner, M.J. et al. (2004) Proc. Natl. Acad. Sci. U.S.A. 101, 8168.
28. Yao, C. et al. (2005) Life Sci. 77, 1116.
9. Ebensperger, G. et al. (2005) J. Physiol. 567, 963.
10. Eftekharpour, E. et al. (2007) J. Neurosci. 27, 3416.
11. Fryatt, A.G. et al. (2009) Mol. Cell Neurosci. 42, 399.
13. Hu, W. et al. (2009) Nat. Neurosci. 12, 996.
14. Jenkins, S.M. and Bennett, V. (2001) J. Cell Biol. 155, 739.
15. Jenkins, S.M. and Bennett, V. (2002) Proc. Natl. Acad. Sci. U.S.A.
99, 2303.
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16. Kazarinova-Noyes, K. et al. (2001) J. Neurosci. 21, 7517.
17. Klein, J.P. et al. (2004) Brain Res. 1000, 102.
18. Krzemien, D.M. et al. (2000) J. Comp. Neurol. 420, 70.
19. Lee, A. and Goldin, A.L. (2009) Channels (Austin) 3, 171.
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Anti-Nav1.5_ ___________________________________
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