Autoimmunity Reviews 12 (2013) 918–923

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Autoimmunity Reviews
journal homepage: www.elsevier.com/locate/autrev

Review

Pathophysiology of myasthenia gravis with antibodies to the

acetylcholine receptor, muscle-specific kinase and low-density
lipoprotein receptor-related protein 4
Jan J.G.M. Verschuuren a,⁎, Maartje G. Huijbers a, Jaap J. Plomp a, b, Erik H. Niks a, Peter C. Molenaar c,
Pilar Martinez-Martinez c, Alejandro M. Gomez c, Marc H. De Baets c, Mario Losen c,⁎
a
Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands
b
Department of MCB-Neurophysiology, Leiden University Medical Centre, Leiden, The Netherlands
c
School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands

a r t i c l e i n f o a b s t r a c t

Article history: Myasthenia gravis is caused by antibodies to the acetylcholine receptor, muscle-specific kinase, low-density
Accepted 12 March 2013 lipoprotein receptor-related protein 4, or possibly yet unidentified antibodies. The mechanisms by which
Available online 25 March 2013 these antibodies interfere with the function of postsynaptic proteins include complement activation, antigen-
ic modulation by crosslinking of the target proteins, competition with ligand binding sites, or steric hindrance
Keywords:
which inhibits conformational changes or binding to associated proteins. Screening for auto-antibodies to dif-
Myasthenia gravis
Neuromuscular junction
ferent postsynaptic targets, and also for low-affinity antibodies, is contributing to a more accurate diagnosis
MuSK of MG patients. Further studies into the specific pathophysiological pathways of the several MG subforms
AChR might help to develop new, more antigen specific, therapies.
Lrp4 © 2013 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 918
2. Myasthenia gravis with antibodies against the acetylcholine receptor (AChR-MG) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
3. “Seronegative” myasthenia gravis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 919
4. Myasthenia gravis with MuSK antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
5. Myasthenia gravis with Lrp4 antibodies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 920
6. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 921
.

1. Introduction forms of myasthenia gravis (MG). The function of several proteins at

Autoimmune reactions to proteins at the postsynaptic neuromuscu-
lar synapse include antibodies to the acetylcholine receptor (AChR),
muscle-specific kinase (MuSK), and low-density lipoprotein receptor-
related protein 4 (Lrp4) [1–3]. These antibodies define three distinct
⁎ Corresponding authors.
E-mail addresses: J.J.G.M.Verschuuren@lumc.nl (J.J.G.M. Verschuuren),
M.Losen@maastrichtuniversity.nl (M. Losen).
the neuromuscular junction can also be disturbed by genetic mutations,
leading to congenital myasthenic syndromes [4]. These syndromes,
which can be hereditary or caused by spontaneous mutations, are not
associated with auto-antibody production, and not reviewed here. Auto-
immune MG is virtually always sporadic with complex genetic and envi-
ronmental risk factors [5], although a few cases of familial autoimmune
MG with AChR or MuSK antibodies have been reported [6–9].
There are several mechanisms by which serum antibodies may
interfere with the function of postsynaptic proteins, including com-
plement activation [10], antigenic modulation by crosslinking of the

1568-9972/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.autrev.2013.03.001
 J.J.G.M. Verschuuren et al. / Autoimmunity Reviews 12 (2013) 918–923
target proteins, competition with ligand binding sites, or steric
hindrance which inhibits conformational changes or binding to asso-
ciated proteins [11].
In different forms of myasthenia these mechanisms are not equally
important, and depend on factors like epitope specificity, antibody
subclass, or antigen density.
2. Myasthenia gravis with antibodies against the acetylcholine
receptor (AChR-MG)
AChR-MG can be categorized according to the clinical symptoms
and pathogenesis in early-onset or late-onset MG, and MG with
thymoma. AChR-MG with thymoma is mainly seen in elderly MG
patients. Thymic abnormalities such as hyperplasia and thymoma
are frequently associated with AChR-MG [12,13].
Early-onset MG begins before the age of 40. It mostly starts with
ocular muscle weakness and patients subsequently often develop
generalized muscle weakness. Early-onset patients usually have a
hyperplastic thymus, containing germinal centers that may be sites of
intense B-cell responses against the AChR [14]. Females predominate
and an association is found with HLA-B8DR3.
In the late-onset AChR-MG subgroup of over 60 years of age,
patients mostly have a normal (i.e. atrophic) thymus [15]. In this
group male patients are more frequent and an association with HLA
DRB1*15:01 has been described [16,17].
Approximately 10% of generalized MG patients have a thymoma
[18]. Their age at onset varies considerably, although thymoma is
more frequent in the elderly patient [19–22]. The association between
thymic pathology and MG, in addition to the fact that thymic lympho-
cytes from patients with follicular hyperplasia produce AChR antibodies
in vitro [23], and that thymectomy improves the clinical symptoms in
some MG patients [24], suggests that the thymus has a special role in
triggering the anti-AChR immune response in MG [25].
AChR antibodies can highly differ in their subclass, type of light
chain, affinity and specificity to different AChR epitopes [26–32]. In
AChR-MG patients, the complement-fixing IgG1 and IgG3 AChR-
specific antibodies predominate; IgG2 and IgG4 are only present in
lower concentrations [33–35]. Generally, the total of the combined
IgGs anti-AChR autoantibody titers correlate poorly with the severity
of disease [32,36–39], although after immunotherapy, such correlations
have been found in individual AChR-MG patients [40,41] and also in MG
models [42]. This disparity could be accounted for by differences in the
functional activities of the antibodies, i.e. the ability to accelerate the
rate of degradation of AChRs or to block acetylcholine binding sites
[43]. In addition, since IgG autoantibody subclasses have distinct immu-
nological properties, another possible explanation for this weak correla-
tion is variation in the isotype distribution. AChR IgG1 (but not IgG2,
IgG3 and IgG4) concentration was found to be significantly correlated
to severity of disease [33]. In rhesus monkeys, passive transfer of
human IgG1, but not IgG4 anti-AChR antibodies caused MG [44].
IgG1 and IgG3 anti-AChR antibodies trigger three pathogenic mech-
anisms [11]: 1) they bind complement factors at the postsynaptic
membrane, ultimately leading to formation of the membrane attack
complex [44–46], 2) they bind and crosslink postsynaptic AChRs,
resulting in an increased endocytosis and degradation (antigenic
modulation) [44,47–50], and 3) they may block the binding of ACh to
the AChR [51–55] or inhibit the opening of this ion channel [56,57].
However, such AChR function impairing antibodies are not generally
found in AChR-MG. The formation of the membrane attack complex in
combination with antigenic modulation leads to: 1) damage of postsyn-
aptic membrane folds, 2) removal of the AChR and 3) removal of
AChR-associated proteins, including utrophin, rapsyn and voltage-
gated sodium channels. Since all of these proteins are involved in
either the synaptic function or the formation and maintenance of the
neuromuscular junction, their loss underlies the myasthenic muscle
weakness [58–62]. Prevention of antigenic modulation (for example
919
by stabilizing AChRs with rapsyn) or of complement activation (using
complement inhibitors) can prevent neuromuscular junction damage
[48,61].
Besides from the immune attack by antibodies, it is conceivable that
the very ability of the muscle to compensate for the loss of AChR and its
associated proteins during the attack by anti-AChR antibodies ultimate-
ly influences the severity of the disease [63]. Compensatory mecha-
nisms that change the expression levels of the AChR after antibody-
mediated damage may vary between individuals [64,65]. There are
also presynaptic compensating changes in MG, e.g. a rise in the ACh
synthesizing enzyme, choline acetyltransferase, and the ACh content
[66,67] as well as an increased release of ACh per nerve impulse
[68–70]. Most likely these compensatory increases are primarily caused
by the reduction in the number of AChRs [71], triggering synaptic
homeostatic mechanisms involving retrograde synaptic signaling [70].
Most generalized AChR-MG patients have antibodies against the
main immunogenic region (MIR) of the AChR alpha subunits. MIR
antibody titers have been shown to correlate well with disease severity
[72]. MIR antibodies are particularly pathogenic because 1) two alpha
subunits and thus two MIRs are present on each AChR, 2) the MIR is
exposed at an angle that allows antibody binding to two adjacent
AChRs, and 3) the MIR is involved in AChR sensitivity to activation by
ACh [73].
Apart from AChR antibodies, auto-antibodies against other muscle
antigens are commonly found in AChR-MG patients [74]. For example,
auto-antibodies against titin and the ryanodine receptor are frequently
present in MG patients with malignancies of the thymus [75]. The role
of these antibodies in the pathogenesis and their contribution to the
clinical symptoms of MG are not completely understood yet, and
some are not specific for MG since they also occur in patients with
other autoimmune diseases [74].
3. “Seronegative” myasthenia gravis
Classically, AChR antibodies have been found in 85% of MG patients,
while the remaining patients were indicated as ‘seronegative’. In 1986,
Mossman and colleagues showed that the crude immunoglobulin frac-
tion, obtained by ammonium sulfate precipitation, of the serum of pa-
tients with AChR-antibody-negative myasthenia gravis could transfer
the disease to mice [76]. Electrophysiological testing showed a signifi-
cant compound muscle action potential decrement upon repetitive
nerve stimulation. Surprisingly, the loss of AChR in the diaphragm was
only around 10%, and no significant amount of antibody bound to the
mouse AChRs was detected. Passive transfer of plasma or IgG from 7 se-
ronegative patients to mice caused reductions in miniature endplate
potential (MEPP) amplitudes and, in addition, the release of ACh
was significantly reduced by plasma or IgG from 4 of the 7 patients.
Unexpectedly, there were no changes in (exogenously applied)
ACh-induced depolarization or single channel properties of the AChR,
and 125I-alpha-bungarotoxin binding studies showed no effect on
AChR number [77]. Together, these results pointed to the presence of
an antibody that interfered with neuromuscular transmission by bind-
ing to non-AChR determinants at the neuromuscular junction. Interest-
ingly, most patients had predominantly bulbar weakness and four of
them had assisted ventilation at some timepoint. This suggests that
these patients might have suffered from MuSK-MG. Later publications
of the same group indeed indicated, that when retested, these sera
were predominantly MuSK antibody positive [78].
The last decade ‘seronegative’ MG has become increasingly rare
with the discovery of anti-MuSK antibodies [79], antibodies against
clustered AChRs, detected in a sensitive cell-based assay [80] and,
very recently, antibodies to Lrp4 [81–83]. With the identification of
these antibodies as sensitive markers, the previously ‘seronegative’
MG patients have split up into subgroups with clear different clinical,
genetic and pharmacological characteristics.
920 J.J.G.M. Verschuuren et al. / Autoimmunity Reviews 12 (2013) 918–923

4. Myasthenia gravis with MuSK antibodies recombining half-antibodies with other IgG4 molecules (‘Fab-arm
exchange’). This produces hybrid antibodies which are bispecific and
IgG antibodies against MuSK were discovered in 2001 in serum of thus do not cross-link identical antigens [44,95,98].
70% of patients with ‘seronegative’ MG [79]. It is now known that These properties notwithstanding, IgG4 appears to be responsible
MuSK-MG differs from AChR-MG in several important aspects: for several autoimmune conditions, including pemphigus [99], idio-
pathic membranous glomerulonephritis with antibodies against
1) The clinical presentation. The distribution of muscle weakness is
M-type phospholipase-A2 receptors [100] and in thrombotic throm-
different, typically involving neck and respiratory muscles, often
bocytopenic purpura, with antibodies against a metalloproteinase
with respiratory crises; often an atrophied tongue is seen [84–86].
ADAMTS13 [101]. Except from pemphigus, the pathogenicity of the
The peak incidence lies in the fourth decade (vs. third decade in
antigen-specific IgG4 in these disorders has not been experimentally
AChR-MG). In contrast to AChR-MG, MuSK-MG has so far been rare-
shown [102].
ly described above the age of sixty years [86]. MuSK-MG patients
Shortly after their discovery it was debated if anti-MuSK antibodies
less often have pure ocular weakness at onset, with 5% never
were the pathogenic factor in MuSK-MG, or that they may only be a
experiencing any ocular weakness, but involvement of bulbar mus-
bystanding disease marker [103,104]. Initial studies could not detect
cles at the start of the disease is more frequent than in AChR-MG
abnormal AChR or MuSK intensities or clear IgG deposits at the neuro-
[2,3,86].
muscular junction [104]. Another study could not demonstrate AChR
2) Acetylcholinesterase inhibiting drugs often do not act at all or can
loss in motor point biopsies from biceps brachii muscles from
even be counterproductive [84–86]. Only 57% of MuSK-MG
MuSK-MG patients nor considerable deposition of immune complexes
patients treated with acetylcholinesterase inhibitor showed a favor-
at the neuromuscular junction [105]. The absence of complement
able effect. On the other hand, side effects of acetylcholinesterase
deposits in muscle tissue of most MuSK-MG patients is compatible
inhibitors are commonly reported, including marked fasciculations,
with IgG4 antibodies not being able to activate complement, suggesting
cramps, and worsening of symptoms [86]. Cholinesterase inhibitor
that other mechanisms play a role in MuSK pathogenesis.
nonresponsiveness was observed in 10 of 14 (71%) MuSK-MG
More recently, a number of studies demonstrated that MuSK-MG
patients, while it appeared in only 4 of 22 (18%) MuSK antibody-
can be transferred from man to mouse using serum or IgG: mice
negative patients and in 13 of 73 (18%) generalized AChR-MG
injected intraperitoneally with total IgG from MuSK-MG patients devel-
patients [87]. The majority of MuSK-MG patients does not experi-
oped weakness and considerable decrement of compound muscle ac-
ence long-term benefit from these drugs and stop to use them. Inter-
tion potentials upon repetitive nerve stimulation, suggesting severe
estingly, rituximab, a monoclonal antibody which depletes B-cells,
AChR loss from neuromuscular junctions [106]. Results from our labora-
seems to give long-term improvement in a more effective way in
tories indicated that mouse muscles regenerating de novo from satellite
MuSK-MG than in AChR-MG [88]. Moreover, rituximab has also
cells are especially prone to effects of MuSK plasma. Thus, MuSK plasma
proven to be very effective in pemphigus foliaceus and pemphigus
caused impairment of nerve stimulus-induced contraction of the flexor
vulgaris, even at a lower dose than is used to treat lymphoma [89].
digitorum brevis muscle and reduced neuromuscular junction size after
Like MuSK-MG, these disorders have been associated with IgG4
local administration of notexin, a potent myotoxin [107]. In detailed
[90]. All 15 pemphigus patients responded to therapy, and eight pa-
morphological analyses, Cole and colleagues demonstrated that passive
tients achieved complete remission in a median period of 51 weeks.
transfer of IgG from MuSK-MG patients to mice reduced the AChR
3) The HLA haplotype association of MuSK-MG is different from
density and that the alignment between the motor nerve terminal and
AChR-MG. MuSK-MG and early onset AChR-MG, which have distinct
the postsynaptic membrane was disturbed [106,108]. Another study
clinical characteristics and pathology of the thymus [91], significant-
indicated that MuSK IgG may interfere with the binding between
ly differ in HLA class II allele frequency. Early onset AChR-MG
collagen-Q and MuSK [109].
is linked with DR3 and DQ2 alleles, while MuSK-MG is associated
Recent work in our laboratories demonstrated that the IgG4 subclass
with DQ5 alleles [92,93]. Within the Northern Hemisphere, in West-
of human MuSK antibodies is myasthenogenic [110]. Mice injected with
ern populations the prevalence seems to correlate with distance
purified MuSK-MG IgG4 became weak and in vivo neuromuscular func-
from the equator (the prevalence being lower at northern latitudes),
tional analyses indicated disturbed neuromuscular transmission. In
suggesting a possible environmental factor or differences in the spe-
detailed electrophysiological studies of the neuromuscular junction
cific HLA frequencies among different populations [78].
we found clear post- and presynaptic deficits, i.e. loss of postsynaptic
4) The antibodies against MuSK in MuSK-MG are predominantly of the
ACh sensitivity and increased rundown of ACh release upon high-rate
IgG4 subclass as opposed to IgG1 and IgG3 antibodies in AChR-MG.
repetitive nerve stimulation. Similar synaptic electrophysiological
Using serially collected sera of six MuSK-MG patients it was abnormalities have recently been found in a total IgG MuSK-MG passive
shown that in individual MuSK-MG patients there is a correlation transfer mouse model [111,112], as well as after active MuSK immuni-
between IgG4 anti-MuSK antibody titer and clinical severity [94]. Of in- zation [113]. AChR loss seems to set in directly after commencing the
terest, one female patient had high titer IgG4 MuSK antibodies when daily IgG injections in the passive transfer mice, and progresses at a
she had severe clinical disease, but after going into clinical remission pace of ~3–4% per day. This matches the physiological rate by which
mostly IgG1 MuSK antibodies were found. Similar findings have been newly synthesized AChRs are inserted in maintenance turn-over at
described in pemphigus vulgaris, in which serum antibodies to peptides the neuromuscular junction, suggesting that MuSK IgG blocks this pro-
that spanned the extracellular domain of desmoglein-3, the antigen in cess [112].
pemphigus vulgaris, were studied [90]. Patients with active pemphigus
had high IgG4 and IgG1 titers against two desmoglein-3 peptide parts, 5. Myasthenia gravis with Lrp4 antibodies
termed Bos1 and Bos 6. Patients in remission had only IgG1 antibodies
to Bos 1, and IgG4 serum antibodies were no longer detectable. Lrp4 is a member of the low-density lipoprotein related receptor
Of the four human IgG subclasses, IgG4 displays remarkable distinct family which was recently identified as the long-sought postsynaptic
characteristics [95,96]: receptor for nerve-derived agrin and, consequently, as an activator of
1) it comprises less than 5% of the total IgG, 2) it is unable to bind MuSK [114]. Its crucial role for the formation of neuromuscular junc-
complement factor C1q and thus does not activate the complement tions was first demonstrated in Lrp4 −/− mice, which lacked AChR
cascade [97], 3) it has only weak Fcγ-receptor binding potency and clusters and died at birth due to respiratory paralysis; a phenotype
thus is not a strong activator of immune cells or antibody-dependent similar to those of MuSK and agrin knock-out mice. Lrp4 can dimerize
cell-mediated cytotoxicity, and 4) it has the unique property of and directly activate MuSK at the surface of the postsynaptic muscle
 J.J.G.M. Verschuuren et al. / Autoimmunity Reviews 12 (2013) 918–923 921

Table 1
Frequency of Lrp4 antibodies in neurological diseases.

AChR-MG MuSK-MG “Double” Lambert-Eaton myasthenic syndrome Neuromyelitis Reference

‘seronegative’ MG (anti-calcium channel antibodies) optica

0/100 3/28 6/272 1/101 Higuchi [81]

1/11 19/38 Pevzner [82]
0/61 1/36 11/120 2/16 Zhang [83]

membrane and, along with Dok-7, it is required for the full activation
of this essential kinase. Recently, three papers described the existence
of Lrp4 antibodies in MG patients [81–83], but also in Lambert–Eaton
myasthenic syndrome (LEMS) and in neuromyelitis optica (NMO)
patients (Table 1). The majority of the patients are female with an
age that ranges from 17 to 79 (Table 2), and the involvement of
IgG1 subclass remind of AChR-MG [81]. However, Lrp4 forms a
multiprotein complex with MuSK, thus the clinical symptoms might
be similar to MuSK-MG. Indeed, a relatively high number of bulbar
and respiratory problems have been described in this small group.
Moreover, Lrp4 fulfills an important role in retrograde synaptic
signaling during development and possibly also in adulthood of the
neuromuscular junction, which could also be disturbed by the Lrp4
immune response [81,82,115].
Both Zhang et al. and Higuchi et al. demonstrated in enzyme-
linked immunosorbent and cellular assays that some sera with Lrp4
antibodies, but without AChR and MuSK antibodies, inhibit the
agrin-Lrp4 interaction and the agrin-induced AChR clustering [81,83].
Blocking of agrin signaling is certainly one of the most plausible patho-
logical mechanisms for Lrp4 antibodies in vivo, given that agrin is
fundamental for embryonic development of the neuromuscular
junction and that it plays also a crucial role in postnatal synapse main-
tenance [116]. Indeed, impaired agrin signaling leads to less stable
neuromuscular junctions, with more dispersed and un-clustered
AChRs, as found in cases of congenital myasthenic syndrome due to
agrin gene mutations [117], and also in agrin knock-out mice models
[118]. However, other pathophysiological mechanisms of Lrp4 antibod-
ies such as blocking the Lrp4-MuSK interaction or a role for comple-
ment, which is implied by the involvement of IgG1 autoantibodies,
cannot be excluded.
6. Conclusion
It is increasingly evident that AChR-MG and MuSK-MG are different
autoimmune conditions that, despite sharing a number of clinical
symptoms, have a distinct pathophysiology. The presence of Lrp-4 auto-
antibodies in ‘seronegative’ MG, but also MuSK-MG, LEMS and NMO is
intriguing. Further research on the phenotypic characteristics of sero-
negative and MuSK-MG patients with LRP-4 antibodies will likely
Table 2
Characteristics of patients with Lrp4 antibodies.
Clinical features
Age Sex Race Symptoms
F:M
n=9 26–72 4:5 n/a MGFA scale:
(Higuchi [81]) 2a,2b
3a,3a,3b,3b
5,5,5
n = 13 17–79 10:3 12/13 Ocular weakness 50%
(Pevzner [82]) Caucasian Facial/bulbar weakness 86%
Neck weakness 86%
Limb weakness 71%
Breathing difficulty 29%
Myasthenic crisis in one patient
facilitate diagnosis and probably also improve the treatment of these
subgroups of patients. Moreover, screening for auto-antibodies to dif-
ferent postsynaptic targets, and also for low-affinity antibodies, is
already positively contributing to a more accurate diagnosis of MG
patients. Further studies into the specific pathophysiological pathways
of the several MG subforms will pave the way towards development
of new therapies that will be more antigen (and patient) specific.
Take-home messages
• AChR-MG and MuSK-MG present with clinically similar symptoms,
but have a distinctly different immunopathogenesis.
• In contrast to AChR and MuSK antibodies, Lrp4 autoantibodies have
been found in more than one form of myasthenia or autoimmune
disease, including MuSK-MG, neuromyelitis optica and Lambert
Eaton myasthenic syndrome, and in ‘seronegative’ MG without
AChR and MuSK autoantibodies.
• IgG1 and IgG3 predominate in AChR-MG patients, IgG4 in MuSK-MG
and IgG1 in MG with LRP4 autoantibodies.
• Thymic hyperplasia and thymoma are characteristic for AChR-MG,
and not for MuSK MG.
• The different types of MG require different treatment strategies;
MuSK MG patients may benefit from rituximab whereas AChE inhib-
itors (regularly used in AChR-MG) often have a counterproductive
effect.
Acknowledgments
Our work is supported by the Prinses Beatrix Spierfonds (WAR09-19),
L'Association Française contre les Myopathies (#15363 and #15853) and
a Veni fellowship of the Netherlands Organization for Scientific Re-
search (#91610148) and a fellowship of the Brain Foundation of the
Netherlands (#F2008(1)28).
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