Group Title: Cough 2009, 5:12
Title: Spatiotemporal regulation of the cough motor pattern
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Title: Spatiotemporal regulation of the cough motor pattern
Series Title: Cough 2009, 5:12
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Saha S
Rose MJ
Davenport PW
Bolser DC
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Spatiotemporal regulation of the cough motor pattern
Cheng Wang', Sourish Saha2, Melanie J Rosel, Paul W DavenportI and
Donald C Bolser*1

Address: 'Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, Florida, 32610, USA and
2Department of Statistics, College of Liberal Arts and Sciences, University of Florida, Gainesville, Florida, 32611, USA
Email: Cheng Wang; Sourish Saha; Melanie J Rose;
Paul W Davenport; Donald C Bolser*
* Corresponding author

Published: 22 December 2009
Cough 2009, 5:12 doi:10.1 186/1745-9974-5-12

Received: 3 March 2009
Accepted: 22 December 2009

This article is available from:
2009 Wang et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.ore/licenses/by/2.0),
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The purpose of this study was to identify the spatiotemporal determinants of the cough motor
pattern. We speculated that the spatial and temporal characteristics of the cough motor pattern
would be regulated separately. Electromyograms (EMG) of abdominal muscles (ABD, rectus
abdominis or transversus abdominis), and parasternal muscles (PS) were recorded in anesthetized
cats. Repetitive coughing was produced by mechanical stimulation of the lumen of the intrathoracic
trachea. Cough inspiratory (CTI) and expiratory (CTE) durations were obtained from the PS EMG.
The ABD EMG burst was confined to the early part of CTE and was followed by a quiescent period
of varying duration. As such, CTEwas divided into two segments with CTEI defined as the duration
of the ABD EMG burst and CTE2 defined as the period of little or no EMG activity in the ABD EMG.
Total cough cycle duration (CTTOT) was strongly correlated with CTE2 (r2>0.8), weakly correlated
with CT, (r2<0.3), and not correlated with CTEI (r2<0.2). There was no significant relationship
between CT, and CTEI or CTE2. The magnitudes of inspiratory and expiratory motor drive during
cough were only weakly correlated with each other (r2<0.36) and were not correlated with the
duration of any phase of cough. The results support: a) separate regulation of CT, and CTE, b) two
distinct subphases of CTE (CTEI and CTE2), c) the duration of CTE2 is a primary determinant of
CTTOT, and d) separate regulation of the magnitude and temporal features of the cough motor

Cough is an important airway defensive behavior. It is
characterized by coordinated ballistic-like bursts of activ-
ity in inspiratory and expiratory muscles. Airflows during
intensive coughs can reach 12 L/s in humans [1].
Although it has been proposed that cough and breathing
share a common neurogenic control system [2], signifi-
cant regulatory differences exist between the two behav-
iors. For example, during eupnea, there are well-known
relationships between inspiratory volume (VI) and inspir-

atory time (TI) and between expiratory volume (VE) and
expiratory time (TE). Smaller VI or VE are associated with
longer TI or TE durations during breathing [3]. This vol-
ume timing behavior is mediated by slowly adapting pul-
monary stretch receptors (PSR) However, Romaniuk et al
[4] suggested that phasic PSR afferent feedback does not
play an important role in the development of cough. This
suggestion was supported by our previous study in which
we found that there was no relationship between volume
and phase durations during repetitive tracheobronchial

Page 1 of 8
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coughing in spontaneously breathing cats [5]. These
observations indicate that the regulation of cough motor
pattern is fundamentally different than that of breathing.
It follows that presumptions of how the cough motor pat-
tern is controlled that are based on our knowledge of the
control of the pattern of breathing may be subject to sig-
nificant error.

In preliminary experiments, we observed that a period of
expiratory motor quiescence existed between the end of
the expiratory motor burst and the onset of the next inspi-
ration during repetitive cough, consistent with the exist-
ence of two subphases within the cough expiratory period
[4,6], as first proposed by Romaniuk et al [4]. The pres-
ence of two subphases within the expiratory interval of
cough is consistent with the control of the expiratory
interval during breathing, and if substantiated, would be
consistent with the synaptic network model of Shannon
and coworkers for cough [2] which accounts for expira-
tory motor discharge that occurs largely restricted in the
early portion of the expiratory phase. However, the extent
to which this network model can fully account for spatio-
temporal features of the cough motor pattern is not well
understood. A significant limiting factor in testing this
model is the relative lack of experimental information
regarding the control of cough phase durations and inten-
sity. In this study, we investigated the spatiotemporal fea-
tures of the cough motor pattern during repetitive coughs.
We hypothesized that the expiratory period during cough
is composed of two subphases each of which is regulated
separately. Furthermore, we speculated that the duration
of the expiratory interval is a primary determinant of the
total cough cycle time.

Fifteen cats (3.6 0.3 kg) were anesthetized with pento-
barbital sodium (35 mg/kg iv). Supplemental anesthetic
was administered when necessary (5 mg/kg, iv). Atropine
sulfate (0.1 mg/kg, iv) was administered to block reflex
airway secretions. The trachea, femoral artery, and femo-
ral vein were cannulated in all animals. The animals were
allowed to spontaneously breathe room air. Blood pres-
sure (mean 139 5 mm Hg) and body temperature were
continuously monitored. End-tidal PCO2 was continu-
ously monitored all animals but only recorded (36 1
mm Hg) in 11/15 animals. Body temperature was control-
led by a heating pad and maintained at 37.5 + 0.5 C.

Electromyograms (EMG) of respiratory muscles were
recorded with bipolar insulated fine wire electrodes by the
technique of Basmajian and Stecko [7]. EMGs were
recorded from the transversus abdominis or rectus
abdominis (ABD, expiratory) muscles and parastemal
(PS, inspiratory) muscles. The PS electrodes were placed at
T3 proximal to the sternum after exposing the ventral sur-

face of the muscle. Transversus abdominis electrodes were
placed 3-4 cm lateral to the linea alba. Rectus abdominis
electrodes were placed about 1 cm lateral to the linea alba.
Proper placement of each set of electrodes was confirmed
by the appropriate inspiratory or expiratory phased activ-
ity during breathing and/or cough.

Repetitive tracheobronchial (TB) coughs were elicited by
mechanical stimulation of the intrathoracic trachea with a
thin flexible polyethylene cannula [8,9]. For TB stimula-
tion, the cannula was introduced into the extrathoracic
trachea and advanced so that its tip was at the approxi-
mate location of the carina. The cannula was rotated at 1-
2 Hz and retracted and advanced repeatedly across a dis-
tance of approximately 2 inches during the stimulus trial.
However, movement of the trachea during coughing may
have resulted in significant variations in how the cannula
contacted the airway mucosa during the stimulus trials.
Each cough stimulus lasted for 10 seconds. One to three
minutes elapsed between stimulus trials.

Cough was defined as a sequence of a large burst in PS
muscle EMG followed by a burst in ABD muscle EMG [8].
These criteria distinguished cough from other airway
defensive behaviors such as expiration reflex [10,11], aug-
mented breath [12], and aspiration reflex [13,14].

All EMGs were amplified, rectified, filtered (300-5000
Hz), and integrated (time constant 100 ms). The ampli-
tude of the ABD muscle EMG, amplitude of the PS muscle
EMG, cough inspiratory (CT1) and expiratory (CTE) dura-
tions were obtained from the moving averages of the
EMGs. The PS and ABD muscle amplitudes were normal-
ized to their peak amplitudes during cough in each ani-
mal. The phases of cough are illustrated in Figure 1. CT, is
the duration from the onset to the peak of PS EMG burst.
CTE was defined as the duration from the peak of PS EMG
burst to the onset of the next PS EMG burst. CTE was fur-
ther subdivided into two subphases CTE1 defined as the
period of the expiratory muscle motor burst during cough
and CTE2, a period of motor quiescence flowing the expir-
atory muscle motor burst. CTToT is the duration from the
onset of one PS EMG burst to the onset of the next PS
EMG burst.

Results are expressed as mean values + SD. Data were ana-
lyzed by linear regression to determine the relationships
between cough phase durations and amplitudes. The runs
test was used to evaluate linearity of the data. We sug-
gested based on our findings in the cat [15] that the ante-
rolateral abdominal muscles acted as a unit during cough.
As such, the normalized data from both abdominal mus-
cles were pooled for the correlation analysis. Multiple
regression analysis (stepwise regression) was performed
to identify primary determinants of the cough cycle time,

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Cough 2009, 5:12





s I





Figure I
An example of individual phase duration relation-
ships during a repetitive series of TB coughs. CTI -
cough T,, CTE cough TE (the sum of CTEI and CTE2), CTTOT
- total cough cycle time (the sum of CTI CTEI and CTE2),
CTEI cough expiratory subphase E CTE2 cough expira-
tory subphase E2. Note CTE2 and CTTOT vary by over 100%
in the selected cough cycles while CTI and CTEI change very
little. RA EMG- rectus abdominis expiratoryy) muscle elec-
tromyogram, PS EMG-parasternal inspiratoryy) muscle elec-

in which CTToT was applied as the dependent variable and
CTI, CTE1, CTE2, inspiratory EMG amplitude, and expira-
tory EMG amplitude were the independent variables. For
clarity, the squares of linear regression correlation coeffi-
cients were designated as r2, and multiple regression coef-
ficients of determination were designated as R2. Multiple
collinearity analysis identified these variables as unrelated
to one another. CTE was not included in the multiple
regression model because multiple collinearity analysis
identified this variable as strongly related to CTE2. To iden-
tify the relative contributions of each independent varia-
ble to the variance in CTToT, we conducted a stepwise
exclusion protocol in which each of these factors were
removed from the dataset and the R2 recalculated [16].
Thus, the contribution of each variable to the variability in
CTToT could be inferred.

A total of 1093 tracheobronchial coughs were elicited in
15 animals. Repetitive tracheobronchial coughing was
characterized by sequential inspiratory and expiratory
bursting separated during the expiratory phase of each
cough cycle by intervals of relative motor quiescence (Fig.
1). These motor quiescent intervals had highly variant
durations, even during an ongoing series of repetitive
coughing (Fig. 1). Based on these observations, we have



separated the cough cycle into three phases: cough inspir-
atory (CTI), cough expiratory phase 1 (CTE1), and cough
expiratory phase 2 (CTE2). CTI is defined by the duration
of the inspiratory phase (Fig. 1). CTE1 is the period of bal-
listic-like expiratory motor discharge (Fig. 1) and CTE2 is
the period of relative motor quiescence between the end
of CTE1 and the onset of the next CTI (Fig. 1). In some
cases, tonic activity in ABD EMGs could be observed dur-
ing CTE2, but it was clearly distinguished from the ballis-
tic-like expiratory motor bursting during CTE1.
Furthermore, tonic activity could sometimes be observed
in the ABD EMGs during CTI, but this activity was much
smaller in amplitude than the ABD burst during CTE1. We
have observed this expiratory co-activation with inspira-
tory muscles before and have termed it pre-expulsive
activity [15].

For all coughs the mean total cough cycle time was 1.76 +
0.81 s. Phase durations for cough were: CT = 0.49 + 0.25
s. CTE1 = 0.31 0.16 s, and CTE2 0.96 + 0.67 s. The aver-
age cough inspiratory amplitude was 49 + 24%% of max-
imum. The average ABD EMG amplitude was 51 + 23% of

Transient increases in the frequency of coughing within a
bout were associated with a larger relative decrease in CTE2
(Fig. 2). Regression analysis revealed strong linear correla-
tions between CTToT and CTE2 (r2 = 0.89 0.04). A weak
correlation existed between CTToT and CTI (r2 = 0.24 +
0.05). There were no significant relationships between
CTToT and CTE1 (r2 = 0.09 0.03), inspiratory (r2 = 0.07 +
0.02), or expiratory amplitudes (r2 = 0.11 0.03) and
CTToT (Table 1). There was only a weak correlation
between inspiratory and expiratory amplitudes during
cough (r2 = 0.29 0.05, Table 2). Values for r2 for relation-
ships between the other variables were all less than 0.13
(Table 2).

Multiple regression analysis of CTTOT to CTI, CTE1, and
CTE2 showed that R2 only decreased by 0.08 when CTI
was excluded from the equation, and 0.034 when CTE1
was excluded. This suggested the exclusion of CTI had a
minimal effect on CTTOT. The R2 value decreased by 0.67
when CTE2 was excluded from the analysis, suggesting
CTE2 was the most important contributor to CTTOT.

The first major finding of this study was that cough expir-
atory phase can be divided into two subphases, CTE1 and
CTE2. The second finding of this study was that CTE,
mainly CTE2, is the primary determinant of CTToT. Fluctu-
ations in the duration of CTToT are primarily the result of
increases or decreases in CTE2. Given that EMG burst
amplitudes were not correlated with phase durations dur-
ing cough, our results also suggest separate regulatory

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Cough 2009, 5:12

mechanisms for the intensity and cycle durations of

This is the first report to quantify that the expiratory phase
during coughing, like that of breathing, can be composed
of two phases. This concept was first proposed by Roma-
niuk and coworkers [4], but some of the temporal rela-
tionships that we illustrate in Figure 1 can be seen in
figures in studies published by other groups [17,18]. In
fact, Korpas and Tomori [18] show figures that suggest
that periods of motor quiescence in the expiratory period
during repetitive coughing exist in cats (Fig 32, p. 76), rab-
bits (Fig 42, p. 107), and in a separate study, dogs [19]
(Fig 1A). During breathing, the activity patterns of spinal
respiratory motoneurons have been used to subdivide the
expiratory phase into two phases, the postinspiratory
phase (El) and active expiration phase (E2) [20-25]. The
El phase of breathing represents the "passive" stage of
expiration in which chest wall and abdominal muscles are
relatively quiescent. The E2 phase can be associated with
"active" expiration in which chest wall and abdominal
muscles can exhibit an augmenting discharge [22,26].
Our evidence for the existence of two phases of the expir-
atory interval during cough is primarily based on observa-
tions related to the expulsive motor burst and the
existence of a variable duration of the subsequent motor
quiescence. The El and E2 phases during cough differ sig-
nificantly from those of breathing. For example, CTE1 is
demarked by ballistic expiratory motor activation,
whereas this phase during breathing represents a period of
relative quiescence of expiratory pump muscles [4,26].

During CTE2, there is a period of motor quiescence, and
during breathing E2 expiratory pump muscles can be very
active [4,22].

Our study showed that the duration of the CTE1 phase dur-
ing repetitive coughing is relatively fixed and that the
duration of CTE2 is variable. Romaniuk reported CTE was
prolonged during obstructed cough in which the trachea
was occluded at the end-inspiration and maintained
throughout the subsequent expiration [4]. Our results are
consistent with the idea that the enhanced vagal afferent
stimulation resulting from airway occlusion has a prefer-
ential effect to prolong the duration of CTE2.

Poliacek et al. reported [27] that CT, during laryngeal
coughs was 50% longer than during TB coughs, and the
two types of coughing had similar CTE1 durations in the
present study. In our protocol, bouts of repetitive TB
coughs were elicited, whereas Poliacek et al. [27] elicited
mostly single coughs. Furthermore, the results of our pre-
vious study, showed that CT, during single TB coughs or
first coughs of a bout is significantly longer than during
repetitive coughs [5]. These observations indicate that
some features of the motor pattern of coughing can
exhibit a high degree of variation depending upon the
region of the airway from which it is elicited and whether
single or repetitive behaviors are produced. In essence, all
coughs are not the same, even within a series of repetitive
coughing. However, selected components of the cough
motor pattern are fixed, such as the duration of CTEi.

Table I: Correlation coefficients (r2) from regression relationships between CTTOT and phase durations and EMG amplitudes during
repetitive TB coughs in individual animals.


CTTOT Simple Linear Regression Coefficients (r2)


0.24 0.05



0.09 0.03



0.89 0.04



0.89 0.04

I Amp


0.07 0.02

E Amp


0.11 0.03

The only high r2 value is for the relationship between CTTOT and CTE2.

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Cough 2009, 5:12

Table 2: Average correlation coefficients (r2) from regression relationships between cough phase durations and EMG amplitudes
during repetitive TB coughs.

Simple linear regression coefficients for cough phase or EMG magnitude (r2 + SE)

I Amp


0.03 0.01


0.09 0.02
0.09 0.03

I Amp

0.08 0.03
0.04 0.01
0.07 0.02

E Amp

0.05 0.01
0.1 0.03
0.12 0.02
0.29 0.05

There were only weak correlations between individual phase durations and a moderate relationship between inspiratory and expiratory EMG
amplitudes during coughing.

The lack of relationship between inspiratory and expira-
tory motor burst amplitudes differs from that reported
previously for the fictive cough model in the cat by our
group [28]. In that study, we showed that there was a lin-
ear relationship between inspiratory and expiratory neu-
rogram amplitudes during fictive cough that was
disrupted by codeine. The effect of codeine was manifest
at doses that did not significantly suppress either inspira-
tory or expiratory amplitudes, but were sufficient to
reduce cough number. The results of that study were con-
sistent with the existence of a neurogenic mechanism for
coordinating inspiratory and expiratory motor drive dur-
ing coughing that was separate from simple inhibition of
excitatory motor drive to one or both of the motoneuron
pools. In the fictive model, cough is produced in the
absence of active or passive muscle movement in decere-
brated, paralyzed animals [2,9,13]. Therefore, the contri-
bution of sensory feedback from active muscle movement
to the cough motor pattern generator is eliminated. The
rate of lung inflation during cough in the fictive cough
model is typically similar to that during fictive breathing
and peak lung volume is likely to be less than that pro-
duced in spontaneously breathing animals, presumably
resulting in altered pulmonary afferent feedback. It is con-
ceivable that these differences in somatic and pulmonary
afferent feedback this may cause changes in the cough
motor pattern in the fictive model relative to the sponta-
neously breathing preparation. However, we believe that
the absence of a coordinating mechanism between inspir-
atory and expiratory motor drive in spontaneously breath-
ing animals is most likely related to the presence of
anesthesia. Sodium pentobarbital was used in the present
experiments and this anesthetic has been successfully
employed in cough studies for many years [13,18,29].
Cats are capable of producing intense coughing while
anesthetized with sodium pentobarbital.

Our results are consistent with the concept that the synap-
tic model of Shannon and coworkers can account for
expiratory phase durations during cough. In Shannon's
model, the expiratory augmenting (E-Aug) neurons in the
Botzinger complex consist of at least two subpopulations

based on their discharge patterns during cough [2]. As
such, these synaptic relationships governing the discharge
patterns of rostral ventral respiratory column expiratory
neurons could account for a cough expiratory interval
composed of two subphases. Our results are significant in
that they show that the expiratory interval during cough
is, in fact, controlled in this fashion. Furthermore, our
findings extend our understanding of the regulation of the
motor pattern of respiratory muscles by the respiratory
pattern generator.

It is not clear how the model of Shannon and coworkers
can account for a fixed CTE1, while CTE2 is highly variant.
Our data showed that the CTE1 was independent of ABD
burst intensity, CTToT, CTE, and the previous CTI. Our data
also indicate that the duration of CTE2 determines CTToT
length. Based on these observations and inspection of the
model of Shannon and coworkers, when the frequency of
repetitive cough is increased (i.e. CTE2 and thus CTIOT
decreased), inspiratory decrementing neurons should
have a stronger inhibition on the activity of the E-Aug late
neurons, an action which would shorten CTE. But the
model cannot answer the question why CTE1 duration is
not also reduced when CTE2 decreases by 50% or more
(Fig 1). Our observation that CTE1 is relatively invariant
indicates that this phase also has an upper limit in dura-

Correlation analysis showed that there was no relation-
ship between cough expiratory amplitude and CTE1 dura-
tion. Similarly, there was no correlation between the
inspiratory amplitude and CT,. These results are consist-
ent with a previous study, showing there was no relation-
ship between expiratory volume and CTE, or between
inspiratory volume and CT, [5]. These observations are
not consistent with what is predicted from Shannon's
model. According to this model, input from rapidly
adapting receptor relay neurons excites neurons that regu-
late both inspiratory and expiratory phase durations as
well as E-Aug early neurons, expiratory premotor neurons,
and inspiratory augmenting premotor neurons that that
provide excitatory motor drive to spinal expiratory and

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Cough 2009, 5:12



&3 -

CT7r (s) "5

r= 19

0 1 2 3 4



~- as

0t 8

0 1 2
CTE2 (S)

3 4


CT'IT(S) 2.5


CTM S) .23


CT, (s)

I amp
(a of maximami)



0 20 40 Io 5 1D 120

E amp (% of maximum)

Figure 2
Regression relationships between cough phase durations and amplitudes during TB coughs from one animal.
Strong linear relationships exist between CTTOTand CTE and CTE2 but CTI and CTEI appear to be relatively constant in spite of
a 300% variation on CTTOT. I amp-inspiratory muscle EMG amplitude, E amp-expiratory muscle EMG amplitude.

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CTBi (s)

3 4

Sr ,

Cough 2009, 5:12

inspiratory motor pathways. This feature of the model
suggests that the magnitude of expiratory motor activa-
tion during cough should be related to expiratory phase
duration, and the magnitude of inspiratory motor activa-
tion should be related to inspiratory phase duration.

It should be noted that the cats in our preparation were
spontaneously breathing whereas Shannon's experiments
were based on a fictive cough model. In the fictive model,
cough was produced in the absence of active or passive
muscle movement in decerebrated, paralyzed animals
[28,30,31]. Therefore, the contribution of sensory feed-
back from active muscle movement to the cough motor
pattern generator was eliminated. The rate of lung infla-
tion during cough in the fictive cough model is typically
similar to that during fictive breathing and peak lung vol-
ume is likely to be less than that produced in spontane-
ously breathing animals, presumably resulting in altered
pulmonary afferent feedback. It is conceivable that these
differences in somatic and pulmonary afferent feedback
may cause changes in the cough motor pattern in the fic-
tive model relative to the spontaneously breathing preap-
aration. Furthermore, we stimulated repetitive cough
whereas Shannon used single cough stimulation. It has
been reported that the first cough in a series or a single
cough compared to repetitive coughs has different cough
motor patterns [5].

Our findings provide information regarding the func-
tional organization of the central neurogenic mechanism
for cough. Reconfiguration of the respiratory pattern gen-
erator to produce coughing not only changes the arrange-
ment of the respiratory neural network but it also changes
fundamental features that govern how the motor pattern
is controlled. Cough and breathing differ in that: a) motor
drive and phase durations are controlled separately for
cough, and b) the E2 subphase is the dominant regulator
of total cycle duration for cough.

ABD: abdominal; CTI: cough inspiratory time; CTE: cough
expiratory time; CTEI: first segment of cough expiratory
phase; CTE2: second segment of cough expiratory phase;
CTToT: total cough cycle time; El: postinspiratory phase of
breathing; E2: active expiratory phase of breathing; E-Aug:
expiratory augmenting neuron; EMG: electromyogram; E-
amp: expiratory amplitude; I-amp: inspiratory amplitude;
PC02: partial pressure of exhaled carbon dioxide; PSR:
pulmonary stretch receptor; PS: parastemal muscle; RA:
rectus abdominis; SD: standard deviation; TB: tracheo-
bronchial; TE: breathing expiratory time; TI: breathing
inspiratory time; VE: expired volume during breathing; VI:
inspired volume during breathing.

Competing interests
The authors declare that they have no competing interests.

Authors' contributions
CY performed experiments, conducted data analysis and
interpretation, and participated in writing the manuscript.
SS conducted statistical analysis of the data. MJR per-
formed experiments and conducted data analysis. PWD
interpreted the data and edited the manuscript. DCB per-
formed experiments, interpreted the data, and partici-
pated in writing the manuscript. All authors have read and
approved the final manuscript.

Supported by HL 70125, HL 89104, James and Esther King Biomedical
Research Program BM-040.

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Cough 2009, 5:12

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