Eur Respir J 2006; 28: 6874

DOI: 10.1183/09031936.06.00043305
CopyrightERS Journals Ltd 2006

Treatment of chronic rhinosinusitis and its

effects on asthma
S. Ragab*, G.K. Scadding#, V.J. Lund# and H. Saleh"

ABSTRACT: The effects of rhinosinusitis treatment upon asthma are disputed.

The first randomised prospective study of surgical compared with medical therapy of chronic
rhinosinusitis in 90 patients with and without nasal polyps was previously reported. Asthma
symptoms, control, forced expiratory volume in one second (FEV1), peak flow, exhaled nitric
oxide, medication use and hospitalisation at 6 and 12 months from the start of the study were also
monitored. This paper reports these results in 43 of those patients with concomitant asthma.
Both medical and surgical treatment of chronic rhinosinusitis were associated with subjective
and objective improvements in asthma. Overall asthma control improved significantly following
both treatment modalities, but was better maintained after medical therapy, where improvement
could also be demonstrated in the subgroup with nasal polyps. Medicine was superior to surgery
with respect to a decrease in exhaled nitric oxide and increase in FEV1 in the polyp patients. Two
patients noted worsening of asthma post-operatively.
Improvement in upper airway symptoms, as assessed using a visual analogue scale, correlated
with improvement in asthma symptoms and control. Treatment of chronic rhinosinusitis, medical
or surgical, benefits concomitant asthma; that associated with nasal polyposis benefits more from
medical therapy.
KEYWORDS: Asthma, chronic rhinosinusitis, endoscopic sinus surgery, exhaled nitric oxide,
forced expiratory volume in one second, nasal polyps

hinosinusitis coexisted with asthma in

34% of patients in one study [1].
Radiological studies have shown abnormal sinus radiographs in 53% [2, 3] and mucosal
thickening on sinus computed tomography (CT)
scans in 74% [4] of patients with asthma.
Recently, .84% of CT scans were found to be
abnormal in severe asthma, with a correlation
between the extent of CT changes, sputum
eosinophilia and pulmonary function [5].

A number of authors have investigated the effect

of surgical treatment of rhinosinusitis upon
asthma, with improvement [68], worsening [9,
10] and equivocal effect [11, 12] being reported.
Only two studies of medical chronic rhinosinusitis (CRS) treatment exist, one included four
medical patients [13], whereas the other considered CRS with polyposis alone and was nonrandomised [14].
MATERIALS AND METHODS
Patients were recruited over 2 yrs from the
Rhinology Clinics of the Royal National Throat,
Nose and Ear Hospital (London, UK). The study
was approved by the Ethics Committee of
the Royal Free Hospital (London, UK). After
68

VOLUME 28 NUMBER 1

application of exclusion criteria, the study was

discussed with 327 consecutive patients with a
primary diagnosis of CRS. Of these, 90 patients
who agreed to the process of randomisation were
finally included and were randomised equally
into the medical and surgical groups. The study
design and flow chart showing the course of the
study are presented in figures 1 and 2, respectively. Diagnosis of CRS was based on the criteria
described by the Staging and Therapy Group
[15]. The criteria for diagnosis of asthma were:
1) reversible airway obstruction that varied
markedly, both spontaneously and with treatment; 2) intermittent experience of wheeze
(usually worse on expiration and characteristically relieved by inhaled b2-agonists), cough
(usually unproductive), shortness of breath (not
always associated with wheeze) and chest tightness; 3) the possibility of being triggered by a
number of factors, including allergens, irritants,
physical factors, emotions, occupational agents,
food additives, changes in the weather, endocrine
factors and upper respiratory tract viral infections; and 4) a reduction in forced expiratory
volume in one second (FEV1; absolute value and/
or percentage of predicted value) and/or peak
expiratory flow (PEF) during the attacks [16].

AFFILIATIONS
*Tanta University Hospitals, Tanta,
Egypt.
#
Royal National Throat, Nose and Ear
Hospital, and,
"
Charing Cross Hospital, London,
UK.
CORRESPONDENCE
G.K. Scadding
Royal National TNE Hospital
London
WC1X 8DA
UK
Fax: 44 2079151674
E-mail: [email protected]
Received:
April 12 2005
Accepted after revision:
February 15 2006
SUPPORT STATEMENT
This study formed part of the doctoral
thesis of S. Ragab, presented to the
University of London (London, UK) in
2002.

European Respiratory Journal

Print ISSN 0903-1936
Online ISSN 1399-3003

EUROPEAN RESPIRATORY JOURNAL

S. RAGAB ET AL.

CHRONIC RHINOSINUSITIS AND ASTHMA

The exclusion criteria included pregnancy, lactation, significant psychological problems, inability to comply with the
study protocol, children aged ,18 yrs, acute upper or lower
respiratory tract infections within 2 weeks, use of systemic
corticosteroids within 4 weeks prior to the inclusion visit,
systemic diseases preventing participation in the study and
medical and/or surgical treatments influencing the study.
The whole study comprised 90 patients (45 males and 45
females) with CRS with a meanSD age of 4313 yrs. Of
these, 55 had CRS without polyposis and 35 CRS with
polyposis. Forty-nine yielded positive skin-prick test results
(25 treated surgically and 24 medically) and 43 were asthmatics
(23 assigned to surgery), three of whom were aspirin-sensitive
(two treated surgically).
The present study reports the results in the subgroup of 43
asthmatic patients with CRS with and without nasal polyposis.
Subjective assessment
Patients were asked about their nasal symptoms using a
validated visual analogue scale. Patients were also requested to
report any chest symptoms. Asthma symptoms were graded as
follows. 0: no symptoms; 1: symptoms present but causing
little or no discomfort; 2: symptoms present and troublesome
but not causing interference with either daily activities or
sleep; 3: symptoms present, troublesome and interfering with
either daily activities or sleep; and 4: symptoms intolerable.
CRS patients
Initial medical treatment
for 6 weeks
Improved

Failed
No persistant changes

Excluded from the study

CT scan
Persistant changes

Consent/randomisation

Conversely, overall asthma control, according to Global

Initiative for Asthma guidelines [17], was scored as follows.
0: not controlled; 1: slightly controlled; 2: adequately controlled; 3: well controlled; and 4: very well controlled.
Objective sinonasal evaluation
A complete nasal examination, including diagnostic nasal
endoscopy, was performed in all patients, who were then
categorised as having polypoid or non-polypoid CRS.
Nasal nitric oxide was evaluated using a nitric oxide (NO) gas
analyser (Model LR2000; Logan Research, Rochester, UK) with
the sampling flow rate adjusted to 250 mL?min-1 [18]. The
value of the last plateau part of the nasal NO trace was
recorded. The mean of three recordings was used as the
estimate of the nasal NO level.
Objective lower airway evaluation
Exhaled NO (eNO) was measured using the same LR2000
analyser. The patient was asked to take a deep inspiration and
then exhale slowly and steadily through the mouthpiece,
keeping 80% of the bio-feedback indicator lighting on in order
to attain a constant exhalation flow rate of 200 mL?s-1 and
maintain a mouth pressure of ,5 cmH2O, as recommended by
the European Respiratory Society task force [19].
Respiratory function tests, including FEV1 (% predicted),
forced vital capacity/FEV1 (%) and PEF, were evaluated using
a spirometer (Model Vitalograph 2160; Vitalograph, Maids
Moreton, UK). The spirometric standards used complied with
European Respiratory Society recommendations [20].
Medical treatment
Initial medical treatment
The initial medical treatment included a 6-week regimen of
Dexa-Rhinaspray Duo (DRS; Boehringer Ingelheim, Bracknell,
UK) and an alkaline nasal douche. DRS was delivered as two
puffs into each nostril twice daily, with each metered dose
containing 20 mg dexamethasone-21-isonicotinate and 120 mg
tramazoline hydrochloride. The alkaline nasal douche powder
was prepared in a 1:1 mixture of sodium chloride and sodium
bicarbonate. The douche was also used twice daily 15 min after
the DRS. Patients with positive skin-prick test result, plus a
relevant history, were given allergen avoidance advice. All
patients were advised to decrease exposure to pollutants such
as cigarette smoke.

tomography.

Medical treatment for the medically randomised group

All patients received a 12-week course of erythromycin,
alkaline nasal douche and intranasal corticosteroid preparations. Erythromycin was prescribed orally at 500 mg b.i.d. for
2 weeks, followed by 250 mg b.i.d. for 10 weeks. The alkaline
nasal douche was prepared and used as instructed above.
Intranasal corticosteroid preparations, in CRS patients without
polyposis, were given as DRS, two puffs into each nostril b.i.d.
for 2 weeks, followed by 100 mg (two sprays) fluticasone
propionate into each nostril b.i.d. for 10 weeks. Conversely,
patients suffering CRS with polyposis received a 12-week
course of 200 mg (six drops) fluticasone propionate into each
nostril b.i.d. In addition, three CRS patients with polyposis
were prescribed a 9-day course of oral prednisolone tablets
(30 mg for 3 days, 20 mg for 3 days and 10 mg for 3 days) after

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VOLUME 28 NUMBER 1

First set of investigations

Medical treatment

Surgery followed by medical

treatment

Second set of investigations after 6 months

Third set of investigations after 1 yr

FIGURE 1.

Study design. CRS: chronic rhinosinusitis; CT: computed

69

CHRONIC RHINOSINUSITIS AND ASTHMA

S. RAGAB ET AL.

Patients with CRS and

asthma assessed for eligibility
n=102

Excluded n=59
Inclusion criteria not met n=8
Refusal to participate n=51
Lost n=0

Randomised n=43

Allocated to medical treatment n=20

Received treatment n=20
Did not receive treatment n=0

FIGURE 2.

6-month follow-up
Lost to follow-up n=0
Patient unavailable n=1
Discontinued treatment n=0
Analysed n=19

6-month follow-up
Lost to follow-up n=0
Discontinued treatment n=0
Analysed n=22

12-month follow-up
Lost to follow-up n=0
Patients unavailable n=0
Discontinued treatment n=2
Analysed n=17

12-month follow-up
Lost to follow-up n=1
Patient unavailable n=0
Discontinued treatment n=0
Analysed n=21

Flow chart showing course of study. CRS: chronic rhinosinusitis.

failure of the above regimen to control their manifestations.

Subsequently, the use of intranasal corticosteroid preparations
was tailored to the patients clinical course, with most patients
maintained on 400 mg fluticasone propionate drops daily.
Surgical treatment
Endoscopic sinus surgery was performed in all patients
following the Messerklinger/Stammberger technique [21]
under general anaesthesia. The extent of the procedure was
tailored to the extent of sinus disease, as documented by nasal
endoscopy and CT scan findings. A microdebrider was used in
some cases of CRS with grade 2 and 3 polyposis. At the end of
the procedure, a piece of Telfa was inserted into the ethmoidal
cavity and taken out on the following day. Operative findings
and complications were recorded.
Medical treatment after surgery
Following endoscopic sinus surgery, all patients were prescribed a 2-week course of 500 mg erythromycin, DRS and
alkaline nasal douche b.i.d. This was followed by a 3-month
course of 100 mg (two sprays) fluticasone propionate intranasal spray into each nostril and alkaline nasal douche b.i.d.
Subsequently, the use of intranasal corticosteroid preparations
was tailored to the patients clinical course, with most patients
receiving two puffs of fluticasone propionate in each nostril
once daily.
Statistical methods
In order to maintain equal treatment numbers in both groups,
randomisation was performed using random blocks, with both
patient and investigator unaware of the group assignment. A
sample size of 66 patients was calculated using a two-sided
Wilcoxon two-sample test at the 5% level of significance to give
70

Allocated to surgical treatment n=23

Received treatment n=22
Did not receive treatment n=0
Patient unavailable n=1

VOLUME 28 NUMBER 1

the study a statistical power of 80%. The primary end-point

was the visual analogue scale for CRS. However, it was
decided to recruit 90 patients in order to raise the power of the
study and compensate for any lost to follow-up. Data are
presented as meanSD. A p-value of ,0.05 was considered
significant. Parametric tests, such as the paired t-test, twosample t-test and ANOVA, were applied for data that followed
or were transformed to a normal distribution. Either logarithmic or square transformation was attempted in order to
normalise the distribution so as to allow the use of parametric
tests. Nonparametric tests, such as the MannWhitney U-test,
Wilcoxon signed-rank test, sign test, Chi-squared test and
KruskalWallis test, were applied for data that did not follow a
normal distribution.
RESULTS
Baseline data
No significant difference between the medical and surgical
groups was found in the baseline data for any of the following:
demographic characteristics, visual analogue scale, nasal NO,
saccharin clearance time, chest score, use of medications,
number of hospitalisations for asthma, overall asthma control
score, eNO, FEV1 (% pred) and PEF.
The patients who declined the study were not significantly
different from those who took part.
Chronic rhinosinusitis parameters
Both medical and surgical treatment of CRS yielded significant
improvements in almost all of the subjective and objective
parameters of CRS (p,0.01), with no significant difference
being found between the medical and surgical groups
(p.0.05), except for total nasal volume in the CRS (p,0.01)
and CRS without polyposis (p,0.01) groups, in which surgical
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S. RAGAB ET AL.

CHRONIC RHINOSINUSITIS AND ASTHMA

treatment demonstrated greater increases. These results have

previously been published [22].
Overall asthma control score
The improvement in the surgical group was significant, with
decreasing significance from the 6- (p,0.01) to 12-month
(p,0.05) scores (table 1). The medical group showed a
constant significant improvement in the total group (p,0.01),
as well as in the CRS with polyposis subgroup (p,0.05). No
significant difference was detected between the 6- and 12month overall asthma control scores (p.0.05 (sign test)).
Differences between the medical and surgical groups were
insignificant (p.0.05 (MannWhitney test)).
Asthma control improvement correlated with improvement in
visual analogue scores for the upper airway (p50.003
(Kendalls tau-b test)).
Asthma symptom score
There was a trend for improvement in asthma scores in both
groups; this reached significance only in the medically treated
group, in which patients reported either improvement or no
change. The surgical group contained variable responses. One
patient with non-polypoid CRS developed new asthma
3 months post-operatively, whereas another with polyps
reported that their asthma after surgery was worse than ever
TABLE 1

before. However, the only patient reporting highly improved

asthma received surgery for non-polypoid CRS. No significant
difference was observed between the 6- and 12-month scores
(p.0.05 (sign test)). Differences in the chest scores between the
medical and surgical groups were insignificant (p.0.05
(MannWhitney test)).
There was a correlation between asthma score improvement and
visual analogue score changes for the upper airway (p50.005).
Medication use
Bronchodilator inhalers
There was a decrease in the mean use of bronchodilator
inhalers in both groups. One patient reported an increase in
bronchodilator use following polyp surgery. Although changes
within the medical groups tended to reach greater significance,
differences between surgical and medical groups were insignificant (p.0.05 (MannWhitney test)).
Corticosteroid inhalers
Changes in the use of corticosteroid inhalers attained no
significance (p.0.05 (sign test)) in either group.
Systemic corticosteroids for asthma
In the surgical group, 10 short courses of systemic corticosteroid therapy were required in the 12 months before surgery,

Changes in overall asthma control score in chronic rhinosinusitis patients

Score

Change
Baseline %

6 months %

p-value#

,0.01

12 months %

p-value#

9.5

,0.05

Surgical group
Total

No polyposis

Polyposis

13.6

13.6

40.9

18.2

28.6

31.8

31.8

28.6

13.6

36.4

10.0

0.0

30.0

40.0

44.4

50.0

10.0

11.1

10.0

50.0

16.7

25.0

50.0

0.0

16.7

16.7

50.0

41.7

16.7

25.0

25

33.3
.0.05

0.0

.0.05

44.4
.0.05

16.7

.0.05

Medical group
Total

No polyposis

Polyposis

10.0

5.3

55.0

31.6

23.5

25.0

42.1

52.9

10.0

21.1

60.0

33.3

30.0

55.6

10.0

11.1

20.0

10.0

50.0

30.0

37.5

20.0

30.0

25.0

10.0

30.0

37.5

,0.01

0.0

,0.01

23.5
.0.05

11.1

.0.05

77.8
11.1
,0.05

0.0

,0.05

: sign test.

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CHRONIC RHINOSINUSITIS AND ASTHMA

S. RAGAB ET AL.

whereas only four courses were needed post-operatively

(p,0.05 (Wilcoxon signed-rank test)). The medical treatment
of CRS also reduced the need for systemic corticosteroid
therapy from seven courses to one (p,0.05 (Wilcoxon signedrank test)). No significant difference was found between the
surgical and medical groups (p.0.05 (MannWhitney test)).
Number of hospitalisations for asthma
Surgery reduced the number of hospitalisations for asthma
from seven admissions in the pre-operative 12 months to two
post-operatively (p,0.05 (Wilcoxon signed-rank test)).
Conversely, the medical treatment of CRS reduced this from
five admissions to one (p,0.05 (Wilcoxon signed-rank test)).
The difference between the surgical and medical groups was
insignificant (p.0.05 (MannWhitney test)).
Objective measurements
Exhaled nitric oxide
Levels of eNO decreased significantly, more so in the medical
group, in which there were lower levels of eNO at 12 months
than at 6 months in the total group (p,0.01) and the polyp
subgroup (p,0.05; tables 2 and 3). Among polyp patients,
medical therapy reduced eNO levels more than surgery at 12
months (p,0.05).
Forced expiratory volume in one second
The 6- and 12-month FEV1 (% pred) of the surgical group
showed significant increases (p,0.05; tables 2 and 3).
In the total medical group, and also in its non-polypoid
subgroup, the 6-month FEV1 (% pred) improved significantly
(p,0.01).
The 12-month FEV1 (% pred) was significantly better in the
total medical group and both subgroups. The difference
between the 6- and 12-month FEV1 (% pred) was significant
in the medical subgroup with polyposis (p,0.05). This also

TABLE 2

Change from baseline in objective lower airway

measurements at 6 months in chronic
rhinosinusitis patients
Surgical group %

Medical group %

p-value#

Total

16.3340.05 (21)

25.1620.71 (19)

.0.05"

No polyposis

23.8338.14 (9)

26.6819.48 (9)

.0.05"

Polyposis

10.7142.16 (12)

23.8022.72 (10)

.0.05"

eNO

differed significantly from its corresponding surgical subgroup

(p,0.05).
Peak expiratory flow
Despite the fact that there was an improvement in PEF in all
groups in the follow-up settings, this reached significance only
in the total medical group and medical non-polypoid subgroup
(tables 2 and 3).
DISCUSSION
This first prospective randomised study demonstrates that
both medical and surgical treatment of CRS are associated with
improvement in concomitant asthma. There was a correlation
between changes in symptoms in the upper respiratory tract
and asthma symptoms and control.
Medical therapy was superior in some respects; asthma control
remained highly improved at 12 months, whereas, following
surgery, the 12-month values were less significantly improved
than those at 6 months. The difference between the medical
and surgical groups was significant for eNO and FEV1 in
polypoid CRS. eNO is a sensitive noninvasive test of lower
airways inflammation, increasing during exacerbations and
decreasing during recovery and in response to antia-sthmatic
anti-inflammatory treatments [23, 24], and also correlating
with sputum eosinophil numbers [25].
The effectiveness of medical treatment could be due to indirect
effects. The combined use of long-term erythromycin and
glucocorticoids seems to provide control of the inflammatory
reaction in the upper airway by decreasing the microbiological
load, reducing the number of leukocytes, and downregulating
a wide range of cytokines and inflammatory mediators [26].
Upper airway inflammation may affect the lungs via several
mechanisms, including systemic activation of eosinophil
precursors from bone marrow [27].

TABLE 3

Change from baseline in objective lower airway

measurements at 12 months in chronic
rhinosinusitis patients
Surgical group %

Medical group %

p-value#

Total

20.0533.32 (21)

36.8918.07 (17)

.0.05

No polyposis

28.9734.80 (9)

32.3020.50 (9)

.0.05

Polyposis

13.3631.99 (12)

42.0614.44 (8)

,0.05

eNO

FEV1 % pred

FEV1 % pred

Total

3.317.90 (21)

3.944.53 (19)

.0.05"

Total

3.957.87 (21)

5.884.05 (17)

.0.05"

No polyposis

6.409.36 (9)

5.314.69 (9)

.0.05"

No polyposis

6.7710.13 (9)

5.103.72 (9)

.0.05"

Polyposis

0.995.50 (12)

2.714.23 (10)

.0.05

Polyposis

1.835.15 (12)

6.764.47 (8)

,0.05

PEF

PEF

Total

4.0312.49 (21)

4.5910.49 (19)

.0.05"

Total

4.1412.30 (21)

7.5912.00 (17)

.0.05"

No polyposis

8.5615.28 (9)

8.0612.39 (9)

.0.05"

No polyposis

8.3915.95 (9)

8.8714.88 (9)

.0.05"

Polyposis

0.649.20 (12)

1.477.81 (10)

.0.05

Polyposis

0.968.04 (12)

6.168.49 (8)

.0.05

Data are presented as meanSD (n). eNO: exhaled nitric oxide; FEV1: forced

Data are presented as meanSD (n). eNO: exhaled nitric oxide; FEV1: forced

expiratory volume in one second; % pred: percentage of the predicted value;

expiratory volume in one second; % pred: percentage of the predicted value;

PEF: peak expiratory flow. #: two-sample test; ": MannWhitney test.

PEF: peak expiratory flow. #: two-sample test; ": MannWhitney test.

72

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S. RAGAB ET AL.

Alternatively, macrolides may play a direct role in control of

asthma through their antibacterial, anti-inflammatory and
glucocorticoid-sparing properties. The antibacterial properties
of erythromycin include action against atypical pathogens such
as Mycoplasma pneumoniae and Chlamydia pneumoniae, which
have been implicated in the pathogenesis of asthma [28]. The
anti-inflammatory properties of erythromycin were thought to
play the main role in the control of the asthmatic inflammatory
response, especially through inhibition of the eosinophilic
response and reduction of levels of cytokines and reactive
oxygen species [2931]. Erythromycin was also reported to
attenuate bronchial hyperresponsiveness in patients with
bronchial asthma, probably through its inhibitory action on
superoxide production and chemotaxis of neutrophils [32].
Erythromycin may also be helpful in asthma management,
through protection of the ciliated airway epithelium from the
action of bioactive phospholipids [33], reduction of mucus
production [34] and improvement of the biophysical properties
of mucus [35]. Finally, it has been suggested that erythromycin
inhibits glucocorticoid clearance and enhances the effect of
steroid therapy on asthma [36].

CHRONIC RHINOSINUSITIS AND ASTHMA

contributes to the burden of inflammatory mediators capable

of causing both upper and lower respiratory tract effects via the
systemic circulation. It is possible that, during surgical
intervention, leukotrienes are released. Therefore, patients
undergoing upper respiratory tract sinus surgery should
receive oral corticosteroids, and possibly anti-leukotrienes,
perioperatively.
Conclusion
Both medical and surgical therapy of chronic rhinosinusitis
improved the clinical course of asthma, with medical treatment
being superior to surgical in chronic rhinosinusitis with
polyposis.

Surgical trauma may induce a change in the upper respiratory

tract cytokine profile, or cytokine release, with the ability to
trigger or aggravate asthma in a special subgroup of patients.
BOLARD et al. [39] demonstrated that microscopic intranasal
sphenoethmoidectomy for CRS with polyposis altered the
cytokine profile in nasal secretions, with significantly higher
levels of interleukin-8, -10 and -1b than in the medically treated
or untreated groups. HIGASHI et al. [40] have recently shown
that sinus surgery increases urinary leukotriene E4 levels and
postulated that upper respiratory tract mucosal inflammation

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Surgically treated patients showed a trend for improvement in

both subjective and objective lower airway measurements. This
reached significance for all parameters except asthma score,
use of corticosteroid inhalers and PEF. There were changes
which did not reach significance in the operated polypoid and
non-polypoid subgroups, which did not differ from each other.
Surgery appears to have a negative effect on asthma in a small
subgroup of CRS patients. The present study included two
(8.7%) patients whose lower airway manifestations worsened
after surgery. Both showed increased use of medication,
elevated eNO levels and reduced FEV1 and PEF. Both also
showed subjective and objective improvement in their upper
respiratory tract manifestations post-operatively. Other
authors have reported an 1840% subjective worsening of
asthma or precipitation of the first attack of asthma [9, 10, 37]
after sinus surgery. There is a suggestion that patients with
nasal polyposis are the most likely group to experience asthma
exacerbations post-operatively. The present study does not
support this observation, since there was a general, although
nonsignificant, subjective and objective tendency for asthma
improvement in the CRS with polyposis surgical group.
Secondly, there was no significant difference between the
CRS surgical groups with and without polyps. Thirdly, the
only patient with new asthma after surgery had no polyps. A
previous study demonstrated no major differences in outcomes
between CRS with and without polyposis [38]. However, the
present study suggests that medical treatment for CRS with
polyposis is more effective in improving asthma.

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