|Year : 2015 | Volume
| Issue : 4 | Page : 127-133
Effect of proton pump inhibitor and voice therapy on reflux-related laryngeal disorders
Hatem Ezzeldin1, Ahmed A Hasseba2
1 Department of Otorhinolaryngology, Sohag University, Sohag, Egypt; Department of Phoniatrics, King Fahd Hospital Jeddah, Jeddah, Kingdom of Saudi Arabia
2 Department of Otorhinolaryngology, El-Minia University, Minya, Egypt
|Date of Submission||01-Jun-2015|
|Date of Acceptance||12-Sep-2015|
|Date of Web Publication||30-Oct-2015|
(Phoniatrics), Department of Phoniatrics, King Fahd Hospital Jeddah, PO Box 8488, Jeddah 21196
The aim of this study was to evaluate the effect of proton pump inhibitor (PPI) in combination with voice therapy (VT) in the treatment of patients with laryngopharyngeal reflux (LPR) and to evaluate the efficacy of 3-month treatment.
This was a prospective comparative study.
Patients and methods
A total of 50 patients having different symptoms of LPR were included. The reflux symptom index and reflux finding score were used to diagnose LPR. The patients were classified into two groups: group A patients were treated with omeprazole and VT, and group B patients were treated with omeprazole alone. The patients were followed up for 3 months. Acoustic analysis of voice and the voice handicap index were used to compare both groups.
Laryngeal findings found in participants of this study were as follows: laryngeal erythema (28%) and posterior commissure hypertrophy and granulation tissue, which represented 16% each. Subglottic edema, ventricular obliteration, diffuse laryngeal edema, and thick endolaryngeal mucus were also observed. Results of acoustic correlates of dysphonia (Jitter, Shimmer, and harmonic-to-noise ratio) and voice handicap index showed significant improvement after 3 months of using PPI. However, marked improvement was observed in patients who received both PPI and VT together.
PPI in combinations with VT was more effective in alleviating laryngeal manifestations in patients with LPR compared with PPI alone. The duration of 3 months was sufficient to improve symptoms and manifestations in both groups.
Keywords: laryngopharyngeal reflux, voice handicap index, voice therapy
|How to cite this article:|
Ezzeldin H, Hasseba AA. Effect of proton pump inhibitor and voice therapy on reflux-related laryngeal disorders. Tanta Med J 2015;43:127-33
|How to cite this URL:|
Ezzeldin H, Hasseba AA. Effect of proton pump inhibitor and voice therapy on reflux-related laryngeal disorders. Tanta Med J [serial online] 2015 [cited 2021 Mar 1];43:127-33. Available from: http://www.tdj.eg.net/text.asp?2015/43/4/127/168728
| Introduction|| |
The role of gastroesophageal reflux (GERD) in causing extraesophageal symptoms is increasingly being recognized. Chronic laryngeal signs and voice disorders associated with GERD are often referred to as reflux laryngitis or laryngopharyngeal reflux (LPR). However, not all episodes of GERD are associated with LPR and not all patients with LPR have typical features of GERD , . Although there are no published figures on the prevalence of LPR in general population, Rodrigues et al.  assumed that 50% of all patients presenting with voice or swallowing disorder associated with LPR. Patients with LPR present with nonspecific symptoms such as foreign body (globus) sensation, vocal fatigue, dysphonia, chronic throat clearing, dysphagia, and chronic cough  . Rafii et al.  mentioned that patients with LPR do not usually have symptoms of GERD. The most frequently observed signs of LPR are interarytenoid erythema or hyperemia, subglottic edema (pseudosulcus), ventricular obliteration, hypertrophy of the posterior glottis and/or granulation tissue formation in the interarytenoid region, and thick excessive endolaryngeal mucus , .
To date, the diagnosis of LPR is a very difficult task and several controversies remain on how to confirm the diagnosis of LPR. Response to empiric treatment with proton pump inhibitor (PPI) (the 'omeprazole test') is a more common and acceptable initial diagnostic strategy for uncomplicated LPR , . Ambulatory 24 h dual-probe or triple-probe pH-metry was once considered a reliable method for GERD testing  . However, the position of the probes makes the measurement difficult to interpret, and there is no consensus about the pathological reflux at the level of laryngopharynx  . Moreover, extraesophageal reflux is also intermittent. A negative pH study does not rule out extraesophageal reflux  . Much effort has been taken in the past years for early detection of LPR with a simple, economic, and noninvasive procedure.
Belafsky et al.  developed simple, noninvasive, economic procedures called the reflux symptom index (RSI) and reflux finding score (RFS) for the diagnosis of LPR.
Standard therapeutic intervention for LPR includes lifestyle modifications, medical treatment, and surgical treatment. PPI have become the treatment of choice even though conflicting results exist in their response. Concurrent voice therapy (VT) including voice hygiene advice might boost the recovery period and may be fundamental to overcome the abnormal vocal behaviors and reduce laryngeal discomfort. Few controlled studies of VT plus medical therapy have been reported. A study conducted by Meyerson  reported that voice exercises relieve voice change and laryngeal symptoms in cases of LPR. There are no enough studies that have objectively evaluated the effectiveness of combination of PPI and VT in LPR patients. The current study compares the results of using PPI (omeprazole) in combination with VT and omeprazole alone in the treatment of patients with LPR.
| Aim of this study|| |
The purpose of this study was to compare the effect of using of omeprazole with VT and omeprazole alone in the management of reflux-related voice disorders and to evaluate the efficacy of 3-month treatment.
This was a prospective comparative study.
| Patients and methods|| |
A total of 50 outpatients visiting the otolaryngology clinic of El-Minya University Hospital having different symptoms of LPR were included in the study. The Arabic version of the RSI  and RFS  was used to diagnose LPR.
Patients with LPR symptoms for the last 1 month and with both RSI greater than 13 and RFS greater than 11, which were assessed using laryngeal endoscopy, were included in the study.
Patients excluded from this study include children (<18 years), pregnant women, cigarette smokers, tobacco users, patients with a history of vocal abuse and misuse behaviors, and patients who presented with vocal fold lesions unrelated to LPR. In addition, exclusion criteria included a history of laryngeal surgery, neurological disorders affecting the larynx, previous treatment of LPR, and recent course of VT.
Evaluation of each patient included detailed history, ENT examination, and flexible laryngoscopy. The diagnosis of LPR depended mainly on the results of the Arabic version of RSI  , which was completed by the patients, and the results of RFS  , which was assessed using laryngeal endoscopy. Endoscopic examination of the larynx was carried out for each patient at the Phoniatric clinic using Hopkins 70°C Telescope (Model 8706 CA; Karl Storz, Tuttlingen, Germany). Two expert Phoniatricians with experience of over 10 years were asked to evaluate the laryngeal examination pictures using RFS. The results of the Arabic version of RSI were obtained based on the questionnaire filled by the patients. A RSI greater than 13 was considered abnormal and suggestive of LPR.
An RFS was obtained based on the laryngeal examination scoring system by Belafsky et al.  . An RFS greater than 11 was considered abnormal and suggestive of LPR.
Computerized voice analysis was performed for all selected patients using Dr Speech software, (Vocal assessment, version 4, 1998; Tigers DRS Inc., Seattle, Washington, USA).
All patients were asked to fill the Arabic version voice handicap index (VHI) questionnaire  before and after 3 months of therapy.
Participants who met all inclusion criteria were classified randomly into two groups:
Group A included 25 patients who received omeprazole 20 mg twice per day in combination with VT sessions twice per week for a period of 3 months.
Group B patients received omeprazole 20 mg twice per day for a period of 3 months.
RFS, RSI, VHI (Arabic version), and acoustic analysis were reassessed after 1 month and after 3 months.
All participants were informed about the nature of the study and signed informed consent was obtained. The Ethics Committee of El-Minya University approved the protocol of our study.
Arabic version of the reflux symptom index 
It is a nine-item, self-assessment questionnaire with high validity and reliability. It is used to analyze patient perception of possible LPR. The questionnaire uses symptoms suggestive of LPR (hoarseness, throat clearing, throat mucus/postnasal drip, dysphagia, coughing after eating or after lying down, breathing difficulties, troublesome or annoying cough, globus pharyngeus, and heartburn). For each item, the scale ranges from 0 (no problem) to 5 (severe problem), with a maximum total score of 45. The authors recommended that an RSI score of 13 or more was abnormal and suggestive of LPR.
Reflux finding score 
Belfasky et al.  developed an eight-item RFS. This score is based on objective findings observed during fiberoptic nasoendoscopy of the larynx. The scores range from a minimum of 0 (no abnormal findings) to a maximum of 26 (worst score possible). RFS greater than 11 is strongly associated with LPR.
Arabic voice handicap index 
The Arabic VHI is reliably applied to the Arabic-speaking population, as it can help in estimating the degree of voice disorder severity. The Arabic version of the VHI is a valid and reliable tool for assessment of patients' self-perception of voice handicap. It has also been shown to be sensitive for a wide variety of voice disorders. This self-administered questionnaire consists of 30 questions; the patient responds according to the appropriateness of each item (0 = none to 4 = always). The Arabic VHI is scored from 0 to 120 with the latter representing the maximum perceived disability due to voice difficulties based on the patient response.
The parameters measured included jitter, shimmer, and harmonic-to-noise ratio (HNR) for the vowel /a/. The software defines normal jitter values up to 0.5% and shimmer values up to 3.0%. Normal values of HNR have not been specified. The procedure consisted of recording the production of three sustained vowels /a/,/I/,/u/, after taking a deep breath and at a comfortable loudness and pitch level. The recording of the voice sample was carried out with a unidirectional condenser microphone, which was held by the patient at a distance of 4 inches from the mouth.
The accent method of voice therapy 
It is a one of the holistic approaches for behavioral modification of the voice. The accent method rests technically on three major principles: (a) optimal abdominodiaphragmatic breath support; (b) rhythmic play of accentuated relaxed vowels with progressive carry over to connected speech; and (c) dynamic rhythmic body and arm movements. The therapeutic procedure consists of (a) respiratory exercise, (b) phonatory exercises, and (c) articulatory exercises, using which the beneficial new vocal habits are transferred to connected speech.
Statistical analyses were performed using statistical package for social science for windows 7, release 22 (SPSS Inc., Chicago, Illinois, USA). Normality of distribution was tested with the Kolmogorov-Smirnov test. Homogenicity of variance and sphericity was verified using Leven's test and Mauchly's test. T-test for independent variables was used to compare the groups as regards the baseline measures. A two-way analysis of variance with repeated measure was conducted to evaluate the efficacy of time and type of therapy on scores of different voice measures. The dependent variable was scores of voice measures. The within-individual factors were type of therapy with two levels (combinations of PPI with VT and PPI alone) and time with three levels (pretreatment, 1 month of therapy, and after 3 months of therapy). The types of treatment×time interaction effect, as well as the treatment type and time main effects, were tested using multivariate criterion of Wilk's lambda (L). Significant differences between the mean scores were tested at 0.05 α level. An effect size was computed for each analysis using the eta-squared statistic (η2 ) to access the practical significance of findings. Cohen's guidelines were used to interpret (η2 ) effect size: 0.01=small, 0.06 medium, and 0.14 = large. This study was approved by the ethical committee at the faculty of medicine, El-Minia University.
| Results|| |
Fifty patients who fulfilled the inclusion criteria and having LPR were included in this study. The age range of the patients was from 23 to 70 years (mean 47.9 and SD 11.34). They were divided into two groups on the basis of the type of treatment. Group 'A' received treatment in the form of combination of PPI together with VT and group 'B' received only PPI. The two groups were matched in age and sex [Table 1].
A T-test of independence revealed that there were insignificant statistical differences between the two groups as regards baseline pretreatment measures (VHI, RSI, RFS, Jitter, Shimmer, and HNR), as illustrated in [Table 2].
|Table 2 Variable descriptions in the pretreatment period (baseline measures) |
Click here to view
The most common laryngeal finding in the initial evaluation (according to RFS) was erythema/hypermia (14 patients; 28% of total cases). Posterior commissure hypertrophy and granulation tissue formation represented (eight patients) 16% of total cases [Figure 1].
|Figure 1: Chart representing numbers and percentage of laryngeal findings|
Click here to view
Two-way analysis of variance with repeated measures and Greenhouse-Geisser correction were conducted to evaluate the effect of treatment type and time period on scores of different voice measures. Voice measure scores showed a significant main effect for both the type of treatment and for time periods, whereas the type of treatment × time period interaction effect was insignificant [Table 3] and [Table 4].
|Table 3 The mean and SD for group 'A' and group 'B' on scores of voice measures in the pretreatment period, after 1 month of therapy, and after 3 months of therapy |
Click here to view
Post-hoc test using the Bonferroni adjustment was conducted to follow-up the significant type of time main effect and assess differences across time period on voice measure scores. Results revealed significant mean differences in voice measure scores between the treatment results after 3 months and the other two time periods across different voice measures [Table 5].
|Table 5 Results of post-hoc test with Bonferroni adjustment for time factor on different voice measures |
Click here to view
| Discussion|| |
Although the evaluation and treatment of LPR has been challenging, promising progress has been made in delineating the complex pathophysiology and realizing the wide array of clinical manifestations. In addition, advancements have been made in developing new diagnostic tools and understanding how to treat patients with LPR , .
Although ambulatory 24-h dual-probe or triple-probe pH-metry is considered the best method for GERD testing  , the position of the probes makes the measurement difficult to interpret, and there is no consensus about the pathological reflux at the level of laryngopharynx  . Moreover, extraesophageal reflux is also intermittent. A negative pH study does not rule out extraesophageal reflux ,, . Much effort has been spent in the past years for early detection of LPR with a simple, economic, and noninvasive procedure. Belfasky et al.  developed simple, noninvasive, economic procedures called the RSI and RFS for the diagnosis of LPR.
We used RSI and RFS to evaluate patients with LPR, as these procedures are considered significant predictors of LPR as reported by Ramzy et al.  , who assumed that RSI and RFS are sensitive and specific for the diagnosis of LPR and both RSI and RFS are significantly proportionate to LPR.
In the current study, all patients diagnosed with LPR using RSI and RFS showed abnormal laryngeal findings with variable degrees. These findings included ventricular obliteration, subglottic edema, diffuse laryngeal edema, and thick mucus. However, the most prevalent laryngeal findings found in participants of this study were laryngeal erythema (28%), posterior commissure hypertrophy and granulation tissue, which represented 16% for each of them. We assume that the effect of LPR on the laryngeal mucosa can be explained using reflux theory or reflex theory. Reflux theory is a direct mechanism involving aspiration that directly stimulates the pharynx and larynx. LPR symptoms result from direct contact between the laryngeal and pharyngeal epithelium and the retrograde flow of gastric contents. Compared with the esophageal mucosa, laryngeal and pharyngeal epithelium are significantly more vulnerable to damage, and even short exposure of direct contact with gastric refluxate can lead to laryngopharyngeal damage. The laryngeal findings observed in this study are in agreement with that obtained by other authors , who stated that erythema and edema, which occur in the mucous membrane between the arytenoids, are the most common findings of reflux laryngitis, considering the positional relationship with the upper esophageal sphincter.
This study proved that all voice symptoms measured using the RSI - namely, hoarseness of voice, clearing of throat, excess throat mucus, difficulty swallowing food, liquids, or pills, coughing after eating or lying down, breathing difficulties or choking episodes, troublesome or annoying cough, sensations of lump in the throat, heartburn, chest pain, indigestion, or acid reflux - improved in all patients in both groups. Moreover, on comparing these symptoms with pretherapy baseline, we found that both groups demonstrated a decrease in total RSI scores. However, this improvement was more better in the group treated with a combination of PPI and VT. Vashani et al.  concluded in their study on 32 patients diagnosed with LPR, who were randomized to receive either omeprazole with VT or omeprazole alone, that improvement in patients who received PPI with VT was significantly better than that in patients who received omeprazole alone. Moreover, Belafsky et al.  found that the mean RSI improved from 19.3 to 13.9 after 2 months of therapy with PPIs in patients with laryngeal symptoms of GERD. In the current study, the improvement in LPR symptoms occurred in patients treated with PPI together with VT, which proved that VT appeared to be effective in alleviating reflux symptoms in patients with LPR when it is used in combination with PPI.
In the current study, laryngeal manifestations observed with RFI improved significantly after 3 months of using PPI. However, marked improvement was observed in patients who received both PPI and VT. These results coincide with those reported in the studies conducted by Vashani et al.  and Belafsky et al.  , who reported alleviation of symptoms and signs in patients with LPR after using regular PPI for 3 months' duration.
In our study, acoustic correlates of dysphonia (jitter, shimmer, and HNR) improved after therapy in both groups, which was more evident in the PPI+VT group. Hanson et al.  found significant improvement in acoustic measures of jitter, shimmer, and signal-to-noise ratio in participants with LPR who presented with dysphonia after treatment with PPI and lifestyle changes.
The use of objective and subjective measures to evaluate the outcome of both groups that used different methods of therapy is valuable. These different tools are used to evaluate the effect of therapy from different perspectives; thus, in the current study, results obtained using VHI, which evaluates patients' self-perception of voice handicap, showed decreased severity of dysphonia after therapy in both groups and was more evident in the PPI+VT group. Malki et al.  mentioned that VHI (self-administered questionnaire) is sensitive and specific for a wide variety of voice disorders.
The duration of therapy using either omeprazole alone or omeprazole in combination with VT was found to be fundamental for patients' relief of LPR. In this study, there was a positive correlation between the duration of therapy and degree of improvement. However, other authors , did not find a change in acoustic measures of voice after antireflux medication for 4 weeks' duration. This might be attributed to the duration of therapy (1 month), which was not enough to relieve laryngeal manifestations compared with our study in which the duration of therapy was 3 months. Moreover, Hanson et al.  mentioned that the duration of effective treatment of LPR patients should be 3-6 months with regular PPI use. Moreover, Ford  supposed that patients with reflux-related laryngitis require higher doses and a longer trial of PPI to achieve an improvement in laryngeal symptoms compared with those with typical GERD symptoms.
The role of noninvasive measures such as behavior readjustment voice therapy (BRAT) is not discussed as a possible line of treatment. However, in the current study, BRAT together with PPI proved to be effective in the management of many of the manifestations attributed to LPR. BRAT includes both vocal hygiene instructions given to the patients to maintain their healthy vocal folds and vocal exercises to correct abnormal vocal behavior and to decrease tension and effort needed to produce good voice; thus, BRAT together with PPI can help patients restore normal anatomical and functional components of the vocal system. Moreover, Martinucci et al.  assumed that the lower esophageal sphincter, surrounded by diaphragmatic muscle, prevents GERD, and, indirectly, the synergy of the function of the lower esophageal sphincter and its surrounding crura of the diaphragm, when superimposed, is of importance for competent closure. When these structures become incompetent, gastric contents may be traced back along the esophagus and cause LPR. Like any other striated muscle of the body, the diaphragm muscle should be amenable to improve performance with physical exercise. For these reasons, alternative therapies for the treatment of reflux disease has recently been studied, and, in particular, VT/relaxation techniques such as training of the diaphragm muscle with maneuvers and breathing exercises have been considered.
Globus pharyngeus (foreign body sensation and sticky mucus) is one of the LPR symptoms observed in our study. We assume that, in patients nonresponsive to traditional PPI therapy (when LPR was diagnosed), alternative therapies may be considered, including VT techniques to improve vocal functions. Eherer et al.  , in a randomized controlled study, showed that actively training the diaphragm muscle by breathing exercise can improve reflux disease. The current study indicated that the improvement in laryngeal manifestations occurred after 3 months of treatment for all patients in both groups.
| Conclusion|| |
PPI in combination with VT was more effective in alleviating laryngeal manifestations in patients with LPR compared with PPI alone. The duration of 3 months was sufficient to improve symptoms and manifestations in both groups. Further research with longer follow-up periods and more cases with LPR is recommended.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Naik RD, Vaezi MF. Extra-esophageal manifestations of GERD: who responds to GERD therapy? Curr Gastroenterol Rep 2013; 15:318.
Toros SZ, Toros AB, Yuksel OD, Ozel L, Akkaynak C, Naiboglu B. Association of laryngopharyngeal manifestations and gastroesophageal reflux. Eur Arch Otorhinolaryngol 2009; 266:403-409.
Rodrigues M, Ralph S, Victor S, Luis P. Influence of obesity on the correlation between laryngopharyngeal reflux and obstructive sleep apnea. Braz J Otorhinolaryngol 2013; 805-10.
Rafii B, Taliercio S, Achlatis S, Ruiz R, Amin MR, Branski RC. Incidence of underlying laryngeal pathology in patients initially diagnosed with laryngopharyngeal reflux. Laryngoscope 2014; 124:1420-1424.
Oridate N, Tokashiki R, Watanabe Y, Taguchi A, Kawamura O, Fujimoto K. Endoscopic laryngeal findings in Japanese patients with laryngopharyngeal reflux symptoms. Int J Otolaryngol 2012; 2012:908154.
Lai YC, Wang PC, Lin JC. Laryngopharyngeal reflux in patients with reflux esophagitis. World J Gastroenterol 2008; 14:4523-4528.
Farrokhi F, Vaezi MF. Extra-esophageal manifestations of gastroesophageal reflux. Oral Dis 2007; 13:349-359.
Hopkins C, Yousaf U, Pedersen M. Acid reflux treatment for hoarseness. Cochrane Database Syst Rev 2006; 25:CD005054.
Richter JE. Ambulatory esophageal pH monitoring. Am J Med 1997; 103:130S-134S.
Belafsky PC, Postma GN, Koufman JA. Validity and reliability of the reflux symptom index (RSI). J Voice.
Meyerson MD. Greene & Mathieson's. The Voice and Its Disorders. Topics in Language Disorders 2003;23:68-69.
Farahat M, Malki KH, Mesallam TA. Development of the Arabic version of reflux symptom index. J Voice 2012; 26:814.e15-819.e15.
Malki KH, Mesallam TA, Farahat M, Bukhari M, Murry T. Validation and cultural modification of Arabic voice handicap index. Eur Arch Otorhinolaryngol.
Kotby MN, El-Sady SR, Basiouny SE, Abou-Rass YA, Hegazi MA. Efficacy of the accent method of voice therapy. J Voice 1991; 5:316-320.
Kwon YS, Oelschlager BK, Merati AL. Evaluation and treatment of laryngopharyngeal reflux symptoms. Thorac Surg Clin 2011; 21:477-487.
Qadeer MA, Phillips CO, Lopez AR. Proton pump inhibitor therapy for suspected GERD-related chronic laryngitis: a meta-analysis of randomized controlled trials. Am J Gastroenterol.
Kotby MN, Hassan O, El-Makhzangy AN, Farahat M, Shadi M, Milad P. Gastroesophageal reflux/laryngopharyngeal reflux disease: a critical analysis of the literature. Eur Arch Otrhinolaryngol 2010; 267:171-179.
Ramzy I, El Shazly M, Marzaban R, Elbaz T, Safwat M, Latif B. Laryngopharengeal reflux in gastroesophageal reflux disease: does 'silent laryngopharengeal reflux' really exist?. Open J Gastroenterol 2014; 4:130-140.
Park KS. Observable laryngopharyngeal lesions during the upper gastrointestinal endoscopy. Clin Endosc 2013; 46:224-229.
Vashani K, Murugesh M, Hattiangadi G. Effectiveness of voice therapy in reflux-related voice disorders. Dis Esophagus 2010; 23:27-32.
Belafsky PC, Rees CJ, Rodriguez K, Pryor JS, Katz PO. Esophagopharyngeal reflux. Otolaryngol Head Neck Surg 2008; 138:57-61.
Hanson DG, Jiang JJ, Chen J, Pauloski BR. Acoustic measurement of change in voice quality with treatment for chronic posterior laryngitis. Ann Otol Rhinol Laryngol 1997; 106:279-285.
Hamdan AL, Sharara AI, Younes A, Fuleihan N. Effect of aggressive therapy on laryngeal symptoms and voice characteristics in patients with gastroesophageal reflux. Acta Otolaryngol 2001; 121:868-872.
Tokashiki R, Okamoto I, Funato N, Suzuki M. Rikkunshito improves globus sensation in patients with proton-pump inhibitor-refractory laryngopharyngeal reflux. World J Gastroenterol 2013; 19:5118-5124.
Ford CN. Evaluation and management of laryngopharyngeal reflux. JAMA 2005; 294:1534-1540.
Martinucci I, de Bortoli N, Savarino E. Optimal treatment of laryngopharyngeal reflux disease. Ther Adv Chronic Dis 2013; 4:287-301.
Eherer AJ, Netolitzky F, Hogenauer C, Puschnig G, Hinterleitne TA, Scheidl S, et al.
Positive effect of abdominal breathing exercise on gastroesophageal reflux disease: a randomized, controlled study. Am J Gastroenterol 2012; 107:372-378.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]