Sialorrhoea (hypersalivation) is the excessive production of saliva and it presents as drooling in children, young people and adults with a neurological condition, such as cerebral palsy or Parkinson's disease. Hypersalivation can also be an adverse effect of drug treatment, such as clozapine.

Drooling is generally defined as excessive pooling and poor control of saliva in the oral cavity that might be caused by impaired salivary clearance, whereas sialorrhoea refers to overproduction or overflow of saliva beyond the margin of the lip.1,2 However, both terms are sometimes used interchangeably.1 

This condition is normal in infants and usually stops by 15 to 18 months of age, but sialorrhoea after four years of age generally is considered to be pathologic.2 If patients have drooling, they might subsequently spill saliva from their oral cavity, or might aspirate the saliva causing aspiration pneumonia. Other possible negative consequences are poor oral hygiene and social embarrassment.

Further reading: What influences how we age?

Further reading: Mild cognitive impairment in Parkinson’s disease

 

Pathophysiology

The normal physiology of human swallowing is composed of three phases: oral, pharyngeal, and oesophageal. The oral phase is voluntary whereas pharyngeal and oesophageal phases are involuntary. When swallowing begins, the oropharyngeal phase uses more than 30 different muscles to coordinate and precisely time moving the food bolus to the esophagus. The upper oesophageal sphincter subsequently opens and the bolus passes through the esophagus by peristalsis into the stomach.1

The medullary swallowing center (which includes a swallowing central pattern generator and its interneurons, such as the nucleus of the solitary tract) provides the outputs to the structures involved in the swallowing process such as the tongue, larynx, pharynx, and upper oesophagus. Lingual muscles are controlled by the motor output of the hypoglossal (XII) nucleus (located between the dorsal motor nucleus of the vagus and the midline of the medulla) while laryngeal, pharyngeal and upper esophageal muscles are controlled by motor output of the nucleus ambiguus.1

Saliva is secreted by the six major salivary glands (two parotid glands, two submandibular, and two sublingual) and several hundred minor salivary glands. The major salivary glands produce 90% of the approximately 1.5 L of saliva that are secreted per day.2 The various functions of saliva include mechanical cleansing of the mouth, contributing to oral homeostasis, and helping to regulate oral pH. Saliva also has bacteriostatic and bacteriocidal properties that contribute to dental health and decrease oral odour. Saliva is important in the lubrication of food boluses, and the amylase in saliva begins the digestion of starches.2

The processes of salivation are controlled by both sympathetic and parasympathetic nervous system.1 However, facilitation of ingestion and swallowing are mainly contributed by parasympathetic nervous system. The parasympathetic afferent pathways receive unconditioned reflex stimulation from the pharynx and oesophagus. Then, signals are conducted via the vagus (X) and spinal splanchnic nerves to the salivary center located in the medulla. The parasympathetic outputs are conducted via two different pathways including the glossopharyngeal (IX) nerve, which then innervates the otic ganglion and subsequently the parotid glands via the auriculo-temporal nerve and the facial (VII) nerve. The latter, through the chorda tympani nerve, innervates the submandibular ganglia and then the submandibular and sublingual glands via the lingual nerve.1

Postganglionic fibers from the otic ganglion provide secretory function to the parotid gland, and fibers from the submandibular ganglion supply secretory function to the submandibular and sublingual glands. The flow of saliva is enhanced by sympathetic innervation, which promotes contraction of muscle fibers around the salivary ducts.2

Sialorrhoea usually is caused by neuromuscular dysfunction, hypersecretion, sensory dysfunction, or anatomic (motor) dysfunction. The most common cause is neuromuscular dysfunction.

The two major factors possibly influencing the pathophysiology of drooling are abnormalities of salivary production and insufficient salivary clearance.1 Insufficient salivary clearance with swallowing dysfunction, in which the oropharyngeal dysfunction is a major component, is a major contributor to sialorrhoea.1 Under normal circumstances, people are able to compensate for increased salivation by swallowing. However, sensory dysfunction may decrease a person's ability to recognize drooling, and anatomic or motor dysfunction may impede the ability to manage increased secretions. Anatomic abnormalities are usually not the sole cause of drooling, but commonly exacerbate other causative conditions. Macroglossia (enlarged tongue) and oral incompetence may predispose patients to salivary spill.2 

Aetiology

Drooling may occur in many neurological disorders including neuromuscular diseases such as myasthenia gravis, amyotrophic lateral sclerosis (ALS) and oculopharyngeal muscular dystrophy, neurodegenerative diseases such as Parkinson's disease (PD), multiple system atrophy (MSA), progressive supranuclear palsy (PSP), dementia with Lewy bodies (DLB) and cortico-basal degeneration (CBD), and cerebrovascular diseases.1

Drooling in Parkinson’s disease

In Parkinson’s disease (PD), drooling is considered a non-motor symptom. Due to the lack of a standard definition and criteria for diagnosing drooling in PD patients, estimates of prevalence vary. Previous studies showed that prevalence ranged from 10 to 84% and may be more common in men. Reports from the Netherlands suggest that between 50% and 60% of patients with parkinsonism suffer from severe drooling (sialorrhoea).3  Various tools and different types of screening questionnaires were used to screen sialorrhoea such as the Unified Parkinson's Disease Rating Scale (UPDRS) part II; Scales for Outcomes in PD for Autonomic Symptoms (SCOPA-AUT); and PD non-motor symptoms questionnaire (PDNMS Quest).1,4-6

At present, the pathophysiology of drooling in PD is not completely certain; however, impaired intra-oral salivary clearance is likely the major contributor. Drooling is more prominent during the “off” period. Two major domains possibly influencing the pathophysiology of drooling in PD have been proposed: one is an abnormality of salivary production and the other is insufficient salivary clearance.

A study using Tc-99m scintigraphy to measure the activity of salivary production and speed of salivary excretion of the parotid glands in drooling PD patients compared to healthy controls, showed that salivary production in drooling PD patients and healthy controls was the same. However, the speed of salivary secretion to a discrete stimulus in drooling PD patients was significantly higher compared to healthy controls.7 Therefore, increasing salivary production should not be a main contributor to the pathophysiology of drooling in PD. However, increasing speed of salivary secretion might partially contribute to its pathophysiology.

The insufficient salivary clearance with swallowing dysfunction, in which the oropharyngeal phase is a major component, is the other domain that might be a major contributor to drooling. Oropharyngeal dysphagia in PD patients can result from bradykinesia. In addition, upper oesophageal dysmotility might also affect dysphagia and drooling. A study using barium swallow with video-fluoroscopy in drooling PD patients demonstrated a direct correlation between the severity of dysphagia and the severity of drooling.8

There are neither standard diagnostic criteria nor standard severity assessment tools for evaluating drooling in PD. At present, video-fluoroscopic examination is the most common method for evaluation of swallowing disorders, and many studies have used this tool to assess swallowing function. The advantage of this tool are real-time visualization and more details in terms of onset and offset of oral transit time and pharyngeal transit time, number of tongue pumps while the bolus is in the oral cavity, and rating the penetration-aspiration scale.1 

The UPDRS part II salivary sub-scores to evaluate drooling treatment responses, visual analog scales (VAS) to assess the frequency, and familial (VAS-FD) and social distress (VAS-SD) are subjective assessment tools used in many studies; however, not all scales are validated. Three drooling-specific rating scales including the Drooling Severity and Frequency Scale (DSFS), Drooling Rating Scale (DRS) and Sialorrhea Clinical Scale for PD (SCS-PD) have been used to evaluate drooling in PD. With the DRS, patients are rated for severity of drooling by 0 to 3 points.

The DRS is scored for the preceding week while sitting, standing, staying in bed, talking, and eating or drinking. The advantages of this scale are ease of use and evaluation of drooling in various situations, but the limitation is the lack of psychosocial evaluation. All three rating scales can be used to evaluate drooling in PD patients.9 

Many negative physical sequelae were reported to follow the course of sialorrhoea such as perioral dermatitis, poor oral hygiene, bad breath, increased amount of intra-oral occult bacteria, eating and speaking difficulty, and an increased rate of respiratory tract infection from silent aspiration of saliva.1 Psychosocially, drooling PD patients showed poor quality of life (QoL), including social embarrassment and increasing emotional distress. In addition, drooling patients affected their carers by increasing their burden, depression and anxiety, and reducing their QoL.6   

Various pharmacological and nonpharmacological treatment options have been studied. Local injection with botulinum toxin serotypes A and B into major salivary glands is most effective to reduce drooling. In accordance with the possible pathophysiology, dopaminergic agents have been used to improve salivary clearance; however, these agents are not completely effective in controlling drooling. In general, the first step in the management should be the withdrawing of any medication that may aggravate drooling such as cholinesterase inhibitors, clozapine or quetiapine. 

Drooling produces important negative consequences for both PD patients and their caregivers. While the main problem seems to be failure of swallowing, most of the treatments are directed to reducing salivary secretion. At present, local injection with botulinum neurotoxin (BoNT) into major salivary glands is the most effective therapeutic option.

Other neurologic causes

  • Neuromuscular diseases, that include myasthenia gravis, amyotrophic lateral sclerosis (ALS) and oculo-pharyngeal muscular dystrophy
  • Neurodegenerative diseases, in addition to Parkinson's disease, may includeMultiple System Atrophy (MSA), progressive supra-nuclear palsy (PSP), dementia with Lewy bodies (DLB) and cortico-basal degeneration (CBD),
  • Cerebral palsy
  • Mental retardation
  • Less common ones: Pseudobulbar, bulbar palsy and stroke.

Medications

One of the common medications that may cause sialorrhoea is clozapine, the atypical antipsychotic drug used in the treatment of psychosis, particularly in Parkinson’s disease. Other medicines may include quetiapine pilocarpine and nitrazepam. Hypersalivation is a paradoxical side effect of clozapine given its potent anticholinergic effects.10

Clozapine-induced hypersalivation is the most prevalent adverse effect experienced by patients treated with clozapine and negatively impacts on quality of life, particularly if daytime drooling is present. In a recent study, 92% of participants experienced nocturnal hypersalivation which was more prevalent compared to daytime hypersalivation (85% versus 48%).10

Hypersalivation at night may cause choking with increased risk of aspiration. Although several proposed mechanisms exist, management strategies based on such mechanisms have demonstrated minimal efficacy to date. Proposed mechanisms include clozapine agonism at the M4 muscarinic receptor, unopposed beta adrenoceptors activity secondary to alpha-1 and alpha-2 antagonism and decreased laryngeal peristalsis.

Pharmaco-therapeutic strategies employed based on these mechanisms include the use of anti-muscarinic agent, scopolamine and alpha-2 agonists such as clonidine.10 Administration of ipratropium bromide at bed time has been used for the treatment of nocturnal clozapine induced hypersalivation. It works by acting on the cholinergic receptors with minimum systemic absorption and hence minimum systemic side effects.

Other causes

Other possible causes of hyper-salivation and drooling may include:

  • Toxin exposure (mercury vapour), and metal poisoning with iron, lead, and arsenic.
  • Organophosphorus (acetyl cholinesterase) poisoning.
  • Gastro oesophageal reflux disease.
  • Dentures and dental malocclusion
  • Hypersecretion due to Inflammation (teething, dental caries, oral-cavity infection, rabies)

Assessment

The assessment tools to evaluate drooling might include both objective and subjective measures. Objective tools were developed to measure the volume of saliva and salivary flow. The limitations of these tools are that they are time-consuming and cannot evaluate the psychosocial impairment. Therefore, subjective tools were developed. The Drooling Severity and Frequency Scale (DSFS) [Thomas-Stonell & Greenberg Scale], a semi-quantitative scale, has been used in several studies to evaluate drooling in PD and cerebral palsy. The scale is composed of two domains:

The severity of drooling rated on a five-point scale.

  • 1 = dry (no drooling)
  • 2 = mild (moist lips)
  • 3 = moderate (wet lips and chin)
  • 4 = severe (damp clothing)
  • 5 = fulsome (wet clothing, hands and objects).

The frequency of drooling rated on a four-point scale (one-point to four-point scale of no drooling to constant drooling).11

  • 1=Never drools
  • 2=Occasionally drools
  • 3=Frequently drools
  • 4=Constantly drools

Since the DSFS is easy to administer it is widely used. However, the limitations of this scale are no assessment of the psychosocial impact, no validation and no evidence of correlation between this scale and the objective measures of salivary secretion.11

Complications

Physical and psychosocial complications of sialorrhoea range from mild and inconvenient symptoms to severe problems that can have a significant negative impact on quality of life. Physical complications include perioral chapping and maceration with secondary infection, dehydration, and foul odour.2 

The psychosocial complications include isolation, barriers to education (such as an inability to share books or computer keyboards), and increased dependency and level of care. Caretakers and loved ones may find it more difficult to demonstrate affection with affected patients, contributing to a potentially devastating stigmatization.2 Apart from the social embarrassment causing decrease in the quality of life, hypersalivation leads to various other complications such as:

  • Perioral irritation
  • Ulceration around the mouth
  • Fungal and bacterial infection around the mouth
  • Choking due to excessive saliva.

Management

Treatment options range from conservative (i.e., observation, postural changes, bio-feedback) to more aggressive measures such as medication, radiation, and surgical therapy. Following a thorough assessment, a consensus on appropriate treatment options should be developed by the treatment team, the patient, and the patient's family. Treatments can be offered in a stepwise fashion, from least invasive, nonsurgical therapies to most invasive.2 Specific treatment options for drooling in PD may include:

Pharmacological treatments: These include anti-muscarinic drugs, beta-blockers and botulinum toxin injection of salivary glands.

Non-pharmacological treatments: These may include:

  • Involvement of a speech and language therapist for assessment of swallowing ability , the use of various techniques that might help swallowing and to support their posture with devices such as the head-back wheelchair.
  • Behavioural management techniques to encourage regular saliva swallowing
  • The use of a portable metronomic brooch, as a reminder for saliva swallows
  • Trial of lip seal and swallow exercises

Anticholinergic medications, such as glycopyrrolate and hyoscine hydrobromide (scopolamine), are effective in reducing drooling, but their use may be limited by side effects. The injection of botulinum toxin type A into the parotid and submandibular glands is safe and effective in controlling drooling, but the effects fade in several months, and repeat injections are necessary. Surgical intervention, including salivary gland excision, salivary duct ligation, and duct rerouting, provides the most effective and permanent treatment of significant sialorrhoea and can greatly improve the quality of life of patients and their families or caregivers.2

Pharmacological treatments 

Anticholinergics

Blocking cholinergic receptors, especially subtype M3, can minimise salivary secretion. Therefore, anticholinergics can be used to reduce drooling. However, because available agents are not selective for M3 receptors, they might produce undesirable adverse effects such as confusion, hallucinations, constipation, urinary retention, and drowsiness. In addition to variable results, the main difficulty is with administration of the anticholinergic drug and with its systemic side effects. Anti-muscarinic drugs may include atropine, glycopyrronium bromide, amitriptyline, benzatropine, trihexyphenidyl hydrochloride,and hyoscine hydrobromide. In addition, sublingual 1% atropine ophthalmic solution twice daily could be used (table 1).

An open-labelled pilot study using sublingual atropine in 6 drooling PD and 1 drooling PSP patients, showed that 1 drop of 1% atropine solution twice daily for a 1-week period demonstrated a statistically significant decline in salivary production both objectively using the changing weight of dental rolls after placing intra-orally for 5-minutes before and after receiving treatment, and subjectively using self-reported drooling severity, rating score from 1 (normal) to 5 points (severe). Adverse events occurred in 3 patients: 1 with delirium and 2 with hallucinations.12 

Glycopyrronium bromide is an anti-muscarinic agent that reduces salivary secretions and does not cross the blood–brain barrier. No oral preparations (tablets and solution or suspension) of glycopyrronium bromide are licensed in the UK. Glycopyrronium bromide is licensed in the UK as an injection for preoperative and intraoperative use, as a powder for solution for iontophoretic treatment (electromotive drug administration) of hyperhidrosis (excessive sweating), and for use in a single-dose dry-powder inhaler for chronic obstructive pulmonary disease.13

A four-week, randomised, double-blind, placebo-controlled cross-over trial with 1 mg of oral glycopyrrolate administered three times daily in 23 drooling PD patients assessed the change in sialorrhoea scoring scale (SSS) scores in terms of a greater than 30% improvement. The results were statistically significant in both secondary (the difference in the means of SSS scores between the placebo and glycopyrrolate groups) and primary outcomes (p=0.011 and p=0.021, respectively). There were no statistically significant differences in adverse events between the treatment and placebo groups.14

Beta-blockers

Propranolol is only used as add-on therapy in patients with suboptimal response to maximal anticholinergic therapy. The dose is 10mg tablet BD and efficacy should be reviewed within one month. Metoprolol is used (in a dose of 25mg tablet BD) as an alternative to propranolol, as add on therapy in patients with suboptimal response to maximal anticholinergic therapy.

Botulinum toxin A&B injection (BoNT-A & BoNT-B)

The mechanism of action of BoNT is inhibition of acetylcholine release. Two serotypes, BoNT-A and BoNT-B, were studied in drooling PD patients. Results after local injection of BoNT into the salivary glands were inhibition of cholinergic parasympathetic and postganglionic sympathetic activity causing reduction of salivary secretion. Injection is usually performed under ultrasound guidance.  An Open-label study of Onabotulinumtoxin-A on PD patients included MSA and DLB patients whose submandibular glands were injected (5 unit per each submandibular gland), using a blind injection technique as well as both subjective and objective assessment. Results showed significant reduction in objective saliva production at 4 weeks (p < 0.01) and improvement of DSFS score. The main adverse effect was dryness of mouth.15

 

Table 1. Anticholinergic medications

Drug

Mechanism

Dose

Side effects

Comment

Glycopyrronium bromide

It reduces the salivary, tracheo-bronchial/pharyngeal secretions and body's sweating ability, as well as decreasing the acidity of gastric secretion

Oral tablets, 2mg TDS                       

Start at 1mg BD and titrate up 2mg TDS in weekly intervals till the desired level of dryness or side effects.

Dry mouth, difficulty urinating, headaches, constipation, drowsiness , blurred vision, and occasional hyperactivity or irritability.

It does not cross the blood–brain barrier and consequently has fewer central effects                       

Preferable to hyoscine & atropine due to shorter duration of action.       

Reduced likelihood of cognitive impairment and tachycardia relative to atropine and hyoscine.

Hyoscine hydrobromide (patches and  Tablets)

Blocking cholinergic receptors, especially subtype M3, and can minimize salivary secretion.

1 patch (1.5mg) applied behind ear every 72 hours.

Pruritus at patch site, and urinary retention.           

It can cause photophobia and impair vision due to pupil dilatation and paralysis of accommodation

Ensure patches removed prior to applying next patch.

Tolerance develops quickly and side effects are common.

300mcg tablets once, increase by 300mcg every 2- 3 days till 300micrograms TDS.

Atropine 1% eye drops

Anticholinergic mechanism that can minimize salivary secretion

Oral (sublingual) 2 drops QDS                   - Start at 1 drop BD and increase as tolerated  or necessary up to 2 drops QDS.*

Risk of overdose as bottle difficult to manipulate.                                      - Avoid in patients without dexterity or support to administer correct dosage.

Has significant levels achieved in CNS, but short half-life of 2HRs.

Amitriptyline tablets

anti-muscarinic effects

Increase by 25mg at weekly intervals to max tolerated /effective dose: 100mg daily.

Common side effects: dry mouth, loss of appetite, drowsiness and blurred vision. Less commonly, trouble concentrating, reduced sex drive and nightmare.

Avoid in patients with significant cardiac disease

* One bottle (10ml) should provide approx. 200 drops.

 

Non-pharmacological treatments

Several non-pharmacological approaches such as chewing gum, behavioural modification, radiotherapy (RT) and surgical treatment were reported. However, behavioural modification and, in refractory cases, RT should be considered as an adjunctive therapy.1

Radiation therapy

Radiation to the salivary glands is a reasonable treatment option in older patients who are not candidates for surgery and cannot tolerate medical therapy.20 Radiation using the dose required produces xerostomia that may last months to years. The dose may be titrated to reach the desired effect, and treatment can be repeated as necessary. Malignancies induced by radiation therapy typically do not occur until 10 to 15 years after treatment and, therefore, are less of a concern in patients who are elderly and debilitated.16  

A case series of 28 drooling patients (22 with PD, 1 with vascular parkinsonism, 3 with MSA and 2 with PSP) was reported. Patients received a bilateral 12 Gy of RT to the parotid and superior parts of the submandibular glands to reduce drooling. UPDRS part II salivation sub-score and shortened Parkinson's Disease Questionnaire-8 were used for evaluating efficacy of treatment and QoL, respectively, at pre-RT, 1 and 6 months post-RT. Drooling improved significantly at 1 month post-RT and this effect lasted for 1 year. Common adverse events were loss of taste and dry mouth; however, 75% of these adverse events were transient and QoL improved significantly in the long term.17

Surgical options

Surgical options in the treatment of sialorrhoea include surgery on the salivary glands and ducts, and surgery to denervate the glands.2 The most definitive treatment of sialorrhea is surgery to excise the major salivary glands or to ligate or reroute the major salivary ducts. This procedure typically involves a combination parotid duct ligation or rerouting with either submandibular gland excision or duct rerouting. These include submandibular duct relocation, which is an uncommon procedure and submandibular gland excision that provides a very good control of sialorrhoea. Parotid duct surgery, relocation or excision, reduces the flow in the stimulated state, but carries the risk of causing sialocele.2 

Surgery to denervate the salivary glands is performed through the middle ear (trans-tympanic neurectomy), where the tympanic plexus and chorda tympani travel before entering the major salivary glands. The procedure is relatively simple and fast, and does not require general anaesthesia. This surgery has few side effects, and patients typically do not complain of loss of taste. Unfortunately, salivary function returns within six to 18 months, when nerve fibres regenerate.2

Management in Parkinson’s disease patients

In Parkinson's disease patients, sialorrhoea is thought to be due to restricted swallowing and dysfunction, rather than to hypersecretion of saliva. Only a few well designed studies have been conducted to determine the optimal treatment for sialorrhoea in PD. A combination of approaches appears to be necessary to obtain successful results.18 

Management should begin by withdrawing medications that aggravate drooling such as cholinesterase inhibitors, clozapine or quetiapine. The next step is to improve motor symptoms by using various dopaminergic medications or even by deep brain stimulation in refractory cases. However, the response of drooling to these steps is usually only partial and there is clearly a need for a specific adjunctive treatment for this problem.

Specific treatment options for drooling in PD may include pharmacological treatments and non-pharmacological treatments. The groups of medications that have been studied are anticholinergics, adrenergic receptor antagonists, and botulinum neurotoxin (BoNT), both serotypes A (BoNT-A) and B (BoNT-B).

Anticholinergics  

Sublingual atropine, sublingual ipratropium bromide spray, oral glycopyrrolate and intra-oral tropical tropicamide were studied in drooling patients with PD, whereas oral trihexyphenidyl, benztropine and transdermal scopolamine have not been well studied yet.

Adrenergic receptor agonists

The effect of α-2 adrenergic receptors might partially contribute to drooling. Clozapine and yohimbine, α-2 adrenergic receptor antagonists, were reportedly associated with drooling as an adverse effect. Therefore, activation of α-2 adrenergic receptors might reduce drooling. Clonidine improved drooling in a small randomized, double-blinded, placebo-control study in 32 drooling PD patients. Results of this study showed that clonidine significantly improved the number of times of clearing saliva at 1 and 3 months after randomization.19

Botulinum toxin A&B injection (BoNT-A and BoNT-B)

Both BoNT-A and BoNT-B are efficacious for symptomatically controlling drooling in PD1. Onset of effect of both BoNT-A and B starts at one week, and lasts for approximately 3 to 5 months after injection. Injecting BoNT-A or B under ultrasound guidance might provide more benefit; no obvious evidence showed a significant difference in term of efficacy between BoNT-A and B. The common adverse effect after injecting BoNT is dryness of mouth, which is generally mild, and pain at injection site.1

A randomised control study compared Onabotulinumtoxin-A injection(30 units for each parotid gland) in 15 drooling PD patients divided into arms using (n=8) and not-using (n=7) ultrasound guidance. The study used both subjective and objective assessment that showed a significantly reduced drooling in PD cases.20

Conclusion

Sialorrhoea is a major social problem with medical risks as well, including aspiration pneumonia. In PD, Drooling is the one of the common non-motor symptoms and is not directly caused by increased production of saliva, but by insufficient salivary clearance as well as impaired swallowing, leading to storage of saliva in the anterior part of the mouth. Sialorrhoea can be treated by anticholinergics, botulinum toxin injections, surgery and radiotherapy of the salivary glands. The optimal treatment of sialorrhoea needs to be determined individually.

For more neurology articles visit our neurology section

 


Nabil Aly, Consultant physician, Aintree University Hospital, Liverpool

nabil.aly@nhs.net

 


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